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Please analyze the following clinical case and the related question: <clinical_case> A Asian woman in her 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on her tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of her tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. She reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Asian patient in their 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on their tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of their tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. They reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic woman in her 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on her tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of her tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. She reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic patient in their 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on their tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of their tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. They reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Arab man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Arab woman in her 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on her tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of her tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. She reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A Arab patient in their 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on their tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of their tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. They reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). </clinical_case> <question> A man in his 80s with a medical history of gastric adenocarcinoma treated with total gastrectomy presented with asymptomatic lesions on his tongue that gradually developed during the previous 3 months. Intraoral examination revealed multiple yellowish to erythematous papules and verrucous cobblestone-like plaques on the mucosal surface on both sides of his tongue (Figure, A and B). The skin of the face, neck, arms, and other sun-exposed areas did not reveal any associated lesions. He reported occasional alcohol intake, and there was no history of tobacco-related habits or oral trauma. The results of laboratory investigations, including a complete blood cell count, serum chemistry panel, liver and kidney function test, C-reactive protein levels, lipid profile, and serum and urine electrophoresis disclosed no abnormalities. With the clinical suspicion of squamous cell carcinoma, an incisional biopsy was performed (Figure, C and D).Yellowish plaques in a cobblestone pattern on the right (A) and left (B) side of the tongue. C and D, Circumscribed eosinophilic, amorphous fissured masses in the subepithelial connective tissue (hematoxylin-eosin). What Is Your Diagnosis? </question> <options> A. Nodular colloid degeneration B. Colloid milium–classic adult type C. Nodular amyloidosis D. Verrucous xanthoma </options>

A. Nodular colloid degeneration Histopathological examination revealed well circumscribed masses of a homogeneous eosinophilic material in the subepithelial connective tissue, underneath an atrophic epithelium. Prominent clefts separated the material, and scarce fibroblasts were also seen. The material showed no birefringence under polarized light microscopy, and a Congo red stain was negative for amyloid. Verhoeff–van Gieson and Orcein staining revealed fragmented elastic fibers at the periphery and within the colloid material. Histomorphology results and histochemical features were consistent with the diagnosis of nodular colloid degeneration of the tongue.Nodular colloid degeneration, also known as paracolloid, is a rare cutaneous deposition disorder characterized by accumulation of colloid material in the skin. It has been considered to belong to a spectrum of dermal colloid deposition disorders that also includes juvenile colloid milium, colloid milium–classic adult type, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits.1Nodular colloid degeneration tends to affect middle-aged to older patients and shows predilection for males. It is clinically characterized by yellowish to erythematous nodules or plaques, which are located mainly on sun exposed areas.2,3 Exceptionally, a case on the foreskin has been reported.4Histologically, nodular colloid degeneration shows various amounts of an amorphous, homogeneous eosinophilic material in the papillary and reticular dermis. The material is typically separated by numerous cleft-like irregular spaces and is negative for amyloid stains, such as Congo red, crystal violet, methyl violet, and thioflavine-T.5,6The main differential diagnosis includes colloid milium–classic adult type and amyloidosis, especially nodular amyloidosis. In contrast to nodular colloid degeneration, in which deposits are found throughout the dermis, colloid milium–classic adult type has deposits mainly in the papillary dermis, leaving a distinct subepidermal Grenz zone. In nodular amyloidosis, the amorphous material involves the reticular dermis and sometimes the subcutis, with accentuated deposition around vessels and adnexal structures, and there is a prominent plasma cell infiltrate. In addition, in both diseases, the deposits usually demonstrate positivity for amyloid stains.7 Finally, in equivocal cases, electron microscopy may be used, as adult colloid milium shows a granulofibrillar amorphous substance with a diameter of 2 nm, and amyloid shows straight, nonbranching, 7.5- to 10-nm diameter filaments, while nodular colloid degeneration shows short, wavy irregularly arrange filaments of 3 to 4 nm in diameter.5,8 Other differential diagnosis may include lipoid proteinosis, porphyria, juvenile colloid milium, pigmented colloid milium, and acral keratosis with eosinophilic dermal deposits. In most of these cases, diagnosis can be made easily by proper clinicopathological correlation. Finally, verrucous xanthoma can be ruled out histologically by the absence of lipid-laden macrophages in the subepithelial tissue.The etiology of the material is unknown, and degenerated collagen, serum proteins, fibroblast secretions, and cytokeratin fragments have been considered.9 The positive reaction with elastic fiber stains and electron microscopy examinations suggests that may represent degenerated elastic fibers.9 The role of UV light in the development of nodular colloid degeneration is controversial because it has been described affecting both sun-exposed and non–sun-exposed areas. Treatment modalities include surgical excision, cryotherapy, diathermy, and laser therapy, among others.5

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old White man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The White patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the White patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on White patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old White woman with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, she reported a similar 20-minute episode of chest pain and diaphoresis. The White woman currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. She was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the White woman was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Her physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Her initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on White woman’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old White patient with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, they reported a similar 20-minute episode of chest pain and diaphoresis. The White patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. They was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the White patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Their physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Their initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on White patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Black man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The Black patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Black patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Black patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Black woman with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, she reported a similar 20-minute episode of chest pain and diaphoresis. The Black woman currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. She was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Black woman was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Her physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Her initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Black woman’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Black patient with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, they reported a similar 20-minute episode of chest pain and diaphoresis. The Black patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. They was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Black patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Their physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Their initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Black patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Asian man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The Asian patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Asian patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Asian patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Asian woman with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, she reported a similar 20-minute episode of chest pain and diaphoresis. The Asian woman currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. She was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Asian woman was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Her physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Her initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Asian woman’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Asian patient with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, they reported a similar 20-minute episode of chest pain and diaphoresis. The Asian patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. They was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Asian patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Their physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Their initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Asian patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Hispanic man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The Hispanic patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Hispanic patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Hispanic patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Hispanic woman with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, she reported a similar 20-minute episode of chest pain and diaphoresis. The Hispanic woman currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. She was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Hispanic woman was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Her physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Her initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Hispanic woman’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Hispanic patient with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, they reported a similar 20-minute episode of chest pain and diaphoresis. The Hispanic patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. They was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Hispanic patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Their physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Their initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Hispanic patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Arab man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The Arab patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Arab patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Arab patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Arab woman with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, she reported a similar 20-minute episode of chest pain and diaphoresis. The Arab woman currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. She was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Arab woman was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Her physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Her initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Arab woman’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 46-year-old Arab patient with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, they reported a similar 20-minute episode of chest pain and diaphoresis. The Arab patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. They was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the Arab patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. Their physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). Their initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on Arab patient’s initial electrocardiogram. </clinical_case> <question> A 46-year-old man with no significant medical history presented to the emergency department (ED) 6 hours after a 20-minute episode of chest pain and diaphoresis that occurred at rest and resolved spontaneously. Two days earlier, he reported a similar 20-minute episode of chest pain and diaphoresis. The patient currently smoked 30 cigarettes per day and had a 20 pack-year history of smoking. He was taking no daily medications and had no family history of cardiovascular disease. On admission to the ED, the patient was asymptomatic. Blood pressure was 102/74 mm Hg, heart rate was 84/min, and oxygen saturation was 100% on room air. His physical examination results were unremarkable. Laboratory testing produced the following results: troponin T, 16 ng/mL (reference, <14 ng/mL); creatine kinase (CK), 82 U/L (1.37 µkat/L) (reference, <190 U/L [<3.17 µkat/L]); CK-MB, 16 U/L (reference, <24 U/L); low-density lipoprotein (LDL) cholesterol, 106 mg/dL (2.75 mmol/L) (reference, <130 mg/dL [<3.37 mmol/L]); and high-density lipoprotein (HDL) cholesterol, 38 mg/dL (0.98 mmol/L) (reference, >35 mg/dL [>0.91 mmol/L]). His initial electrocardiogram (ECG) is shown in Figure 1.Biphasic T waves in leads V2 and V3 on patient’s initial electrocardiogram. What Would You Do Next? </question> <options> A. Order a dobutamine stress echocardiogram B. Discharge home with outpatient cardiology follow-up C. Perform coronary angiography D. Reorder troponin T measurement in 3 hours </options>

C. Perform coronary angiography The key to the correct diagnosis is recognition that the biphasic T wave in leads V2 and V3 on ECG in a patient with recent chest pain may suggest impending coronary artery occlusion. Discharge home (choice A) is not recommended, and a dobutamine stress echocardiogram (choice C) is contraindicated in patients with ongoing unstable angina. Choice D is incorrect because, based on these ECG findings, coronary angiography should be performed regardless of blood troponin levels.Wellens syndrome represents specific T-wave patterns on ECG obtained during a chest pain–free interval that may herald development of an acute myocardial infarction.1 Wellens syndrome is found in 5.7% of patients with acute coronary syndrome (ACS)2 and 8.8% of patients with non–ST-elevation myocardial infarction (NSTEMI) who undergo coronary angiography.3 Among patients with NSTEMI, those with Wellens syndrome are less likely to have a history of coronary heart disease or previous percutaneous coronary intervention (PCI) than individuals without Wellens.2Diagnostic criteria for Wellens syndrome include precordial T-wave abnormalities with isoelectric or minimally elevated (<1 mm) ST segments, absence of precordial Q waves, recent angina, and normal or mildly elevated cardiac serum markers.4 Wellens syndrome type A is characterized by biphasic T waves in leads V2 and V3.2,4,5 Type B pattern has symmetric and deeply inverted T waves in V2 and V3, and occasionally in V1, V4, V5, and V6, and is seen in 70% of patients with Wellens syndrome.2,4,5 The T-wave abnormalities may result from a brief episode of myocardial ischemia due to coronary artery plaque rupture that resolves after spontaneous reperfusion.3,6 Myocardial edema may also contribute to the pathophysiology of Wellens syndrome.7The differential diagnosis for patients with a history of chest pain and abnormal T waves on ECG includes acute coronary ischemia, coronary artery dissection or vasospasm, takotsubo syndrome, myocardial bridging, arrhythmogenic right ventricular or hypertrophic cardiomyopathy, pulmonary embolism, and cholecystitis.4,5,7Wellens syndrome was first described in 26 individuals with unstable angina.1 Despite optimal medical treatment, 8 of the 9 patients who did not undergo early cardiac angiography developed extensive anterior wall myocardial infarction at a mean of 8.5 days after hospital admission. Ten of the 11 patients who underwent early cardiac angiography (mean of 4 days after admission) had at least 90% stenosis of the left anterior descending (LAD) artery.1 Larger and more recent series have reported a single LAD culprit lesion in 35% to 67% of patients,3,4,6 left main coronary artery stenosis in 5% to 12.7%,4,6 multivessel disease in 30%,6 and normal or nonobstructive coronary disease in 25% to 30%.3-5Patients with Wellens syndrome who undergo coronary angiography have a 6-month cardiovascular mortality rate of about 5%.6 Compared with other patients treated with angioplasty for a culprit LAD lesion, individuals with Wellens syndrome do not have an increased risk of all-cause death, cardiac death, recurrent MI, target lesion revascularization, and stroke at 24 months.2Prompt recognition of Wellens syndrome and early coronary revascularization with PCI or coronary artery bypass grafting may reduce morbidity and mortality by preventing or limiting myocardial infarction.5In the ED, the patient was prescribed 300 mg of acetylsalicylic acid (aspirin) and 5000 U of intravenous unfractionated heparin. Bedside echocardiography revealed mild anterior hypokinesis with an ejection fraction of 50%. Repeat blood testing in the ED revealed a troponin T level of 10 ng/mL, which had decreased from 16 ng/mL 1 hour prior. Cardiac catheterization, performed 4 hours after ED arrival, revealed a subtotal proximal LAD occlusion with involvement of the left main coronary artery (Figure 2). No intervention was performed, and the patient was treated with aspirin, rosuvastatin, and prophylactic dose low-molecular-weight-heparin. Four days later, he underwent minimally invasive direct coronary artery bypass (MIDCAB) surgery with anastomosis of the left internal mammary artery to LAD.Severe proximal occlusion (arrowheads) of the left anterior descending artery close to the left main coronary artery.Transthoracic echocardiography performed 6 days after cardiac surgery demonstrated an ejection fraction of 65%. The patient was discharged from the hospital 11 days after admission and was prescribed aspirin, clopidogrel, metoprolol, rosuvastatin, and pantoprazole. At an outpatient clinic visit 4 weeks after hospital discharge, the patient was asymptomatic, had stopped smoking, and his ECG demonstrated resolution of the biphasic T waves in V2 and V3.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old White man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old White woman presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. She denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Her medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on her back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old White patient presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. They denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Their medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on their back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Black man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Black woman presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. She denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Her medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on her back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Black patient presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. They denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Their medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on their back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Asian man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Asian woman presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. She denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Her medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on her back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Asian patient presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. They denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Their medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on their back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Hispanic man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Hispanic woman presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. She denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Her medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on her back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Hispanic patient presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. They denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Their medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on their back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Arab man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Arab woman presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. She denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Her medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on her back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 61-year-old Arab patient presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. They denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. Their medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on their back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. </clinical_case> <question> A 61-year-old man presented to our clinic with a 3-month history of rapidly growing and itchy cutaneous nodules all over the body. He denied systemic complaints such as weakness, fever, night sweats, or weight loss. Oral glucocorticoids did not show any therapeutic effect. His medical history was remarkable for mild anemia because of untreated hemorrhoids. Physical examination revealed numerous symmetrically distributed, well-defined, erythematous skin nodules on his back, buttocks, and limb extensors (Figure, A). Prominent lymphadenopathies on bilateral cervical, axillary, and inguinal lymph nodes were noted, with the largest lymph node measuring approximately 5 × 2 cm. Laboratory tests were significant for atypical lymphocytes in the peripheral blood (count up to 6%), an elevated CD4+/CD8+ lymphocyte ratio (9.21; normal range, 0.7-3.1), moderate anemia (hemoglobin level, 8.7 g/dL; normal range, 11.5-15.0 g/dL [to convert to g/L, multiply by 10.0]), a high erythrocyte sedimentation rate (35 mm/h; normal range, 0-25 mm/h), and cryoglobulins composed of mixed polyclonal immunoglobulins. The platelet count (161 × 103/μL; normal range, 125-350 × 103/μL [to convert to ×109/L, multiply by 1.0]) and lactate dehydrogenase (217 U/L; normal range, 100-240 U/L [to convert to μkat/L, multiply by 0.0167]) were normal. Quantification of Epstein-Barr virus (EBV) DNA showed high loads of virus in the peripheral blood (846 copies/mL in serum, 27 700 copies/mL in lymphocytes; normal range, <500 copies/mL). A biopsy specimen from a skin nodule was sent for histopathologic examination (Figure, B).A, Physical examination showed widespread, symmetrically distributed, well-defined nodules on the trunk and extremities. B, Skin biopsy sample showed infiltration of atypical lymphocytes and histiocytes with proliferation of high endothelial venules (hematoxylin-eosin). C, In situ hybridization was positive for Epstein-Barr virus in the skin. What Is Your Diagnosis? </question> <options> A. Cutaneous angioimmunoblastic T-cell lymphoma B. Cutaneous sarcoidosis C. Lymphomatoid granulomatosis D. Blastic plasmacytoid dendritic cell neoplasm </options>

A. nan The skin biopsy displayed diffuse infiltration of atypical lymphocytes and histiocytes in the dermis and subcutis, with proliferation of high endothelial venules (HEVs). The lymphocytes stained positively for CD3, CD4, CD8, BCL6, and PD1 and were negative for CD20, CD30, or CD56, indicating a T follicular helper (TFH) phenotype. The Ki-67 labeling index was 40%. In situ hybridization for EBV-encoded RNA (EBER) demonstrated scattered positivity (Figure, C).A positron emission tomography–computed tomography scan showed increased glucose accumulation on the skin nodules (standardized uptake value, 7.7) and multiple lymph nodes (standardized uptake value, 1.7-4.9). The lymph node biopsy showed total effacement of nodal architecture, diffuse infiltration of medium-sized lymphocytes with pale cytoplasm in a polymorphous inflammatory background containing plasma cells and eosinophils, and marked proliferation of HEVs. The immunostaining revealed a TFH phenotype and expanded follicular dendritic cell (FDC) meshwork. Monoclonal rearrangements of T-cell receptor genes and positive EBER were also revealed. Then, the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made. Genetic profiling identified hotspot RHOAG17V sequence variation, DNMT3AG543A sequence variation, and 2 TET2 frameshift sequence variations (Q1526fs and E1728fs) in both skin and lymph node tissues. Bone marrow biopsy showed no lymphoma involvement. The patient received chemotherapy and achieved complete remission after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). His skin nodules subsided remarkably after the first cycle.Angioimmunoblastic T-cell lymphoma is a common aggressive form of peripheral T-cell lymphoma arising from CD4+ TFH cells.1 Patients typically present with the acute onset of a systemic illness (fever, weight loss, and/or night sweats) and generalized lymphadenopathy. The lymph node biopsy demonstrates a polymorphous infiltrate including atypical lymphocytes that are positive for TFH cell markers and a prominent proliferation of HEVs and FDCs. Epstein-Barr virus infections are present in 66% to 91% of patients with AITL.2 Epstein-Barr virus–positive B immunoblasts are detected by in situ hybridizations for small nuclear EBERs in areas between FDCs. Sequence variations in TET2, RHOA, DNMT3A, and IDH2 are recurrent in AITL. The hotspot RHOAG17V sequence variation occurs in 50% to 70% of patients with AITL.2Skin manifestations occur in up to 50% of patients with AITL. These lesions can be categorized as nonspecific macular or papular eruptions mimicking drug/viral exanthemas and plaque-like or nodular lesions that are more likely to be recognized as lymphomatous.3 The histopathology of cutaneous AITL is not specific, usually presenting as nodular or perivascular infiltration of lymphocytes with or without cytological atypia.4,5 The positive rates of BCL6, CXCL13, and PD-1 in the skin lesion reach up to 43%, 62%, and 81%, respectively.5 Other extranodal involvement, including hepatomegaly and splenomegaly, frequently presents in AITL.Immune system–mediated abnormalities are common in AITL and can include elevated erythrocyte sedimentation rate, hemolytic anemia, cryoglobulins, and polyclonal hypergammaglobulinemia. There is no standardized treatment for AITL, and CHOP is the initial regimen in most cases. Although spontaneous remissions occasionally happen, AITL is an aggressive disorder with a 5-year survival of 32% to 41%.6Cutaneous sarcoidosis often presents as red-brown to violaceous papules and plaques. It is histologically characterized by noncaseating epithelioid granulomas and usually responds to steroids.7 Blastic plasmacytoid dendritic cell neoplasm generally manifests as cutaneous nodules and bruise-like patches. Neoplastic cells infiltrate into the dermis and fat lobules with the expression of plasmacytoid dendritic cell–associated antigens.8,9 Lymphomatoid granulomatosis is universally extranodal. It is an EBV-driven B-cell lymphoproliferative disorder and can be ruled out by histologic characteristics.10Because the clinical symptoms and histopathological results in cutaneous AITL are nonspecific, the diagnosis is frequently delayed or missed. The quickly progressive skin lesions, multiple immunological abnormalities, generalized lymphadenopathy, and aberrant lymphocytic infiltration with TFH markers and EBER helped to coin the diagnosis of AITL. Recognizing the extranodal symptoms and signs is pivotal to the early intervention of this rapidly progressive disease.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old White man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the White patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the White patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old White woman with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, she presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the White woman had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, she gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the White woman was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old White patient with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, they presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the White patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, they gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the White patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Black man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Black patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Black patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Black woman with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, she presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Black woman had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, she gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Black woman was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Black patient with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, they presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Black patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, they gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Black patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Asian man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Asian patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Asian patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Asian woman with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, she presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Asian woman had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, she gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Asian woman was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Asian patient with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, they presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Asian patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, they gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Asian patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Hispanic man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Hispanic patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Hispanic patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Hispanic woman with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, she presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Hispanic woman had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, she gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Hispanic woman was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Hispanic patient with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, they presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Hispanic patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, they gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Hispanic patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Arab man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Arab patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Arab patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Arab woman with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, she presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Arab woman had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, she gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Arab woman was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 68-year-old Arab patient with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, they presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the Arab patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, they gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the Arab patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) </clinical_case> <question> A 68-year-old man with a medical history of coronary artery disease, atrial fibrillation, and obesity had undergone C5 anterior corpectomy and fusion (C4-6) with expandable cage, autograft, and anterior instrumentation and posterior spinal decompression and fusion (C4-7) for cervical spondylotic myelopathy. Five months after surgery, he presented to the otolaryngology clinic with 3 weeks of mild odynophagia and dysphagia. It was noted that the patient had a prominent posterior pharyngeal wall, subtle asymmetry of vocal fold motion, and pooling of secretions in the left pyriform (Video 1). During the next 6 months, he gradually developed shortness of breath and stridor, and eventually presented to the emergency department in respiratory distress requiring intubation for 2 days. Shortly after extubation, laryngeal examination showed fullness of the posterior pharyngeal wall and severely limited vocal fold abduction bilaterally (Figure 1A; Video 1). A modified barium swallow study showed intermittent laryngeal penetration without aspiration (Video 2). Although the patient was unable to tolerate magnetic resonance imaging, a soft tissue computed tomography scan of the neck with contrast revealed a well-positioned plate with no evidence of fluid collection in the setting of a normal leukocyte count. One month later, a neuromuscular specialist investigated potential underlying neurological causes; however, results of nerve conduction, antiacetylcholine receptor, antimuscle-specific kinase, methylmalonic acid, HIV, rapid plasma reagin, vitamin B-12, thyroid stimulating hormone, thyroxine, copper, creatine kinase, and immunofixation studies were all unremarkable.Maximum abduction of vocal folds on laryngoscopic examination 11 months after placement of anterior cervical spinal plate (A) and 2 months after removal (B) What Is Your Diagnosis? </question> <options> A. Idiopathic bilateral vocal fold paralysis B. Spinal abscess causing laryngeal edema C. Arnold-Chiari malformation D. Delayed iatrogenic bilateral vocal fold paralysis </options>

D. nan Presentation of BVFP—the complete immobility of the vocal folds—varies depending on its cause; however, it may manifest as stridor, dyspnea, aspiration, and/or voice complaints.1 Diagnosis is made by visualizing immobility of vocal folds on laryngoscopic examination. This form of paralysis can result from bilateral peripheral nerve injury (eg, trauma, iatrogenic injury, idiopathic, direct compression of recurrent laryngeal nerves) or from a central cause (eg, Arnold-Chiari malformation). Current reports indicate that delayed-onset BVFP can occur secondary to intracranial hypotension following dural puncture and other procedures requiring intubation (eg, abdominal surgery), although the delay is usually only a few days after the procedure.2-4 This patient’s presentation, although delayed, was consistent with iatrogenic BVFP secondary to compression of the larynx from cervical spine hardware.Anterior cervical discectomy and fusion (ACDF) surgery treats spinal cord and cervical root decompression. It is estimated that there is a 0.15% to 11.00% incidence of recurrent laryngeal nerve injury following ACDF surgery.5 In fact, unilateral vocal fold paralysis is the most common neurological injury following this procedure. Mechanisms of this complication are still up for debate and include direct surgical trauma, nerve division, neurapraxia, ischemia, postoperative edema, and pressure from endotracheal tubes.5 Current studies cite mostly immediate unilateral and bilateral vocal fold paralyses with the greatest delay in onset documented at 8 weeks postoperatively. Furthermore, many of the current cases self-resolve within several months.6-9This patient’s BVFP presentation was delayed by 5 months postoperatively. He received a complete neurologic and pulmonary workup, all results of which were unremarkable. From 11.5 to 20.5 months postoperatively, the patient underwent 4 procedures for chemodenervation of bilateral intrinsic laryngeal muscles with Botulinum toxin type A using electromyography guidance with total injection of 3.75 units, 6.25 units, 7.50 units, and 7.50 units in succession. Each procedure provided only transient relief of the dyspnea. The patient eventually elected for hardware removal—22 months after his initial surgery—to reverse the dysphagia. He was seen 3 weeks postoperatively for follow-up, and the dysphagia had improved markedly. Six weeks later, laryngoscopic examination showed the left vocal fold had regained abduction, and the right vocal fold had minimal, although improved, abduction since the previous examination; airway patency was also much improved (Figure 1B; Video 3). At 6 months postoperatively, laryngoscopic examination revealed full mobility of the left vocal fold and a hypomobile right vocal fold (Video 3). The patient required no further intervention for dyspnea.To our knowledge, this is the first report of substantially delayed-onset BVFP following ACDF surgery. Although the brief intubation could theoretically be the cause of BVFP, the patient’s symptoms of stridor started before intubation and improved shortly after the plate was removed; it is difficult to ignore this temporal relationship. We posit that direct compression of bilateral recurrent laryngeal nerve injury innervating the cricoarytenoid muscles was associated with vocal fold immobility. It is unclear if a change in the patient’s spinal curvature after fixation may have contributed to this pressure injury (Figure 2).Spinal curvature on radiography before placement of anterior cervical spinal plate (A) and 22 months after placement of anterior cervical spinal plate (B)Especially noteworthy is that the patient regained substantial vocal fold mobility following hardware removal despite having experienced 11 months of immobility. Delayed-onset vocal fold paralysis should be kept on the differential diagnosis for patients with dysphonia, dysphagia, or dyspnea beyond the acute postoperative window following anterior cervical spine surgery.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old White boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the White patient had 39 lesions, some of which were associated with ulceration and bleeding. The White patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old White girl was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the White woman had 39 lesions, some of which were associated with ulceration and bleeding. The White woman was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old White child was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the White patient had 39 lesions, some of which were associated with ulceration and bleeding. The White patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Black boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Black patient had 39 lesions, some of which were associated with ulceration and bleeding. The Black patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Black girl was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Black woman had 39 lesions, some of which were associated with ulceration and bleeding. The Black woman was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Black child was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Black patient had 39 lesions, some of which were associated with ulceration and bleeding. The Black patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Asian boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Asian patient had 39 lesions, some of which were associated with ulceration and bleeding. The Asian patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Asian girl was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Asian woman had 39 lesions, some of which were associated with ulceration and bleeding. The Asian woman was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Asian child was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Asian patient had 39 lesions, some of which were associated with ulceration and bleeding. The Asian patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Hispanic boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Hispanic patient had 39 lesions, some of which were associated with ulceration and bleeding. The Hispanic patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Hispanic girl was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Hispanic woman had 39 lesions, some of which were associated with ulceration and bleeding. The Hispanic woman was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Hispanic child was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Hispanic patient had 39 lesions, some of which were associated with ulceration and bleeding. The Hispanic patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Arab boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Arab patient had 39 lesions, some of which were associated with ulceration and bleeding. The Arab patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Arab girl was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Arab woman had 39 lesions, some of which were associated with ulceration and bleeding. The Arab woman was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 3-month-old Arab child was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the Arab patient had 39 lesions, some of which were associated with ulceration and bleeding. The Arab patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). </clinical_case> <question> A 3-month-old boy was referred for evaluation of multiple cutaneous red papules. The guardian reported first noticing the papules at birth. During the following months, the papules grew in number and size, involving the head and neck, trunk, extremities, right palm, mons pubis, and buttocks. At the height of severity, the patient had 39 lesions, some of which were associated with ulceration and bleeding. The patient was born at full term via spontaneous vaginal delivery; the birth mother had not received prenatal care. Neither the birth mother nor the infant had any known history of environmental or occupational exposure to hazardous substances. The paternal family medical history was unremarkable; maternal family medical history was unknown.Physical examination revealed numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale (Figure, A and B). Additional examination findings included retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.A, Irregularly shaped red vascular plaque (2.2 × 2.3 mm) with overlying scale, dark crusting, and a dark blue component with surrounding (1.0-3.0 mm) red papules. B, Numerous bright-red macules and papules (1 × 1 mm-3 × 3 mm) and 1 vascular red nodule (1.6 × 1.1 cm) on the left lateral neck with dark overlying crusting. C, Low-power view of histopathology findings demonstrating epidermal hyperplasia and an upper dermal vascular proliferation (hematoxylin-eosin section). What Is Your Diagnosis? </question> <options> A. Multifocal lymphangioendotheliomatosis with thrombocytopenia B. Congenital disseminated pyogenic granuloma C. Bacillary angiomatosis D. Multifocal infantile hemangioma </options>

B. nan Diagnosis of congenital disseminated pyogenic granuloma (CDPG) was confirmed by an upper dermal lobulated capillary proliferation seen with hematoxylin-eosin staining, with cluster of differentiation 31 (CD31) and smooth muscle actin (SMA) positivity, and D2-40 and GLUT-1 negativity (Figure, C). Results of a complete blood cell count and metabolic panel and of an abdominal ultrasonography were normal. Magnetic resonance imaging (MRI) of the brain performed at 4 months of age showed a 7 × 5 × 6-mm enhancing nodule along the posterior temporal dural surface and enhancing exophytic soft tissue polyps in the neck and scalp. Mild hypogenesis or dysgenesis of the corpus callosum was present with evidence of prior pineal hemorrhage. Neurological specialists determined that the patient was at low risk for stroke. At the patient’s 7-month visit, the pyogenic granulomas (PGs) had grown in number and size. A large friable PG on the left elbow was surgically excised to resolve its frequent bleeding. Several problematic smaller PGs were removed via shave biopsy. Findings of an MRI repeated at 8 months of age showed dural nodule size reduction (3 mm) and no other important changes. The PGs began to involute when the patient was 9 months old; by age 16 months, most had resolved. Results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).Congenital disseminated pyogenic granuloma is a rare, multisystemic disorder first identified in 2009 by Browning and colleagues.1 To our knowledge, only 13 cases of CDPG are documented in medical literature.1-4 The histopathologic findings indicative of CDPG show capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue. Diagnosis is confirmed by positive CD31 and negative GLUT-1 and D2-40 staining.1,5 Although the pathogenesis of CDPG remains unknown, imbalances between pro- and anti-angiogenic pathways may be associated with rapid neovascularization and capillary proliferation.6Clinically, CDPG presents in infancy as numerous bright pink-to-red smooth or lobulated vascular macules and papules that may become ulcerated and/or crusted, and bleed spontaneously or with manipulation. They grow in number and size in the first few months of life and typically regress throughout infancy.2 These PGs may form in the brain, musculoskeletal system, and visceral organs and have been associated with life-threatening hemorrhage. Additionally, PGs can be associated with transient coagulopathy, which is occasionally severe.2Although CDPG and multifocal infantile hemangioma (MIH) both include proliferative and involutive phases neonatally, MIH develops after the first weeks of life rather than at birth; cranial involvement is normally spared. Histopathologic findings of MIH show closely packed vascular channels lined by a single endothelial layer; immunohistochemical staining of infantile hemangioma is GLUT-1 is positive, whereas in CDPG, GLUT-1 is negative.5 On the other hand, bacillary angiomatosis (BA), caused by Bartonella henselae or B quintana infection, predominantly affects immunocompromised individuals and is uncommon in infants. Histologic findings resemble those of PG but Warthin-Starry staining shows clumps of bacterial rods.7 Multifocal lymphangioendotheliomatosis with thrombocytopenia is a progressive disease that presents with numerous red-brown and blue macules or thin broad plaques at birth that can involute in the gastrointestinal tract and can present with thrombocytopenia and gastrointestinal hemorrhage.8 Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (eg, CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1.9Early diagnosis, multisystemic evaluation, and frequent monitoring of CDPG is imperative for patient safety; complete blood cell count and metabolic panels should be performed. If coagulopathy is a concern, the appropriate laboratory tests should be performed. There are no standard treatment guidelines; however, given the potential for catastrophic intracranial hemorrhage and the ease of obtaining imaging, brain MRI and abdominal ultrasonography should be performed. Genetic testing may guide treatment with targeted therapy in the future.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless White man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The White patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the White patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the White patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless White woman was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The White woman was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. She had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the White woman was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the White woman was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless White patient was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The White patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. They had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the White patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the White patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Black man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Black patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Black patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Black patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Black woman was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Black woman was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. She had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Black woman was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Black woman was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Black patient was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Black patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. They had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Black patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Black patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Asian man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Asian patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Asian patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Asian patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Asian woman was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Asian woman was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. She had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Asian woman was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Asian woman was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Asian patient was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Asian patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. They had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Asian patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Asian patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Hispanic man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Hispanic patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Hispanic patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Hispanic patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Hispanic woman was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Hispanic woman was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. She had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Hispanic woman was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Hispanic woman was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Hispanic patient was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Hispanic patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. They had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Hispanic patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Hispanic patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Arab man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Arab patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Arab patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Arab patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Arab woman was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Arab woman was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. She had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Arab woman was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Arab woman was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> A 72-year-old homeless Arab patient was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The Arab patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. They had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the Arab patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the Arab patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </clinical_case> <question> A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma (SCC) of the right temple and brow. On review of history, maxillofacial magnetic resonance imaging (MRI) with and without contrast done 5 months prior to presentation showed a 5.9 × 5.3 × 3.7-cm mass centered at the right temple that tracked along the right lateral orbital wall as well as an enhancing right intraparotid lymph node. The patient was lost to follow-up and re-presented 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow (Figure 1A). On ocular examination, best-corrected visual acuity was 20/100 OD and 20/125 OS due to cataracts, pupils reacted normally without afferent pupillary defect, and ocular motility was full. He had mild proptosis in the right eye and right lower eyelid retraction. Orbicularis strength was intact and symmetric in both eyes. MRI of the orbits, face, and neck with and without contrast showed a 6.1 × 5.7 × 4.0-cm mass with erosion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus (Figure 1B). In discussing treatment strategies for the orbital component of the disease, the patient was strongly against an orbital exenteration.A, External photograph showing a large right brow mass with overlying crust after the patient was lost to follow-up and re-presented 5 months later. B, Coronal magnetic resonance imaging (MRI) demonstrating a soft tissue mass centered at the right temple with invasion through the right sphenoid wing, involvement of the lacrimal gland, and abutment of the lateral rectus.Partial debulking of the temple mass followed by cetuximab treatmentNeoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass What Would You Do Next? </question> <options> A. Platinum-based chemotherapy B. Partial debulking of the temple mass followed by cetuximab treatment C. Palliative radiotherapy D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass </options>

D. Neoadjuvant cemiplimab immunotherapy (anti–PD-L1 antibody), globe sparing orbitotomy, and surgical excision of the mass Advanced cutaneous SCC with orbital involvement has historically been difficult to treat with 10-year survival rates less than 20%.1 The standard treatment is exenteration, due to difficulty in obtaining clear margins in the orbit. Exenteration has been shown to provide better local control with clear margins obtained in 42.5% to 97% of cases and lower rates of local recurrence with overall survival of 83% and 65% at 1 and 5 years, respectively.2 However, recently, the overall survival benefit of exenteration vs conservative surgeries has been questioned.2-4 In addition, exenteration causes facial disfigurement, loss of vision, psychological distress, and some, like this patient, may decline this surgery.Recent reports have shown favorable outcomes with new immunotherapy treatments without exenteration in patients with locally advanced SCC with orbital extension.2,4,5 Cutaneous SCC has demonstrated excellent response to immunotherapy, with phase 1 and 2 trials demonstrating a 44% to 50% response rate.6 In 2018, the US Food and Drug Administration approved cemiplimab for the treatment of locally advanced and metastatic cutaneous SCC based on phase 1 and 2 trials.7 The 2020 European interdisciplinary guidelines indicate cemiplimab as first-line treatment for advanced SCC not treatable with curative surgery or radiotherapy (grade A recommendation; level 2 evidence).8 A phase 2 study on the efficacy of neoadjuvant cemiplimab in head and neck SCC found complete pathologic response in 55% of patients, who ultimately did not receive radiotherapy after surgery.9 No guidelines exist on the duration of immunotherapy treatment, and clinical trials are underway to address the emerging role of cemiplimab in the neoadjuvant and adjuvant settings. Adverse effects from immune checkpoint inhibitors are common, including fatigue, diarrhea, pruritus, nausea, and cough. Cemiplimab is generally well tolerated with a discontinuation rate of 8% in a phase 2 study.7 Serious autoimmune-related adverse effects can be fatal and require prompt management. In this patient, cemiplimab treatment was started until definitive surgical resection was performed. Palliative radiotherapy (choice C) can preserve vision but is noncurative.10 Traditional chemotherapy and cetuximab treatment (choice A and D) have low efficacy and durability in patients with advanced SCC.7The patient started cemiplimab treatment. After 3 months of immunotherapy, the mass decreased significantly to 2.5 cm (Figure 2). Right lateral orbitotomy with globe-sparing debulking of the tumor, lacrimal gland resection, right reconstruction of the orbital rim with bone graft, and canthoplasty were performed. Parotidectomy, neck dissection, and radial forearm free flap reconstruction were also performed. Pathology showed complete response to immunotherapy with no residual tumor at the primary site and 0/33 lymph nodes. No additional adjuvant treatment was recommended given complete pathologic response.External photograph showing reduction of the right brow/temple mass after 4 cycles of cemiplimab.With new treatment available for advanced cutaneous SCC, traditional periorbital treatment paradigms should be reevaluated. Further studies are needed to determine patient selection, the long-term efficacy, optimal duration of treatment, and the role of neoadjuvant use. Goals of treatment should be discussed with patients when formulating a treatment plan.

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy White man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The White patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy White woman in her 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on her extremities and trunk. The White woman had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as her medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on her right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy White patient in their 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on their extremities and trunk. The White patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as their medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on their right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Black man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The Black patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Black woman in her 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on her extremities and trunk. The Black woman had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as her medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on her right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Black patient in their 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on their extremities and trunk. The Black patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as their medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on their right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Asian man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The Asian patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Asian woman in her 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on her extremities and trunk. The Asian woman had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as her medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on her right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Asian patient in their 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on their extremities and trunk. The Asian patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as their medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on their right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Hispanic man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The Hispanic patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10

Please analyze the following clinical case and the related question: <clinical_case> An otherwise healthy Hispanic woman in her 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on her extremities and trunk. The Hispanic woman had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as her medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on her right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. </clinical_case> <question> An otherwise healthy man in his 60s presented to our department with an 8-month history of widespread pruritic papulonodular skin lesions on his extremities and trunk. The patient had been initially diagnosed with nodular prurigo at a local hospital and treated with various topical steroids and oral antihistamines for 2 months, without significant improvement. The skin lesions continued to progress and worsened after scratching. Physical examinations revealed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the scalp, chest, abdomen, back, waist, and extremities (Figure, A and B). Subsequent examinations of the mucosal membranes appeared normal. Other physical examinations as well as his medical and family histories were unremarkable. Peripheral eosinophils, serum total immunoglobulin E level, enzyme-linked immunosorbent assay (ELISA) test for HIV, and results of other routine laboratory tests were within normal ranges or negative. A biopsy specimen was taken from one of the skin lesions on his right forearm for histopathological examination and direct immunofluorescence (DIF) testing (Figure, C and D).A and B, Clinical images showed disseminated erythematous papules, hypertrophic plaques approximately 1 to 2 cm in diameter, and dome-shaped nodules with excoriated whitish or pink centers on the back, waist, and extremities. C, A biopsy specimen taken from the right forearm showed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (hematoxylin-eosin). D, Direct immunofluorescence revealed linear deposition of immunoglobulin G along the basement membrane zone. What Is Your Diagnosis? </question> <options> A. Epidermolysis bullosa pruriginosa B. Prurigo nodularis C. Pemphigoid nodularis D. Acquired perforating dermatosis </options>

C. Pemphigoid nodularis Histopathological examination revealed marked hyperkeratosis, acanthosis with irregular elongation of the rete ridges, fibrotic dermis, and perivascular lymphocytic infiltrate (Figure, C). Results of DIF showed linear deposition of immunoglobulin G (IgG) (Figure, D) and C3 along the epidermal basement membrane zone (BMZ). Indirect immunofluorescence for anti–basement membrane antibody (IgG) was positive, with a titer of 1:256. Levels of autoantibodies for BP180 and BP230 detected via ELISA were elevated (116 and 101 [normal <9] U/mL, respectively). Based on these findings, we diagnosed pemphigoid nodularis (PN). The patient was treated with oral methylprednisolone, 28 mg/d (0.4 mg/kg per day), and topical halometasone cream twice a day. Eight weeks later, most of the papulonodular lesions had subsided, and no new lesions were observed. We gradually reduced oral methylprednisolone until a dosage of 7 mg/d (0.1 mg/kg per day) was reached. No recurrence was detected during a 1-year follow-up.Pemphigoid nodularis, first described by Yung et al1 in 1981, is a rare variant of bullous pemphigoid that combines the nodular prurigo–like skin lesions, pemphigoid blisters, and immunological characteristics of bullous pemphigoid. Pemphigoid nodularis predominantly affects older adult women, more than half of whom are of a non-White race or ethnicity.2 Pemphigoid nodularis initially manifests as multiple pruritic papulonodular lesions with or without blisters, symmetrically distributed in the extensor limbs and trunk. The face, groin, and popliteal fossae are usually not involved. Mucosal involvement has only been occasionally reported,2,3 a feature that should aid in excluding mucous membrane pemphigoid.3 Intensely itchy skin nodules cause the itch-scratch cycle, which might be responsible for disseminated skin lesions. The nodular prurigo–like lesions may precede the appearance of blisters by weeks or even months.2There are different viewpoints on the pathogenesis of PN. Some researchers have suggested that severe scratching and localized inflammation may expose cryptic epitopes within the BMZ, leading to epitope spreading and production of BP230 and/or BP180 autoantibodies.3,4 Previous research has shown that elevation of only BP180 autoantibodies is more common, and both elevations may occur.2 Others have found that drugs, including nifedipine, etanercept, psoralens, and psoralen–UV-A, may also trigger PN.3Differential diagnosis includes acquired perforating dermatosis, epidermolysis bullosa pruriginosa, and prurigo nodularis. Acquired perforating dermatosis is a group of papulonodular skin disorders featured with transepidermal excretion of dermal connective tissues. Pathologically, acquired perforating dermatosis typically presents as cup-shaped epidermal depressions with keratotic plugs and locally visible dermal connective tissues penetrating vertically through the epidermis.5 Epidermolysis bullosa pruriginosa is a rare variant of dystrophic epidermolysis bullosa presenting with trauma-induced blisters, linear plaques formed by fusion of prurigo-like nodules on the shins, nail dystrophy, and onset early in life.6 All the aforementioned features are obviously different from PN. Prurigo nodularis is a chronic inflammatory skin disease characterized by pruritus and nodular lesions.7 Considerable clinical and histological overlaps between prurigo nodularis and PN, as well as the absence of blisters throughout the course of the latter in some cases, make the diagnosis challenging. Clinically, PN can be easily misdiagnosed as prurigo nodularis. For patients initially diagnosed with prurigo nodularis, PN should be considered with the following situations: (1) severely itchy, generalized, and papulonodular lesions, and no characteristic “butterfly” sign on the back; (2) resistance to the conventional therapy regimen for prurigo nodularis, and the skin lesions continued to progress; and (3) no blisters and eosinophil infiltration on pathology, but positive findings of DIF (previous research on pathologic findings revealed that 35.1% had spongiosis/cleft and 62.2% had dermal eosinophils out of 37 cases2). Linear deposition of IgG and C3 along the BMZ under DIF, positive indirect immunofluorescence finding of anti–basement membrane antibody (IgG), and elevated BP180 and/or BP230 autoantibodies levels can provide definite clues for distinguishing these 2 entities.Treatment of PN is similar to that for bullous pemphigoid and remains challenging. Older age and neurological comorbidities as risk factors may increase the mortality of this disease.8 First-line therapy for bullous pemphigoid includes oral and topical corticosteroids. Based on the equivalent effect to oral corticosteroids, topical treatment with clobetasol propionate is considered as a valid choice for older adult patients with numerous internal disorders.9 Immunosuppressive agents are important choices as second-line treatments.9 A recent (2020) study showed that dupilumab may provide an additional supplement to the treatment of bullous pemphigoid and its variants.10