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JAMA_Chen2024

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https://jamanetwork.com/journals/jamadermatology/fullarticle/2811083

A man in his 30s with AIDS presented with acute-onset painful scattered umbilicated papulopustules and ovoid ulcerated plaques with elevated, pink borders on the face, trunk, and extremities (Figure, A). The patient also had a new-onset cough but was afebrile and denied other systemic symptoms. Due to his significant immunocompromise, the clinical presentation was highly suspicious for infection. For rapid bedside differentiation of multiple infectious etiologies, a Tzanck smear was performed by scraping the base of an ulcerated lesion and inner aspect of a pseudopustule and scraping its base with a #15 blade. These contents were placed on a glass slide, fixed, and stained with Wright-Giemsa and subsequently Papanicolaou staining to further characterize the changes seen.A, Clinical image demonstrating papulopustules and ovoid ulcerated plaques with elevated, pink borders on the elbows. B, Tzanck smear using Wright-Giemsa staining of specimen demonstrating ballooning of keratinocytes and peripheralization of nuclear material (original magnification ×20). What Is Your Diagnosis?

Herpes simplex virus

Histoplasmosis

Molluscum contagiosum

Mpox

D. Mpox

D

Mpox

The photographs demonstrate a Tzanck smear using Wright-Giemsa stain (Figure, B) with large ballooning keratinocytes with peripheral nuclear staining seen in a patient with subsequently polymerase chain reaction (PCR)-confirmed mpox. Mpox is a member of the pox virus family, which presents with nonspecific symptoms such as fever followed by characteristic skin changes including macules, papules, vesicles, and pustules progressing with cephalocaudal spread or in the genital and/or gluteal region in the most recent outbreak. On histopathologic findings, mpox features vary depending on the stage of the lesion.1,2 Early lesions tend to demonstrate ballooning degeneration, whereas later lesions have few viable keratinocytes.2 The viral cytopathic changes, most often seen in pseudopustular lesions, include multinucleated keratinocytes with ground glass appearance and nuclear contents pushed to the periphery, resulting in a basophilic halo.2 The lack of a true pustule with collections of neutrophils in the stratum corneum have led some to describe these lesions as pseudopustular.Tzanck smear is an inexpensive, rapid, and simple technique to perform cytologic analysis from skin. Initially described in 1947 by Arnault Tzanck for diagnosing vesiculobullous disorders, it is commonly used in diagnosing herpetic infections, which have characteristic features of acantholysis, acute inflammation, and keratinocytic ballooning and specific nuclear changes of molding, multinucleation, and chromatin margination.3 The findings of acantholysis and nuclear cytopathic changes are similarly seen in histopathologic examination of herpes simplex virus (HSV). Herpetic infections may present with clustered vesicles with a pink inflammatory rim, although more verrucous lesions have been described in immunosuppressed patients.In the Tzanck smear from a lesion of mpox in this patient (Figure, B), enlarged keratinocytes were seen with expanded cytoplasm and nuclear material pushed to the periphery, and the nuclear changes associated with HSV were all absent. The observed difference in cytologic features including the nuclear material rimming or pushed to the periphery of the cells is due to the location of viral replication; herpes viruses replicate in the nucleus, whereas mpox replicates in the cytoplasm.4 Although not part of routine practice, Papanicolaou staining was performed in this case to confirm infected cells and provide additional nuclear detail because Tzanck smears in patients with mpox were not previously reported. The findings highlighted the peripheralization of nuclear material in cells with eosinophilic staining, confirming the keratinocyte origin to the cells. A background inflammatory infiltrate was noted and can be seen in most infections.Tzanck smear can also be used to diagnose other viral and fungal infections. Molluscum contagiosum, which presents with multiple umbilicated papules, demonstrates the characteristic large (30-40 µm) ovoid homogenous basophilic staining keratinocytes called Henderson-Patterson bodies that correspond to the identically named intracytoplasmic inclusions seen on histopathologic findings.5,6 Using bedside diagnostics (including Wright Giemsa staining), blastomycosis is diagnosed with 8- to 15-µm spores with broad-based budding, similar in appearance to the organism in histologic examination.5 Histoplasmosis has small (2 to 3 µm) intracellular organisms in macrophages with artifactual clearing (pseudocapsule).5 Both of these fungal infections may manifest clinically as nonhealing ulcerations, verrucous plaques, or multiple papules or nodules and can histologically demonstrate pseudoepitheliomatous hyperplasia with characteristic organisms. The use of the Tzanck smear in diagnosis of any infection depends on the timing of the lesion and is most sensitive with vesicular or pustular lesions.6 Although we only tested 1 stage of lesions, we hypothesize this test will similarly be more sensitive for earlier lesions in patients with mpox.Tzanck smear is a useful technique that can be used to differentiate mpox from other infections at the bedside or in remote settings where PCR or additional culture techniques are not easily accessible. Infection prevention and control precautions are important to help prevent additional spread of this virus with sharp injuries, and caution with unroofing of the lesions is critical to avoid additional spread.7 Knowledge of the cytologic differences of mpox compared with other viral infections is important in the early recognition, diagnosis, and treatment of these patients.

Dermatology

A man in his 30s with AIDS presented with acute-onset painful scattered umbilicated papulopustules and ovoid ulcerated plaques with elevated, pink borders on the face, trunk, and extremities (Figure, A). The patient also had a new-onset cough but was afebrile and denied other systemic symptoms. Due to his significant immunocompromise, the clinical presentation was highly suspicious for infection. For rapid bedside differentiation of multiple infectious etiologies, a Tzanck smear was performed by scraping the base of an ulcerated lesion and inner aspect of a pseudopustule and scraping its base with a #15 blade. These contents were placed on a glass slide, fixed, and stained with Wright-Giemsa and subsequently Papanicolaou staining to further characterize the changes seen.A, Clinical image demonstrating papulopustules and ovoid ulcerated plaques with elevated, pink borders on the elbows. B, Tzanck smear using Wright-Giemsa staining of specimen demonstrating ballooning of keratinocytes and peripheralization of nuclear material (original magnification ×20).

what is your diagnosis?

What is your diagnosis?

Herpes simplex virus

Mpox

Histoplasmosis

Molluscum contagiosum

b

male

31-40

original

https://jamanetwork.com/journals/jama/fullarticle/2810596

An 80-year-old man with stage II bladder carcinoma (T2NXM0) and atrial fibrillation treated with apixaban presented to the emergency department with 1 week of fatigue and 2 days of dyspnea on exertion. One week prior to presentation, he received a fourth cycle of carboplatin/gemcitabine for bladder carcinoma with 6 mg of pegylated granulocyte colony-stimulating factor (G-CSF). The patient reported no anorexia, fever, melena, hematemesis, hematuria, cough, orthopnea, or peripheral edema.His vital signs were normal except for a heart rate of 103/min. His white blood cell count was 22 × 103/μL (reference, 4-11 × 103/μL), increased from 4.8 × 103/μL 8 days prior. His manual differential, which was previously normal, showed 18% bands (0%-10%), 2% metamyelocytes, 7% myelocytes, 7% promyelocytes, and 6% blasts. His hemoglobin level was 5.2 g/dL (reference, 13-17 g/dL), decreased from 7.4 g/dL, and platelets were 25 × 103/μL (reference, 150-420 × 103/μL), decreased from 268 × 103/μL 8 days prior. Ferritin was 1423 ng/mL (reference, 300-400 ng/mL). Mean corpuscular volume, prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, haptoglobin, vitamin B12, and methylmalonic acid values were normal, and results of a direct antiglobulin test were negative. A computed tomography (CT) scan of his abdomen and pelvis was normal. He received 2 units of packed red blood cells and was admitted to the hospital. Flow cytometry identified a small population of CD34+/CD117+ cells (Figure).Left, Peripheral blood smear showing normocytic anemia with anisopoikilocytosis and leukocytosis with 6% to 8% blast forms. Right, Flow cytometry of peripheral blood demonstrating a small population of white blood cells that stained positive for CD34 and CD117, which are markers of immature myeloblasts.Esophagogastroduodenoscopy revealed 2 nonbleeding angioectasias in the stomach that were treated with argon plasma coagulation. Three days after admission, his white blood cell count was 27.7 × 103/μL with 4% peripheral blasts, hemoglobin was 7.3 g/dL, and platelet count had increased to 92 × 103/μL without a platelet transfusion.Repeat complete blood cell count with differential in 1 to 2 weeks What Would You Do Next?

Perform a bone marrow biopsy

Prescribe all-trans retinoic acid

Repeat complete blood cell count with differential in 1 to 2 weeks

Start cytoreductive therapy with hydroxyurea

Granulocyte colony-stimulating factor (G-CSF)–induced increase in peripheral blasts

C

Repeat complete blood cell count with differential in 1 to 2 weeks

The key to the correct diagnosis is recognizing that leukocytosis with immature granulocytes and mildly elevated blasts in the peripheral blood can occur after G-CSF administration. Bone marrow biopsy (choice A) is incorrect because his platelet count increased spontaneously 3 days after presentation, making malignant infiltration of his bone marrow unlikely, and recent G-CSF administration can alter bone marrow biopsy results. All-trans retinoic acid and cytoreductive therapy (options B and D) should not be prescribed because the patient did not have biopsy-proven acute promyelocytic leukemia or acute leukemia.Myeloblasts are immature leukocytes that arise from progenitor stem cells in the bone marrow, and their presence in peripheral blood suggests a perturbation of normal hematopoietic differentiation. Myeloblasts are characterized by the presence of CD34 and CD1171 antigens, identified with flow cytometry. A peripheral blood myeloblast count of greater than 20% is diagnostic of acute myeloid leukemia (AML), although AML can occur with a lower myeloblast count.2 Increased peripheral blood myeloblasts with leukopenia may be due to AML, myelodysplastic syndrome (MDS), chemotherapy, or occasionally severe infection. Causes of elevated peripheral blood myeloblasts with leukocytosis include AML, myelodysplastic syndrome, myeloproliferative neoplasms, severe infection, bone marrow damage or infiltration by fibrosis, malignancy or infection,3,4 and administration of G-CSF.G-CSF, which is produced by macrophages, T cells, endothelial cells, and fibroblasts,5 causes proliferation and differentiation of hematopoietic stem cells and progenitor cells, generating polymorphonuclear neutrophils via the precursor stages of myeloblast, promyelocyte, myelocyte, metamyelocyte, and bands. G-CSF therapy stimulates neutrophil production in the bone marrow, causing a rapid increase in peripheral blood neutrophils (emergency granulopoiesis) during severe infections. G-CSF also acts to maintain a neutrophil reserve in the bone marrow and regulates the slow release of neutrophils into the peripheral circulation.3Recombinant human G-CSF (filgrastim) received US Food and Drug Administration (FDA) approval in 1991 for prevention of chemotherapy-induced neutropenia.3,5 In 2002, the FDA approved pegfilgrastim, which is administered once per chemotherapy cycle, with at least 12 days between doses.6,7 G-CSF use is typically recommended during all chemotherapy cycles in which there is greater than 20% risk of febrile neutropenia.7 G-CSF can also be given to prevent infection in patients who experienced neutropenic complications during a prior round of chemotherapy.Patients treated with G-CSF may have peripheral blasts as high as 40% of circulating leukocytes.8 Although the mechanism of action is uncertain, induction of peripheral blasts by G-CSF may be related to differential expression of isoforms or gene variants in the G-CSF receptor. G-CSF–induced transient increase in peripheral blasts, which is most commonly reported in patients with MDS, AML, and other hematologic malignancies, is treated by withholding G-CSF therapy.3,8-10 Peripheral blasts typically resolve 1 to 2 weeks after peak blast count,8,9 at which point G-CSF therapy can be reinitiated with close monitoring of blood counts.After a 3-day hospitalization, the patient had a white blood cell count of 22.7 × 103/μL with 9% bands, 2% metamyelocytes, 2% myelocytes, 2% promyelocytes, and 4% blasts; hemoglobin was 7.3 g/dL, and platelets were 92 × 103/μL. Ten days after hospital discharge, his white blood cell count was 7.4 × 103/μL with a normal differential and no blasts; hemoglobin was 8.9 g/dL, and platelets were 384 × 103/μL. Two months later, he underwent cystectomy and received treatment with nivolumab for 5 months. However, his cancer progressed, and the patient died 5 months after his initial presentation.

General

An 80-year-old man with stage II bladder carcinoma (T2NXM0) and atrial fibrillation treated with apixaban presented to the emergency department with 1 week of fatigue and 2 days of dyspnea on exertion. One week prior to presentation, he received a fourth cycle of carboplatin/gemcitabine for bladder carcinoma with 6 mg of pegylated granulocyte colony-stimulating factor (G-CSF). The patient reported no anorexia, fever, melena, hematemesis, hematuria, cough, orthopnea, or peripheral edema.His vital signs were normal except for a heart rate of 103/min. His white blood cell count was 22 × 103/μL (reference, 4-11 × 103/μL), increased from 4.8 × 103/μL 8 days prior. His manual differential, which was previously normal, showed 18% bands (0%-10%), 2% metamyelocytes, 7% myelocytes, 7% promyelocytes, and 6% blasts. His hemoglobin level was 5.2 g/dL (reference, 13-17 g/dL), decreased from 7.4 g/dL, and platelets were 25 × 103/μL (reference, 150-420 × 103/μL), decreased from 268 × 103/μL 8 days prior. Ferritin was 1423 ng/mL (reference, 300-400 ng/mL). Mean corpuscular volume, prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, haptoglobin, vitamin B12, and methylmalonic acid values were normal, and results of a direct antiglobulin test were negative. A computed tomography (CT) scan of his abdomen and pelvis was normal. He received 2 units of packed red blood cells and was admitted to the hospital. Flow cytometry identified a small population of CD34+/CD117+ cells (Figure).Left, Peripheral blood smear showing normocytic anemia with anisopoikilocytosis and leukocytosis with 6% to 8% blast forms. Right, Flow cytometry of peripheral blood demonstrating a small population of white blood cells that stained positive for CD34 and CD117, which are markers of immature myeloblasts.Esophagogastroduodenoscopy revealed 2 nonbleeding angioectasias in the stomach that were treated with argon plasma coagulation. Three days after admission, his white blood cell count was 27.7 × 103/μL with 4% peripheral blasts, hemoglobin was 7.3 g/dL, and platelet count had increased to 92 × 103/μL without a platelet transfusion.Repeat complete blood cell count with differential in 1 to 2 weeks

what would you do next?

What would you do next?

Start cytoreductive therapy with hydroxyurea

Prescribe all-trans retinoic acid

Repeat complete blood cell count with differential in 1 to 2 weeks

Perform a bone marrow biopsy

c

male

71-80

White

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2810537

A 68-year-old man presented with progressive right-sided facial numbness and weakness, vision changes, and headaches. His symptoms began 5 years earlier with right temple numbness, which expanded to include the entire right face and mouth. He then developed progressive right facial weakness with a droop, slurred speech, and eyelid ptosis. Finally, binocular vertical and horizontal diplopia and periorbital headaches began. Trials of gabapentin and steroids provided no relief. His history was significant for a left cheek melanoma completely excised years prior, numerous cutaneous squamous and basal cell carcinomas of the bilateral head and neck removed without issue, type 2 diabetes, and hyperlipidemia. His medications included metformin and simvastatin; he had no history of smoking or drinking.On examination, he had right-sided ptosis and severe right facial weakness in a lower motor neuron pattern with temporal wasting. The right pupil was fixed and dilated. There was no afferent pupillary defect. The left pupil was appropriately sized and reactive. His right-sided vision was impaired (20/250) with blurriness. Vertical and horizontal binocular diplopia was present. Right extraocular movements were significantly limited in all directions and painful, and right-sided facial sensation was diminished to pinprick in all cranial nerve (CN) V distributions. His speech was slightly slurred. Left-sided extraocular movements were intact. His left facial sensation was intact to pinprick, and his strength was without deficit. There were no other neurological abnormalities.Initial magnetic resonance images (MRIs) were unremarkable. A biopsy of CN VII was nondiagnostic. Hemoglobin A1c was 6.8%. Tests for infection and autoimmune disease had negative results. Cerebrospinal fluid (CSF) studies showed mildly elevated protein values. Figure 1 shows the MRI at presentation.T1 turbo spin-echo fat-saturated magnetic resonance images of the brain through the skull base at presentation. What Is Your Diagnosis?

Primary leptomeningeal lymphoma

Tolosa-Hunt syndrome

Perineural spread of cutaneous malignancy

Sphenoid wing meningioma

C. Perineural spread of cutaneous malignancy

C

Perineural spread of cutaneous malignancy

The MRI of the brain and orbits revealed asymmetric enhancement of the right CNs V and VII, with denervation atrophy of the masticator space (Figure 2). Biopsy of the infraorbital nerve revealed squamous cell carcinoma, thought to have originated from a cutaneous source given his history. Immunotherapy was initiated with cemiplimab. MRI findings have remained stable over the past 2 years with no progression of disease or worsening symptoms.Same magnetic resonance image as in Figure 1B with an arrowhead denoting asymmetric enhancement of the right maxillary nerve in the foramen rotundum.The onset of multiple cranial neuropathies presents a diagnostic dilemma. Oncological diagnosis is often difficult in the absence of an obvious lesion and normal or equivocal imaging.1 This can lead to diagnostic delays and worse outcomes. This patient was seen by 20 different physicians over 5 years, including general, autonomic, and neuromuscular neurologists and neuro-ophthalmologists, before a diagnosis of malignancy was made. It can take time for perineural invasion (PNI) to become radiographically apparent, and a high index of suspicion for underlying malignancy must be maintained even with initially negative imaging.Primary leptomeningeal lymphoma (A) is a rare manifestation of primary central nervous system lymphoma that can present with multiple cranial neuropathies.2 CSF results are usually abnormal and progression of symptoms more rapid.2 Tolosa-Hunt syndrome (B) can present with painful ophthalmoplegia and multiple cranial neuropathies; however, steroids are typically effective.3 When located along the sphenoid wing, meningiomas (D) can cause multiple progressive cranial neuropathies.4 Typically visible on MRI as extra-axial homogenously enhancing masses,4 no such lesion was observed here. In this patient, the symptomatology, history, and radiographic findings are best explained by PNI of cutaneous squamous cell carcinoma (cSCC), which a biopsy confirmed.One of the most common cancers in the world, cSCC occurs frequently in the head and neck secondary to sun exposure.5 PNI refers to the process of tumor spread into nerves and the space surrounding them.6 An estimated 2% to 6% of patients with cSCC of the head and neck will have PNI.1,6 Cranial nerves V and VII are most commonly involved given their extensive anatomical distributions.1,5,6 Clinically or radiographically apparent PNI confers a poor prognosis with a reported 5-year absolute survival rate of 50%.5Treatment for cSCC of the head and neck includes surgery (if resectable) and high-dose radiotherapy and systemic therapy as appropriate. Immunotherapy with checkpoint inhibition is being used with increasing frequency and notable effectiveness.5-9 Early-phase studies demonstrated impressive response rates near 50% for advanced, unresectable, and metastatic cSCC of the head and neck, earning US Food and Drug Administration approval for 2 checkpoint inhibitors in this setting.7,8 Recently, a landmark phase 2 trial of neoadjuvant cemiplimab for stage II through IV (M0) cSCC before surgery was published, with 51% complete pathological response rates and 68% objective response rates on imaging.9 Similarly, in a recent report of 11 patients with cSCC of the head and neck with clinical PNI treated with checkpoint inhibitors, radiographic disease control was observed in 9 of 11 patients at extended follow-up.5 Many of these responses are durable and curative.The presence of both CN V and VII symptoms in a patient with a history of head and neck cSCC should raise suspicion for perineural recurrence of disease. While initial MRI may be negative, radiographic manifestation of PNI often occurs over time as the disease progresses and symptoms worsen. Expert review by a neuroradiologist can be helpful in identifying this finding earlier in the disease course. Mounting evidence suggests that immunotherapy is a promising treatment option for this population and should be considered as first-line therapy.

Neurology

A 68-year-old man presented with progressive right-sided facial numbness and weakness, vision changes, and headaches. His symptoms began 5 years earlier with right temple numbness, which expanded to include the entire right face and mouth. He then developed progressive right facial weakness with a droop, slurred speech, and eyelid ptosis. Finally, binocular vertical and horizontal diplopia and periorbital headaches began. Trials of gabapentin and steroids provided no relief. His history was significant for a left cheek melanoma completely excised years prior, numerous cutaneous squamous and basal cell carcinomas of the bilateral head and neck removed without issue, type 2 diabetes, and hyperlipidemia. His medications included metformin and simvastatin; he had no history of smoking or drinking.On examination, he had right-sided ptosis and severe right facial weakness in a lower motor neuron pattern with temporal wasting. The right pupil was fixed and dilated. There was no afferent pupillary defect. The left pupil was appropriately sized and reactive. His right-sided vision was impaired (20/250) with blurriness. Vertical and horizontal binocular diplopia was present. Right extraocular movements were significantly limited in all directions and painful, and right-sided facial sensation was diminished to pinprick in all cranial nerve (CN) V distributions. His speech was slightly slurred. Left-sided extraocular movements were intact. His left facial sensation was intact to pinprick, and his strength was without deficit. There were no other neurological abnormalities.Initial magnetic resonance images (MRIs) were unremarkable. A biopsy of CN VII was nondiagnostic. Hemoglobin A1c was 6.8%. Tests for infection and autoimmune disease had negative results. Cerebrospinal fluid (CSF) studies showed mildly elevated protein values. Figure 1 shows the MRI at presentation.T1 turbo spin-echo fat-saturated magnetic resonance images of the brain through the skull base at presentation.

what is your diagnosis?

What is your diagnosis?

Tolosa-Hunt syndrome

Perineural spread of cutaneous malignancy

Sphenoid wing meningioma

Primary leptomeningeal lymphoma

b

male

61-70

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2810749

A 31-year-old man presented with left cervical and left inguinal masses. He reported intermittent itching and night sweats for 2 years. He denied fever, weight loss, shortness of breath, rashes, diarrhea, and neurological symptoms. On a preemployment evaluation, the patient was told he had a high white blood cell count 2 years ago. On examination, there was left cervical and inguinal lymphadenopathy and no other organomegaly. Complete blood cell count and peripheral blood smear showed marked leukocytosis, with a white blood cell count of 22 340/μL, an absolute neutrophil count of 5360/μL, and 55% eosinophils with an absolute eosinophil count of 12 290/μL (to convert all to cells ×109/L, multiply by 0.001). Vitamin B12 was markedly elevated at more than 4000 pg/mL (to convert to pmol/L, multiply by 0.7378). The erythrocyte sedimentation rate was 5 mm/h. Lactate dehydrogenase was 180 U/L, and alkaline phosphatase was 81 U/L (to convert both to μkat/L, multiply by 0.0167). Evaluations for HIV and hepatitis B and C were all negative. Serum creatinine was 0.76 mg/dL (to convert to μmol/L, multiply by 88.4); alanine aminotransferase and aspartate aminotransferase were 11 U/L and 9.9 U/L, respectively (to convert to μkat/L, multiply by 0.0167); and total bilirubin was 0.35 mg/dL (to convert to μmol/L, multiply by 17.104). Bone marrow biopsy showed hypercellular marrow (cellularity of 100%), myeloid hyperplasia, increased eosinophils with some dysplasia, and a blast count of 2%. Positron emission tomographic–computed tomographic scan showed a left upper cervical lymph node of 2.6 cm and a left inguinal lymph node of 3.1 × 2.3 cm with an standardized uptake value max of 5.7 (Figure, A). Left inguinal lymph node biopsy showed partial involvement by atypical cells with high proliferation index (Ki-67 >95%) that were positive for CD3, CD4, CD8, BCL2, and TDT, suggestive of T-cell lymphoblastic lymphoma/leukemia (Figure, B).A, Positron emission tomographic–computed tomographic (PET/CT) scan of the head and neck at presentation showing a left upper cervical lymph node of 2.6 cm (arrowhead). B, Lymph node biopsy immunohistochemical stain with terminal deoxynucleotidyl transferase. The inset shows interphase fluorescence in situ hybridization for FIP1L1::PDGFRA rearrangement (positive). C, PET/CT 12 weeks after treatment initiation.Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions What Is Your Diagnosis?

Kimura disease

Classic Hodgkin lymphoma

T-cell acute lymphoblastic lymphoma/leukemia

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions

D. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions

D

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions

The differential diagnoses in young men with eosinophilia and a neck mass can be wide. The typical presentation of Kimura disease is a painless, unilateral swelling of cervical lymph nodes in young adult male patients with peripheral blood eosinophilia and elevated immunoglobulin E levels. Histological evaluation, however, would show hyperplastic reactive follicles with eosinophilic infiltrates in a background of polymorphous inflammatory cells, a picture inconsistent with the presented case. Although Hodgkin lymphoma can present with eosinophilia and neck mass in young adults, the biopsy was inconsistent with the typical morphology of Reed-Sternberg cells in the background of nonneoplastic inflammatory cells. The diagnosis of T-cell acute lymphoblastic lymphoma/leukemia is reasonable given the morphology from lymph node biopsy; however, in the diagnosis hierarchy, myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) would supersede other myeloid and lymphoid cancers.1In the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours, MLN-TK refers to BCR::ABL1–negative myeloid or lymphoid neoplasms with gene rearrangements leading to an activated tyrosine-kinase domain that results in cell-signaling dysregulation.1 This includes PDGFRA, PDGFRB, FGFR1, JAK2, and FLT3 rearrangements, in addition to ETV6::ABL1, ETV6::FGFR2, ETV6::LYN, ETV6::NTRK3, RANBP2::ALK, BCR::RET, and FGFR1OP::RET fusions.1 An increase in vitamin B12 is often found in patients with PDGFRA and PDGFRB disease.2,3 Most patients are male with chronic myeloid neoplasms with eosinophilia; however, patients rarely present with acute myeloid or T-cell leukemia or extramedullary disease.2Fluorescence in situ hybridization (FISH) was positive for FIP1L1::PDGFRA (4q12) fusion in 91% of nuclei, while karyotype was normal (46, XY in 18 cells), as a cryptic loss of the CHIC2 gene causes this fusion. Next, generation sequencing panel for myeloid neoplasms was negative for variants in targeted regions of the genes commonly involved in myeloid neoplasms. Combining imatinib with chemotherapy is acceptable in patients with acute leukemia or extramedullary diseases, although monotherapy with imatinib has shown promising results.4 The patient was concerned about fertility, as he and his partner were starting a family, and decided to avoid chemotherapy. The patient was concomitantly initiated on 1 mg/kg of prednisone for 7 days and imatinib at 600 mg daily. The eosinophil counts normalized after 2 days, and bone marrow evaluation after 4 weeks showed resolution of eosinophilic infiltration; however, FISH results were 3% positive for FIP1L1::PDGFRA fusion. Repeat bone marrow evaluation after 8 weeks showed complete resolution of the FISH abnormality, and the imatinib dose was reduced to 400 mg daily. Although studies have confirmed deep and durable remission with a starting dose of imatinib, 100 mg, we elected to start with a high dose given the patient’s young age and blastic presentation.5,6 Follow-up positron emission tomographic–computed tomographic scan 12 weeks after initiation of imatinib was consistent with complete metabolic remission (Figure, C). Complete hematological remission is achieved in more than 95% of patients with imatinib and is typically seen early (within weeks of treatment initiation). Cytogenetic/molecular response can be achieved within 3 to 6 months of treatment initiation.7 In patients who achieved molecular remission, the imatinib dose can be reduced to 100 thrice weekly or weekly.8 Treatment-free remission as the experience with chronic myeloid leukemia has been tried, although with limited experience. The success rate is around 60%, with most patients relapsing within the first 10 months. Reinitiating of imatinib restores hematological remission in almost all patients.9,10The current patient was in complete remission 12 months from his treatment and receiving imatinib. Evaluating patients suspected of MLN-TK is critical, as treatment and prognosis may drastically change.

Oncology

A 31-year-old man presented with left cervical and left inguinal masses. He reported intermittent itching and night sweats for 2 years. He denied fever, weight loss, shortness of breath, rashes, diarrhea, and neurological symptoms. On a preemployment evaluation, the patient was told he had a high white blood cell count 2 years ago. On examination, there was left cervical and inguinal lymphadenopathy and no other organomegaly. Complete blood cell count and peripheral blood smear showed marked leukocytosis, with a white blood cell count of 22 340/μL, an absolute neutrophil count of 5360/μL, and 55% eosinophils with an absolute eosinophil count of 12 290/μL (to convert all to cells ×109/L, multiply by 0.001). Vitamin B12 was markedly elevated at more than 4000 pg/mL (to convert to pmol/L, multiply by 0.7378). The erythrocyte sedimentation rate was 5 mm/h. Lactate dehydrogenase was 180 U/L, and alkaline phosphatase was 81 U/L (to convert both to μkat/L, multiply by 0.0167). Evaluations for HIV and hepatitis B and C were all negative. Serum creatinine was 0.76 mg/dL (to convert to μmol/L, multiply by 88.4); alanine aminotransferase and aspartate aminotransferase were 11 U/L and 9.9 U/L, respectively (to convert to μkat/L, multiply by 0.0167); and total bilirubin was 0.35 mg/dL (to convert to μmol/L, multiply by 17.104). Bone marrow biopsy showed hypercellular marrow (cellularity of 100%), myeloid hyperplasia, increased eosinophils with some dysplasia, and a blast count of 2%. Positron emission tomographic–computed tomographic scan showed a left upper cervical lymph node of 2.6 cm and a left inguinal lymph node of 3.1 × 2.3 cm with an standardized uptake value max of 5.7 (Figure, A). Left inguinal lymph node biopsy showed partial involvement by atypical cells with high proliferation index (Ki-67 >95%) that were positive for CD3, CD4, CD8, BCL2, and TDT, suggestive of T-cell lymphoblastic lymphoma/leukemia (Figure, B).A, Positron emission tomographic–computed tomographic (PET/CT) scan of the head and neck at presentation showing a left upper cervical lymph node of 2.6 cm (arrowhead). B, Lymph node biopsy immunohistochemical stain with terminal deoxynucleotidyl transferase. The inset shows interphase fluorescence in situ hybridization for FIP1L1::PDGFRA rearrangement (positive). C, PET/CT 12 weeks after treatment initiation.Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions

what is your diagnosis?

What is your diagnosis?

T-cell acute lymphoblastic lymphoma/leukemia

Kimura disease

Classic Hodgkin lymphoma

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions

d

male

31-40

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2810850

A 28-year-old woman presented with a 5-day history of painful cervical lymphadenopathy along with fever, nausea, and vomiting. Treatment with antibiotics and corticosteroids was started, without improvement of symptoms. She denied recent travel, sick contacts, or autoimmune disease. Her medical history was significant for α-thalassemia but otherwise noncontributory.On examination, she had tender lymphadenopathy involving right level V. A computed tomography scan of the neck revealed a collection of enlarged, matted nodes without evidence of an abscess. Fine-needle aspiration (FNA) biopsy showed nondiagnostic reactive lymph nodes. She was subsequently admitted to the hospital, where the lymphadenopathy progressed to the left side of the neck and a skin eruption developed over her face, back, and trunk. Results of an infectious disease and rheumatological workup, including bone marrow biopsy, were negative. Given her persistent symptoms, the ear, nose, and throat service consulted for excisional biopsy.On pathologic examination, the lymph nodes showed extensive coagulative necrosis, apoptosis, and karyorrhectic debris (Figure 1). Cellular components included histiocytes and dendritic cells, with absent neutrophils and hematoxylin bodies.Well-defined areas of fibrinoid necrosis in paracortical areas (hematoxylin-eosin, original magnification ×20). What Is Your Diagnosis?

Lymphoma

Kikuchi-Fujimoto disease

Systemic lupus erythematosus

Rosai-Dorfman disease

B. Kikuchi-Fujimoto disease

B

Kikuchi-Fujimoto disease

Common diagnostic considerations of lymphadenopathy alongside recurrent fever in young adults include infection, autoimmune disorders, and malignant neoplasms. Failure of conservative management with antibiotics reduces the likelihood of bacterial infection, whereas lack of cutaneous findings is atypical for a patient with classic systemic lupus erythematosus (SLE) (option C). Furthermore, both FNA and bone marrow biopsy results were not concerning for malignancy. Due to her relatively nonspecific and persistent symptoms, excisional biopsy was performed, giving the final diagnosis of Kikuchi-Fujimoto disease (KFD).Kikuchi-Fujimoto disease (also known as Kikuchi-Fujimoto lymphadenopathy, Kikuchi lymphadenitis, and necrotizing lymphadenitis of unknown etiology) is a benign, self-limiting disease that commonly affects young adults. This rare disease was first reported in Japan in 1972, with the highest prevalence in Asia.1 Patients typically present with painful cervical lymphadenopathy alongside fever and leukopenia.2 It commonly affects women younger than 40 years. Recent studies, however, suggest a more equal distribution among men and women.3Although the etiology is unknown, both autoimmune and viral causes are suspected. Involvement of Epstein-Barr and other herpesviruses is controversial and can be distinguished with periodic acid–Schiff, Grocott methenamine silver, and Ziehl-Nielsen stains. An inappropriate immune reaction has been hypothesized, as KFD is a T-cell–mediated response in those with a specific genetic profile.3 Individuals with KFD have a significantly higher incidence of human leukocyte antigen class II genes (specifically, the DPA1*01 and DPB1*0202 alleles, which are more common in Asian individuals).3 Interestingly, KFD has also occurred in conjunction with SLE, preceding its onset in 30% of cases.4The FNA biopsy is not specific in diagnosing KFD, with an accuracy of 56.7%.5 Therefore, excisional biopsy of the affected lymph nodes is often required. Figure 1 shows a typical necrotic phase of Kikuchi lymphadenitis with well-defined areas of fibrinoid necrosis in paracortical areas of affected lymph nodes. The necrotic foci show abundant karyorrhectic and cellular debris, fibrin deposition, and mononuclear cells (Figure 2). There are no intact neutrophils or eosinophils and only rare plasma cells. Crescentic histiocytes with phagocytized debris are seen along with numerous plasmacytoid dendritic cells/monocytes, macrophages, and activated T cells, which can simulate the appearance of a peripheral T-cell lymphoma. Some cases show prominent xanthomatous inflammation with foamy histiocytes.The necrotic foci show abundant karyorrhectic and cellular debris, fibrin deposition, and mononuclear cells. There are no intact neutrophils or eosinophils and only rare plasma cells. Crescentic histiocytes with phagocytized debris as well as plasmacytoid dendritic cells/monocytes are seen (hematoxylin-eosin, original magnification ×100).This disease is self-limited, lasting 1 to 4 months; although recurrence has been reported, the incidence is 3% to 4%.3 The fatality rate is low and has been reported in only 3 patients. Treatment is largely supportive with analgesic agents, antipyretic agents, and corticosteroids. In patients with recurrent symptoms, low doses of corticosteroids may achieve remission.6The differential diagnosis includes lymphoma with necrosis (option A), cat-scratch disease, and lupus lymphadenitis. Cat-scratch disease is confirmed by serologic testing for Bartonella henselae antibodies.5 Patients with lupus present with lymphadenopathy, fever, skin eruption, and hepatosplenomegaly. In contrast, patients with KFD present with predominantly cervical lymphadenopathy alongside fever and skin eruption.6 Although nonspecific, serologic testing may show leukopenia, anemia, thrombocytopenia, or atypical lymphocytes on peripheral blood smear.At last follow-up, this patient’s fever and lymphadenopathy had resolved, but the skin eruption had progressed to her hands and feet. She is currently receiving prednisone therapy and undergoing an autoimmune workup due to high suspicion of disease progression to SLE or myositis. She will continue to follow up with rheumatology, hematology/oncology, infectious disease, and otolaryngology services.

General

A 28-year-old woman presented with a 5-day history of painful cervical lymphadenopathy along with fever, nausea, and vomiting. Treatment with antibiotics and corticosteroids was started, without improvement of symptoms. She denied recent travel, sick contacts, or autoimmune disease. Her medical history was significant for α-thalassemia but otherwise noncontributory.On examination, she had tender lymphadenopathy involving right level V. A computed tomography scan of the neck revealed a collection of enlarged, matted nodes without evidence of an abscess. Fine-needle aspiration (FNA) biopsy showed nondiagnostic reactive lymph nodes. She was subsequently admitted to the hospital, where the lymphadenopathy progressed to the left side of the neck and a skin eruption developed over her face, back, and trunk. Results of an infectious disease and rheumatological workup, including bone marrow biopsy, were negative. Given her persistent symptoms, the ear, nose, and throat service consulted for excisional biopsy.On pathologic examination, the lymph nodes showed extensive coagulative necrosis, apoptosis, and karyorrhectic debris (Figure 1). Cellular components included histiocytes and dendritic cells, with absent neutrophils and hematoxylin bodies.Well-defined areas of fibrinoid necrosis in paracortical areas (hematoxylin-eosin, original magnification ×20).

what is your diagnosis?

What is your diagnosis?

Lymphoma

Systemic lupus erythematosus

Kikuchi-Fujimoto disease

Rosai-Dorfman disease

c

female

21-30

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2810393

A woman in her 90s presented to the emergency department with symptoms of fever, hemoptysis, and syncopal episodes. She had a history of breast cancer and pulmonary nodules with biopsy findings negative for metastatic disease but positive for granulomatous inflammation. Initial vital signs included blood pressure of 103/66 mm Hg, heart rate of 190 bpm, and temperature of 38.7 °C. Electrocardiogram showed monomorphic ventricular tachycardia with a morphology suggesting right ventricular (RV) origin (Figure 1). In addition to receiving intravenous amiodarone hydrochloride, she had correction of mild hypokalemia (3.1 mEq/L [reference range, 3.5-5.2 mEq/L]; to convert to mmol/L, multiply by 1.0). Successful arrhythmia termination occurred shortly thereafter, and her vital signs remained stable. Chest computed tomographic angiography excluded pulmonary embolism but showed pulmonary nodules and mediastinal lymphadenopathy that had progressed compared with her previous computed tomography. An echocardiogram showed severe RV and left ventricular (LV) systolic dysfunction with multiple areas of hypokinesis.Patient electrocardiogram showing monomorphic regular wide complex tachycardia with a left bundle branch block morphology, with a precordial transition at V3 and inferior axis suggesting right ventricular origin. What Would You Do Next?

Cardiac magnetic resonance imaging

Electrophysiology study

Genetic testing

Implantation of cardiac defibrillator

Cardiac sarcoidosis

A

Cardiac magnetic resonance imaging

The patient underwent cardiac magnetic resonance imaging, which demonstrated areas of nonischemic near-transmural late gadolinium enhancement (LGE) of the interventricular septum and epicardium to midmyocardium of the LV basal to midanterior and basal inferior walls extending to the RV walls and septal papillary muscle (Figure 2A). However, T2 mapping revealed only discrete evidence of edema of a small region of the midanterior LV wall. Taken together, these findings raised the possibility of end-stage cardiac sarcoidosis (CS).A, Cardiac magnetic resonance imaging using phase-sensitive inversion recovery with motion correction demonstrates multiple areas of subepicardial, midmyocardial, and transmural and near-transmural late gadolinium enhancement in the left ventricle (pink arrowhead) and extending to the right ventricular wall and septal papillary muscle (blue arrowhead). B, Selected matched contiguous short-axis rubidium-82 (top row) and fluorodexoyglucose F 18 (FDG) positron emission tomographic images (bottom row) demonstrate reduced perfusion in the midseptum with marked FDG uptake in the septum and inferior wall, sparing the lateral wall.Cardiac fluorodeoxyglucose F 18 (FDG) and rubidium-82 positron emission tomography (PET) for CS was obtained with a strict high-fat, low-carbohydrate diet, followed by 12 hours of fasting prior to the examination per American Society of Nuclear Cardiology recommendations.1 Because the patient was hospitalized, dietary compliance was ensured. Furthermore, FDG uptake was segmental and the LV blood pool maximum standard uptake value was only 1.1, demonstrating adequate suppression of normal myocardial glucose utilization. There was an extensive FDG uptake (Figure 2B), with maximum standard uptake value of 10.4 in the LV septum. There was also extracardiac FDG uptake in hilar and mediastinal lymph nodes and in multiple pulmonary nodules. Rubidium-82 PET showed only mildly reduced perfusion in the basal to apical septal wall.This case highlights multiple learning points in the use of multimodality imaging for evaluation of patients with CS and understanding its complex pathophysiology. First, the utility of T2 mapping for detecting myocardial edema, a potential surrogate for active inflammation, needs to be better understood, as this can be challenging and in this case underrepresented the extensive positive FDG uptake seen on cardiac PET. Despite extensive LV and RV LGE and depressed biventricular systolic function, substantial myocardial inflammation in this patient is consistent with active rather than end-stage CS. Second, determining individual patient prognosis and assessment of immunosuppression response in patients with CS using cardiac imaging remains challenging. It has been demonstrated that patients without LGE are at an extremely low risk of arrhythmic events.2,3 However, although there is increased risk of arrhythmic events in patients with cardiac involvement identified by LGE, only a fraction of these patients experience arrhythmic events. Patients with both RV and LV LGE are at elevated risk of cardiovascular events compared with patients with only LV enhancement.2-4 Last, while CS is extremely rare after 70 years of age, as the oldest patient reported in the literature was 80 years old,5 this patient presented with CS in her 90s, reminding us that CS remains on the differential diagnosis in patients with sustained ventricular arrythmias regardless of age.Heart failure guideline–directed medical treatment, oral amiodarone, and immunosuppressive therapy consisting of a high, tapering dose of prednisone with mycophenolate mofetil were started. The patient remained stable with no more arrythmias. After shared decision discussions with the patient, a cardiac defibrillator was not implanted given the patient’s age and out of respect for her wishes. She will undergo follow-up FDG-PET to monitor her response to therapy and disease activity.

Cardiology

A woman in her 90s presented to the emergency department with symptoms of fever, hemoptysis, and syncopal episodes. She had a history of breast cancer and pulmonary nodules with biopsy findings negative for metastatic disease but positive for granulomatous inflammation. Initial vital signs included blood pressure of 103/66 mm Hg, heart rate of 190 bpm, and temperature of 38.7 °C. Electrocardiogram showed monomorphic ventricular tachycardia with a morphology suggesting right ventricular (RV) origin (Figure 1). In addition to receiving intravenous amiodarone hydrochloride, she had correction of mild hypokalemia (3.1 mEq/L [reference range, 3.5-5.2 mEq/L]; to convert to mmol/L, multiply by 1.0). Successful arrhythmia termination occurred shortly thereafter, and her vital signs remained stable. Chest computed tomographic angiography excluded pulmonary embolism but showed pulmonary nodules and mediastinal lymphadenopathy that had progressed compared with her previous computed tomography. An echocardiogram showed severe RV and left ventricular (LV) systolic dysfunction with multiple areas of hypokinesis.Patient electrocardiogram showing monomorphic regular wide complex tachycardia with a left bundle branch block morphology, with a precordial transition at V3 and inferior axis suggesting right ventricular origin.

what would you do next?

What would you do next?

Implantation of cardiac defibrillator

Electrophysiology study

Cardiac magnetic resonance imaging

Genetic testing

c

female

91-100

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2810455

A 27-year-old woman presented to her primary care physician with primary complaints of headaches and visual-spatial difficulties when driving at night. In addition, the patient described a progressively enlarging lesion on her left scalp, which she had initially noted in high school. She denied any overlying loss of hair, sharp pain, or bleeding from the scalp lesion, and she only reported pain with prolonged pressure. On her scalp examination, a 7-cm ill-defined spongy and pulsatile mass was noted with an overlying gray patch of hair. Magnetic resonance imaging (MRI) of the brain/orbit was initially performed (Figure, A and B), which demonstrated an ill-defined, diffuse, intensely enhancing scalp lesion in the left frontoparietal region with very prominent vascularity and underlying calvarial thickening. No osseous destruction or intracranial extension was present. Subsequent catheter angiography (Figure, C) confirmed the hypervascular mass, supplied via hypertrophied superficial temporal and occipital arteries with marked internal vascularity without direct involvement of the calvarium or intracranial structures. The patient underwent biopsy under general anesthesia; the specimen showed an ill-defined deep dermal/subcutaneous proliferation of spindle cells without significant nuclear pleomorphism or mitotic activity. The lesions stained positive for S100 and SOX10 immunostains.Coronal T2-weighted (A) and postcontrast T1-weighted (B) fat-saturated images show the large left T2 hyperintense scalp lesion (double arrowheads; A and B), with underlying calvarial thickening (asterisk; A and B) without invasion, prominent vascularity (single arrowhead; A), and enhancement (B). Note the preservation of the overlying skin. Catheter angiography (C) shows the hypervascular scalp lesion being supplied by hypertrophied branches arising from the left superficial temporal and occipital arteries, with marked internal vascularity (arrowheads). R indicates right. What Is Your Diagnosis?

Arteriovenous malformation of the scalp

Solitary fibrous tumor

Diffuse-type neurofibroma

Dermatofibrosarcoma protuberans

C. Diffuse-type neurofibroma

C

Diffuse-type neurofibroma

Neurofibromas, which are common in the head and neck, arise from endoneurium and connective tissues of peripheral nerve sheaths. From a morphologic and imaging perspective, there are 3 main types of neurofibromas: localized, diffuse, and plexiform.1 Diffuse neurofibromas are rare and represent less than 5% to 10% of all neurofibromas. The localized type, which is more common (>90%) and is the most well recognized and documented, is usually not a diagnostic conundrum. Plexiform neurofibromas, the other subtype, also have a pathognomonic imaging appearance and are frequently associated with neurofibromatosis 1, with findings of multiple lesions at different sites, which makes the diagnosis easier. Diffuse neurofibromas, however, are frequently solitary and are mostly sporadic, with few reported cases of associated with neurofibromatosis 1 (NF1).2 These lesions are more often seen in children and young adults. They are unusually large and frequently multispatial, with ill-defined margins, which appear to infiltrate and grow around tissues rather than invade them.On imaging, these are frequently plaquelike infiltrative lesions, unlike the more rounded or nodular appearance of localized neurofibromas, with frequent involvement of the subcutaneous/deep fascia both underlying the skin and overlying the musculature. Another characteristic is preservation of the overall morphologic features of the involved tissue space due to its unusual infiltrative pattern.2 A lesser known feature of these lesions is that many also demonstrate marked internal vascularity with prominent flow voids, arterial feeders, and draining veins, which can sometimes mimic vascular malformations.3 On MRI, these are isointense to mildly hyperintense to muscle on T1-weighted imaging and mild to markedly hyperintense on T2-weighted imaging to muscle, with marked enhancement. The lesions are usually solid without any necrotic or cystic changes, calcification, or hemorrhage.Solitary fibrous tumors (option B) (previously referred to as hemangiopericytomas) are rare mesenchymal-origin lesions, usually in older adults. On MRI, these are homogeneous lesions, with usually low to intermediate signals on both T1- and T2-weighted sequences (relative to muscle), with intense enhancement. They can be plaquelike and are frequently hypervascular, with numerous flow voids.4 Rarely, they may have a heterogeneous appearance secondary to internal hemorrhage or necrosis. They frequently mimic meningiomas when they arise intracranially.Scalp arteriovenous malformations (option A) are rare, and they present in children and young adults. On imaging, a predominant vascular lesion is identified with numerous flow voids due to its high flow state. The imaging features can be variable if there are associated abnormalities as well as other low-flow lesions, such as venous or lymphatic malformations. Vascular imaging, such as computed tomographic and magnetic resonance angiography, ultrasonography, and catheter angiography, is frequently done for both diagnosis and treatment planning.5Dermatofibrosarcoma protuberans (option D) are rare superficial lesions of the dermis, usually presenting in the third to fourth decade of life. These are locally aggressive, infiltrative masses that can arise in the head and neck, including the scalp. They present as a painless, slow-growing, nodular mass–like firm lesion. On imaging, these are markedly enhancing lesions, usually T1 hypointense and T2 hyperintense, with no vascular flow voids, underlying osseous invasion, or perineural spread.6 However, underlying calvarial thinning is seen in a few cases.Given the findings of the large scalp neurofibroma and her age, the patient was advised to undergo comprehensive genetic testing for NF1. Although NF1 is autosomal dominant and the patient had a negative family history, almost half of all individuals with NF1 are the first person in their family to have NF1 (de novo variant).7 The patient tested negative for identifiable pathogenic variants in the NF1 or SPRED1 genes, decreasing her risk of having NF1 and confirming that this was likely a sporadic neurofibroma.

General

A 27-year-old woman presented to her primary care physician with primary complaints of headaches and visual-spatial difficulties when driving at night. In addition, the patient described a progressively enlarging lesion on her left scalp, which she had initially noted in high school. She denied any overlying loss of hair, sharp pain, or bleeding from the scalp lesion, and she only reported pain with prolonged pressure. On her scalp examination, a 7-cm ill-defined spongy and pulsatile mass was noted with an overlying gray patch of hair. Magnetic resonance imaging (MRI) of the brain/orbit was initially performed (Figure, A and B), which demonstrated an ill-defined, diffuse, intensely enhancing scalp lesion in the left frontoparietal region with very prominent vascularity and underlying calvarial thickening. No osseous destruction or intracranial extension was present. Subsequent catheter angiography (Figure, C) confirmed the hypervascular mass, supplied via hypertrophied superficial temporal and occipital arteries with marked internal vascularity without direct involvement of the calvarium or intracranial structures. The patient underwent biopsy under general anesthesia; the specimen showed an ill-defined deep dermal/subcutaneous proliferation of spindle cells without significant nuclear pleomorphism or mitotic activity. The lesions stained positive for S100 and SOX10 immunostains.Coronal T2-weighted (A) and postcontrast T1-weighted (B) fat-saturated images show the large left T2 hyperintense scalp lesion (double arrowheads; A and B), with underlying calvarial thickening (asterisk; A and B) without invasion, prominent vascularity (single arrowhead; A), and enhancement (B). Note the preservation of the overlying skin. Catheter angiography (C) shows the hypervascular scalp lesion being supplied by hypertrophied branches arising from the left superficial temporal and occipital arteries, with marked internal vascularity (arrowheads). R indicates right.

what is your diagnosis?

What is your diagnosis?

Diffuse-type neurofibroma

Dermatofibrosarcoma protuberans

Solitary fibrous tumor

Arteriovenous malformation of the scalp

a

female

21-30

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2810452

A woman in her 30s presented for evaluation of asymptomatic erythematous scaly plaques over the face and proximal extremities. The lesions started as an erythematous papule on the face, which had progressed to larger plaques within 10 years. There was involvement of the upper respiratory tract, causing palatal perforation and stridor, necessitating a tracheostomy a year ago. In addition, there was history of wheezing and breathlessness. There was no history of preceding trauma, fever, malaise, joint pain, cough, epistaxis, hemoptysis, or hematuria.Examination revealed multiple well-defined brown erythematous scaly plaques with central scarring measuring 2 × 1 to 8 × 7 cm on the face, arm, and thighs. The patient also had saddle nose deformity, perforation of the hard palate, and necrotic plaques on the ear, causing destruction of ear cartilage (Figure, A and B). There was cervical lymphadenopathy: multiple, nontender, discrete nodes, ranging from 1.5 to 2 cm without any surface changes. The results of sensory examination and peripheral nerve examination were within normal limits. Respiratory examination and chest radiography results were normal. Hemogram showed anemia (hemoglobin, 10.1 g/dL [to convert to g/L, multiply by 10.0]); the results of a kidney function test, a liver function test, a fasting blood glucose test, and routine urinalysis were within normal limits. Serologic analysis results for HIV-1/2, antinuclear antibody, and antineutrophil cytoplasmic antibodies were negative. Punch skin biopsy was obtained for histopathologic analysis and culture (Figure, C).A, Multiple well-defined brown erythematous scaly plaques with central scarring, saddle nose deformity, and necrotic lesions on the ear with loss of ear cartilage. B, Perforation of the hard palate. C, Infiltrate of foamy histiocytes and pigmented yeasts without multiaxial septation (Fontana-Masson). What Is Your Diagnosis?

Chromoblastomycosis

Hyalohyphomycosis

Blastomycosis

Phaeohyphomycosis

D. Phaeohyphomycosis

D

Phaeohyphomycosis

Histopathologic results showed pseudoepitheliomatous hyperplasia, parakeratosis, dense dermal infiltrate of histiocytes, foamy histiocytes, neutrophils, and multinucleate giant cells along with pigmented hyphae. Fungal skin culture showed black yeastlike colonies characteristic of Exophiala spinifera species. Based on clinical presentation, histopathologic analysis, and fungal culture, the diagnosis of phaeohyphomycosis was made. The patient will be treated with intravenous amphotericin B, followed by itraconazole.Phaeohyphomycosis is a rare subcutaneous mycosis caused by dematiaceous fungi found in soil, wood, and decomposing vegetation. The disease, caused by dematiaceous fungi, is classified into 2 types based on fungal forms in the tissue: phaeohyphomycosis (presence of yeasts and hyphae) and chromoblastomycosis (muriform bodies). The literal meaning of phaeohyphomycosis is dark fungus with hyphae. The pigment melanin in the fungus is a virulence factor that inhibits phagocytosis by scavenging free radicals produced by the host. The common etiological agents are Exophiala, Aureobasidium, Cladosporium, Alternaria, Phialophora, Wangiella, and Curvularia.1 Phaeohyphomycosis can affect skin, subcutaneous tissue, paranasal sinuses, and, rarely, the central nervous system. Commonly, it presents as asymptomatic cystic swelling on exposed areas, usually after traumatic inoculation involving the hands, feet, and legs. Facial involvement is uncommon and can extend to involve the upper respiratory tract, causing perforation of the palate and destruction of the nasal bridge, leading to mutilation and disfigurement.2-4 Other rare presentations include verrucous plaques, erythematous papules, and noduloulcerative lesions. The diagnosis can be confirmed by demonstration of pigmented septate hyphae with occasional globose swelling on histopathologic analysis and fungal culture. Panfungal real-time polymerase chain reaction is an emerging tool in the diagnosis of phaeohyphomycosis. Treatment with azole antifungal agents (itraconazole, posaconazole, or voriconazole) is the mainstay of treatment. Other treatment options include amphotericin B, terbinafine, flucytosine, and griseofulvin along with physical modalities, such as excision, heat therapy, and cryotherapy.5The common deep mycoses that can cause mutilation include chromoblastomycosis, hyalohyphomycosis, blastomycosis, and phaeohyphomycosis. Both chromoblastomycosis and phaeohyphomycosis are caused by dematiaceous fungi. Chromoblastomycosis (option A) is commonly caused by Fonsecaea pedrosoi, Fonsecaea monophora, and Cladophialophora carrionii and usually presents with localized, verrucous, hyperkeratotic, irregular plaque on distal extremities with scarring.6 Hyalohyphomycosis (option B) is a rare opportunistic fungal infection caused by various fungi, which produce nonpigmented septate hyphae. It has myriad presentations, which include erythematous macules, papules, vesicles, indurated verrucous plaques, necrotic ulcers, and discharging sinus.7 Blastomycosis (option C) is a suppurative fungal infection caused by Blastomyces dermatitidis, endemic in the Ohio and Mississippi River valleys, the Great Lakes, and the Saint Lawrence River. It presents with papulopustular lesions, violaceous nodules, plaques, abscesses, ulcers, and verrucous or crusted lesions on exposed body parts.8 All these infections can have systemic involvement. Chromoblastomycosis involves lungs, lymph nodes, and bone, and hyalohyphomycosis primarily affects paranasal sinuses and lungs. Blastomycosis involves lymph nodes, bone, prostate, and testis, and phaeohyphomycosis commonly involves lungs and heart.All the differential diagnoses show suppurative granuloma on histopathologic analysis; the establishment of the respective fungal form helps in confirming the diagnosis. Chromoblastomycosis is characterized by thick-walled, multicellular, globe-shaped, cigar-colored inclusion bodies with multiaxial septation called sclerotic bodies (Medlar bodies).6 Hyphae in cross-sections in the index case resembled Medlar bodies, and the absence of septation was a clue indicating phaeohyphomycosis.7 Hyalohyphomycosis is characterized by nonpigmented septate hyphae, and culture helps in confirming the diagnosis.8 Large (8-15 μm) thick-walled yeast cells, prominent broad-based budding, and centrally retracted cytoplasm help in the diagnosis of blastomycosis.9Although many clinical differential diagnoses were considered in the case presented, histopathologic analysis and culture played decisive roles in arriving at a diagnosis of phaeohyphomycosis. This case highlights the importance of recognition of rare presentation of deep mycosis and the value of histopathologic analysis and fungal cultures in establishing the right diagnosis.

Dermatology

A woman in her 30s presented for evaluation of asymptomatic erythematous scaly plaques over the face and proximal extremities. The lesions started as an erythematous papule on the face, which had progressed to larger plaques within 10 years. There was involvement of the upper respiratory tract, causing palatal perforation and stridor, necessitating a tracheostomy a year ago. In addition, there was history of wheezing and breathlessness. There was no history of preceding trauma, fever, malaise, joint pain, cough, epistaxis, hemoptysis, or hematuria.Examination revealed multiple well-defined brown erythematous scaly plaques with central scarring measuring 2 × 1 to 8 × 7 cm on the face, arm, and thighs. The patient also had saddle nose deformity, perforation of the hard palate, and necrotic plaques on the ear, causing destruction of ear cartilage (Figure, A and B). There was cervical lymphadenopathy: multiple, nontender, discrete nodes, ranging from 1.5 to 2 cm without any surface changes. The results of sensory examination and peripheral nerve examination were within normal limits. Respiratory examination and chest radiography results were normal. Hemogram showed anemia (hemoglobin, 10.1 g/dL [to convert to g/L, multiply by 10.0]); the results of a kidney function test, a liver function test, a fasting blood glucose test, and routine urinalysis were within normal limits. Serologic analysis results for HIV-1/2, antinuclear antibody, and antineutrophil cytoplasmic antibodies were negative. Punch skin biopsy was obtained for histopathologic analysis and culture (Figure, C).A, Multiple well-defined brown erythematous scaly plaques with central scarring, saddle nose deformity, and necrotic lesions on the ear with loss of ear cartilage. B, Perforation of the hard palate. C, Infiltrate of foamy histiocytes and pigmented yeasts without multiaxial septation (Fontana-Masson).

what is your diagnosis?

What is your diagnosis?

Blastomycosis

Phaeohyphomycosis

Hyalohyphomycosis

Chromoblastomycosis

b

female

31-40

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2808316

A 64-year-old man with a 2-year history of seizure disorder presented to the emergency department (ED) at an outside hospital with breakthrough seizures. One month prior to his ED visit, he had been treated with oral antibiotics when he presented to an urgent care center with left-sided otorrhea, otalgia, and hearing loss. In the ED, he denied headaches, fever, otalgia, otorrhea, or hearing loss. Magnetic resonance imaging of the brain with contrast showed diffuse enhancement and possible coalescence in the left mastoid process with adjacent dural enhancement and sigmoid sinus occlusion. He received intravenous vancomycin and cefepime and was started on a heparin drip before being transferred to our facility. On presentation at our facility, the patient appeared well with normal vital signs. There was no periauricular swelling or erythema. Otoscopic examination showed no inflammation of the external auditory canals, and the tympanic membranes were translucent without evidence of retraction or effusion. Computed tomographic venogram confirmed occlusion of the left transverse and sigmoid sinuses, and computed tomography of the temporal bone showed coalescence of mastoid air cells with erosion into the sigmoid sinus. Mastoidectomy was performed for biopsy and culture specimens. Histologic findings from the specimens demonstrated cells with oval nuclei and abundant cytoplasm arranged in syncytial clusters with occasional whorls, pseudoinclusions, and psammomatous calcifications (Figure, A). Immunohistochemical stains were positive for epithelial membrane antigen (EMA) and vimentin (Figure, B).Hematoxylin-eosin stain (A) and immunohistochemical stain (B) after mastoidectomy for biopsy and culture specimens. What Is Your Diagnosis?

Langerhans cell histiocytosis

Meningioma

Acute coalescent mastoiditis with sigmoid sinus thrombosis

Cholesteatoma

B. Meningioma

B

Meningioma

This patient presented to the ED with an acute exacerbation of a seizure disorder. The recent history of left-sided otorrhea and otalgia with magnetic resonance imaging enhancement in the mastoid along with dehiscence and occlusion of the adjacent venous sinuses suggested that the seizure may have been triggered by an indolent suppurative complication of mastoiditis. However, because the patient’s otologic symptoms had resolved and he did not appear septic, temporal bone neoplasm was considered. Mastoidectomy revealed solid tumor attached to the sigmoid sinus with no evidence of mastoid suppuration or inflammatory process, and the biopsy was diagnostic for intraosseous meningioma.Meningiomas typically are intracranial neoplasms, but 2% present as extracranial intraosseous lesions.1,2 Extracranial meningiomas present in the middle ear, external auditory canal, petrous bone, squamous temporal bone, and paranasal sinuses.1 Histologic sections in this case showed findings consistent with a meningothelial variant of meningioma World Health Organization grade I.1,3 Immunohistochemistry studies confirmed the diagnosis with positive EMA and vimentin staining.3 However, somatostatin receptor subtype 2A and progesterone receptors are more sensitive for diagnosis. Intraosseous meningiomas originate from arachnoid cap cells associated with the sigmoid sinus or adjacent dura. As was the case with this patient, most patients with temporal bone intraosseous meningiomas are asymptomatic, and observation with serial imaging is appropriate. Surgical debulking or resection is considered when tumors grow and extend into the middle ear causing hearing loss, compromising patency of the external auditory canal, or compressing the facial nerve. Fractionated external-beam radiation therapy or stereotactic radiation therapy are also options for treating growing tumors, but there is a high risk of profound hearing loss.2Coalescent mastoiditis can present with intracranial complications such as sigmoid sinus thrombosis or subperiosteal abscess.4 Typically, patients with acute mastoiditis present with headaches, vomiting, seizures, otalgia, otorrhea, and fever.5 Physical findings include tenderness and swelling inferior to the temporal line, purulent middle ear effusion, and conductive hearing loss. Cholesteatoma can be the source of infection in patients with acute mastoiditis, but otomicroscopic findings would reveal a retraction of the tympanic membrane, scutal erosion, or secondary acquired cholesteatoma associated with a tympanic membrane perforation. The absence of these symptoms and physical findings make these diagnoses less likely, yet it is possible to have an indolent progressive suppurative mastoid infection that remains isolated from the middle ear and erodes the thin bony plate over the sigmoid sinus. Mastoidectomy was critical to differentiate an infectious process from neoplastic pathology. Histologic results for a cholesteatoma would reveal keratinizing stratified squamous epithelium with stromal fibrosis. Biopsy in patients with mastoiditis shows granulation tissue, acute and chronic leukocyte infiltration, and hemorrhage with negative EMA and vimentin staining. Mastoidectomy in patients with acute coalescent mastoiditis provides drainage of the infection and cultures to select intravenous antibiotics. Anticoagulation may be recommended when acute coalescent mastoiditis results in sigmoid sinus thrombosis.6,7Langerhans cell histiocytosis of the temporal bone is extremely rare in older adults. Patients present with otorrhea, subjective hearing loss, otalgia, and soft-tissue postauricular swelling.8 Physical examination shows granulation tissue in the external ear canal, middle ear effusion, conductive hearing loss, and external auditory canal stenosis.8 The absence of these symptoms and physical examination findings make this diagnosis less likely. Computed tomography of the temporal bone shows erosion of mastoid air cells and destruction of the mastoid cortex while the otic capsule is spared.9 Computed tomographic imaging is critical for diagnosing and following Langerhans cell histiocytosis, but biopsy is required to confirm the diagnosis. Histological sections typically demonstrate mononuclear cells with coffee bean nuclei that are CD1a, S100, and langerin positive.8,9 For focal lesions, surgery is recommended, and for multifocal lesions chemotherapy (typically vincristine and steroids) and surgery is recommended.8,10

General

A 64-year-old man with a 2-year history of seizure disorder presented to the emergency department (ED) at an outside hospital with breakthrough seizures. One month prior to his ED visit, he had been treated with oral antibiotics when he presented to an urgent care center with left-sided otorrhea, otalgia, and hearing loss. In the ED, he denied headaches, fever, otalgia, otorrhea, or hearing loss. Magnetic resonance imaging of the brain with contrast showed diffuse enhancement and possible coalescence in the left mastoid process with adjacent dural enhancement and sigmoid sinus occlusion. He received intravenous vancomycin and cefepime and was started on a heparin drip before being transferred to our facility. On presentation at our facility, the patient appeared well with normal vital signs. There was no periauricular swelling or erythema. Otoscopic examination showed no inflammation of the external auditory canals, and the tympanic membranes were translucent without evidence of retraction or effusion. Computed tomographic venogram confirmed occlusion of the left transverse and sigmoid sinuses, and computed tomography of the temporal bone showed coalescence of mastoid air cells with erosion into the sigmoid sinus. Mastoidectomy was performed for biopsy and culture specimens. Histologic findings from the specimens demonstrated cells with oval nuclei and abundant cytoplasm arranged in syncytial clusters with occasional whorls, pseudoinclusions, and psammomatous calcifications (Figure, A). Immunohistochemical stains were positive for epithelial membrane antigen (EMA) and vimentin (Figure, B).Hematoxylin-eosin stain (A) and immunohistochemical stain (B) after mastoidectomy for biopsy and culture specimens.

what is your diagnosis?

What is your diagnosis?

Acute coalescent mastoiditis with sigmoid sinus thrombosis

Meningioma

Cholesteatoma

Langerhans cell histiocytosis

b

male

61-70

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2808660

A 62-year-old healthy man with no recent travel history or sick contacts presented with 2 weeks of midline sore throat without systemic signs, such as fever, myalgia, or rash. A physical examination, including flexible laryngoscopy, revealed cobbling, adherent, thick yellow mucus and ulceration of the uvula (Figure 1A).A, Nasopharyngoscopic imaging revealed infected nasal surface of uvula. B, Physical examination showed recurrent skin lesions at incision site and in the surrounding skin.Empirical treatment with augmentin and nystatin oral suspension for possible bacterial or fungal pharyngitis was unsuccessful, with symptoms worsening during the subsequent 2 weeks. Results of laboratory testing for group A Streptococcus, COVID-19, and mononucleosis were negative. A tissue biopsy was performed, and results of pathology revealed epithelial hyperplasia with suppurative granulomatous inflammation without evidence of dysplasia or malignancy. There was no evidence of fungal or acid-fast organisms. Tissue culture revealed only normal respiratory flora. Additional treatment with fluconazole, augmentin, doxycycline, omeprazole, prednisone, and bactrim failed to improve symptoms.Further exploration of the patient’s history revealed that 5 years earlier, he had traveled to Guyana in South America. After that trip, he sought medical care for multiple neck subcutaneous nodules as well as for a 4-cm focus of neck cellulitis. After failed treatment with empirical antibiotics, the largest lesion was excised. Findings of pathologic testing revealed dense granulomatous inflammation. However, results of stains for bacteria, fungus, and acid-fast bacillus were negative (Figure 1B). The remaining cutaneous and subcutaneous nodules had resolved spontaneously. What Is Your Diagnosis?

Leishmaniasis

Tuberculosis

Leprosy

Lethal midline granuloma

A. Leishmaniasis

A

Leishmaniasis

Polymerase chain reaction (PCR) testing of the uvular tissue confirmed the presence of Leishmania braziliensis. A reevaluation of Giemsa (May-Grunwald) stains of the original cutaneous lesion revealed intracytoplasmic organisms, morphologically consistent with Leishmania species (Figure 2). These organisms were not visible in the uvular biopsy specimen. Treatment with 50 mg of miltefosine 3 times daily for 28 days led to complete resolution of the mucosal lesion and associated symptoms.Results of hematoxylin-eosin staining (original magnification, ×60) intracytoplasmic organisms consistent with leishmaniasis.Infection with L (Viannia) complex, particularly L (Viannia) braziliensis, results in cutaneous leishmaniasis, which tends to be persistent and may be complicated by mucosal leishmaniasis (ML).1 Risk factors for development of ML include large and/or multiple cutaneous lesions; male sex; lesions above the waist, head, and neck localization; and long-standing skin lesions for which adequate systemic treatment has not been administered.3The overall lifetime risk of ML from L (Viannia) braziliensis was reported as being 12.8% among a cohort of 3000 patients in Brazil.4 A case series of 145 patients with cutaneous leishmaniasis caused by L (Viannia) braziliensis reported a 41% incidence of ML among untreated patients and 3.3% in patients who had received appropriate treatment.5 The median time to presentation for ML is approximately 8 months after exposure or cutaneous lesion, ranging from concurrent skin lesions to 20 years after untreated lesion or exposure. Likely caused by early hematogenous or lymphatic spread from cutaneous lesions through parasitic infection and replication within macrophages of the naso-oropharyngeal mucosa, ML produces a destructive inflammatory process.For ML diagnosis, PCR is performed as the standard criterion for diagnosis. Biopsy specimens consistently reveal granulomatous inflammation; however, amastigote identification is uncommon.2In the case of this patient, tuberculosis was unlikely given the absence of pulmonary symptoms, no acid-fast bacilli on pathology and culture results, and the nonnecrotizing granulomatous inflammation. Leprosy was also not likely because it is not endemic to the places where this patient traveled, and it tends to affect nasal rather than pharyngeal mucosa. Lastly, natural killer or T-cell lymphomas, which are clinically very aggressive, were also unlikely considering this patient’s relatively indolent disease course as well as the PCR findings.

General

A 62-year-old healthy man with no recent travel history or sick contacts presented with 2 weeks of midline sore throat without systemic signs, such as fever, myalgia, or rash. A physical examination, including flexible laryngoscopy, revealed cobbling, adherent, thick yellow mucus and ulceration of the uvula (Figure 1A).A, Nasopharyngoscopic imaging revealed infected nasal surface of uvula. B, Physical examination showed recurrent skin lesions at incision site and in the surrounding skin.Empirical treatment with augmentin and nystatin oral suspension for possible bacterial or fungal pharyngitis was unsuccessful, with symptoms worsening during the subsequent 2 weeks. Results of laboratory testing for group A Streptococcus, COVID-19, and mononucleosis were negative. A tissue biopsy was performed, and results of pathology revealed epithelial hyperplasia with suppurative granulomatous inflammation without evidence of dysplasia or malignancy. There was no evidence of fungal or acid-fast organisms. Tissue culture revealed only normal respiratory flora. Additional treatment with fluconazole, augmentin, doxycycline, omeprazole, prednisone, and bactrim failed to improve symptoms.Further exploration of the patient’s history revealed that 5 years earlier, he had traveled to Guyana in South America. After that trip, he sought medical care for multiple neck subcutaneous nodules as well as for a 4-cm focus of neck cellulitis. After failed treatment with empirical antibiotics, the largest lesion was excised. Findings of pathologic testing revealed dense granulomatous inflammation. However, results of stains for bacteria, fungus, and acid-fast bacillus were negative (Figure 1B). The remaining cutaneous and subcutaneous nodules had resolved spontaneously.

what is your diagnosis?

What is your diagnosis?

Leprosy

Lethal midline granuloma

Leishmaniasis

Tuberculosis

c

male

61-70

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2808228

A 53-year-old woman with a history of stage IVA1 (T4N1M0B2) mycosis fungoides presented with a new 1-month history of hyperpigmentation of the oral mucosa (Figure 1). Examination of the mouth revealed multiple coalescing painless nonpruritic black macules and patches on the tongue, roof of the mouth, and buccal mucosa. Examination of the skin was notable for erythematous and hyperpigmented patches covering 90% of the body surface area, consistent with her known mycosis fungoides. Other notable findings on examination were 1- to 2-cm lymphadenopathy in the bilateral inguinal folds and axillae. Review of systems was notable for fatigue. The patient had previously received 5 cycles of romidepsin with progression of disease, followed by 4 doses of pegylated liposomal doxorubicin hydrochloride, which was followed by partial response.Black macules and patches on the tongue, roof of the mouth, and buccal mucosa. What Is Your Diagnosis?

Laugier-Hunziker syndrome

Melanoma

Medication adverse effect

Oral involvement of mycosis fungoides

C. Medication adverse effect

C

Medication adverse effect

Oral hyperpigmentation is a rare adverse effect of certain chemotherapy agents, such as doxorubicin. The exact mechanism of this phenomenon is not well understood. One hypothesis is that chemotherapy drugs can trigger increased melanin deposition in the oral mucosa. The risk is thought to be higher in individuals of African descent.1,2 However, this adverse effect is underreported, and it is important for treating physicians to be familiar with this adverse effect to avoid unnecessary testing and undue stress to the patient.Doxorubicin is an anthracycline-based chemotherapy that is frequently used as a single agent or in combination therapy to treat various types of cancer, such as breast cancer, multiple myeloma, and non-Hodgkin lymphoma.3 Doxorubicin directly inhibits topoisomerase II, thereby preventing DNA synthesis.3 There are several formulations, including pegylated liposomal doxorubicin and nonliposomal conventional formulations.3 Single-agent pegylated liposomal doxorubicin is typically used for treatment of advanced mycosis fungoides.4 Although this is often an effective treatment option in cases of refractory and recalcitrant mycosis fungoides, it is also associated with several oral adverse effects, including mucositis, altered taste, and oral hyperpigmentation.5Doxorubicin-induced oral hyperpigmentation is a rare adverse effect that typically presents with multiple coalescing, painless black macules and patches on the tongue, roof of the mouth, and buccal mucosa.2,6,7 The hyperpigmented areas may be uniform in color or have a speckled appearance.2,6,7 These lesions are benign and do not cause any pain or discomfort.2,6,7 However, they may sometimes be accompanied by other oral mucosal changes associated with chemotherapy, such as candidiasis or mucositis.2,6,7 Oral hyperpigmentation usually occurs within the first few weeks of treatment, and it is usually reversible within a few months after discontinuation of doxorubicin.2,6,7Doxorubicin-induced tongue hyperpigmentation is usually a clinical diagnosis based on the patient’s history of chemotherapy and the characteristic appearance of the oral lesions.2,6,7 It is important to rule out other potential causes of oral hyperpigmentation, such as melanoma (choice B) or oral involvement of mycosis fungoides (choice D). Melanoma usually presents as a solitary, asymmetric, and irregularly shaped lesion, in contrast to the multiple black macules and patches seen in this patient.8 Oral involvement of cutaneous lymphoma is a rare complication; prior case reports describe flesh-colored or erythematous plaques and ulcerated nodules that are associated with global disease progression.9 Laugier-Hunziker syndrome (choice A) is a rare idiopathic condition that usually presents with nail hyperpigmentation in addition to mucosal pigmentation.10 This is a diagnosis of exclusion and would not resolve with cessation of medications.As doxorubicin-induced oral hyperpigmentation is benign and self-limiting, the inciting chemotherapy can be continued for treatment of the patient’s primary illness. Additional therapy is not needed, and the hyperpigmentation will slowly resolve during the course of months to years after completion of chemotherapy. In the meantime, the patient should be reassured that the hyperpigmentation is a benign adverse effect of chemotherapy and is unrelated to the underlying cancer.In this case, the patient developed oral mucosal hyperpigmentation after receiving 4 doses of pegylated liposomal doxorubicin. The patient was reassured that mucosal hyperpigmentation is a rare benign adverse effect of pegylated liposomal doxorubicin that is more common in Black women and unrelated to mycosis fungoides. She continued receiving pegylated liposomal doxorubicin for 33 total doses, with an overall good partial response. She did not develop any other types of hyperpigmentation. Once the course of doxorubicin was completed, the oral mucosal hyperpigmentation resolved during the course of the next several months (Figure 2).Resolution of oral pigmentation after cessation of doxorubicin therapy.

Oncology

A 53-year-old woman with a history of stage IVA1 (T4N1M0B2) mycosis fungoides presented with a new 1-month history of hyperpigmentation of the oral mucosa (Figure 1). Examination of the mouth revealed multiple coalescing painless nonpruritic black macules and patches on the tongue, roof of the mouth, and buccal mucosa. Examination of the skin was notable for erythematous and hyperpigmented patches covering 90% of the body surface area, consistent with her known mycosis fungoides. Other notable findings on examination were 1- to 2-cm lymphadenopathy in the bilateral inguinal folds and axillae. Review of systems was notable for fatigue. The patient had previously received 5 cycles of romidepsin with progression of disease, followed by 4 doses of pegylated liposomal doxorubicin hydrochloride, which was followed by partial response.Black macules and patches on the tongue, roof of the mouth, and buccal mucosa.

what is your diagnosis?

What is your diagnosis?

Laugier-Hunziker syndrome

Medication adverse effect

Melanoma

Oral involvement of mycosis fungoides

b

female

51-60

Black

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2809279

A 33-year-old man with no prior ocular problems presented to the emergency department in central Florida with a chief complaint of a “pulling and popping” sensation in his left eye that had occurred the previous night. Ophthalmology was consulted to evaluate for a conjunctival foreign body of the left eye. At the time of the examination, his symptoms had resolved; however, he had a photograph from a cellular phone taken during the episode (Figure 1). The photograph shows an irregular, serpiginous extension from beneath the plica semilunaris toward the corneal limbus with localized conjunctival hyperemia. He reported a similar sensation of movement in his left eye that occurred for 1 night about 5 years ago for which he visited an urgent care center where he was diagnosed with allergic conjunctivitis. He also reported recent swelling of the left side of his face with associated numbness and occasional swelling of his left hand, all of which resolved after a few days. He had immigrated from Nigeria 10 years prior, had not returned since, and was working as a traveling nurse. A slitlamp examination did not reveal any conjunctival hyperemia, foreign bodies, or other abnormalities like those shown in the photograph. His uncorrected visual acuity was 20/20, extraocular movements were full and without pain or abnormal sensation, and intraocular pressure was normal. His dilated fundus examination was unremarkable. A comprehensive blood cell count revealed mild elevation in the relative (but not absolute) eosinophil count (6.9% reference; 6.0% of white blood cells).Patient cellular phone photograph of the left eye shows an irregular serpiginous extension from beneath the plica semilunaris toward the corneal limbus with localized conjunctival hyperemia.Exploration of conjunctiva and removal of foreign body What Would You Do Next?

Treatment with diethylcarbamazine

Peripheral blood smear

Serological testing for onchocerciasis

Exploration of conjunctiva and removal of foreign body

Loa loa infection

B

Peripheral blood smear

In this Nigerian patient with a sensation of movement of the left eye, a photograph showing serpiginous conjunctival elevation, and intermittent swelling of the dorsum of the hand, the most likely diagnosis is Loa loa. Also known as the African eye worm, Loa loa is a filarial nematode transmitted by day-biting flies of the genus Chrysops endemic to Western and Central Africa.1 After a bite from an infected fly, filarial larvae introduced into the subcutaneous tissue mature into adult worms that shed microfilariae that migrate into the spinal fluid, urine, sputum, and peripheral blood.2 Most infections are asymptomatic despite high numbers of circulating microfilaria; however, patients may have characteristic symptoms that include migratory angioedema of the extremities (so-called Calabar swellings) and migration of adult worms into the subconjunctival space as in this patient.3,4The recommended next step in the treatment of this patient is a peripheral blood smear for species identification and quantification of circulating microfilariae (choice B). Blood should be drawn between 10 am and 2 pm during the migration of microfilaria from the lungs into the peripheral circulation; this diurnal pattern coincides with the biting activity of the vector. Diethylcarbamazine is the first-line therapy due to its ability to eradicate both microfilaria and adult worms, while empirical therapy (choice A) can result in intense inflammatory reactions during the rapid death of the nematodes. Due to the risk of fatal encephalopathy in patients with microfilarial concentrations greater than 8000 per mL of blood, it is recommended to first measure the concentration prior to treatment with diethylcarbamazine.4 Treatment with diethylcarbamazine in patients who are coinfected with onchocerciasis can also lead to vision loss and blindness.5 Therefore, in patients from coendemic areas such as Nigeria, serological testing (choice C) should be used to rule out onchocerciasis prior to treatment, but only after identification of microfilariae in peripheral blood.6 Surgical removal of the adult worm from the conjunctiva (choice D) may treat localized symptoms and provide an opportunity for species identification; however, removal is not necessary for diagnosis and treatment with curative antiparasitic medication.Peripheral blood smears with Wright and Geimsa stains (Figure 2) revealed microfilaria (1000/mL) with characteristic morphology of Loa loa that included an approximate length of 250 μm, shortened headspace, a dense nuclear column continuous to the tip of the tail, and the presence of a sheath.7 The patient was prescribed albendazole, which is only effective against adult worms and decreases the load of microfilariae through the reduction in shedding of microfilariae.8 Serologic testing for onchocerciasis was ordered, and the US Centers for Disease Control and Prevention was contacted to obtain diethylcarbamazine, which is no longer US Food and Drug Administration–approved or commercially available in the US due to the low incidence of this disease in the US.9 The results of the onchocerciasis serology were negative, and the patient was given the diethylcarbamazine obtained from the US Centers for Disease Control and Prevention. Three weeks later, he reported no recurrence of his symptoms, and there were no eye worms on examination.Peripheral thick blood smears stained with Wright and Geimsa (main panel [original magnification ×400] and inset panel [original magnification ×200], respectively) revealed microfilaria (1000/mL) with characteristic morphology of Loa loa that included an approximate length of 250 μm, shortened headspace (pink arrowhead), a dense nuclear column continuous to the tip of the tail (blue arrowhead), and the presence of a sheath (black arrowhead).

Ophthalmology

A 33-year-old man with no prior ocular problems presented to the emergency department in central Florida with a chief complaint of a “pulling and popping” sensation in his left eye that had occurred the previous night. Ophthalmology was consulted to evaluate for a conjunctival foreign body of the left eye. At the time of the examination, his symptoms had resolved; however, he had a photograph from a cellular phone taken during the episode (Figure 1). The photograph shows an irregular, serpiginous extension from beneath the plica semilunaris toward the corneal limbus with localized conjunctival hyperemia. He reported a similar sensation of movement in his left eye that occurred for 1 night about 5 years ago for which he visited an urgent care center where he was diagnosed with allergic conjunctivitis. He also reported recent swelling of the left side of his face with associated numbness and occasional swelling of his left hand, all of which resolved after a few days. He had immigrated from Nigeria 10 years prior, had not returned since, and was working as a traveling nurse. A slitlamp examination did not reveal any conjunctival hyperemia, foreign bodies, or other abnormalities like those shown in the photograph. His uncorrected visual acuity was 20/20, extraocular movements were full and without pain or abnormal sensation, and intraocular pressure was normal. His dilated fundus examination was unremarkable. A comprehensive blood cell count revealed mild elevation in the relative (but not absolute) eosinophil count (6.9% reference; 6.0% of white blood cells).Patient cellular phone photograph of the left eye shows an irregular serpiginous extension from beneath the plica semilunaris toward the corneal limbus with localized conjunctival hyperemia.Exploration of conjunctiva and removal of foreign body

what would you do next?

What would you do next?

Exploration of conjunctiva and removal of foreign body

Treatment with diethylcarbamazine

Serological testing for onchocerciasis

Peripheral blood smear

d

male

31-40

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2809480

A 13-year-old boy with a history of sports-related blunt trauma to the left eye was referred for evaluation of an asymptomatic, pigmented iris lesion in the left eye. On examination, his best-corrected visual acuity was 20/20 OU, and intraocular pressures were normal in both eyes. Results of slitlamp examination of the right eye were unremarkable. Slitlamp examination of the left eye revealed a round, pigmented lesion measuring 3 × 3 mm in basal dimension and with gravitational shifting within the anterior chamber fluid with patient head tilt (Video). There was no corneal guttatae or edema. Anterior segment optical coherence tomography depicted the lesion in the anterior chamber angle abutting the corneal endothelium and resting on the iris stroma with no internal fluid level and no solid component. Ultrasound biomicroscopy confirmed the lesion to be cystic with a thickness of 1.6 mm. Dilated fundus examination revealed normal findings in both eyes. What Would You Do Next?

Fine-needle aspiration biopsy with cytology and cytogenetics

Iodine 125 plaque radiotherapy

Observe with no additional testing or intervention

Cyst paracentesis with complete drainage

Free-floating iris pigment epithelium cyst

C

Observe with no additional testing or intervention

A pigmented mass in the anterior chamber could represent a benign entity but also raises suspicion for malignancy, such as iris melanoma. Iris tumors are predominantly characterized as solid (79% of cases) or cystic (21% of cases).1 Solid tumors include melanocytic lesions, with the 3 most common being benign iris nevus (60%), iris melanoma (26%), and iris freckle (4%).1,2 Cystic iris tumors are subclassified based on their tissue layer of origin, arising from either the iris stroma or iris pigment epithelium (IPE). Iris stromal cysts appear translucent, located on the anterior iris surface and with smooth lobulated surface, typically in young children.1,2 By contrast, IPE cysts appear on the posterior iris surface with brown or black color simulating solid melanocytic tumors, such as iris melanoma or IPE adenoma.1,2 For this reason, some IPE cysts have historically been mistaken for melanoma, even leading to enucleation. As iris melanoma is malignant with risk for metastasis, proper treatment for life protection with consideration of the potential for ocular adverse sequelae should be realized. Differentiation of the various iris tumors is paramount to management.Ultrasound biomicroscopy and anterior-segment optical coherence tomography are useful tools in assessing the internal quality of iris tumors and differentiation of solid from cystic tumors.3 These technologies are critical for defining tumor basal dimension and thickness to monitor change over time or response to treatment. In this patient, slitlamp biomicroscopy (Figure) demonstrated the gravitational shifting of the mass (Video), and both ultrasound biomicroscopy (Figure, inset) and anterior-segment optical coherence tomography documented the mass to be cystic with no internal fluid or solid component. The Video demonstrates the superior-to-inferior descent of an IPE cyst across the visual axis, coursing purely through the aqueous humor with gravity, offering insight into the dynamic behavior of this lesion.Slitlamp biomicroscopy of the left eye showing a round, pigmented lesion in the inferior anterior chamber angle abutting the corneal endothelium and resting on the iris stroma measuring 3 × 3 mm in basal dimension. Inset, Ultrasound biomicroscopy scan of the free-floating cyst showing central lucency, no fluid level, and no solid component.Free-floating IPE cysts occur when the cyst becomes separated from the IPE, speculated to occur following ocular trauma, as in this patient.4,5 These free-floating IPE cysts are benign and rarely cause endothelial decompensation or visual sequelae.2,5 Fine-needle aspiration biopsy with cytology and cytogenetics (choice A) was not appropriate because the lesion in question was not solid or within the iris, so iris melanoma was not likely. Iodine 125 plaque radiotherapy (choice B) was not appropriate, as this was a cystic, benign mass that was unlikely to be malignant. Cyst paracentesis with complete drainage (choice D) was not necessary in this case because the cyst did not affect the visual axis and was visually asymptomatic. Additionally, drainage of a free-floating cyst without any portion anchored to the iris would likely prove to be technically difficult.In summary, free-floating IPE cysts are benign epithelial cysts that can dislodge into the aqueous or vitreous following trauma, as in this patient. This form of cyst is benign and rarely leads to adverse sequelae; therefore, conservative observation is advised.This patient was counseled on the benign nature of the free-floating IPE cyst and advised to follow up in 12 months for repeated examination with imaging. There was no expectation that this cyst would grow, rupture, transform into a malignant process, or cause damage to the cornea.

Ophthalmology

A 13-year-old boy with a history of sports-related blunt trauma to the left eye was referred for evaluation of an asymptomatic, pigmented iris lesion in the left eye. On examination, his best-corrected visual acuity was 20/20 OU, and intraocular pressures were normal in both eyes. Results of slitlamp examination of the right eye were unremarkable. Slitlamp examination of the left eye revealed a round, pigmented lesion measuring 3 × 3 mm in basal dimension and with gravitational shifting within the anterior chamber fluid with patient head tilt (Video). There was no corneal guttatae or edema. Anterior segment optical coherence tomography depicted the lesion in the anterior chamber angle abutting the corneal endothelium and resting on the iris stroma with no internal fluid level and no solid component. Ultrasound biomicroscopy confirmed the lesion to be cystic with a thickness of 1.6 mm. Dilated fundus examination revealed normal findings in both eyes.

what would you do next?

What would you do next?

Fine-needle aspiration biopsy with cytology and cytogenetics

Cyst paracentesis with complete drainage

Iodine 125 plaque radiotherapy

Observe with no additional testing or intervention

d

male

11-20

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2808886

A woman in her 60s with long-standing thickening and induration of the legs presented with 1 week of left leg pain. The patient had previously been diagnosed with elephantiasis nostras verrucosa, and she was advised to elevate and compress the leg but was unavailable for follow-up. Her medical history was notable for morbid obesity, hypertension, diabetes, and stroke. She reported no fever, fatigue, weight changes, gastrointestinal symptoms, difficulty concentrating, anxiety, or hyperhidrosis. Physical examination results revealed multiple firm skin-colored papules and nodules coalescing to form a large plaque on the anterior aspect of the left lower leg, whereas the right lower leg had diffuse induration and hyperpigmentation (Figure 1). There was no palpable lymphadenopathy. Laboratory analysis revealed normal complete blood cell count, thyroid function, serum protein electrophoresis, and serum immunofixation. A biopsy of a left leg nodule was performed.Multiple firm skin-colored papules and nodules coalesce to form a large plaque on the anterior aspect of the left lower leg. What Is Your Diagnosis?

Pretibial myxedema

Elephantiasis nostras verrucosa

Lobomycosis

Euthyroid pretibial mucinosis

D. Euthyroid pretibial mucinosis

D

Euthyroid pretibial mucinosis

Histopathologic examination showed an atrophic epidermis, angioplasia with vertically oriented vessels, horizontal fibrosis, hemosiderin deposits, and increased mucin deposition, extending from the papillary to the reticular dermis (Figure 2). Pretibial mucinosis in a patient with euthyroid due to obesity and venous stasis was diagnosed. The patient’s cutaneous mucinosis was complicated by cellulitis, which resolved with a short course of antibiotics. Weight loss was recommended, and compression and leg elevation were suggested for the management of chronic skin changes. Detailed vascular studies to explain the asymmetry were planned, but the patient was unavailable for follow-up after multiple hospital admissions for her comorbidities.A and B, Histologic examination shows atrophic epidermis, angioplasia with vertically oriented vessels, and horizontal fibrosis (hematoxylin-eosin). C, Colloidal iron staining with increased mucin deposition extending from the papillary to the reticular dermis.Classically, accumulation of mucin on the shins is associated with pretibial myxedema (choice A), prompting thyroid function testing. However, in a small percentage of patients with pretibial mucinosis, thyroid dysfunction is not identified.1 Pretibial mucinosis in patients with euthyroid has been described in states of chronic stasis, such as venous insufficiency and obesity with lymphedema, termed pretibial stasis mucinosis and obesity-associated lymphedematous mucinosis (OALM).1,2 These conditions often overlap and share a similar pathogenesis. Chronic venous insufficiency and/or obesity-associated lymphedema have been suggested to induce hypoxia, leading to angiogenesis and plasma protein extravasation, ultimately resulting in increased production and deposition of mucopolysaccharides.3Patients with stasis mucinosis and OALM present with skin-colored to yellow-red papules, plaques, and/or nodules. Symptoms can be bilateral or asymmetric, involving a single extremity. Distinct histopathologic findings, such as epidermal atrophy, angioplasia with vertically oriented capillaries, increased stellate fibroblasts, and hemosiderin deposition, aid in confirming the diagnosis and differentiating it from other forms of cutaneous mucinosis.4 Treatment entails weight loss and modalities that improve lymphatic and venous blood flow, such as compression stockings. Second- and third-line therapeutics include topical corticosteroids or intralesional corticosteroids, pentoxifylline, octreotide, plasmapheresis, and intravenous immunoglobulins.Differential diagnosis of multiple long-standing papules and nodules on the lower legs includes pretibial myxedema and elephantiasis nostras verrucosa (choice B) and lobomycosis (choice C). Clinical and histologic features are essential to differentiate these conditions. Pretibial myxedema in thyroid disease often precedes skin manifestations, and it is commonly associated with coexisting orbitopathy in Graves disease.4 Histologically, it is characterized by mucin deposition in the upper dermis, with a grenz zone present in the superficial dermis.5 Euthyroid pretibial mucinosis lacks this feature, showing mucin deposition throughout the dermis. Elephantiasis nostras verrucosa may be distinguished clinically from pretibial mucinosis, as it develops on the dorsa of the feet and extends proximally over time. It can be differentiated histologically by the presence of pseudoepitheliomatous hyperplasia and exhibits dilated lymph channels in the early stages and extensive dermal fibrosis in the later stages. Mucin is absent.6 Pretibial mucinosis nodules can be mistaken for lobomycosis, an uncommon fungal infection acquired in tropical areas of Central and South America, that is histopathologically is characterized by granulomas containing sclerotic bodies.7

Dermatology

A woman in her 60s with long-standing thickening and induration of the legs presented with 1 week of left leg pain. The patient had previously been diagnosed with elephantiasis nostras verrucosa, and she was advised to elevate and compress the leg but was unavailable for follow-up. Her medical history was notable for morbid obesity, hypertension, diabetes, and stroke. She reported no fever, fatigue, weight changes, gastrointestinal symptoms, difficulty concentrating, anxiety, or hyperhidrosis. Physical examination results revealed multiple firm skin-colored papules and nodules coalescing to form a large plaque on the anterior aspect of the left lower leg, whereas the right lower leg had diffuse induration and hyperpigmentation (Figure 1). There was no palpable lymphadenopathy. Laboratory analysis revealed normal complete blood cell count, thyroid function, serum protein electrophoresis, and serum immunofixation. A biopsy of a left leg nodule was performed.Multiple firm skin-colored papules and nodules coalesce to form a large plaque on the anterior aspect of the left lower leg.

what is your diagnosis?

What is your diagnosis?

Elephantiasis nostras verrucosa

Pretibial myxedema

Euthyroid pretibial mucinosis

Lobomycosis

c

female

61-70

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2809085

A female patient in her early 50s presented with multiple (approximately 10) bluish, partially keratotic papules and nodules on the lower legs (Figure, A). Since the age of 24 years, the lesions had been growing very slowly in number and size and had been bleeding occasionally after a trauma. The patient used a wheelchair due to a right-sided hemiparesis and hemianopsia caused by an intracranial hemorrhage. At the age of 4 years, recurrent seizures had led to the diagnosis of cerebral venous malformations. Clinical examination also demonstrated a lipolymphedema of the lower legs that had been attributed to a functional venous insufficiency with insufficient venous pump activity. The patient had been wearing compression stockings for years. The family history was positive for cerebral venous malformations involving the patient’s father and aunt, the father having died of an intracranial hemorrhage in his early 70s.A, Clinical picture. B and C, Hematoxylin-eosin stain.Sonography of the skin lesions demonstrated intradermal slow-flow vascular malformations with a maximum diameter of 1.2 cm. A biopsy of a lower-extremity papule was performed (Figure, B and C). Mutational analysis resulted in the detection of a heterozygous pathogenic KRIT1 variant. What Is Your Diagnosis?

Blue rubber bleb nevus syndrome

Familial cerebral cavernous malformations

Glomuvenous malformations

Verrucous venous malformations

B. Familial cerebral cavernous malformations

B

Familial cerebral cavernous malformations

Skin biopsy revealed a well-circumscribed lesion with hyperkeratosis and acanthosis of the epidermis overlying a conglomerate of dilated venous-like malformations with continuous smooth muscle in the upper dermis, partly showing thrombosis. Histomorphology together with a positive personal and family history of venous malformations and the identification of a pathologic KRIT1 variant led to the diagnosis of familial cerebral cavernous malformations (CCMs) in the current patient.Cerebral cavernous malformations or cavernomas (International Society for the Study of Vascular Anomalies [ISSVA] simple vascular malformations III) are slow-flowing venous malformations that are lined by a single layer of endothelium with no involvement of brain parenchyma.1 They can occur in sporadic (80%) or familial (20%) form, affecting up to 0.5% in the general population.2 Familial CCMs are frequently inherited as multiple lesions in an autosomal dominant manner. Following the Knudson hypothesis, they are caused by germline loss-of-function variants in KRIT1, CCM2, or PDCD10 in association with a somatic “second hit” in the other allele.3 Among patients with CCMs, 40% to 70% present with neurological symptoms, such as seizures, focal deficits, and headaches due to intracranial hemorrhages. Extraneurological manifestations may involve the skin, retina, kidney, and liver. In a study of 417 patients with familial CMMs, 38 patients (9%) had cutaneous venous malformations, which is a higher rate than in the general population (0.3%).4 In this study, the lesions were associated with KRIT1 variants and further classified as hyperkeratotic capillary-venous malformations, capillary malformations, and venous malformations. Prognosis and management are determined by the location, number, and size of the cerebral venous malformations. Recent advances in understanding CCM pathophysiology have revealed new strategies to control disease progression, ie, Rho kinase inhibition by atorvastatin.5Blue rubber bleb nevus syndrome (BRBNS; ISSVA simple vascular malformations III) is another rare disorder characterized by multiple, most commonly cutaneous and gastrointestinal venous malformations.1 Skin lesions present as rubbery, bluish, easily compressible nodules since birth or early childhood.6 Histopathology reveals large, thin-walled vessels with discontinuous or no smooth muscle separated by variable amounts of fibrous tissue scattered through the dermis.7 Gastrointestinal malformations typically cause recurrent hemorrhages resulting in chronic anemia and may occasionally lead to volvulus, intussusception, or perforation. Thirteen percent of patients have central nervous system involvement.8 Familial occurrence is extremely rare, as BRBNS is due to somatic double (cis) variants in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2.9Glomuvenous malformations or glomangiomas (ISSVA simple vascular malformations III) are bluish, tender, noncompressible papules and nodules of the cutis that histologically represent venous-like channels surrounded by 1 or 2 layers of glomus cells, and no intracranial involvement is seen.1 Glomuvenous malformations are inherited in over 60% of cases in an autosomal dominant manner and are due to loss-of-function variants in the glomulin gene.7 Verrucous venous malformations (ISSVA simple vascular malformations III) are sporadic congenital hyperkeratotic nodules—mainly on the legs—that show a deep vascular component and no further associations and, in particular, no intracranial involvement.1 Histopathology reveals a compact hyperkeratosis, papillomatosis, and acanthosis overlying dilated vessels extending into the deep dermis and the subcutis.7 A somatic missense MAP3K3 variant has been recently identified.10

Dermatology

A female patient in her early 50s presented with multiple (approximately 10) bluish, partially keratotic papules and nodules on the lower legs (Figure, A). Since the age of 24 years, the lesions had been growing very slowly in number and size and had been bleeding occasionally after a trauma. The patient used a wheelchair due to a right-sided hemiparesis and hemianopsia caused by an intracranial hemorrhage. At the age of 4 years, recurrent seizures had led to the diagnosis of cerebral venous malformations. Clinical examination also demonstrated a lipolymphedema of the lower legs that had been attributed to a functional venous insufficiency with insufficient venous pump activity. The patient had been wearing compression stockings for years. The family history was positive for cerebral venous malformations involving the patient’s father and aunt, the father having died of an intracranial hemorrhage in his early 70s.A, Clinical picture. B and C, Hematoxylin-eosin stain.Sonography of the skin lesions demonstrated intradermal slow-flow vascular malformations with a maximum diameter of 1.2 cm. A biopsy of a lower-extremity papule was performed (Figure, B and C). Mutational analysis resulted in the detection of a heterozygous pathogenic KRIT1 variant.

what is your diagnosis?

What is your diagnosis?

Blue rubber bleb nevus syndrome

Familial cerebral cavernous malformations

Verrucous venous malformations

Glomuvenous malformations

b

female

51-60

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2810142

An 81-year-old White woman noted decreased vision in her left eye for 6 months. She was referred to the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, for suspected choroidal melanoma. She disclosed a history of macular degeneration in both eyes and retinal detachment in the left eye that was treated 35 years previously. Medical history revealed cutaneous basal cell carcinoma and squamous cell carcinoma, both treated surgically.On examination, visual acuity was 20/50 OD and 20/400 OS. External examination showed posterior-chamber intraocular lenses in both eyes and conjunctival scarring in the left eye from circumferential scleral buckle surgery with no visible extraocular tumor. Fundus evaluation showed macular drusen in the right eye and a pale optic disc with geographic macular atrophy in the left eye, explaining her visual acuity of 20/400 OS. In addition, a shallow circumferential buckle effect and an inferotemporal mass measuring 15.0 × 10.0 mm in basal dimension and 9.1 mm in thickness (Figure, A) were seen in the left eye. The mass appeared elevated, amelanotic with overlying retinal vasculature, and with chorioretinal atrophy. No retinal detachment or breaks were seen. By ultrasonography the mass was echolucent (Figure, A inset). Magnetic resonance imaging (MRI) revealed a T1, T2-hypointense shallow circumferential band in the left eye. In addition, there was an inferotemporal nodular mass in the left eye showing T1 (gadolinium) hypointense, T2-hyperintense features, underlying the encircling buckle, and with adjacent subtle delineation. There was no enhancement with gadolinium (Figure, B).Fundus photograph and magnetic resonance imaging of the left eye. A, Fundus photograph of left eye showed a pale optic disc, geographic macular atrophy, and an inferotemporal amelanotic mass (white arrowhead); inset shows ultrasonography revealing an echolucent mass (white arrowhead). B, Magnetic resonance imaging (MRI) (T2-weighted axial orientation) revealed a shallow hypointense circumferential band in the left eye (pink arrowheads), inferotemporal hyperintense nodular mass (asterisk), and inward compressed sclera (white arrowhead); inset (T1-weighted coronal orientation with gadolinium) shows hypointense encircling band (pink arrowhead), subtle scleral indentation (white arrowhead), and no gadolinium enhancement of mass (asterisk). What Would You Do Next?

Whole-body positron emission tomography scan

Fine-needle aspiration biopsy

Plaque radiotherapy

Observation

Expanded hydrogel scleral sponge

D

Observation

In this case, based on MRI and the lack of gadolinium enhancement, the final diagnosis was expanded hydrogel sponge from previous retinal detachment repair. This mass did not show MRI features of choroidal melanoma. The mass showed complete ultrasonographic acoustic hollowness, potentially suggestive of choroidal melanoma, but MRI confirmed a subtle delineation on the inner portion of the mass (Figure, B) suggestive of thinned sclera, indicating that the mass was episcleral and indenting the globe. The mass was hypointense on T1-weighted (gadolinium-enhanced) imaging suggesting a nonvascular mass and hyperintense on T2-weighted imaging suggesting a hydrophilic mass, possibly a hydrogel sponge. We suspect that the sponge, over time, had slowly expanded underneath the circumferential buckle, leading to inward indentation of the globe and the appearance of an intraocular tumor (Figure).Scleral buckle is one of the highly effective options for retinal detachment repair with success rates ranging from 63% to 99% between various studies.1 The hydrogel scleral buckle was introduced in the 1980s and was deemed safe with low risk of infection when soaked in antibiotics, owing to the hydrophilic nature. In addition, the buckle slowly expanded over time, a presumed beneficial effect to further buckle the retina.2 However, delayed complications were later recognized as this implant continued expansion disproportionately, leading to extreme scleral buckle effect, resulting in diplopia, dysmotility, pseudotumor formation in the orbit, eyelid, conjunctiva, and globe, occasionally with inflammation and pain.2,3Our group has previously described expanding hydrogel (MIRAgel) scleral sponge mimicking orbital cysts and tumors.4 This patient had no symptom of an enlarging orbital mass but was clinically found to have an asymptomatic intraocular mass, suspicious for uveal melanoma. However, the clinical features of the episcleral mass combined with imaging that demonstrated the nonvascular mass overlying markedly thinned sclera, confirmed our suspicion of a hydrogel sponge that presumably expanded over 35 years.Swollen hydrogel implants can be managed by careful surgical excision or close observation.3,4 Despite various techniques described for excision of this discohesive, distended material, complete excision is challenging and risks include continued swelling of remnant implant, retinal detachment recurrence, and thinned scleral wall leading to perforation.3 In the absence of intervention, continued enlargement of the buckle effect can lead to complications; hence, long-term surveillance is advised. In view of this patient’s age and absence of symptoms, observation (option D) was recommended. On subsequent follow-up, if enlargement, extrusion, or any signs of infection are noted, implant removal may be considered. Since the absence of tumor or malignancy was suggested by MRI, there was no need for positron emission tomography scan (option A), biopsy (option B), or radiotherapy (option C).

Ophthalmology

An 81-year-old White woman noted decreased vision in her left eye for 6 months. She was referred to the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, for suspected choroidal melanoma. She disclosed a history of macular degeneration in both eyes and retinal detachment in the left eye that was treated 35 years previously. Medical history revealed cutaneous basal cell carcinoma and squamous cell carcinoma, both treated surgically.On examination, visual acuity was 20/50 OD and 20/400 OS. External examination showed posterior-chamber intraocular lenses in both eyes and conjunctival scarring in the left eye from circumferential scleral buckle surgery with no visible extraocular tumor. Fundus evaluation showed macular drusen in the right eye and a pale optic disc with geographic macular atrophy in the left eye, explaining her visual acuity of 20/400 OS. In addition, a shallow circumferential buckle effect and an inferotemporal mass measuring 15.0 × 10.0 mm in basal dimension and 9.1 mm in thickness (Figure, A) were seen in the left eye. The mass appeared elevated, amelanotic with overlying retinal vasculature, and with chorioretinal atrophy. No retinal detachment or breaks were seen. By ultrasonography the mass was echolucent (Figure, A inset). Magnetic resonance imaging (MRI) revealed a T1, T2-hypointense shallow circumferential band in the left eye. In addition, there was an inferotemporal nodular mass in the left eye showing T1 (gadolinium) hypointense, T2-hyperintense features, underlying the encircling buckle, and with adjacent subtle delineation. There was no enhancement with gadolinium (Figure, B).Fundus photograph and magnetic resonance imaging of the left eye. A, Fundus photograph of left eye showed a pale optic disc, geographic macular atrophy, and an inferotemporal amelanotic mass (white arrowhead); inset shows ultrasonography revealing an echolucent mass (white arrowhead). B, Magnetic resonance imaging (MRI) (T2-weighted axial orientation) revealed a shallow hypointense circumferential band in the left eye (pink arrowheads), inferotemporal hyperintense nodular mass (asterisk), and inward compressed sclera (white arrowhead); inset (T1-weighted coronal orientation with gadolinium) shows hypointense encircling band (pink arrowhead), subtle scleral indentation (white arrowhead), and no gadolinium enhancement of mass (asterisk).

what would you do next?

What would you do next?

Plaque radiotherapy

Observation

Whole-body positron emission tomography scan

Fine-needle aspiration biopsy

b

female

81-90

White

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2809657

A woman in her 30s presented with progressive, multiple itchy erythematous to violaceous papules and plaques localized to the left shin for more than 10 years (Figure, A and B). On close inspection, milia and a few erosions with partially detached epidermis were identified. There were no abnormalities of the mucous membranes, nails, hair, or teeth. No extracutaneous involvement was observed.A, Multiple pruritic erythematous to violaceous lichenified papules and plaques on the left shin. B, Close-up of the skin lesions showing an erosion with partially detached epidermis and multiple milia. C, Histopathologic examination revealed dermoepidermal separation (hematoxylin-eosin stain). D, Histopathologic examination revealed several milia (hematoxylin-eosin stain). What Is Your Diagnosis?

Pretibial pruritic papular dermatitis (PPPD)

Hypertrophic lichen planus (HLP)

Epidermolysis bullosa pruriginosa (EBP)

Lichen amyloidosis (LA)

C. Epidermolysis bullosa pruriginosa (EBP)

C

Epidermolysis bullosa pruriginosa (EBP)

We performed a skin biopsy under the impression of prurigo nodularis and to exclude hypertrophic lichen planus. Histopathologic examination revealed a dermoepidermal cleft (Figure, C) and several milia (Figure, D) in the superficial dermis, features that were inconsistent with either PN or HLP but suggestive of epidermolysis bullosa (EB). Whole-exome sequencing using genomic DNA extracted from the patient’s peripheral blood mononuclear cells identified a novel heterozygous missense variant, c.6832G>T, p.Gly2278Trp, in COL7A1 (NM_000094), which was graded as “likely pathogenic” based on American College of Medical Genetics and Genomics guidelines. Further inquiry of the patient led to identification of 2 other affected family members: 1 who had typical EBP (intensely itchy, symmetric, hypertrophic papules and plaques on both shins) and nail dystrophy, and another, who only had dystrophic toenails. Sanger sequencing confirmed cosegregation of this variant with variable phenotypes, supporting its pathogenicity and the patient’s diagnosis of autosomal dominant EBP. The patient had a 2-year old relative who had only very mild nail dystrophy and no skin disease who also harbored this pathogenic variant.Epidermolysis bullosa is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility, blister formation, and abnormal wound healing.1 It is categorized into 4 major subtypes, EB simplex, junctional EB, dystrophic EB (DEB), and Kindler EB, based on the ultrastructural level of skin cleavage and inherent molecular pathology.2 Dystrophic EB is caused by pathogenic variants in the COL7A1 gene, which encodes type 7 collagen. Epidermolysis BP is a rare subtype of DEB characterized by intensely pruritic, prurigo-like nodules and plaques affecting the lower legs, thighs, and arms, often associated with nail dystrophy.3 Unlike other forms of EB, except for some localized subtypes of EB simplex and some rare late-onset forms of junctional EB, it is not uncommon for patients with EBP to present beyond the neonatal/childhood period, and sometimes well into adult life.Epidermolysis BP is traditionally considered a rare subtype of DEB, but it seems to be more prevalent in some countries, including Taiwan.4 So far, no clear genotype-phenotype correlation has been established in EBP.5 Epidermolysis BP is also often misdiagnosed as other dermatoses because blisters are often inconspicuous. Diagnostic clues of EBP include nail dystrophy, the most common associated feature of EBP,6 as well as a history of blistering during infancy and family medical history of other subtypes of DEB,1 which makes it distinct from factitial dermatitis. Although the histopathologic features of factitial dermatitis are nonspecific, milia are usually absent. In this case, however, the unilateral, localized presentation of EBP and undisclosed family medical history of EB at the patient’s initial visit made the diagnosis difficult. It was the milia and dermoepidermal separation on histopathologic findings that prompted subsequent genetic investigations. Still, had we been more vigilant, we might have noticed the milia and partially detached epidermis and put DEB in our initial differential diagnoses.The present case needs to be distinguished from PPPD, HLP, and LA. Overall, PPPD is characterized by extremely pruritic, discrete, smooth, flesh-colored to erythematous papules, caused by persistent rubbing of the anterior surface of the legs. Histopathologic features include minimal compact orthokeratosis, mild acanthosis with flattening of the rete ridges, and superficial and middermal perivascular lymphohistiocytic infiltrates with a variable number of eosinophils.7 In most cases, there is evidence of superficial dermal fibrosis, characterized by the presence of multinucleated fibroblasts and thickened collagen bundles arranged in a random pattern, without the dermoepidermal cleft and milia seen in EBP. Hypertrophic lichen planus presents as extremely pruritic, violaceous, hyperkeratotic flat-topped papules and plaques affecting the extremities.8 Histopathologic findings of HLP show compact orthokeratosis, acanthosis, wedge-shaped hypergranulosis, saw-tooth appearance of the undersurface of the epidermis with necrotic keratinocytes, and a band-like infiltrate of lymphocytes at the dermoepidermal junction, which is distinct from EBP. Generally, LA is the most common form of primary localized cutaneous amyloidosis, clinically characterized by pruritic, discrete hyperkeratotic hyperpigmented papules with a predilection for the shins.9 The key component of the histologic findings is the deposition of pink amorphous amyloid material in the papillary dermis, which exhibits a bright apple-green birefringence under polarized light when stained with Congo red. These findings distinguish LA from EBP, despite both conditions presenting similar epidermal changes induced by chronic scratching.10To our knowledge, this is the first case of unilateral EBP ever reported. This case highlights the importance of considering EBP even when the prurigo-like lesions are unilateral and without nail involvement. Milia and erosions provide diagnostic clues for such atypical cases, as in other subtypes of DEB.

Dermatology

A woman in her 30s presented with progressive, multiple itchy erythematous to violaceous papules and plaques localized to the left shin for more than 10 years (Figure, A and B). On close inspection, milia and a few erosions with partially detached epidermis were identified. There were no abnormalities of the mucous membranes, nails, hair, or teeth. No extracutaneous involvement was observed.A, Multiple pruritic erythematous to violaceous lichenified papules and plaques on the left shin. B, Close-up of the skin lesions showing an erosion with partially detached epidermis and multiple milia. C, Histopathologic examination revealed dermoepidermal separation (hematoxylin-eosin stain). D, Histopathologic examination revealed several milia (hematoxylin-eosin stain).

what is your diagnosis?

What is your diagnosis?

Pretibial pruritic papular dermatitis (PPPD)

Lichen amyloidosis (LA)

Hypertrophic lichen planus (HLP)

Epidermolysis bullosa pruriginosa (EBP)

d

female

31-40

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2809652

A 13-year-old girl with a 7-day history of painless vision loss and central scotoma in her left eye was referred to the department of ophthalmology. Three weeks prior, she had presented with mild fever and flulike symptoms, associated with a severe frontal headache that was mildly relieved by analgesics. Her medical history was positive for relapsing urinary tract infections since early infancy without adequate follow-up. Findings of an ophthalmological examination 1 year prior were reported as normal.At initial examination, she was conscious but somewhat lethargic. Her best-corrected visual acuity was 20/20 OD and 20/80 OS. Pupillary light responses, extrinsic ocular motility, anterior segment biomicroscopy, and intraocular pressure were normal in both eyes. Dilated fundus examination revealed a bilateral sectorial macular star that was more extended in the left eye, with retinal veins slightly dilated and tortuous, attenuated arterioles, some juxta and peripapillary nerve fiber layer infarcts, and optic disc edema with marked papillary telangiectasia; in addition, some faint, small, tan-yellow dots were observed at the level of the retinal pigment epithelium in the posterior pole, some of them already grayish and with a hypopigmented halo (Figure 1). Optical coherence tomography displayed elevated optic discs and hyperreflective material in the outer plexiform layer temporal to the optic disc in both eyes and a macular neurosensory detachment in the left eye. Results of visual field testing were normal in the right eye and showed a central scotoma in the left eye.Fundus image of the right eye (A) and left eye (B) showing slight dilation of retinal veins (magenta arrowheads), intraretinal lipid deposits in the papillomacular bundle and the inferonasal macular quadrant forming an incomplete macular star (yellow arrowheads), optic disc edema and epipapillary telangiectasia (blue arrowheads), nerve fiber layer infarcts or cotton-wool nodules (green arrowheads) over the inferior margin of the optic disc in the right eye and juxta and parapapillary in the left eye, and paramacular temporal light-pigmented subretinal dots at the level of the retinal pigment epithelium (white arrowheads) in both eyes, with some already scarred (pigmented dot surrounded by a pale halo; gold arrowhead). What Would You Do Next?

Prescribe systemic corticosteroids

Order serologic testing for infectious neuroretinitis

Rule out brain tumor

Check blood pressure

Hypertensive retinopathy

D

Check blood pressure

Option D is the correct approach. The child underwent immediate hospitalization and systemic evaluation. Clinical examination revealed severe systemic hypertension (225/160 mm Hg). Laboratory test results showed leukocytosis, elevated erythrocyte sedimentation rate (35 mm), hypercholesterolemia, hypokalemia, proteinuria, and microalbuminuria.Echocardiography showed left ventricle hypertrophy, and kidney doppler ultrasonography revealed advanced bilateral kidney atrophy with parenchymal scarring that was presumed to be the consequence of undertreated relapsing urinary tract infections. Results of magnetic resonance imaging of the brain and orbits were normal.The most common masquerader for neuroretinitis is malignant hypertension.1 Systemic hypertension in children is rare, potentially underrecognized,2 and its prevalence ranges from 2% to 5%.3 Mostly asymptomatic, pediatric hypertension may manifest by symptoms originating from target organ disease, and most cases present secondary hypertension from kidney disorders, especially kidney parenchymal disease.4 Hypertensive retinopathy occurs in 8% to 18% of children with severe hypertension, figures substantially lower than those observed in adults with hypertension, with the highest prevalence in those with kidney and renovascular disease.5Malignant hypertension is an acute, severe rise of more than 180 mm Hg in systolic pressure and/or more than 120 mm Hg in diastolic pressure, associated with severe hypertensive retinopathy and papilledema. It constitutes a medical emergency, where severe acute increase in blood pressure results in end-organ damage.6 The bilateral retinal disease, the presence of nerve fiber layer infarcts and Elschnig spots (focal signs of choroidal ischemia at the level of the retinal pigment epithelium), and the accompanying neurologic symptoms (severe headache and lethargy) suggested a severe systemic disease and were the presenting signs of malignant hypertension, which is a life-threatening condition in this patient secondary to kidney parenchymal disease from undertreated relapsing urinary tract infections since early infancy.Option A is incorrect. It is not advisable to prescribe corticosteroids before ruling out an infectious condition. Also, corticosteroids are contraindicated in the context of malignant hypertension. For option B, in the presence of the triad unilateral vision loss, macular star, and optic disc swelling in a child, infectious neuroretinitis must be ruled out, with cat scratch disease (CSD) its most frequent cause. However, neuroretinitis is a rare complication of cat scratch disease, occurring in only 1% to 2% of cases, and it generally presents unilaterally and self-limited.1 In this patient, results of serum tests for infective causes were negative. Besides, retinal and optic nerve disease were bilateral, and the child presented with neurologic signs. Option C is incorrect. Although this patient had neurologic symptoms with bilateral optic disc edema, other features, like macular lipid deposits, nerve fiber layer infarcts, and Elschnig spots, are not clinical signs that accompany papilledema from intracranial hypertension.Treatment with amlodipine, 5 mg, every 12 hours, daily losartan, 50 mg, and a hyposodic diet reduced blood pressure drastically and slowly normalized the retinal disease. Visual acuity progressively improved in the left eye, as did the macular star, optic disc edema, and nerve fiber layer infarcts in both eyes. One year later, blood pressure was generally within normal values under treatment but with intermittent episodes of high values. Best-corrected visual acuity was 20/20 OD and 20/25 OS, and optic discs were nonedematous but moderately pale in both eyes (Figure 2). Optical coherence tomography performed during follow-up showed a diffuse thinning of the neurosensory retina and the peripapillary nerve fiber layer.Fundus image of the left eye (panel) and the right eye (insert) at 1-year follow-up showing a pronounced sclerotic appearance of arteries, a complete resolution of both optic discs’ edema and the macular stars, a moderate optic disc pallor, and no evidence of nerve fiber layer infarcts.

Ophthalmology

A 13-year-old girl with a 7-day history of painless vision loss and central scotoma in her left eye was referred to the department of ophthalmology. Three weeks prior, she had presented with mild fever and flulike symptoms, associated with a severe frontal headache that was mildly relieved by analgesics. Her medical history was positive for relapsing urinary tract infections since early infancy without adequate follow-up. Findings of an ophthalmological examination 1 year prior were reported as normal.At initial examination, she was conscious but somewhat lethargic. Her best-corrected visual acuity was 20/20 OD and 20/80 OS. Pupillary light responses, extrinsic ocular motility, anterior segment biomicroscopy, and intraocular pressure were normal in both eyes. Dilated fundus examination revealed a bilateral sectorial macular star that was more extended in the left eye, with retinal veins slightly dilated and tortuous, attenuated arterioles, some juxta and peripapillary nerve fiber layer infarcts, and optic disc edema with marked papillary telangiectasia; in addition, some faint, small, tan-yellow dots were observed at the level of the retinal pigment epithelium in the posterior pole, some of them already grayish and with a hypopigmented halo (Figure 1). Optical coherence tomography displayed elevated optic discs and hyperreflective material in the outer plexiform layer temporal to the optic disc in both eyes and a macular neurosensory detachment in the left eye. Results of visual field testing were normal in the right eye and showed a central scotoma in the left eye.Fundus image of the right eye (A) and left eye (B) showing slight dilation of retinal veins (magenta arrowheads), intraretinal lipid deposits in the papillomacular bundle and the inferonasal macular quadrant forming an incomplete macular star (yellow arrowheads), optic disc edema and epipapillary telangiectasia (blue arrowheads), nerve fiber layer infarcts or cotton-wool nodules (green arrowheads) over the inferior margin of the optic disc in the right eye and juxta and parapapillary in the left eye, and paramacular temporal light-pigmented subretinal dots at the level of the retinal pigment epithelium (white arrowheads) in both eyes, with some already scarred (pigmented dot surrounded by a pale halo; gold arrowhead).

what would you do next?

What would you do next?

Check blood pressure

Order serologic testing for infectious neuroretinitis

Prescribe systemic corticosteroids

Rule out brain tumor

a

female

11-20

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2809348

An otherwise healthy 13-month-old male was scheduled to undergo excisional biopsy of a left anterior tongue submucosal intramuscular mass (Figure 1). This firm-to-palpation mass was noted at birth and remained proportional in size with the child’s somatic growth, measuring approximately 1 cm in diameter on presentation. Preoperative magnetic resonance imaging (MRI) documented the mass to be uniformly solid and well circumscribed without cystic components or flow voids, hypointense on T2, and hyperintense with homogeneous contrast enhancement on T1. His head, neck, and general examination findings were otherwise normal with no cervical lymphadenopathy or additional masses. What Is Your Diagnosis?

Hemangioma

Rhabdomyoma

Rhabdomyosarcoma

Teratoma

B. Rhabdomyoma

B

Rhabdomyoma

Neonatal tongue lesions have a broad differential diagnosis, including cystic, solid, and mixed composite lesions.1 Differentiation of cystic from solid lesions is important, as each warrants a unique differential diagnosis. Ultrasonography, computed tomography, and MRI are modalities that can be used to make this differentiation. If sedation is required, MRI with contrast is preferable given the excellent soft tissue detail without risk of radiation.Common congenital cystic tongue lesions include foregut duplication cysts, dermoid cysts, and ranulas. Foregut duplication cysts and dermoid cysts tend to be midline lesions, the former lined by gastrointestinal mucosa and the latter lined by squamous epithelium with adnexal structures.2 Ranulas and alternative pseudocysts of sublingual gland origin are more commonly unilateral lesions with a floor of mouth rather than tongue focality. Lymphatic and venous vascular malformations need to also be considered.This child’s lesion, based on physical examination and MRI characteristics, was solid. The differential diagnosis of solid tongue masses is broad, but neonatal presentation favors congenital and neoplastic causes. Common benign solid tongue masses in this age group include hemangiomas, hamartomas, choristomas, and teratomas.Hamartomas are benign growths composed of a proliferation of tissue native to the site of the lesion, whereas choristomas are proliferations of tissues not normally found in that anatomical location. Both hamartomas and choristomas can be solid depending on their tissue of origin.The World Health Organization Classification of Tumors lists 4 subtypes of extracardiac rhabdomyoma: fetal, adult, intermediate, and genital.3 Fetal rhabdomyoma may present at any age; however, over 50% of fetal rhabdomyoma cases have been diagnosed in infants and children younger than 3 years, with 25% being congenital.4 Fetal rhabdomyoma is the most common type found in the head and neck.5Although rare, malignant tongue masses should be considered, as delayed diagnosis can have devastating consequences. Rhabdomyosarcoma is the most common pediatric tongue malignant neoplasm, with leiomyosarcoma and fibrosarcoma being additional possibilities.6 Specifically, embryonal rhabdomyosarcoma should be considered, given the location.The pathology findings key to making the diagnosis in this case are highlighted in Figure 2. The histopathology demonstrated a circumscribed lesion composed of irregular bundles of primitive-appearing spindle cells and striated immature skeletal muscle cells, resembling fetal microtubules, within a myxoid background. Minimal mitotic activity was noted; no necrosis or atypia was present. These features supported a diagnosis of fetal rhabdomyoma.A, Histopathology findings of the excised lesion demonstrating irregular bundles of primitive cells and immature striated skeletal muscle fibers (hematoxylin-eosin). B, Desmin immunohistochemical stain highlighting the lesional cells.The myxoid background is important for the diagnosis of a classical fetal-type rhabdomyoma. Rhabdomyomas generally do not show atypia or necrosis, and mitoses are uncommon. Both the spindle cells and rhabdomyoblasts will be positive for myogenin and MyoD1 by immunohistochemistry. Adult rhabdomyoma can also be considered if the characteristic spider cells are present. Embryonal rhabdomyosarcoma is a poorly circumscribed lesion that shows both primitive round-to-spindle cells to differentiating rhabdomyoblasts (“tadpole cells” and/or “strap cells”) to cross-striated myofibers present in zones of hypocellularity to hypercellularity, embedded within a myxoid background. Embryonal rhabdomyosarcoma generally shows increased mitotic activity (sometimes with atypical mitoses), necrosis, and atypia; anaplasia may be seen.Heterotopic fetal rhabdomyoma, similar to choristoma, is managed by surgical excision for diagnosis and therapy.7 A recurrence rate of 4% over a median follow-up of 4 years has been reported for fetal rhabdomyoma of the head and neck.4 Recurrence likely reflects incomplete resection and, rarely, multicentricity.8The decision to wait to perform surgery was purposeful given the benign characteristics of the lesion and anesthesia exposure concerns. The patient was admitted for overnight monitoring with discharge home the following morning. At 6-month postoperative follow-up, the child demonstrated tongue symmetry, no functional impairment, and no evidence of recurrence.

General

An otherwise healthy 13-month-old male was scheduled to undergo excisional biopsy of a left anterior tongue submucosal intramuscular mass (Figure 1). This firm-to-palpation mass was noted at birth and remained proportional in size with the child’s somatic growth, measuring approximately 1 cm in diameter on presentation. Preoperative magnetic resonance imaging (MRI) documented the mass to be uniformly solid and well circumscribed without cystic components or flow voids, hypointense on T2, and hyperintense with homogeneous contrast enhancement on T1. His head, neck, and general examination findings were otherwise normal with no cervical lymphadenopathy or additional masses.

what is your diagnosis?

What is your diagnosis?

Teratoma

Hemangioma

Rhabdomyosarcoma

Rhabdomyoma

d

male

0-10

original

https://jamanetwork.com/journals/jama/fullarticle/2809109

A 42-year-old woman with asthma, seasonal allergies, and invasive ductal breast carcinoma presented to the dermatology clinic for rash and poor wound healing 2 weeks after bilateral mastectomy. Five days after surgery, the patient noted erythema, edema, pain, pruritus, and serous fluid drainage at the mastectomy incision sites (Figure 1). Two days later, she developed an erythematous papulovesicular rash on her trunk and upper and lower extremities. A skin swab was sent for bacterial culture, and she was prescribed cefadroxil (500 mg twice daily for 1 week). The skin swab bacterial culture result was negative, and her skin findings did not improve with antibiotics. The patient reported having a similar episode of rash and delayed wound healing after laparoscopy 1 year prior to presentation.Erythema and crusting along incision sites surrounded by a papulovesicular rash.Perform a skin biopsy at the mastectomy incision sitePrescribe acyclovir (400 mg orally 3 times daily for 7 days)Start topical steroids and perform a skin patch testTreat with doxycycline (100 mg orally twice daily for 7 days) What Would You Do Next?

Perform a skin biopsy at the mastectomy incision site

Prescribe acyclovir (400 mg orally 3 times daily for 7 days)

Start topical steroids and perform a skin patch test

Treat with doxycycline (100 mg orally twice daily for 7 days)

Allergic contact dermatitis due to use of surgical skin glue

C

Start topical steroids and perform a skin patch test

The key to the correct diagnosis is recognizing that an acute pruritic papulovesicular rash involving a surgical incision site is characteristic of allergic contact dermatitis due to use of surgical skin glue. Skin biopsy (choice A) would not be helpful because histopathologic findings of allergic contact dermatitis are nonspecific. Prescribing acyclovir (choice B) is not recommended because the patient did not have typical findings of herpes simplex virus such as grouped vesicles on an erythematous base. Doxycycline (choice D) is not indicated because her bacterial culture result was negative, and she had already been treated with a course of antibiotics.Allergic contact dermatitis (ACD) is a cutaneous type IV (delayed) hypersensitivity reaction caused by activation of allergen-specific T cells that develop after initial exposure to an allergen in contact with the skin.1 Activation of these T cells causes cytokine release and cellular infiltrates that result in the clinical symptoms of ACD.2Acute ACD presents with intense pruritus or burning, and the affected skin typically has a weepy erythematous appearance with surrounding erythematous papulovesicles and honey-colored crusting. Bullae and oozing may arise in severe cases.2,3 Skin findings may occur as early as 1 to 2 days after exposure in sensitized individuals or up to 1 month with initial allergen exposure.4 The differential diagnosis of ACD includes irritant contact dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis, tinea, mycosis fungoides, and surgical site infection in patients who have undergone recent surgery.2,3ACD affects approximately 72 million individuals in the US annually and is diagnosed more commonly in females than in males.1,2,4 Risk factors for ACD include atopic dermatitis, a family history of ACD, and exposure to acrylates, which are chemical agents commonly used in glues, adhesives, and plastics.1,3 Occupations with increased risk of ACD due to acrylate exposure include medical and dental practitioners, beauticians, chemical plant workers, construction workers, metal workers, and mechanics.1,3Patients who have undergone recent surgery can develop ACD from exposure to tissue adhesives, sutures, staples, antiseptic preparations, topical antibiotics, joint implants, and bone cement5-7 ACD causes inflammation of the skin that may impair wound healing, cause wound dehiscence, and increase the risk of wound infections.5,7ACD due to surgical skin glue occurs in 1.5% to 2.8% of exposed patients,3,4 and the most common allergens are acrylates (methacrylates or cyanoacrylates). ACD caused by one acrylate may lead to cosensitization to another acrylate.1 Surgical skin glue adhesives reside in the dermis and can cause sensitization and skin reactions up to 1 month after application.4 Approximately one-half of patients with allergic contact dermatitis due to surgical skin glue also develop a skin eruption in areas of the body remote from the site of application.4ACD is typically diagnosed with standard skin patch testing performed by an allergist or dermatologist. However, standard patch testing does not include cyanoacrylate, methacrylate, or suture materials and fails to identify approximately 25% of allergens that cause ACD.2,7 A specialized (“open”) patch test can be performed for patients who have exposure to specific known allergens not typically included in standard skin patch testing.2,7Treatment of ACD includes removal of the allergen and daily treatment with topical or systemic steroids for at least 2 to 3 weeks, at which point the skin findings typically resolve.2 However, patients must be informed that ACD will recur with reexposure, so strict avoidance of the specific allergen and cross-reacting allergens is required.2 Patients with a history of ACD due to use of surgical skin glue should inform their surgeon and anesthesiologist prior to surgery to avoid reexposure to an allergen that caused ACD.5An open patch test was performed to assess for an allergic reaction to the sutures and surgical skin glue used during the patient’s mastectomy. At 48 hours, she demonstrated a “strong positive” skin reaction to surgical skin glue (Figure 2). Acetone was used to remove the remaining surgical skin glue on her mastectomy incision sites, and triamcinolone was prescribed (0.1% cream twice daily for 2 weeks). Three days later, the patient noted a substantial decrease in pruritus and erythema at the incision sites. She was advised to avoid future contact with surgical skin glue and other potentially cross-reacting adhesives and was provided a handout detailing safe alternative products. At 2-week follow-up, the skin over her mastectomy incision sites appeared healthy, and the rash on her trunk and upper and lower extremities had resolved.Open skin patch test with materials used during the patient’s mastectomy showed a 2+ (strong positive) reaction to surgical skin glue observed 48 hours after application. No suture reactions occurred.

General

A 42-year-old woman with asthma, seasonal allergies, and invasive ductal breast carcinoma presented to the dermatology clinic for rash and poor wound healing 2 weeks after bilateral mastectomy. Five days after surgery, the patient noted erythema, edema, pain, pruritus, and serous fluid drainage at the mastectomy incision sites (Figure 1). Two days later, she developed an erythematous papulovesicular rash on her trunk and upper and lower extremities. A skin swab was sent for bacterial culture, and she was prescribed cefadroxil (500 mg twice daily for 1 week). The skin swab bacterial culture result was negative, and her skin findings did not improve with antibiotics. The patient reported having a similar episode of rash and delayed wound healing after laparoscopy 1 year prior to presentation.Erythema and crusting along incision sites surrounded by a papulovesicular rash.Perform a skin biopsy at the mastectomy incision sitePrescribe acyclovir (400 mg orally 3 times daily for 7 days)Start topical steroids and perform a skin patch testTreat with doxycycline (100 mg orally twice daily for 7 days)

what would you do next?

What would you do next?

Treat with doxycycline (100 mg orally twice daily for 7 days)

Start topical steroids and perform a skin patch test

Prescribe acyclovir (400 mg orally 3 times daily for 7 days)

Perform a skin biopsy at the mastectomy incision site

b

female

41-50

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2807476

A 56-year-old woman with a history of multiple myeloma complicated by therapy-related acute myeloid leukemia was admitted for myeloablative conditioning in preparation for allogeneic hematopoietic cell transplant. Her course was complicated by severe mucositis, acute kidney injury, and neutropenic fever. During her admission, the patient also developed painful necrotic skin lesions, a nonproductive cough, and altered mental status.Physical examination findings demonstrated dusky, purpuric, and pink papulonodules, some with overlying eschar, scattered on the scalp, neck, trunk, and extremities (Figure, A). Laboratory study results revealed a white blood cell count of 150/μL (reference range, 3500/μL to 10 500/μL), an absolute neutrophil count of 130/μL (reference range, 1500/μL to 7400/μL), and a platelet count of 19 ×103/μL (reference range, 150 ×103/μL to 400 ×103/μL). (To convert the white blood cell and neutrophil counts to cells ×109/L, multiply by 0.001; conversion of the platelet count to cells ×109/L is 1:1.) Blood culture results were negative. The results of a computed tomography (CT) scan of the brain showed no acute intracranial hemorrhage, territorial infarction, or mass effect. The results of a CT scan of the chest demonstrated multifocal bilateral ground-glass patchy opacities, scattered solid bilateral pulmonary nodules, and a moderately sized pericardial effusion. A biopsy specimen from a skin nodule on the left lateral thigh was obtained for histopathologic examination and tissue culture, and wet mount preparation of a tissue culture colony was performed (Figure, B).A, Physical examination findings demonstrate dusky and pink papulonodules, some with overlying eschar, scattered on the scalp, neck, and extremities. B, Lactophenol cotton blue staining of a tissue culture colony reveals septated hyphae and oval microconidia. What Is Your Diagnosis?

Disseminated fusariosis

Invasive aspergillosis

Pseudomonal ecthyma gangrenosum

Sweet syndrome

A. Disseminated fusariosis

A

Disseminated fusariosis

Wet mount preparation of a tissue culture mold colony with lactophenol cotton blue staining revealed septated hyphae and oval microconidia (Figure, B). A fungal culture grew Fusarium solani.Fusarium species are ubiquitous in soil and air, and transmission occurs through inhalation or direct cutaneous inoculation from a contaminated source.1 Localized infections can present as onychomycosis, superficial cutaneous infections, and keratitis in immunocompetent hosts; invasive and disseminated disease is more common in those who are immunocompromised, particularly those with neutropenia.2 In those with hematologic cancer, disseminated fusariosis most frequently involves the skin, blood, lungs, and sinuses.3Although the incidence of fusariosis among patients undergoing hematopoietic transplant is less than 1%, invasive fusariosis has a mortality rate of approximately 80% in individuals with hematologic cancer.4 Thus, early recognition is crucial for prompt treatment of the infection. Purpuric patches or papulonodules in this population should be evaluated urgently with skin biopsy and tissue culture. It is also recommended that patients with hematologic cancer who are about to receive chemotherapy and/or bone marrow transplant first undergo a thorough examination for skin findings of onychomycosis, which has been associated with Fusarium infections.1,3,5The patient’s physical examination findings of scattered and painful purpuric papulonodules are similar to those found in invasive aspergillosis, which has an incidence of 2.7% in patients undergoing hematopoietic stem cell transplant.4 Invasive aspergillosis is an infection caused by the fungal Aspergillus species, which is ubiquitous in the environment.6 As transmission is primarily through inhalation, invasive aspergillus most commonly presents with pulmonary or sinus disease that can then progress to dissemination in immunocompromised individuals. Both Aspergillus and Fusarium may cause elevated serum galactomannan antigen. Chest CT findings of invasive aspergillosis and disseminated fusariosis are similar, and both may show ground-glass opacities, segmental consolidation, cavitary lesions, and the “halo sign” (ground-glass opacities representing hemorrhage surrounding central fungal nodules). Lactophenol cotton blue staining of mold colony can differentiate between the 2 pathogens, as Aspergillus species have septate hyphae and flask-shaped vesicles.1,7Ecthyma gangrenosum is a cutaneous infection caused by hematogenous spread of bacteria, most commonly Pseudomonas aeruginosa. It most frequently occurs in immunocompromised individuals, including those with chemotherapy-induced neutropenia.8 As this represents bacterial angioinvasion, ecthyma gangrenosum presents as purpuric macules that may become pustular or bullous before progressing to ulcers with overlying eschar most commonly in the anogenital and axillary areas. In most cases, Pseudomonas can be detected from tissue specimens, but blood culture results are often negative.9Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a rare disorder that is commonly associated with hematologic cancers, such as acute myeloid leukemia. Sweet syndrome can also be associated with other states, such as autoimmune disease, or be due to medications, such as granulocyte colony-stimulating factor. Classic Sweet syndrome presents as tender, erythematous, and edematous plaques associated with fever and leukocytosis. Cutaneous involvement generally does not show overlying eschar, as seen in disseminated fusariosis. Skin biopsy histopathologic features can mimic infection with dermal edema and a dense infiltrate of neutrophils; however, the results of infectious stains and tissue culture will be negative. Systemic corticosteroids are often first-line treatments for Sweet syndrome.10The patient was treated with intravenous amphotericin B and voriconazole for disseminated fusariosis, with resolution of her cutaneous lesions over the course of 6 weeks. This case highlights the importance of early diagnosis of disseminated fusariosis, especially for those who are immunocompromised or undergoing immunosuppressive therapy.

Oncology

A 56-year-old woman with a history of multiple myeloma complicated by therapy-related acute myeloid leukemia was admitted for myeloablative conditioning in preparation for allogeneic hematopoietic cell transplant. Her course was complicated by severe mucositis, acute kidney injury, and neutropenic fever. During her admission, the patient also developed painful necrotic skin lesions, a nonproductive cough, and altered mental status.Physical examination findings demonstrated dusky, purpuric, and pink papulonodules, some with overlying eschar, scattered on the scalp, neck, trunk, and extremities (Figure, A). Laboratory study results revealed a white blood cell count of 150/μL (reference range, 3500/μL to 10 500/μL), an absolute neutrophil count of 130/μL (reference range, 1500/μL to 7400/μL), and a platelet count of 19 ×103/μL (reference range, 150 ×103/μL to 400 ×103/μL). (To convert the white blood cell and neutrophil counts to cells ×109/L, multiply by 0.001; conversion of the platelet count to cells ×109/L is 1:1.) Blood culture results were negative. The results of a computed tomography (CT) scan of the brain showed no acute intracranial hemorrhage, territorial infarction, or mass effect. The results of a CT scan of the chest demonstrated multifocal bilateral ground-glass patchy opacities, scattered solid bilateral pulmonary nodules, and a moderately sized pericardial effusion. A biopsy specimen from a skin nodule on the left lateral thigh was obtained for histopathologic examination and tissue culture, and wet mount preparation of a tissue culture colony was performed (Figure, B).A, Physical examination findings demonstrate dusky and pink papulonodules, some with overlying eschar, scattered on the scalp, neck, and extremities. B, Lactophenol cotton blue staining of a tissue culture colony reveals septated hyphae and oval microconidia.

what is your diagnosis?

What is your diagnosis?

Pseudomonal ecthyma gangrenosum

Sweet syndrome

Invasive aspergillosis

Disseminated fusariosis

d

female

51-60

White

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2807704

A man in his 80s presented to the dermatology clinic with a 3-month history of a violaceous plaque with blackish papules and nodules on his left cheek, neck, and chest. He reported that the lesion had been asymptomatic but was increasing in size, with progression from his face to anterior chest. He received a diagnosis of primary salivary duct carcinoma of the hard palate 1 year prior and had been receiving treatment with oral bicalutamide and radiotherapy. A partially regressive change of the palatal tumor was noted radiographically during regular follow-up 3 months previously. On clinical examination, a hemorrhagic and erythematous plaque with multiple purpuric-to-blackish infiltrative papules and nodules extending from cheek, lateral neck, to the interclavicular area was found (Figure 1). An incisional biopsy from the infiltrative nodule on cheek was performed and submitted for histopathologic analysis.Hemorrhagic and erythematous plaque with multiple infiltrative purpuric-to-blackish papules and nodules with varying sizes extending from left cheek, neck, to chest. What Is Your Diagnosis?

Radiotherapy-induced epithelioid angiosarcoma

Kaposi sarcoma

Acquired angiokeratomas

Carcinoma hemorrhagiectoides

D. Carcinoma hemorrhagiectoides

D

Carcinoma hemorrhagiectoides

Hematoxylin-eosin staining of the lesion revealed a diffuse infiltrate of large, ovoid tumor cells that formed tumor nests and tumor emboli, with marked erythrocytes extravasation in the dermis (Figure 2A). The cells had an abundant eosinophilic cytoplasm and were hyperchromatic, with nuclear pleomorphism and comedonecrosis (Figure 2B). Androgen receptor and GATA3 were diffusely strong positive in the tumor cells, while other endothelial markers, including CD31, CD34, and ERG1, were negative. A diagnosis of carcinoma hemorrhagiectoides due to metastatic salivary duct carcinoma (SDC) was made. Further image study results revealed multiple metastases in the lung, liver, and bone. A combination of oral bicalutamide and chemotherapy with carboplatin and fluorouracil was administered. Four months later, partial regression of the liver and lung metastases was noted radiographically.Hematoxylin-eosin staining of the lesion from the biopsy specimens. A, Scanning magnification showed a diffuse infiltrate of tumor cells with marked erythrocyte extravasation. B, The tumor cells were characterized by an abundant eosinophilic cytoplasm, nuclear atypia, and pleomorphism, with comedonecrosis on higher magnification.Salivary duct carcinoma is an aggressive cancer of the primary salivary gland origin and is generally associated with a high rate of local recurrence and distant metastasis.1 It accounts for 5% to 10% of salivary gland cancer and has a tendency of developing in male individuals older than 50 years. While the most common sites of metastatic SDC are the lungs and bones,2 rare cases of cutaneous metastasis have been reported.3-5 Clinically, metastatic SDC on the skin may present as pink pebble-like papules, subcutaneous nodules, or, rarely, as carcinoma hemorrhagiectoides, as in this case. Carcinoma hemorrhagiectoides is characterized as a purpuric indurated plaque with overlying angiokeratoma-like black keratotic papules and nodules. A shield sign, a term derived from the similarity in shape to a medieval knight’s shield, has been described on the anterior chest of affected individuals.4 Studies have suggested that the pathomechanism of carcinoma hemorrhagiectoides may be associated with direct tumor invasion of blood vessels and lymphatic ducts in the dermis.4 A biopsy was needed for exclusion of other differential diagnoses in this case. The histopathological findings of SDC typically show tumor cells with abundant eosinophilic cytoplasm, large pleomorphic nuclei, and conspicuous nucleoli. Comedonecrosis and a cribriform growth pattern can be variably presented. Immunohistochemically, the tumor cells show a strong and diffuse positive staining for androgen receptor in more than 90% of the cases.1 GATA3 and GCDFP-15 positivity with negative p63 expression can also aid the diagnosis toward SDC. In addition, the histopathologic and immunohistochemical profiles of metastatic SDC may closely resemble invasive ductal carcinoma of the breast; thus, a definite diagnosis is made on a thorough clinicopathological correlation.The differential diagnosis in this case included radiotherapy-induced epithelioid angiosarcoma, Kaposi sarcoma (KS), and acquired angiokeratomas. Radiotherapy-induced angiosarcoma is a late complication of radiotherapy, with a median latency period of 8 years after treatment.6 It occurs mostly in those with breast and gynecological cancers7 and typically presents as a diffuse purplish discoloration in the previously irradiated skin area. Pathologically, crowded atypical endothelial cells with nuclear atypia, necrosis, hemorrhage, occasional formation of intracytoplasmic lumina, and positivity for endothelial cell markers, such as CD31, CD34, and ERG1, can be found. Epithelioid angiosarcoma is a high-grade variant of angiosarcoma with poor prognosis and should be carefully distinguished from this case, given that it is composed of mostly epithelioid cells with minimal vasoformation.8 Additional immunohistochemical features of epithelioid angiosarcoma include positivity of Friend leukemia integration 1 transcription factor and von Willebrand factor, variable positivity for creatine kinase, focal positivity of epithelial membrane antigen A, and negativity of CD34. Kaposi sarcoma is an angioproliferative disorder due to human herpesvirus type 8 infection with intermediate cancer potential. It mostly involves the trunk, limbs, and mucosa as violaceous patches, plaques, or nodules, while craniofacial manifestation is less observed except in AIDS-associated KS.9 The pathological features depend on the different stages of the disease, as characterized by slit-like spaces and a proliferation of bland spindle cells stating positive for CD31 and herpesvirus type 8. Lastly, acquired angiokeratomas are characterized by multiple bluish-to-reddish hyperkeratotic papules with a wide range of anatomic distribution. Microscopically, dilated vascular spaces in the dermis extending into the epidermis with hyperkeratosis, acanthosis, papillomatosis, and elongation of the rete ridges can be found.

Dermatology

A man in his 80s presented to the dermatology clinic with a 3-month history of a violaceous plaque with blackish papules and nodules on his left cheek, neck, and chest. He reported that the lesion had been asymptomatic but was increasing in size, with progression from his face to anterior chest. He received a diagnosis of primary salivary duct carcinoma of the hard palate 1 year prior and had been receiving treatment with oral bicalutamide and radiotherapy. A partially regressive change of the palatal tumor was noted radiographically during regular follow-up 3 months previously. On clinical examination, a hemorrhagic and erythematous plaque with multiple purpuric-to-blackish infiltrative papules and nodules extending from cheek, lateral neck, to the interclavicular area was found (Figure 1). An incisional biopsy from the infiltrative nodule on cheek was performed and submitted for histopathologic analysis.Hemorrhagic and erythematous plaque with multiple infiltrative purpuric-to-blackish papules and nodules with varying sizes extending from left cheek, neck, to chest.

what is your diagnosis?

What is your diagnosis?

Acquired angiokeratomas

Kaposi sarcoma

Radiotherapy-induced epithelioid angiosarcoma

Carcinoma hemorrhagiectoides

d

male

81-90

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2808313

A previously healthy 16-year-old girl presented to our department with a red tumor on her right upper arm that enlarged over 6 months. The lesion initially started as a small cutaneous nodule without obvious triggers that gradually developed and enlarged to form a red-colored tumor with a hard nodule inside. There was no history of local trauma or insect bite. Her personal, past, and family histories were unremarkable.On physical examination, there was a 6 × 6-cm protuberant, thick-walled, and well-defined red bullalike tumor on the right upper arm, which extended 1 to 3 cm from the epidermal surface (Figure, A). Inside the tumor, a nontender, firm-to-hard nodule was palpated. There was no regional lymphadenopathy, and results of the rest of the physical and systemic examinations were normal. Laboratory examinations of hematologic, biochemical, and urinalysis tests were normal. The tumor was excised completely under local anesthesia, and part of the tissue was sent for pathological examination.A, A tumor on the patient’s right shoulder. B, The excisional tumor showed multilocular spaces below the epidermis and a solid tumor present in the deep dermis with a chalky-white cut surface and lobulated appearance. C and D, Histological examination revealed basophilic cells and shadow cells as well as dilated lymphatic vessels (hematoxylin-eosin; original magnification ×100). What Is Your Diagnosis?

Matrical carcinoma

Panfolliculoma

Bullous pilomatricoma

Trichodiscoma

C. Bullous pilomatricoma

C

Bullous pilomatricoma

The gross specimen of excised material showed multilocular spaces below the epidermis and a solid tumor present in the deep dermis with a chalky-white cut surface and lobulated appearance (Figure, B). Histopathological examination revealed basophilic cells and shadow cells in the deep dermis (Figure, C) and dilated lymphatic vessels in the dermis above the tumor (Figure, D).Based on the clinical morphology and histological features, the diagnosis of bullous pilomatricoma was confirmed. The patient is under regular outpatient follow-up, with no recurrence detected in 1 year of follow-up.Bullous pilomatricoma is a rare variant of pilomatricoma with a bullous appearance.1 It most commonly occurs on the shoulder and upper arm but also can be found on the neck, trunk, eyelid, and scalp. The peak age of presentation is 10 to 20 years old, and there is a predilection for female individuals.2 Clinically, bullous pilomatricoma usually presents as a solitary, semitransparent, erythematous, bluish or skin-colored, heavily folded or striaelike, flaccid, thick-walled, bullalike tumor with an underlying palpable hard nodule.1-3 It is rare for patients with bullous pilomatricoma to have multiple lesions.4The present patient’s lesion was increasing in size gradually but always had a clear border. When the bullalike tumor was punctured, a jellylike substance could be seen exuding out.4 Unlike some typical pilomatricomas, bullous pilomatricoma is not associated with Turner syndrome, myotonic dystrophy, Gardner syndrome, or Rubinstein-Taybi syndrome.2The etiopathogenesis of bullous pilomatricoma is not clear. There are 2 proposed theories. In the first, obstruction of lymphatic vessels and congestion of lymphatic fluid caused by the growth of the tumor nodule causes dilatation of lymphatic vessels, leakage of lymphatic fluid, and edema in the dermis surrounding the tumor, which further produces the bullous appearance.2,5 The second theory suggests that the presence of matrix metalloproteinases (MMP-9 and MMP-12), released by fibroblasts and inflammatory cells surrounding the tumor, may be associated with the degradation of elastic fibers and collagen, resulting in the bullouslike/anetodermic appearance.6Histologically, bullous pilomatricoma not only has the hallmarks of pilomatricoma, including basaloid cells and eosinophilic keratinized (shadow) cells, but also shows dilated lymphatic vessels, giant cell reaction, lymphoedema, disruption of collagen fibers, dilated blood vessels, fibrous capsule, calcification, nests of transitional cells, and necrosis.2 The presence of dilated lymphatic vessels and lymphedema have been described as a common pathologic feature in bullous pilomatricomas2,7 and can be used to distinguish bullous pilomatricomas from common pilomatricomas. Moreover, as a low-cost, noninvasive tool, ultrasonography (specifically high-frequency ultrasonography8) has been used as a diagnostic tool and is more appropriate for younger children to demonstrate the superficial position, continuity of the lesion with deeper structures, and degree of calcification.The diagnosis of bullous pilomatricoma may be difficult clinically, due to its atypical presentation. The common differential diagnoses should include matrical carcinoma, panfolliculoma, and trichodiscoma. Matrical carcinoma is a locally aggressive tumor, which is typically featured with a nontender, firm dermal swollen nodule and occurs most commonly in the area of the head and neck. Histologically, both matrical carcinomas and pilomatricomas are composed of nodular aggregates of basaloid keratinocytes that transform into shadow cells.9 Cellular pleomorphism and asymmetry, undefined circumscription, and tumor necrosis can help distinguish these 2 entities. Panfolliculoma typically presents as a slow-growing cystic or dome-shaped nodule, which may develop ulcers and crusts in the center, mainly affecting the face and scalp, though sometimes the limbs, of elderly patients.10 Histologically, cellular aggregates can differentiate into any components of the hair follicle, not just the hair matrix cells and shadow cells. Trichodiscoma, a follicular mesenchymal hamartoma, is characterized by multiple, small, 2- to 4-mm, dome-shaped, skin-colored papules on the face, scalp, ears, or upper trunk. Histopathological examination can show a central zone of fibro-mucinous stroma, with surrounding sebaceous glands in a mittlike configuration. The first-line treatment is surgical excision or curettage, and incomplete resection almost always results in recurrence.

Dermatology

A previously healthy 16-year-old girl presented to our department with a red tumor on her right upper arm that enlarged over 6 months. The lesion initially started as a small cutaneous nodule without obvious triggers that gradually developed and enlarged to form a red-colored tumor with a hard nodule inside. There was no history of local trauma or insect bite. Her personal, past, and family histories were unremarkable.On physical examination, there was a 6 × 6-cm protuberant, thick-walled, and well-defined red bullalike tumor on the right upper arm, which extended 1 to 3 cm from the epidermal surface (Figure, A). Inside the tumor, a nontender, firm-to-hard nodule was palpated. There was no regional lymphadenopathy, and results of the rest of the physical and systemic examinations were normal. Laboratory examinations of hematologic, biochemical, and urinalysis tests were normal. The tumor was excised completely under local anesthesia, and part of the tissue was sent for pathological examination.A, A tumor on the patient’s right shoulder. B, The excisional tumor showed multilocular spaces below the epidermis and a solid tumor present in the deep dermis with a chalky-white cut surface and lobulated appearance. C and D, Histological examination revealed basophilic cells and shadow cells as well as dilated lymphatic vessels (hematoxylin-eosin; original magnification ×100).

what is your diagnosis?

What is your diagnosis?

Trichodiscoma

Panfolliculoma

Matrical carcinoma

Bullous pilomatricoma

d

female

11-20

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2807444

A 15-year-old girl presented with a 2-month history of decreased vision and a dark spot in the central vision in her right eye. She had a history of optometric examinations with no known ocular disease. Visual acuity with correction was 20/40 in the right eye and 20/20 in the left eye. Anterior segment examination of both eyes was unremarkable, and the retina in the left eye appeared normal. In the right eye, there was an area of superior macular whitening with associated intraretinal hemorrhages and exudates. Fluorescein angiography showed abnormally dilated and tortuous retinal vessels, irregular capillary branching patterns, and bulblike telangiectasis with late leakage in the superior macula. Optical coherence tomography showed disorganized and hyperreflective inner retinal thickening (Figure, A) and intraretinal and subretinal fluid in the central macula. On review of systems, the patient noted a long-standing growth on her cheek, which on examination was a 4 × 3-mm exophytic, brownish-red vascular papule (Figure, B), as well as a history of lightly pigmented patches of skin and multiple subungual fibromas on her toes. Systemic blood pressure was normal.Features of tuberous sclerosis complex. A, An area of superior macular whitening following the superior arterial arcade with associated intraretinal hemorrhages and exudate. Two optical coherence tomography line scans inset through the main lesion (orange) and through the fovea (blue) with relative location marked with dotted lines, demonstrating disorganized and hyperreflective inner retinal thickening consistent with type 1 astrocytic hamartoma of the retina and associated macular edema. Arrowhead indicates bulblike telangiectasis on fluorescein angiography and blocking from intraretinal hemorrhage. B, Elevated papule. The lesion is a well-demarcated, exophytic, brownish-red vascular papule with an irregular surface.Order brain magnetic resonance imaging to look for associated central nervous system tumors What Would You Do Next?

Initiate anti–vascular endothelial growth factor treatment

Order brain magnetic resonance imaging to look for associated central nervous system tumors

Perform hypercoagulable workup

Order echocardiogram and carotid ultrasonography

Astrocytic hamartoma (with secondary branch retinal vein occlusion) associated with tuberous sclerosis complex

B

Order brain magnetic resonance imaging to look for associated central nervous system tumors

Astrocytic hamartomas of the retina (AHR) are benign tumors that can be associated with tuberous sclerosis complex (TSC). TSC is a phacomatosis with neurocutaneous manifestations characterized by multiple tumors of the embryonic ectoderm involving skin, eyes, and nervous systems.1 Hamartomas of the retina are part of the major features for the diagnosis of TSC.2The clinical diagnostic criteria for TSC include 11 major and 7 minor features. Major features are 3 or more hypomelanotic macules at least 5 mm in diameter, 3 or more angiofibromas or fibrous cephalic plaques, 2 or more ungual fibromas, shagreen patch (a large nevus with irregular, firm plaquelike features typical of TSC), multiple retinal hamartomas, multiple cortical tubers or radial migration lines, 2 or more subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, and 2 or more angiomyolipomas. Minor features of TSC are 1- to 2-mm hypomelanotic macules, also known as confetti skin lesions; 3 or more dental enamel pits; 2 or more intraoral fibromas; retinal achromic patch; multiple renal cysts; nonrenal hamartomas; and sclerotic bone lesions.The diagnostic certainty of TSC depends on the number of major and minor features. Definite TSC requires 2 major features or 1 major and 2 or more minor features. Possible TSC requires either 1 major feature or 2 or more minor features.3 Genetic testing is also available, and the identification of either a TSC1 or TSC2 pathogenic variant from nonlesional tissue is sufficient to make a definite diagnosis of TSC regardless of clinical findings.3History should be obtained and focused physical examination is recommended for skin and the central nervous system. The association between TSC and astrocytic hamartoma can be observed in up to half of patients with TSC.2 There are several phenotypes of astrocytic hamartoma associated with TSC, including slow-growing flat lesions (similar to that observed in this patient), as well as more aggressive, rapidly growing tumors that can lead to enucleation.2 Histology shows that astrocytic hamartomas are composed of glial astrocytes and blood vessels with hyaline and calcium deposits.4If TSC is suspected, the primary concern must be initiating the systemic workup with neuroimaging (choice B), as the central nervous system manifestations of TSC can be life threatening. Secondarily, treatment for the ophthalmic complications of the disease can be considered, such as with anti–vascular endothelial growth factor (anti-VEGF) medications for secondary exudation (choice A).5 Retinal hamartomas are not typically associated with a hypercoagulable state or cardiac concerns (choices C and D).The patient was referred for neuroimaging, which revealed multiple subcortical tubers and lateral ventricle subependymomas consistent with the diagnosis of TSC. Genetic testing revealed a pathogenic variant in the TSC1 gene labeled c.733C>T(p.R245*), which is most commonly a de novo variant. Excisional biopsy of the facial lesion was consistent with angiofibroma, a benign cutaneous hamartoma frequently found in tuberous sclerosis complex. Because the central nervous system lesions were asymptomatic, the patient was referred for annual imaging and observation in pediatric neurology.Retinal hamartomas are classified into 3 morphological subtypes. Type 1 AHR is the most common and is characterized by flat and smooth lesions semitransparent without calcifications. Type 2 AHR lesions are raised, multinodular, opaque, and with calcification. Type 3 AHR lesions are transitional lesions with features of types 1 and 2.6Treatment of AHR lesions is determined on a case-by-case basis. Photodynamic therapy, laser, radiation, and anti-VEGF have been described.7 Due to the secondary exudation and hemorrhages consistent with a small branch retinal vein occlusion with edema affecting the central macula, we performed a systemic hypercoagulable workup, which was unrevealing. Because the exudation affected the central macula, we started treatment with intravitreal anti-VEGF to treat the macular edema. Two years later, the patient was stable with visual acuity 20/25 in the affected eye but has required monthly treatment with worsening edema and vision with an attempted treat-and-extend strategy. The tumor slowly expanded for the first year but was stable for the following year.

Ophthalmology

A 15-year-old girl presented with a 2-month history of decreased vision and a dark spot in the central vision in her right eye. She had a history of optometric examinations with no known ocular disease. Visual acuity with correction was 20/40 in the right eye and 20/20 in the left eye. Anterior segment examination of both eyes was unremarkable, and the retina in the left eye appeared normal. In the right eye, there was an area of superior macular whitening with associated intraretinal hemorrhages and exudates. Fluorescein angiography showed abnormally dilated and tortuous retinal vessels, irregular capillary branching patterns, and bulblike telangiectasis with late leakage in the superior macula. Optical coherence tomography showed disorganized and hyperreflective inner retinal thickening (Figure, A) and intraretinal and subretinal fluid in the central macula. On review of systems, the patient noted a long-standing growth on her cheek, which on examination was a 4 × 3-mm exophytic, brownish-red vascular papule (Figure, B), as well as a history of lightly pigmented patches of skin and multiple subungual fibromas on her toes. Systemic blood pressure was normal.Features of tuberous sclerosis complex. A, An area of superior macular whitening following the superior arterial arcade with associated intraretinal hemorrhages and exudate. Two optical coherence tomography line scans inset through the main lesion (orange) and through the fovea (blue) with relative location marked with dotted lines, demonstrating disorganized and hyperreflective inner retinal thickening consistent with type 1 astrocytic hamartoma of the retina and associated macular edema. Arrowhead indicates bulblike telangiectasis on fluorescein angiography and blocking from intraretinal hemorrhage. B, Elevated papule. The lesion is a well-demarcated, exophytic, brownish-red vascular papule with an irregular surface.Order brain magnetic resonance imaging to look for associated central nervous system tumors

what would you do next?

What would you do next?

Initiate anti–vascular endothelial growth factor treatment

Order echocardiogram and carotid ultrasonography

Perform hypercoagulable workup

Order brain magnetic resonance imaging to look for associated central nervous system tumors

d

female

11-20

original

https://jamanetwork.com/journals/jama/fullarticle/2807957

A 73-year-old man with a history of gastroesophageal reflux disease and Raynaud disease but no history of cigarette smoking presented to the emergency department with 4 weeks of dysphagia and a 4.54-kg (10-lb) weight loss over 3 months. He had no nausea, vomiting, abdominal pain, melena, or hematochezia but reported a cough productive of yellow sputum, dyspnea on exertion, and fatigue. The patient had been treated for presumed pneumonia with 3 courses of azithromycin over the prior 3 months due to infiltrates on a chest radiograph. He reported no known ill contacts or recent travel outside the US. At presentation, his heart rate and blood pressure were normal, and oxygen saturation was 95% on room air. Physical examination revealed a maculopapular rash over his neck and chest (Figure, left panel) and bibasilar crackles on lung auscultation. Laboratory testing showed a white blood cell count of 14.3 × 103/μL (reference, 4.2-9.1 × 103/μL); creatine kinase level, 2060 U/L (34.40 μkat/L) (reference, 44-196 U/L [0.73-3.27 μkat/L]), aldolase level, 18 U/L (0.30 μkat/L) (reference, <8 U/L [<0.13 μkat/L]), C-reactive protein level, 30 mg/L (reference, <8 mg/L), and erythrocyte sedimentation rate, 35 mm/h (reference, <20 mm/h). Antinuclear antibody immunofluorescent assay findings were positive. Results from testing for HIV, hepatitis B, and hepatitis C were negative. A barium swallow study showed no visualized aspiration. Endoscopy revealed clean-based esophageal and duodenal ulcers and nonspecific gastritis. Chest computed tomography (CT) showed bibasilar pulmonary consolidations and ground glass opacities (Figure, right panel).Left, Shawl-like rash on patient’s chest. Right, Computed tomography scan of the chest showing bibasilar pulmonary consolidations and ground glass opacities.Prescribe 10 days of prednisone (60 mg daily) What Would You Do Next?

Arrange a percutaneous lung tissue biopsy

Check an antisynthetase antibody panel

Perform a quadriceps muscle biopsy

Prescribe 10 days of prednisone (60 mg daily)

Antisynthetase syndrome

B

Check an antisynthetase antibody panel

The key to the correct diagnosis is recognition that cough, dyspnea on exertion and pulmonary infiltrates, and elevated levels of creatine kinase, aldolase, and inflammatory markers in a patient with Raynaud disease are characteristic of antisynthetase syndrome. Choices A and C are not recommended because lung and muscle biopsy are invasive procedures and may not provide a definitive diagnosis. Prednisone (choice D) should not be prescribed before a diagnosis has been made.Antisynthetase syndrome is a rare autoimmune disease classified as a subgroup of idiopathic inflammatory myopathic disorders.1 A characteristic feature of antisynthetase syndrome is presence of an autoantibody to one of the aminoacyl–transfer RNA (tRNA) synthetases, which are intracellular enzymes that attach amino acids to tRNA during protein synthesis.2,3 Antisynthetase syndrome has been associated with HLA haplotype DRB1*0301 and with exposures to tobacco, cleaning chemicals, mold, bird droppings, and airborne particles from the September 11, 2001, World Trade Center attack.2 Of the 10 identified antiaminoacyl-tRNA synthetases, the most common are anti–Jo-1 antibody (60%), anti–PL-12 (17%), and anti–PL-7 (12%).2,3The classic triad of antisynthetase syndrome consists of interstitial lung disease (ILD), myositis, and nonerosive arthritis. Although these 3 conditions develop in up to 90% of patients with antisynthetase syndrome, approximately 25% present only with symptoms of arthritis, 25% present with myositis, and 15% to 30% have ILD as their presenting manifestation.2,3 Other conditions associated with antisynthetase syndrome include Raynaud phenomenon, gastroesophageal reflux disease, fever, and fissured eruptions on the hands (“mechanic hands”).2,4,5ILD affects approximately 70% to 95% of patients with antisynthetase syndrome and is the most common cause of morbidity and mortality.4 High-resolution CT findings include ground glass opacities, bibasilar fibrosis, and traction bronchiectasis.4 Pulmonary function testing (PFT) typically shows a restrictive ventilatory defect.2 Approximately 9% of patients with antisynthetase syndrome have rapidly progressive ILD2; others have gradual onset of respiratory symptoms, and some are asymptomatic, with ILD diagnosed based on imaging or PFT.2 The incidence of ILD and pulmonary hypertension is higher in patients with anti–PL-7 and anti–PL-12 antibodies compared with anti–Jo-1 antibodies.2,4,6-8 Overall survival for patients with anti–Jo-1 antibody was 70% at 10 years vs 47% for patients with non–anti–Jo-1 synthetase antibodies.2Diagnosis of antisynthetase syndrome requires identification of an autoantibody to aminoacyl-tRNA synthetase. Most commercially available myositis panels test only for anti–Jo-1 antibody, so an antisynthetase antibody panel should be ordered if antisynthetase syndrome is being considered.4 On diagnosis, patients with antisynthetase syndrome should undergo a high-resolution chest CT scan to evaluate for ILD and PFT to assess lung function.2 An echocardiogram may be useful to evaluate for pulmonary hypertension in patients with ILD.4Limited evidence is available regarding optimal drug therapy for antisynthetase syndrome. Patients often receive multidisciplinary care from specialists in rheumatology, pulmonology, and dermatology and may be treated with glucocorticoids, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, rituximab, cyclophosphamide, and nintedanib.2,4,5,9 Within the first year of treatment, approximately two-thirds of patients with antisynthetase syndrome experience clinical and radiographic improvement, and 1 study reported that approximately 24% of patients had full resolution of ILD.2 However, approximately one-third of patients develop fibrotic lung disease, which is associated with increased morbidity and mortality.2 Lung transplant should be considered for patients with severe or rapidly progressive ILD.2,5The patient tested positive for anti–PL-7 antibody, which confirmed the diagnosis of antisynthetase syndrome. Antibody testing results were negative for antisignal recognition particle, antinuclear helicase, anti-RNA helicase, anti–Scl-70, antipolymerase III, anti-U1RNP, anticentromere antibody, anti-U3RNP, anti-Ro/SSA and anti-La/BB, and rheumatoid factor. On PFT, forced vital capacity was 83% of predicted and diffusing capacity for carbon monoxide was 66% of predicted. He was initially treated with prednisone (10 mg daily) for 6 weeks, then transitioned to mycophenolate (500 mg twice daily) and nintedanib (150 mg twice daily), which are his current medications. At 1-year follow-up, he reported a decrease in his cough and dyspnea on exertion, and high-resolution chest CT showed decreased bibasilar consolidation compared with chest CT on presentation.

General

A 73-year-old man with a history of gastroesophageal reflux disease and Raynaud disease but no history of cigarette smoking presented to the emergency department with 4 weeks of dysphagia and a 4.54-kg (10-lb) weight loss over 3 months. He had no nausea, vomiting, abdominal pain, melena, or hematochezia but reported a cough productive of yellow sputum, dyspnea on exertion, and fatigue. The patient had been treated for presumed pneumonia with 3 courses of azithromycin over the prior 3 months due to infiltrates on a chest radiograph. He reported no known ill contacts or recent travel outside the US. At presentation, his heart rate and blood pressure were normal, and oxygen saturation was 95% on room air. Physical examination revealed a maculopapular rash over his neck and chest (Figure, left panel) and bibasilar crackles on lung auscultation. Laboratory testing showed a white blood cell count of 14.3 × 103/μL (reference, 4.2-9.1 × 103/μL); creatine kinase level, 2060 U/L (34.40 μkat/L) (reference, 44-196 U/L [0.73-3.27 μkat/L]), aldolase level, 18 U/L (0.30 μkat/L) (reference, <8 U/L [<0.13 μkat/L]), C-reactive protein level, 30 mg/L (reference, <8 mg/L), and erythrocyte sedimentation rate, 35 mm/h (reference, <20 mm/h). Antinuclear antibody immunofluorescent assay findings were positive. Results from testing for HIV, hepatitis B, and hepatitis C were negative. A barium swallow study showed no visualized aspiration. Endoscopy revealed clean-based esophageal and duodenal ulcers and nonspecific gastritis. Chest computed tomography (CT) showed bibasilar pulmonary consolidations and ground glass opacities (Figure, right panel).Left, Shawl-like rash on patient’s chest. Right, Computed tomography scan of the chest showing bibasilar pulmonary consolidations and ground glass opacities.Prescribe 10 days of prednisone (60 mg daily)

what would you do next?

What would you do next?

Arrange a percutaneous lung tissue biopsy

Check an antisynthetase antibody panel

Perform a quadriceps muscle biopsy

Prescribe 10 days of prednisone (60 mg daily)

b

male

71-80

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2806318

A 15-year-old male presented to the pediatric otolaryngology clinic with dysphagia to solid foods, and dyspnea when lying on the right side that was progressive during 8 months. He denied pain, aspiration, noisy breathing, obstructive episodes, dysphonia, and weight loss.A physical examination revealed fullness in the left oropharynx and left level 3 of the neck. Findings of flexible laryngoscopy showed a submucosal mass in the left oropharynx extending inferiorly into the hypopharynx, obliterating the left pyriform sinus, abutting the base of tongue with hooding over the epiglottis. The supraglottis and glottis were unremarkable. Computed tomography imaging with contrast of the neck revealed a 4.6 × 4.0 × 8.0-cm heterogeneously enhancing mass in the left oropharynx and hypopharynx with cystic components and clear planes separating the mass from the spinal musculature and carotid sheath (Figure 1).Computed tomography imaging with contrast of the neck with the coronal cut demonstrating the well-circumscribed heterogeneous mass involving the retropharyngeal space, abutting the great vessels, and extending from superiorly in the oropharynx to inferiorly in the hypopharynx. What Is Your Diagnosis?

Perineurioma

Fibroblastic lipoblastoma

Pediatric fibromyxoid soft tissue tumor

Schwannoma

C. Pediatric fibromyxoid soft tissue tumor

C

Pediatric fibromyxoid soft tissue tumor

Direct laryngoscopy with an incisional biopsy procedure was performed. The texture of the mass was fibrous, and the color was pale white. Histopathologic analysis demonstrated morphologic features suggestive of perineurioma with immunophenotypic findings of GLUT1+, EMA+, and desmin+ (Figure 2A and B). Molecular sequencing by a targeted gene fusion panel confirmed a PTCH1-PLAG1 fusion (not shown).A, Representative section of the tumor shows variably fibrotic to myxoid mesenchymal tissue in a somewhat plexiform pattern with numerous blood vessels and interspersed fibroblastic cells without substantial atypia or mitotic activity (original magnification ×100). B, Variable immunohistochemical reactivity for desmin, a feature consistent with this unusual tumor type, was also observed.The patient underwent complete surgical excision via external approach. The mass was lateral to the laryngeal cartilages, extending from the thyroid cartilage to the oropharynx. After complete excision, there was a small defect at the intraoral biopsy specimen site, which was closed primarily. A nasogastric tube was placed and the patient received nothing by mouth for 48 hours. A swallow study confirmed no leakage, and the patient advanced his diet without complications. Final pathologic evaluation revealed fibromyxoid tissue without adipose tissue with next-generation sequencing identifying a patched 1 gene (PTCH1)-pleomorphic adenoma gene 1 (PLAG1) fusion.As molecular genetic techniques such as next-generation sequencing panels become more commonly applied, it is becoming clear that many previously unclassified neoplasms have histopathologic findings that allow for identification of unique diagnostic entities. For example, in 2020, the first report of a pediatric fibromyxoid soft tissue tumor with PLAG1 fusion was described by Chung et al.1 They described 3 children with soft tissue tumors displaying purely fibromyxoid histologic results. Each of these cases had positive immunostaining for overexpression of the PLAG1 protein and genetic sequencing demonstrating novel PLAG1 gene fusion partners. Chung et al1 suggested that these unique fusion partners demonstrated a distinct clinical entity, which they proposed naming “pediatric fibromyxoid soft tissue tumor.” The PLAG1 gene has been described in pleomorphic adenoma, myoepithelial tumors, and fibroblastic lipoblastomas.2-4 The absence of a fatty component differentiates lipoblastomas from pediatric fibromyxoid soft tissue tumors.1,5To our knowledge, this is the first reported case of a head and neck location of a pediatric fibromyxoid soft tissue tumor. An important feature of the initial biopsy specimen findings was that although GLUT1 and EMA are suggestive of perineurioma, desmin positivity would be atypical for perineurioma because it is a marker for neoplasms with myogenic differentiation.6 Additionally, PLAG1 fusion and desmin positivity are described in lipoblastoma; however, this patient’s older age and absence of adiposity prompted this specific diagnosis. Although a small number of studies have begun to categorize novel PLAG1 fusion partners in recent years, to our knowledge none have described a PLAG1-PTCH1 fusion such as what we observed in this patient.4,7,8Clinically and pathologically, this is a benign neoplasm; however, surgical excision was indicated because of the progressive airway and swallowing compromise that the patient was experiencing. There is also no long-term data regarding the malignant potential of these tumors; however, this may be confounded by being previously classified under broader nomenclature as “unclassified spindle cell neoplasm.”1 As these evolving histopathologic diagnoses become more well-defined, more studies and longer follow-up will be needed to better understand the clinical course of these tumors.

General

A 15-year-old male presented to the pediatric otolaryngology clinic with dysphagia to solid foods, and dyspnea when lying on the right side that was progressive during 8 months. He denied pain, aspiration, noisy breathing, obstructive episodes, dysphonia, and weight loss.A physical examination revealed fullness in the left oropharynx and left level 3 of the neck. Findings of flexible laryngoscopy showed a submucosal mass in the left oropharynx extending inferiorly into the hypopharynx, obliterating the left pyriform sinus, abutting the base of tongue with hooding over the epiglottis. The supraglottis and glottis were unremarkable. Computed tomography imaging with contrast of the neck revealed a 4.6 × 4.0 × 8.0-cm heterogeneously enhancing mass in the left oropharynx and hypopharynx with cystic components and clear planes separating the mass from the spinal musculature and carotid sheath (Figure 1).Computed tomography imaging with contrast of the neck with the coronal cut demonstrating the well-circumscribed heterogeneous mass involving the retropharyngeal space, abutting the great vessels, and extending from superiorly in the oropharynx to inferiorly in the hypopharynx.

what is your diagnosis?

What is your diagnosis?

Perineurioma

Fibroblastic lipoblastoma

Schwannoma

Pediatric fibromyxoid soft tissue tumor

d

male

11-20

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2806644

A 3-year-old girl with no medical history presented to the emergency department with 1 day of abnormal gait and bilateral mydriasis. Two weeks prior, she had upper respiratory symptoms and bacterial conjunctivitis treated with topical ofloxacin. On examination, pupils were fixed and dilated to 8 mm, extraocular movements were intact, and fundus examination was normal. She had brisk reflexes, poor coordination, and a wide-based unsteady gait. Bloodwork revealed leukocytosis and an elevated erythrocyte sedimentation rate; cultures remained without growth. Lumbar puncture with cerebrospinal fluid studies, computed tomography scan, and magnetic resonance imaging of brain and orbits were normal. The patient was discharged 3 days later following improvement in lethargy and gait with a diagnosis of acute cerebellar ataxia.When she presented to ophthalmology for 1-week follow-up, her visual acuity was central, steady, and maintained in both eyes. She demonstrated sluggish but reactive pupils and new-onset ophthalmoplegia. She was unable to move either eye in any direction, including with doll’s head maneuver. She was readmitted to the hospital and demonstrated diminished reflexes bilaterally and unsteady gait. Repeat magnetic resonance imaging demonstrated diffuse enhancement of the lower thoracic and cauda equina nerve roots and enhancement of the left oculomotor nerve (Figure).Magnetic resonance imaging of the spine (A) showing diffuse enhancement of the lower thoracic and equina nerve roots and of the brain (B) showing asymmetric enhancement of the left oculomotor nerve (arrowhead).Order anti-GQ1b antibody and start intravenous immune globulin What Would You Do Next?

Repeat blood cultures and start antibiotics

Repeat lumbar puncture with cerebrospinal fluid studies

Order anti-GQ1b antibody and start intravenous immune globulin

Start intravenous corticosteroids

Miller Fisher syndrome

C

Order anti-GQ1b antibody and start intravenous immune globulin

Miller Fisher syndrome is a rare, acute, and self-limited disorder that is considered a variant of Guillain-Barré syndrome. While the exact pathophysiology is unknown, it is thought to be an inappropriate autoimmune response to a preceding infection caused by molecular mimicry of viral components to peripheral nerve antigens. It presents with a clinical triad of ophthalmoplegia, ataxia, and areflexia.1 Bilateral mydriasis is frequently present in typical Miller Fisher syndrome cases, but an initial presentation with bilateral mydriasis as the only symptom has rarely been reported.2 Other atypical symptoms could include headache, facial palsy, taste impairment, tachycardia, and hypertension.3,4Miller Fisher syndrome is typically associated with infectious etiologies. The most common bacterial pathogen is Campylobacter jejuni, followed by Haemophilus influenzae.5 Viral cases have been reported with Epstein-Barr virus, influenza virus, HIV, and varicella-zoster virus.5 Autoimmune and neoplastic etiologies have rarely been reported,1,6 as well as cases following vaccinations.7Imaging is important to rule out other possible diagnoses, such as brainstem abnormalities or compressive lesions.2 Magnetic resonance imaging results of the brain are usually normal, but there can be enhancement of the cranial or spinal nerve roots.8 Workup should include lumbar puncture with cerebrospinal fluid analysis to assure the absence of an infectious etiology for symptoms. Cerebrospinal fluid analysis can be normal or can indicate high protein with low white blood cell counts (albuminocytologic dissociation).4 In this case, the patient had previously had an extensive workup, including blood cultures (choice A) and lumbar puncture with cerebrospinal fluid studies (choice B), which were unrevealing. Given there were no additional symptoms suggesting an infectious etiology, these tests were of low utility.The most likely diagnosis at this time was Miller Fisher syndrome, the most appropriate next step would be to order the associated antibody and start intravenous immune globulin (choice C). The anti-GQ1b antibody is detected in the serum and has an 80% to 90% sensitivity for this condition.4,8 In practice, it may take several days to weeks following serum collection for the laboratory to process, so if the patient is clinically presenting with this syndrome, then intravenous immune globulin should be started prior to the official laboratory result. This laboratory test is not necessary for diagnosing the disease but can be helpful in narrowing a diagnosis. Generally, this condition is self-limited with a good prognosis, and recurrence is rare. Patients are typically treated with intravenous immune globulin or, less preferably, plasmapheresis. There is no proven improvement in overall prognosis, but it does shorten the time to recovery compared to supportive care alone.9 Starting steroids (choice D) is not an appropriate option as steroids are no longer recommended, given they do not hasten recovery or prove effective for this condition.10The patient was treated with 2 doses of intravenous immune globulin prior to discharge. Anti-GQ1b antibodies were positive with a 1:400 titer. She presented to the ophthalmology clinic 3 months later. At that time, extraocular movements were full without strabismus. Pupils remained dilated at 6.5 mm in the dark but were mildly reactive to 5.5 mm in the light. Visual acuity was 20/25 and 20/20 in the right and left eyes, respectively. Neurologically, the patient was nearly at her baseline with normal reflexes and gait.

Ophthalmology

A 3-year-old girl with no medical history presented to the emergency department with 1 day of abnormal gait and bilateral mydriasis. Two weeks prior, she had upper respiratory symptoms and bacterial conjunctivitis treated with topical ofloxacin. On examination, pupils were fixed and dilated to 8 mm, extraocular movements were intact, and fundus examination was normal. She had brisk reflexes, poor coordination, and a wide-based unsteady gait. Bloodwork revealed leukocytosis and an elevated erythrocyte sedimentation rate; cultures remained without growth. Lumbar puncture with cerebrospinal fluid studies, computed tomography scan, and magnetic resonance imaging of brain and orbits were normal. The patient was discharged 3 days later following improvement in lethargy and gait with a diagnosis of acute cerebellar ataxia.When she presented to ophthalmology for 1-week follow-up, her visual acuity was central, steady, and maintained in both eyes. She demonstrated sluggish but reactive pupils and new-onset ophthalmoplegia. She was unable to move either eye in any direction, including with doll’s head maneuver. She was readmitted to the hospital and demonstrated diminished reflexes bilaterally and unsteady gait. Repeat magnetic resonance imaging demonstrated diffuse enhancement of the lower thoracic and cauda equina nerve roots and enhancement of the left oculomotor nerve (Figure).Magnetic resonance imaging of the spine (A) showing diffuse enhancement of the lower thoracic and equina nerve roots and of the brain (B) showing asymmetric enhancement of the left oculomotor nerve (arrowhead).Order anti-GQ1b antibody and start intravenous immune globulin

what would you do next?

What would you do next?

Start intravenous corticosteroids

Repeat lumbar puncture with cerebrospinal fluid studies

Order anti-GQ1b antibody and start intravenous immune globulin

Repeat blood cultures and start antibiotics

c

female

0-10

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2806274

A 46-year-old man presented with a left shoulder mass. It began with a quarter-size maculopapular lesion and continued to progress during the next 3 years. He reported limited shoulder movements and denied other symptoms. There was no medical or surgical history, and he had a negative personal or familial oncologic history. The patient was a construction worker and used tobacco daily. On physical examination, there was a 24 × 15-cm fungating, necrotic, and ulcerated left shoulder mass (Figure 1A). A punch biopsy showed sheets of highly pleomorphic atypical spindle and epithelial cells within the superficial and deep dermis, extending into the subcutaneous tissue, and with 18 mitoses/mm2. Immunohistochemistry demonstrated SOX10-positive and pankeratin-negative tumor cells. A whole-body positron emission tomographic and computed tomographic scan revealed an intensely hypermetabolic left shoulder mass and multiple hypermetabolic enlarged left axillary lymph nodes, with no distant metastases (Figure 1B). Brain magnetic resonance imaging was negative for intracranial metastasis.A, Left shoulder giant fungating mass in a 46-year-old man. B, Positron emission tomographic and computed tomographic (PET-CT) scan shows the hypermetabolic left shoulder mass and no distant metastases. What Is Your Diagnosis?

Squamous cell carcinoma

Basal cell carcinoma

Melanoma

Merkel cell carcinoma

C. Melanoma

C

Melanoma

The biomarker SOX10 is highly sensitive and specific in diagnosing melanoma,1 in conjunction with histologic findings and negative keratin staining, making melanoma the most likely diagnosis. Mutational testing revealed no BRAF or other sequence variations. An outside hospital staged the patient’s melanoma as cT4bN2bM0 (stage IIIC) and recommended a clinical trial of pembrolizumab plus cabozantinib for unresectable melanoma. After 10 cycles of treatment, there was continued local progression but slightly decreased uptake on a positron emission tomographic and computed tomographic scan. The patient then received weekly local immunotherapy with talimogene laherparepvec injections in the later course for 6 weeks with further progression. The patient presented to our center for a second opinion before proceeding with palliative radiotherapy.Although radiotherapy has beneficial outcomes in adjuvant and palliative settings,2,3 our multidisciplinary team recommended resection and reconstruction, followed by adjuvant therapy. The patient underwent left shoulder mass radical resection, including muscles, partial scapulectomy, left complete axillary lymph node dissection, and immediate lymphatic reconstruction (a microsurgical technique to reconnect lymphatics after nodal dissection to lower the risk of lymphedema). The muscles were imbricated over the pared-down scapular spine, and a collagen glycosaminoglycan dermal substitute was placed. Reconstruction was completed with a split-thickness skin graft. Surgical pathologic findings revealed invasive melanoma involving adjacent skeletal muscles, and it was 22.2 cm in its greatest dimension. All 33 resected axillary lymph nodes were normal, with no evidence of previously treated melanoma (ypT4bN0M0). Two years after resection, he had a well-healed skin graft with full range of motion and no evidence of lymphedema, and he returned to work in construction (Figure 2). He completed 1 year of adjuvant pembrolizumab therapy with no adverse events; his most recent systemic imaging showed no evidence of disease.Two years after radical left shoulder mass resection and reconstruction with collagen glycosaminoglycan dermal substitute followed by split-thickness skin graft.Locally advanced fungating melanomas are rare, and the anatomical location and size can pose challenges in management. There are case reports of fungating melanomas, mainly in the upper and lower extremities, and the treatment plans and outcomes varied in these cases.4,5 In the present case, because of the lack of surgical evaluation on initial presentation at the outside hospital, possible curative resection and nodal evaluation were not performed promptly. The patient did not have good clinical response to pembrolizumab plus cabozantinib in the trial; however, the subsequent imaging showed reduced uptake in the mass and axillary nodes. On histologic results, the left axillary lymph nodes were pathologically enlarged, but no pathologic metastases were observed; rather, there were reactive lymph nodes. A possible explanation is that there might never have been metastases in the axillary lymph nodes, and an initial axillary biopsy could have been pursued. Another theory could be that there was pathologic response. The original clinical trial could be considered as neoadjuvant therapy after our resection, and the treatment plan could have been further tailored on the basis of index lymph node response in the light of the PRADO (Personalized Response-Directed Surgery and Adjuvant Therapy After Neoadjuvant Ipilimumab and Nivolumab in High-Risk Stage III Melanoma) trial results.6-8 In addition, there are emerging clinical data on neoadjuvant treatments for advanced melanoma.9,10 The SWOG (Southwest Oncology Group) S1801 study, a phase 2 trial, reported that neoadjuvant pembrolizumab therapy improved event-free survival compared with standard adjuvant pembrolizumab therapy in high-risk resectable melanomas.10In conclusion, this educational case challenge demonstrates a rare presentation of a common malignant tumor. Multidisciplinary discussion is crucial for solidifying the best therapeutic options for patients with advanced melanomas. Surgical evaluation and lymph node pathologic information are crucial to tailor the plan.

Oncology

A 46-year-old man presented with a left shoulder mass. It began with a quarter-size maculopapular lesion and continued to progress during the next 3 years. He reported limited shoulder movements and denied other symptoms. There was no medical or surgical history, and he had a negative personal or familial oncologic history. The patient was a construction worker and used tobacco daily. On physical examination, there was a 24 × 15-cm fungating, necrotic, and ulcerated left shoulder mass (Figure 1A). A punch biopsy showed sheets of highly pleomorphic atypical spindle and epithelial cells within the superficial and deep dermis, extending into the subcutaneous tissue, and with 18 mitoses/mm2. Immunohistochemistry demonstrated SOX10-positive and pankeratin-negative tumor cells. A whole-body positron emission tomographic and computed tomographic scan revealed an intensely hypermetabolic left shoulder mass and multiple hypermetabolic enlarged left axillary lymph nodes, with no distant metastases (Figure 1B). Brain magnetic resonance imaging was negative for intracranial metastasis.A, Left shoulder giant fungating mass in a 46-year-old man. B, Positron emission tomographic and computed tomographic (PET-CT) scan shows the hypermetabolic left shoulder mass and no distant metastases.

what is your diagnosis?

What is your diagnosis?

Squamous cell carcinoma

Melanoma

Basal cell carcinoma

Merkel cell carcinoma

b

male

41-50

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2806495

A 68-year-old man with a remote history of B-cell lymphoma and active renal cell carcinoma (RCC), receiving cabozantinib therapy, was referred for worsening hazy vision in the right eye after recent outside retinal detachment (RD) repair of the left eye, with pars plana vitrectomy and gas. The patient noted blurry vision started around the time of cabozantinib therapy initiation. Cabozantinib therapy was discontinued for surgery and resumed 3 days later. The referring retina specialist noted vitritis and vasculitis intraoperatively, but the result of vitreous biopsy cytology was negative for malignant cells.At presentation to our institution, the patient was taking oral prednisone, 40 mg/d. His visual acuity was 20/500 OD and hand motions OS, with an intraocular pressure of 18 mm Hg in both eyes. Right eye slitlamp examination results showed pigmented cells in the anterior chamber and lens capsule; the left eye showed prolapsed pigmented vitreous at the pupillary margin. Right eye fundus examination results revealed sheets of pigmented cell and vascular sheathing with optic nerve pallor. The left eye had a poor view, with 90% gas fill. Fluorescein angiography illustrated disc and vessel leakage (predominantly arteriole), capillary dropout, and peripheral nonperfusion in the right eye (Figure 1A) with no view in the left eye. Optical coherence tomography revealed debris at the vitreoretinal interface (Figure 1B).Fluorescein angiography and optical coherence tomography on presentation demonstrate retinal vasculitis and vitritis (right eye results shown). A, Fluorescein angiography shows dense vitritis, predominantly arteriole leakage (arrowheads), and nonperfusion. Inset is a magnified view, with arrowheads pointing to arteriole leakage. B, Optical coherence tomography shows disorganization of the outer retina with debris at the vitreoretinal interface (arrowheads).Vitreous tap and inject intravitreal foscarnet, vancomycin, and ceftazidimeMagnetic resonance imaging of the orbits followed by lumbar puncture What Would You Do Next?

Vitreous tap and inject intravitreal foscarnet, vancomycin, and ceftazidime

Stop prednisone and proceed with diagnostic vitrectomy

Stop cabozantinib and admit for intravenous solumedrol

Magnetic resonance imaging of the orbits followed by lumbar puncture

Renal cell carcinoma bilateral ocular metastasis

B

Stop prednisone and proceed with diagnostic vitrectomy

Given the patient’s history of B-cell lymphoma and active RCC, recurrent lymphoma or metastatic RCC must be ruled out. Thus, prednisone therapy was stopped, and the patient underwent diagnostic vitrectomy (choice B). Renal cell carcinoma is an uncommon tumor from the renal cortex, accounting for approximately 2% of systemic malignant tumors.1 Renal cell carcinoma most commonly metastasizes to the lung, bone, liver, and brain,2 and it rarely metastasizes to orbital or intraocular tissue, with fewer than 80 cases reported in the literature.1Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of metastatic RCC. There have been 3 case reports of cabozantinib causing cutaneous vasculitis but no reported ocular adverse effects.3-5 Tyrosine kinase inhibitor–associated retinal vasculitis would be a diagnosis of exclusion. If a subsequent biopsy result is negative, then it is appropriate to stop cabozantinib therapy and consider intravenous corticosteroids (choice C). The patient’s examination findings and clinical history (no hypopyon, lack of pain, and nonseptic appearance) make infectious endophthalmitis less likely (choice A). If ocular metastasis is diagnosed, obtaining a magnetic resonance image of the orbit followed by a lumbar puncture (choice D) may be a necessary next step to evaluate for brain metastasis.The most common cause of malignant intraocular tumors in adults is metastases from systemic malignant tumors. Choroidal metastases of RCC are typically dome shaped and yellow on examination, although some RCC metastases may appear reddish orange due to the high vascularity. In a review of 68 cases of ocular metastases of RCC, 50% had extraocular involvement and 50% were intraocular.1 The most frequently involved site was the orbit (36.8%), followed by the choroid (29.4%), and RCC metastases were predominantly unilateral, with only 4 bilateral reported cases.1 There is a single report in the literature of unilateral RCC ocular metastasis presenting as vitritis with no retinal or choroidal mass,6 although retinal metastasis presenting as retinal vascular sheathing and retinitis has been reported previously in other solid organ tumors.7The patient’s diagnostic vitrectomy confirmed RCC metastasis in the vitreous. The patient then developed an RD in the right eye and a redetached left eye. He underwent bilateral sequential RD repair and subsequent diagnostic vitrectomy, with aqueous and retinal biopsy of the left eye. The biopsy results demonstrated malignant cells positive for RCC (Figure 2). The patient underwent palliative radiotherapy to the orbits, but due to continued disease progression, he passed away shortly thereafter.Full-thickness retinal biopsy specimen from the left eye, with immunohistochemistry positive for CK7 (pictured with arrowheads) and PAX8 and negative for CK20 and TTF1, pointing to renal cell carcinoma metastasis (arrowheads).To our knowledge, this is the first reported case of RCC ocular metastases with aqueous and retinal biopsies and positive bilateral vitreous biopsy results. The patient initially presented with “retinal vasculitis” and panuveitis after RD repair; however, it is possible that the sclerotic vessels were a result of metastatic cellular intravascular deposits causing occlusive disease and severe nonperfusion. Metastatic RCC is a highly vascular tumor type—due to both the overproduction of vascular endothelial growth factor and other proangiogenic cytokines6 and alterations in the von Hippel–Lindau tumor suppressor gene.8 Renal cell carcinoma is metastatic in 30% of patients,9 and it portends a poor prognosis, with a median survival of approximately 13 months and a 5-year survival of less than 10%.10

Ophthalmology

A 68-year-old man with a remote history of B-cell lymphoma and active renal cell carcinoma (RCC), receiving cabozantinib therapy, was referred for worsening hazy vision in the right eye after recent outside retinal detachment (RD) repair of the left eye, with pars plana vitrectomy and gas. The patient noted blurry vision started around the time of cabozantinib therapy initiation. Cabozantinib therapy was discontinued for surgery and resumed 3 days later. The referring retina specialist noted vitritis and vasculitis intraoperatively, but the result of vitreous biopsy cytology was negative for malignant cells.At presentation to our institution, the patient was taking oral prednisone, 40 mg/d. His visual acuity was 20/500 OD and hand motions OS, with an intraocular pressure of 18 mm Hg in both eyes. Right eye slitlamp examination results showed pigmented cells in the anterior chamber and lens capsule; the left eye showed prolapsed pigmented vitreous at the pupillary margin. Right eye fundus examination results revealed sheets of pigmented cell and vascular sheathing with optic nerve pallor. The left eye had a poor view, with 90% gas fill. Fluorescein angiography illustrated disc and vessel leakage (predominantly arteriole), capillary dropout, and peripheral nonperfusion in the right eye (Figure 1A) with no view in the left eye. Optical coherence tomography revealed debris at the vitreoretinal interface (Figure 1B).Fluorescein angiography and optical coherence tomography on presentation demonstrate retinal vasculitis and vitritis (right eye results shown). A, Fluorescein angiography shows dense vitritis, predominantly arteriole leakage (arrowheads), and nonperfusion. Inset is a magnified view, with arrowheads pointing to arteriole leakage. B, Optical coherence tomography shows disorganization of the outer retina with debris at the vitreoretinal interface (arrowheads).Vitreous tap and inject intravitreal foscarnet, vancomycin, and ceftazidimeMagnetic resonance imaging of the orbits followed by lumbar puncture

what would you do next?

What would you do next?

Magnetic resonance imaging of the orbits followed by lumbar puncture

Vitreous tap and inject intravitreal foscarnet, vancomycin, and ceftazidime

Stop cabozantinib and admit for intravenous solumedrol

Stop prednisone and proceed with diagnostic vitrectomy

d

male

61-70

original

https://jamanetwork.com/journals/jama/fullarticle/2807531

A 67-year-old man with thoracolumbar scoliosis, poor mobility, and history of frequent falls presented to the emergency department with 2 months of left shoulder pain, stiffness and reduced range of motion, and numbness and paresthesias in his left upper extremity. Ten years prior to presentation, he underwent surgical decompression for syringomyelia. A magnetic resonance imaging (MRI) scan of his cervical and thoracic spine performed 2 years prior to presentation revealed a recurrent syrinx extending from C1 to T11, which was not resected because it did not cause symptoms at that time. On physical examination, he had mild tenderness to palpation and reduced range of motion of the left shoulder with abduction and flexion limited to 120° (normal range of motion, 180°). The left scapular muscles were atrophic, and pain and temperature sensation were reduced in his proximal left arm, and dorsal aspect of his left shoulder. His complete blood cell count, serum glucose levels, C-reactive protein levels, and erythrocyte sedimentation rate were normal. Results of tests for rheumatoid factor and antinuclear antibody were negative. Left shoulder radiograph showed complete absence of the left humeral head and a well-demarcated smooth osseous margin of the proximal humerus with associated soft tissue swelling and periarticular calcification (Figure 1). A chest radiograph taken 2 years prior revealed a normal left shoulder joint. The patient was hospitalized for further evaluation and treatment.Anteroposterior radiograph of the patient’s left shoulder demonstrating complete destruction of the proximal humeral head. What Would You Do Next?

Obtain MRI of the left shoulder

Order serum tumor marker testing

Orthopedic surgery evaluation for shoulder replacement surgery

Perform an urgent left shoulder joint aspiration

Neuropathic arthropathy of the shoulder (Charcot shoulder)

A

Obtain MRI of the left shoulder

The key to the correct diagnosis of neuropathic arthropathy of the shoulder is the radiographic finding of an absent left humeral head in a patient with a history of syringomyelia. Choices B and D are incorrect because the well-defined linear margins of the proximal humerus made septic arthritis or osteolysis due to malignancy unlikely. Shoulder replacement surgery (choice C) is not recommended for most patients with Charcot shoulder.Neuropathic arthropathy of the shoulder joint, also known as Charcot shoulder, is a rare progressive disorder characterized by rapid joint destruction and associated soft tissue swelling.1,2 Patients typically present with gradually increasing shoulder swelling, which may or may not be painful, weakness in the shoulder, and decreased range of motion of the shoulder. Patients may report paresthesias or numbness in the affected upper extremity.1,2 Approximately 80% of people with Charcot shoulder have syringomyelia, characterized by a fluid-filled cavity (syrinx) in the spinal cord.2 Other conditions associated with Charcot shoulder include diabetes, syphilis, alcohol use disorder, Arnold-Chiari malformations, cervical spondylosis, amyloidosis, end-stage kidney disease, myelodysplasia, multiple sclerosis, peripheral neuropathy, intra-articular steroid injection, tuberculosis, leprosy (Hansen disease), and gigantism.2-4Syringomyelia may be congenital or secondary to trauma, infection, tumors, vascular abnormalities, or spinal degeneration.4 As it expands, a syrinx damages spinothalamic tract fibers and may compress dorsal column and anterior horn cells, resulting in loss of sensation of pain and temperature, decreased muscle strength, muscle atrophy, and arreflexia.5,6 Approximately 6% of patients with syringomyelia develop Charcot shoulder, and 80% have involvement of only 1 joint.1,6The pathophysiology of neuropathic arthropathy, such as Charcot shoulder, is incompletely understood. A syrinx may decrease shoulder joint sensory innervation, leading to loss of somatic muscle reflexes that protect the joint from injury, resulting in recurrent subclinical trauma that causes inflammation and progressive shoulder joint destruction.2,6 A syrinx may also cause loss of autonomic vascular control, increasing blood flow to the joint, and activating osteoclasts, which results in accelerated bone resorption.1,7Patients with Charcot shoulder may have atrophic changes on radiographs, consisting of substantial bone resorption or shoulder joint destruction, and hypertrophic reactions, with osteophytes, sclerosis, and accumulation of osseous debris.2 MRI of the shoulder can confirm the presence of Charcot shoulder and facilitates assessments for other associated conditions, such as rotator cuff tear.2The diagnosis of Charcot shoulder should be made only after exclusion of other causes of joint destruction, including septic arthritis, osteolytic lesions from malignancy, rheumatoid arthritis, synovial chondromatosis, trauma, soft tissue sarcoma, and Milwaukee shoulder syndrome, a destructive arthropathy caused by deposition of hydroxyapatite crystals.1,3Upon diagnosis of Charcot shoulder, the underlying cause should be identified and treated, in an attempt to slow or halt further joint destruction. Surgical resection of a syrinx in patients with Charcot shoulder due to syringomyelia may slow joint deterioration and improve neurologic symptoms.2 Treatments for Charcot shoulder include nonsteroidal anti-inflammatory medications, joint aspiration if an effusion is present, patient education about avoidance of mechanical trauma, physical therapy, and rehabiliation.1-3 Shoulder surgery is not typically recommended, but may be considered for a subset of patients with Charcot shoulder who do not improve with nonoperative management.2,7The patient was treated with acetaminophen (paracetamol), topical nonsteroidal anti-inflammatory drugs, and short-acting opioids as needed. MRI showed destructive osteolysis of the left humeral head with well-defined, linearly demarcated margins of the proximal humerus with surrounding osseous debris and a moderate glenohumeral joint effusion (Figure 2). After consultation by clinicians in neurosurgery, orthopedic surgery, geriatrics, and radiology, the patient was advised to undergo intensive physical and occupational therapy. After 4 weeks of inpatient physical therapy 5 days per week, his left shoulder pain resolved, and left shoulder flexion and abduction was 160° to 170°. At his most recent outpatient clinic visit, 3 months after hospital discharge, the patient reported no left shoulder pain and had no change in shoulder range of motion. A follow up radiograph revealed a slight decrease in the left glenohumeral effusion.T1-weighted MRI of the left shoulder showing destructive osteolysis of the left proximal humeral head with clear linear margins and associated joint effusion.

General

A 67-year-old man with thoracolumbar scoliosis, poor mobility, and history of frequent falls presented to the emergency department with 2 months of left shoulder pain, stiffness and reduced range of motion, and numbness and paresthesias in his left upper extremity. Ten years prior to presentation, he underwent surgical decompression for syringomyelia. A magnetic resonance imaging (MRI) scan of his cervical and thoracic spine performed 2 years prior to presentation revealed a recurrent syrinx extending from C1 to T11, which was not resected because it did not cause symptoms at that time. On physical examination, he had mild tenderness to palpation and reduced range of motion of the left shoulder with abduction and flexion limited to 120° (normal range of motion, 180°). The left scapular muscles were atrophic, and pain and temperature sensation were reduced in his proximal left arm, and dorsal aspect of his left shoulder. His complete blood cell count, serum glucose levels, C-reactive protein levels, and erythrocyte sedimentation rate were normal. Results of tests for rheumatoid factor and antinuclear antibody were negative. Left shoulder radiograph showed complete absence of the left humeral head and a well-demarcated smooth osseous margin of the proximal humerus with associated soft tissue swelling and periarticular calcification (Figure 1). A chest radiograph taken 2 years prior revealed a normal left shoulder joint. The patient was hospitalized for further evaluation and treatment.Anteroposterior radiograph of the patient’s left shoulder demonstrating complete destruction of the proximal humeral head.

what would you do next?

What would you do next?

Perform an urgent left shoulder joint aspiration

Orthopedic surgery evaluation for shoulder replacement surgery

Order serum tumor marker testing

Obtain MRI of the left shoulder

d

male

61-70

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2806695

A woman in her early 40s, gravida 3, para 3, with a history of migraines and recurrent preeclampsia and who was 11 weeks post partum presented with acute pleuritic chest pain, shortness of breath, and nausea that started several hours after a flight from Florida to New York City. She was noted to have tachycardia (110 beats/min) and hypoxemia (90% receiving room air) with a blood pressure of 106/81 mm Hg. Cardiac, respiratory, and pulse examination results were unremarkable. She denied any clear physical or emotional triggers preceding presentation. Before presentation, the patient reported good health with satisfactory employment-mandated routine physical examinations. She denied a history of smoking, alcohol, or illicit drug use. She was not taking hormonal birth control or hormone therapy. Laboratory values demonstrated a normal complete blood cell count and metabolic panel. Chest radiograph results were unremarkable. A computed tomographic chest scan excluded pulmonary embolism but suggested pulmonary and interstitial edema. Results of an electrocardiogram revealed sinus tachycardia with premature ventricular contractions, subcentimeter ST-segment elevation in leads I and aVL and 1-mm ST-segment depression in leads II, III, aVF, and V5 through V6. Initial high-sensitivity troponin was 110 000 ng/mL (to convert to micrograms per liter, multiply by 1). Results of cardiac point-of-care ultrasonography demonstrated a severely reduced left ventricular ejection fraction of 40%, with hypokinesis of the anterolateral and posterior walls. Emergent cardiac catheterization revealed spontaneous coronary artery dissection (SCAD) of the left main coronary artery (Figure 1 and Video).Angiographic image of left main spontaneous coronary artery dissection (A) and intravascular ultrasonography image of left main spontaneous coronary artery dissection (B). What Would You Do Next?

Observation

Medical management

Percutaneous coronary intervention

Coronary artery bypass grafting

Spontaneous coronary artery dissection of the left main coronary artery

C

Percutaneous coronary intervention

SCAD has been increasingly recognized as an important cause of acute coronary syndromes, especially in young healthy women without traditional cardiovascular risk factors. The prevalence of SCAD is approximately 0.5% of patients who present with acute coronary syndromes.1 Extracoronary fibromuscular dysplasia (FMD), depression, rheumatoid arthritis, anxiety, genetic disorders, peripartum, and migraine disorder are associated with SCAD.2,3 Genetic disorders, peripartum SCAD, and FMD were independent predictors of 3-year adverse cardiac events.4 Although mortality is low, one-fourth of patients with SCAD had recurrent SCAD.There are important educational points from this case. First, in experienced, high-volume centers, percutaneous coronary intervention (PCI) is safe in selected patients with SCAD with high-risk features. Conservative therapy may not be appropriate in patients with SCAD with high-risk features including ongoing ischemia, left main artery dissection, or hemodynamic instability.5 In the 2 largest SCAD registries, PCI was appropriate and safe for patients with SCAD with high-risk features such as cardiogenic shock, active/ongoing ischemia, hemodynamic instability, ventricular arrhythmias, ST-segment elevation myocardial infarction, and high-risk anatomy.4,5 The role of intracoronary imaging is crucial to ensure that the wire is in the true lumen distally and to ensure that the stent covers the entire intramural hematoma. Coronary artery bypass grafting (CABG) should also be considered when PCI is technically challenging or has been attempted and unsuccessful.6,7 Given the clinical scenario and angiographical features in this case, the decision was made to pursue revascularization, and PCI with a drug-eluting stent was successfully performed.Second, we demonstrated that radial approach is safe for patients with SCAD. In a meta-analysis of undergoing PCI, radial access was associated with a significant risk reduction in bleeding, vascular complications, and mortality compared with femoral access.8 There are no data comparing radial vs femoral access in the subgroup of patients with SCAD undergoing PCI, particularly peripartum SCAD. Theoretically, femoral access could potentially cause more complications and bleeding due to its association with kidney FMD and arteriopathies compared with radial access.Third, pregnancy should be considered a high-risk feature in patients with SCAD. It has been hypothesized that hormonal changes and hemodynamic variations might be significant contributors to SCAD in pregnant patients by alterations in the architecture of the arterial wall, but the cause is unknown. Investigators suggested that unsuccessful PCI was common for SCAD in pregnant individuals (35%).5 Three patients subsequently underwent CABG due to unsuccessful PCI, and 1 had CABG because of SCAD progression despite conservative management.5Once SCAD is diagnosed, screening for FMD is needed.4 Post PCI, lifelong low-dose aspirin is recommended. Other antiplatelet agents and duration of dual antiplatelet therapy after PCI is primarily tailored individually based on the location of SCAD, the number and size of stents used, etc. β-Blockers and cardiac rehabilitation are recommended in patients with SCAD; statins and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers may be considered selectively when other clinical indications exist. Management of SCAD in pregnant patients can be challenging, particularly when the dissection involves the left main coronary artery. PCI performed at an experienced center can offer a good outcome for selected patients. Further study is needed to identify whether recurrent preeclampsia is a risk factor for SCAD in pregnant patients.The patient underwent PCI of the left main successfully without complications (Figure 2). The patient recovered well after PCI and returned safely to her hometown to undergo further evaluation for FMD and connective tissue disorders.Angiographic image of left main coronary artery after percutaneous coronary intervention.

Cardiology

A woman in her early 40s, gravida 3, para 3, with a history of migraines and recurrent preeclampsia and who was 11 weeks post partum presented with acute pleuritic chest pain, shortness of breath, and nausea that started several hours after a flight from Florida to New York City. She was noted to have tachycardia (110 beats/min) and hypoxemia (90% receiving room air) with a blood pressure of 106/81 mm Hg. Cardiac, respiratory, and pulse examination results were unremarkable. She denied any clear physical or emotional triggers preceding presentation. Before presentation, the patient reported good health with satisfactory employment-mandated routine physical examinations. She denied a history of smoking, alcohol, or illicit drug use. She was not taking hormonal birth control or hormone therapy. Laboratory values demonstrated a normal complete blood cell count and metabolic panel. Chest radiograph results were unremarkable. A computed tomographic chest scan excluded pulmonary embolism but suggested pulmonary and interstitial edema. Results of an electrocardiogram revealed sinus tachycardia with premature ventricular contractions, subcentimeter ST-segment elevation in leads I and aVL and 1-mm ST-segment depression in leads II, III, aVF, and V5 through V6. Initial high-sensitivity troponin was 110 000 ng/mL (to convert to micrograms per liter, multiply by 1). Results of cardiac point-of-care ultrasonography demonstrated a severely reduced left ventricular ejection fraction of 40%, with hypokinesis of the anterolateral and posterior walls. Emergent cardiac catheterization revealed spontaneous coronary artery dissection (SCAD) of the left main coronary artery (Figure 1 and Video).Angiographic image of left main spontaneous coronary artery dissection (A) and intravascular ultrasonography image of left main spontaneous coronary artery dissection (B).

what would you do next?

What would you do next?

Percutaneous coronary intervention

Coronary artery bypass grafting

Medical management

Observation

a

female

41-50

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2806311

A man in his 60s presented to our clinic with a 5-year history of diffuse erythematous, edematous annular plaques (Figure 1); low-grade fevers; and mild leukopenia. The result of a skin biopsy performed 4 years prior was interpreted as subacute cutaneous lupus erythematosus (SCLE). Treatments included hydroxychloroquine, 400 mg/d, for 4 years; mycophenolate mofetil, 1000 mg/d, for 6 months; and oral prednisone tapers, starting at 40 mg/d. Of these, only prednisone appeared to elicit a response. Review of symptoms was negative for fatigue, weight loss, cough, shortness of breath, joint pain, ocular symptoms, mucosal ulcerations, history of blood clots, photosensitivity, pleurisy, urine changes, and diarrhea. Medical history included hypertension, for which he took losartan, and seasonal allergies, for which he used fexofenadine and fluticasone. Laboratory evaluation revealed mild neutropenia and lymphopenia with normal hemoglobin and platelet counts. Antinuclear antibody screening results were negative. The results of a comprehensive metabolic panel, C3, C4, serum protein electrophoresis, serum free light chains, methylmalonic acid, homocysteine, ferritin, copper, zinc, haptoglobin, HIV, hepatitis B and C serologic tests, and rapid plasma reagin were negative. Lactate dehydrogenase was mildly elevated. Erythrocyte sedimentation rate was elevated at 41 mm/h. Routine cancer screening was up to date. Therapeutic trials of dapsone and dapsone in combination with colchicine were not effective. What Is Your Diagnosis?

Drug-induced SCLE

VEXAS syndrome

Histiocytoid Sweet syndrome

Halogenoderma

B. VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome

B

VEXAS syndrome

Subsequent skin biopsy results (Figure 2A) revealed subepidermal clefting; a superficial and deep perivascular, interstitial, and periadnexal infiltrate of lymphocytes; and myeloperoxidase- and CD68-positive immature nonblastic myeloid and histiocytic cells.A, Hematoxylin-eosin, original magnification ×200. B, Aspirate smear (Wright-Giemsa, original magnification ×630).Because of the lack of response to therapy, the possibility of myelodysplasia, and diagnostic uncertainty, a bone marrow biopsy specimen was obtained (Figure 2B), which revealed normocellular marrow with cytoplasmic vacuoles in the myeloid and erythroid precursors. Molecular diagnostics revealed a somatic variant in UBA1 (GenBank 7317) p.M41L, diagnostic of VEXAS syndrome.VEXAS syndrome is an acquired, autoinflammatory disorder caused by a somatic variant of the X-linked UBA1 gene.1 The UBA1 gene encodes E1, a master enzyme of cellular ubiquination.2 The variant occurs at p.Met41, within the translation initiation codon, which leads to loss of the normally active cytoplasmic isoform, UBA1b, and development of an enzymatically impaired, novel isoform, UBA1c.2 Impaired cellular ubiquitination activates the unfolded protein response and ultimately upregulates type 1 interferons.3 Three amino acid substitutions have been described: threonine, valine, and leucine.4 The amino acid substitution portends disease phenotype and prognosis.2,5 VEXAS syndrome has predominantly been described in men aged 55 to 65 years, although women with monosomy X have also been reported.4-6 A recent observational study suggests VEXAS syndrome prevalence is 1 in 13 591 individuals.6 Patients typically present with fever, skin lesions (usually neutrophilic dermatosis), and hematologic abnormalities (eg, macrocytic anemia and thrombocytopenia). Additional signs of inflammation (eg, arthritis, pulmonary infiltrates, venous thrombosis, chondritis, periorbital edema, vasculitis, uveitis, episcleritis, and hearing loss) are frequently reported, as are elevated inflammatory markers.1,2,4-7 Biopsy specimens of skin manifestations typically reveal superficial dermal infiltration of immature nonblastic myeloid cells, histiocytes, and lymphocytes.7 Bone marrow biopsy reveald hypercellular marrow with cytoplasmic vacuoles in the myeloid and erythroid precursors. Most patients develop myelodysplastic syndrome (MDS), monoclonal gammopathy of unknown significance, or multiple myeloma. Patients with VEXAS syndrome often meet criteria for other autoimmune diseases, specifically Sweet syndrome, polyarteritis nodosa, relapsing polychondritis, and granulomatosis with polyangiitis.1 Classically, these patients do not respond as expected to standard-of-care therapies and are dependent on systemic corticosteroid therapy. Dapsone, colchicine, hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil, tumor necrosis factor inhibitors, anakinra, and Janus kinase inhibitors (with the exception of ruxolitinib in patients with VEXAS syndrome with MDS) have been reported as ineffective therapies.4 Tocilizumab may have steroid-sparing effects.4 Patients who develop high-risk MDS have been treated with azacitidine and stem cell transplant.4 VEXAS syndrome is a highly morbid disease, with mortality of approximately 50% at 5 years.Drug-induced SCLE (DI-SCLE) presents as erythematous scaling and annular plaques on the chest, back, and upper outer arms. Like idiopathic SCLE, patients with DI-SCLE commonly have positive antinuclear antibody anti–Sjögren syndrome–related antigens A and B. Although DI-SCLE may be clinically indistinguishable from idiopathic SCLE, concomitant bullae, vasculitis, and erythema-multiforme–like lesions may be seen.8 More than 40 medications have been implicated in the development of DI-SCLE.8 Typically, the causative medication is started weeks to months before the development of DI-SCLE. Biopsy results reveal superficial perivascular infiltrate of lymphocytes, interface dermatitis, and increased mucin.Sweet syndrome classically presents with fever; abrupt onset of edematous, pseudovesiculated papules and nodules; and neutrophilia. Histiocytoid Sweet syndrome is a histopathological variant of Sweet syndrome with a diffuse dermal infiltrate of immature nonblastic myeloid cells and histiocytes that are myeloperoxidase and CD68 positive.9 The present patient met clinical criteria for Sweet syndrome, which is common in patients with VEXAS syndrome with leucine substitution; however, his prolonged course, persistent leukopenia, lack of associated medication or underlying activating condition, and nonresponse to antineutrophilic medications ultimately led to bone marrow biopsy and testing of UBA1.Halogenoderma is a rare dermatosis caused by exposure to high levels of iodine or bromide. Halogenoderma most often presents with papulopustular lesions, but the morphologic features may include urticarial papules, nodules, and ulcerative plaques,10 and systemic symptoms of halogenoderma are rare. Histopathology reveals epidermal neutrophilic abscesses and a neutrophilic dermal infiltrate. Given the histopathologic overlap with neutrophilic dermatoses, halogenoderma is a diagnosis of exclusion.

Dermatology

A man in his 60s presented to our clinic with a 5-year history of diffuse erythematous, edematous annular plaques (Figure 1); low-grade fevers; and mild leukopenia. The result of a skin biopsy performed 4 years prior was interpreted as subacute cutaneous lupus erythematosus (SCLE). Treatments included hydroxychloroquine, 400 mg/d, for 4 years; mycophenolate mofetil, 1000 mg/d, for 6 months; and oral prednisone tapers, starting at 40 mg/d. Of these, only prednisone appeared to elicit a response. Review of symptoms was negative for fatigue, weight loss, cough, shortness of breath, joint pain, ocular symptoms, mucosal ulcerations, history of blood clots, photosensitivity, pleurisy, urine changes, and diarrhea. Medical history included hypertension, for which he took losartan, and seasonal allergies, for which he used fexofenadine and fluticasone. Laboratory evaluation revealed mild neutropenia and lymphopenia with normal hemoglobin and platelet counts. Antinuclear antibody screening results were negative. The results of a comprehensive metabolic panel, C3, C4, serum protein electrophoresis, serum free light chains, methylmalonic acid, homocysteine, ferritin, copper, zinc, haptoglobin, HIV, hepatitis B and C serologic tests, and rapid plasma reagin were negative. Lactate dehydrogenase was mildly elevated. Erythrocyte sedimentation rate was elevated at 41 mm/h. Routine cancer screening was up to date. Therapeutic trials of dapsone and dapsone in combination with colchicine were not effective.

what is your diagnosis?

What is your diagnosis?

VEXAS syndrome

Histiocytoid Sweet syndrome

Drug-induced SCLE

Halogenoderma

a

male

0-10

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2806818

A Chinese woman in her late 20s presented with a 20-year history of progressive skin laxity. In early childhood, she had developed asymptomatic yellowish coalesced papules confined to flexural areas. Subsequently, severe skin sagging occurred on her abdomen with loss of elasticity, then spread extensively with developmental growth. The results of a physical examination showed thick and leathery skinfolds on the neck, axillae, inguinal regions, abdomen, and limbs (Figure, A), with yellowish papules scattered on the dorsal neck. The patient had no extracutaneous involvement and was born to healthy nonconsanguineous parents. However, her younger sister had developed the same skin symptoms. Coagulation-related tests indicated a low clotting activity of factor X (52.2%; reference range, 77%-131%) and a prolonged prothrombin time (12.8 seconds; reference range, 10.4-12.6 seconds). The results of other laboratory investigations were unremarkable. Echocardiographic and fundoscopic examination results were normal. A skin biopsy specimen was obtained from her neck for histopathologic examination (Figure, B).A, Clinical image of the neck, axillae, and abdomen. Severe skin laxity with deep cutaneous folds on the cervical, axillary, and abdominal regions. B, Skin biopsy specimen taken from the neck shows excessive calcification of elastic fiber fragments scattered in the reticular dermis (von Kossa). What Is Your Diagnosis?

Pseudoxanthoma elasticum

Inherited cutis laxa syndrome

Pseudoxanthoma elasticum–like disorder with coagulation deficiency

Pseudoxanthoma elasticum/pseudoxanthoma elasticum–like overlap syndrome

C. Pseudoxanthoma elasticum–like disorder with coagulation deficiency

C

Pseudoxanthoma elasticum–like disorder with coagulation deficiency

Histopathologic examination, including von Kossa staining, showed fragmented and calcified elastic fibers wildly spread in the reticular dermis. Whole-exome sequencing revealed a novel compound heterozygous sequence variation located in the GGCX gene (OMIM 137167; namely, c.1167_1172delCTGGACinsGGGAA [p. Asn389Lys fs*13] in exon 8 and c.824C>T [p. Ser275Leu] in exon 7). Her sibling shared the same frameshift and nonsense sequence variations. A diagnosis of pseudoxanthoma elasticum–like disorder with coagulation deficiency (PXE-like disorder with CD) was made. Neck lift surgery was performed and resulted in cosmetic improvement.Pseudoxanthoma elasticum–like disorder with CD (OMIM 610842) is a rare subtype of autosomal recessive GGCX-associated diseases.1 As noted by De Vilder et al,1 the first known case was described by G. H. Goldsmith Jr in 1982. The causative GGCX gene is located on the reverse strand of 2p11.2, encoding the γ-glutamyl carboxylase. This specific enzyme promotes γ-carboxylation, an essential process for vitamin K–dependent protein activation. Previous studies reported missense or nonsense variants of the GGCX gene, including c.247C>T, c.763G>A, c.896T>C, c.1186G>A, c.1120C>T, c.1211A>C, c.1426C>T, c.1427G>A, c.1478G>C, c.1506G>C, c.1538G>A, c.1609G>T, and c.1610G>C; and a deletion variant (namely, c.200_201delTT).1-6 All these variants result in nonfunctional carboxylase. Because both the mineralization inhibitor in reticular dermis and the clotting factors II, VII, IX, and X are vitamin K dependent, reduced γ-carboxylase activity usually leads to ectopic calcium precipitation and clotting factor deficiency.1-4 Corresponding typical cutaneous manifestations are overlapping skin lesions of PXE and cutis laxa (CL) (namely, loose and redundant skin located at the trunk, limbs, and flexural areas but leaving the face, hands, and feet unaffected). Patients are also characterized by detectable coagulation deficits, especially factor X deficiency.1,5 Common ophthalmological symptoms include angioid streaks and peau d’orange, which seldom decreases visual acuity.1,7 Histopathologic results reveal polymorphous, fragmented, and mineralized elastic fibers in the upper and mid dermis.6 Electron microscopy further indicates that calcification can also occur in the marginal areas of elastic fibers.3Pseudoxanthoma elasticum is a rare inherited multisystem disease caused by sequence variations in the ABCC gene. Dysfunction of multidrug resistance protein 6 can result in accumulation of compounds with calcium affinity.7 The lesions are typically yellowish papules and reticular rashes. Some patients also presented with skin wrinkling simulating CL but rather milder symptoms, which preferentially involved the flexural regions of the large joint and neck.7,8 Histopathologic features include circumscribed nodular foci of calcification with irregular clumped elastic fibers restricted in the mid dermis.7 Ultrastructurally, mineralization occurs only in the core of elastic fibers, without peripheral deposits.8Inherited CL syndromes comprise a rare group of multisystem disorders characterized by loose redundant skinfolds. Underlying gene defects mainly include ELN, FBLN5, LTBP4, PYCR1, and ATP7A, impairing elastic fiber assembly and homeostasis. Patients with autosomal dominant CL have typical facial features (namely, large ears, sagging cheeks, prominent nasolabial folds, and a long philtrum).9 Different subtypes of autosomal recessive CL are usually accompanied by cardiopulmonary complications, skeletal involvement, or neuromotor delay.9 Coagulation disorder has not been reported, except for a single patient who presented with a decreased von Willebrand factor activity to antigen ratio.10 The characteristic pathologic changes of CL syndromes are dermal elastic fiber reduction and fragmentation without abnormal mineralization.9In diagnosing PXE-like disorder with CD, it is important to exclude the other 2 subtypes of GGCX-associated diseases. They share the same excessive redundant skinfolds and histopathologic features. However, rather than clotting deficits, patients diagnosed with PXE/PXE-like overlap syndrome also present with abdominal micromineralizations.8 Pseudoxanthoma elasticum and pigmentary retinopathy are characterized by ophthalmic symptoms, including nondetectable rod responses or reduced amplitude, and prolonged implicit time.1At present, only symptomatic treatments are available for PXE-like disorder with CD. Plastic surgery is often selected to improve appearance and prevent restriction of daily activities or infection caused by redundant skin, such as abdominoplasty and neck lift surgery in the present case.3 For patients with obvious coagulation abnormality or bleeding tendency, vitamin K supplement should be taken. According to previous studies, both dermatological and ophthalmological follow-up visits are advised for the patient and her sibling.1

Dermatology

A Chinese woman in her late 20s presented with a 20-year history of progressive skin laxity. In early childhood, she had developed asymptomatic yellowish coalesced papules confined to flexural areas. Subsequently, severe skin sagging occurred on her abdomen with loss of elasticity, then spread extensively with developmental growth. The results of a physical examination showed thick and leathery skinfolds on the neck, axillae, inguinal regions, abdomen, and limbs (Figure, A), with yellowish papules scattered on the dorsal neck. The patient had no extracutaneous involvement and was born to healthy nonconsanguineous parents. However, her younger sister had developed the same skin symptoms. Coagulation-related tests indicated a low clotting activity of factor X (52.2%; reference range, 77%-131%) and a prolonged prothrombin time (12.8 seconds; reference range, 10.4-12.6 seconds). The results of other laboratory investigations were unremarkable. Echocardiographic and fundoscopic examination results were normal. A skin biopsy specimen was obtained from her neck for histopathologic examination (Figure, B).A, Clinical image of the neck, axillae, and abdomen. Severe skin laxity with deep cutaneous folds on the cervical, axillary, and abdominal regions. B, Skin biopsy specimen taken from the neck shows excessive calcification of elastic fiber fragments scattered in the reticular dermis (von Kossa).

what is your diagnosis?

What is your diagnosis?

Pseudoxanthoma elasticum–like disorder with coagulation deficiency

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum/pseudoxanthoma elasticum–like overlap syndrome

Inherited cutis laxa syndrome

a

female

11-20

Chinese

original

https://jamanetwork.com/journals/jama/fullarticle/2807273

A previously healthy 7-year-old boy was admitted to the hospital with 1 week of temperatures up to 40.2 °C (104.4 °F), productive cough, and lethargy, which did not improve after 3 days of oral cefuroxime. He lived in rural China and had close contact with dogs, cattle, and sheep. His blood pressure was 93/60 mm Hg; heart rate, 100/min; respiratory rate, 26/min; and oxygen saturation, 94% on room air. Lung auscultation revealed absent breath sounds on the right hemithorax. His abdomen was soft and nontender, without hepatosplenomegaly. His white blood cell count was 8000/μL, with 25.8% eosinophils (reference range, 0%-9%). C-reactive protein level and results from tuberculin skin test, interferon-γ release assay, nucleic acid amplification testing for tuberculosis, acid-fast bacilli smear microscopy, and HIV antibody testing were normal. A thoracoabdominal computed tomography (CT) scan showed a ruptured 10 × 9 × 5–cm right upper lobe pulmonary cyst compressing the right main bronchus and 3 liver cysts (Figure 1).Left, Chest computed tomography (CT) scan (transverse view) showing a giant cystic mass in the right upper lobe of the lung with rupture and compression of the right main bronchus. Right, Abdominal CT scan (coronal view) showing 3 round water-density cysts in the right anterior lobe, right posterior lobe, and left lateral lobe of the liver. What Would You Do Next?

Check stool for Echinococcus granulosus eggs

Obtain serologic testing for E granulosus antibodies

Order a lung biopsy

Perform a liver biopsy

Cystic echinococcosis

B

Obtain serologic testing for E granulosus antibodies

The key to the correct diagnosis is recognition that cysts in the lung and liver are highly suggestive of cystic echinococcosis. Organ biopsy (choices C and D) is not recommended because of the risk of secondary spread of infection, and cyst content spillage may cause anaphylaxis. Choice A is incorrect because humans with cystic echinococcosis do not excrete E granulosus eggs in stool.Cystic echinococcosis is caused by infection with the larval stage of a tapeworm called E granulosus. More than 1 million people annually are infected with E granulosus worldwide. Endemic regions include western China, Central Asia, South America, Mediterranean countries, and east Africa.1-3 Cystic echinococcosis is rare in the US and typically occurs in immigrants from endemic countries.4Definitive hosts for E granulosus are domestic or wild dogs and wolves (canids), who acquire the infection after eating animal organs containing hydatid cysts. Inside canids, the cysts develop into adult tapeworms, which shed eggs in their stool. Intermediate hosts, such as sheep, goats, pigs, and cattle, become infected after ingesting tapeworm eggs in contaminated soil.3 Humans can become hosts through consumption of contaminated soil, food, or water, or after close contact with animal hosts.1 After reaching the intestine, E granulosus eggs hatch and embryos penetrate the intestinal wall, migrating through blood or lymphatic vessels to organs, where they develop into hydatid cysts that gradually enlarge and produce more cysts.3,5Approximately 70% of adults with cystic echinococcosis have liver cysts, and approximately 10% to 30% have pulmonary cysts.6 In children, pulmonary cysts are the most common manifestation of cystic echinococcosis.7,8 Less frequently, hyatid cysts develop in the brain, spleen, kidney, pancreas, and heart. Complications of cystic echinococcosis result from compression of adjacent organs, cyst rupture, superinfection, and immunoallergic reactions to Echinococcus, including urticaria, angioedema, and, rarely, anaphylaxis.8Liver cysts typically grow slowly over many years in adults, but cysts often increase in size at a faster rate in the lung and in children.4,6,7 Pulmonary cysts typically range from 1 cm to 20 cm, with giant cysts defined as having a diameter of 10 cm or greater.6 Individuals with uncomplicated pulmonary hyatid cysts are typically asymptomatic, while those with complicated (ruptured or infected) cysts may experience cough, dyspnea, chest pain, hemoptysis, and fever.6 Pulmonary cyst rupture can cause cough productive of salty-tasting fluid or membrane fragments, empyema, and hydropneumothorax.7The diagnosis of cystic echinococcosis is made based on history, imaging, serology, and histology. Typical imaging findings are pulmonary cysts on chest radiographs or CT and liver cysts on abdominal ultrasound or CT. Detection of antibodies against Echinococcus can confirm the diagnosis of cystic echinococcosis, although the sensitivity and specificity of serology each vary from 60% to 90%, and the sensitivity of serology is not well defined in children.4,7 Eosinophilia occurs in approximately 25% of patients with confirmed cystic echinococcosis.9Treatment for cystic echinococcosis depends on cyst size and location, presence or absence of complications, and availability of medical expertise and equipment.4 Cure can be achieved by surgical resection of the cyst. Other treatments include PAIR (percutaneous puncture, aspiration, injection, and reaspiration), antihelminth therapy, and watchful waiting for smaller cysts. Limited evidence is available regarding optimal drug therapy. However, albendazole or albendazole-praziquantel may be considered for patients with inoperable cysts in the liver, cysts in multiple organs, or isolated small or medium-sized cysts. Antihelminth therapy as an adjunct to surgery or interventional procedures decreased the risk of echinococcosis dissemination and recurrence.4,8,10 Approximately 6.5% of patients experience a relapse after treatment for cystic echinococcosis.1Enzyme-linked immunosorbent assay antibodies to Echinococcus were detected, confirming the diagnosis of cystic echinococcosis. Albendazole (15 mg/kg/d orally twice daily) was started 1 week before right upper lobectomy and continued for 5 months postoperatively. During surgery, a 12 × 12 × 8–cm pulmonary cyst was removed (Figure 2). Histopathology showed extensive necrosis and calcification, and E granulosus was seen on hematoxylin and eosin stain. Five months after his initial surgery, the patient underwent laparotomy and complete removal of the 3 liver cysts, with no spillage of their contents. He was prescribed albendazole for 3 months postoperatively. When seen in the clinic 2 months after liver surgery, the patient had recovered well and an abdominal ultrasound showed no cyst recurrence.Gross pathology of the resected right upper lobe of the lung, showing a giant cyst with a ruptured gray endocyst structure with its contents enclosed by the pericyst.

General

A previously healthy 7-year-old boy was admitted to the hospital with 1 week of temperatures up to 40.2 °C (104.4 °F), productive cough, and lethargy, which did not improve after 3 days of oral cefuroxime. He lived in rural China and had close contact with dogs, cattle, and sheep. His blood pressure was 93/60 mm Hg; heart rate, 100/min; respiratory rate, 26/min; and oxygen saturation, 94% on room air. Lung auscultation revealed absent breath sounds on the right hemithorax. His abdomen was soft and nontender, without hepatosplenomegaly. His white blood cell count was 8000/μL, with 25.8% eosinophils (reference range, 0%-9%). C-reactive protein level and results from tuberculin skin test, interferon-γ release assay, nucleic acid amplification testing for tuberculosis, acid-fast bacilli smear microscopy, and HIV antibody testing were normal. A thoracoabdominal computed tomography (CT) scan showed a ruptured 10 × 9 × 5–cm right upper lobe pulmonary cyst compressing the right main bronchus and 3 liver cysts (Figure 1).Left, Chest computed tomography (CT) scan (transverse view) showing a giant cystic mass in the right upper lobe of the lung with rupture and compression of the right main bronchus. Right, Abdominal CT scan (coronal view) showing 3 round water-density cysts in the right anterior lobe, right posterior lobe, and left lateral lobe of the liver.

what would you do next?

What would you do next?

Obtain serologic testing for E granulosus antibodies

Order a lung biopsy

Perform a liver biopsy

Check stool for Echinococcus granulosus eggs

a

male

0-10

White

original

https://jamanetwork.com/journals/jama/fullarticle/2807108

A previously healthy individual in his 20s presented to the dermatology clinic for evaluation of annular skin lesions that appeared first on his right ankle and then on other areas of his body over a 3-month period. He reported numbness and paresthesia in the areas of affected skin and an inability to fully extend his fingers. The patient did not take any prescription medications or herbal supplements and had immigrated to the US from Samoa 4 years prior. Physical examination revealed multiple tattoos and annular erythematous plaques on his face, chest (Figure, left panel), back, arms, and legs. The patient had bilateral palpable thickened auricular and ulnar nerves, claw-hand deformity (Figure, right panel), foot drop bilaterally, and decreased sensation to temperature over the areas of skin plaque. Results of testing for rapid plasma reagin, antinuclear antibodies, and rheumatoid factor were negative. Examination of punch biopsy samples from 2 plaques on his back revealed granulomatous periadnexal and perivascular dermatitis with diffuse granulomatous infiltrate and foamy histiocytes. Findings on acid-fast bacilli stains and mycobacterial polymerase chain reaction (PCR) testing were negative. Repeat biopsy of a skin plaque revealed no fungal organisms, and Mycobacterium leprae was not identified on Fite Faraco stain.Trunk cutaneous lesions (left) and bilateral hand contractures (right) at initial presentation.Obtain serologic testing for M leprae phenolic glycolipid 1Send skin biopsy specimen to the US National Hansen’s Disease Program for PCR testing What Would You Do Next?

Incubate skin biopsy specimen on chocolate agar

Obtain serologic testing for M leprae phenolic glycolipid 1

Send skin biopsy specimen to the US National Hansen’s Disease Program for PCR testing

Treat with dapsone, rifampin, and clofazimine

Multibacillary leprosy

C

Send skin biopsy specimen to the US National Hansen’s Disease Program for PCR testing

The key to the correct diagnosis was the presence of skin lesions with associated hypoesthesia and peripheral nerve abnormalities in a patient from Samoa, where leprosy is endemic. Choice A is incorrect because the mycobacteria causing leprosy cannot be cultured on chocolate agar.1 Serologic testing for M leprae phenolic glycolipid 1 (choice B) is not commonly performed due to low sensitivity.2 Choice D is incorrect because the diagnosis of leprosy must be confirmed before starting dapsone, rifampin, and clofazimine.Leprosy, also known as Hansen disease, is an infection caused by the acid-fast bacilli M leprae and Mycobacterium lepromatosis, which are obligate intracellular organisms that cannot be cultured on artificial media.1 Humans are the primary carriers of infection, and in the US, the 9-banded armadillo is a zoonotic reservoir.1,3 Approximately 200 000 individuals worldwide and 200 to 300 people in the US are diagnosed with leprosy annually.4,5 The most common route of transmission is through respiratory secretions, but skin contamination with tattooing and vertical transmission have been reported.1,6 Risk factors include close contact with a patient recently diagnosed with leprosy, immunosuppression, immunodeficiency, genetic predisposition, and exposure to armadillos.1 The differential diagnosis of leprosy includes interstitial granulomatous dermatitis, granuloma annulare, granulomatous dermatitis of immune deficiency, granulomatous drug eruption, psoriasis, and other mycobacterial or fungal infections.7The World Health Organization (WHO) classifies leprosy as multibacillary if there are 6 or more skin lesions or as paucibacillary if there fewer than 6 skin lesions.7 The Ridley-Jopling classification system defines 5 categories of leprosy: tuberculoid, borderline tuberculoid, borderline, borderline lepromatous, and lepromatous.7The clinical diagnosis of leprosy is based on the typical signs of skin lesions with hypoesthesia and nerve enlargement.7 Some patients may develop an immune response to M leprae, called a leprosy reaction, which presents as urticarial swelling of skin lesions, fever, neuritis, erythema nodosum, and permanent loss of motor and sensory nerve function.2,8 Leprosy reactions can occur before, during, or after treatment for leprosy.5,8Skin biopsy is the only laboratory test that can definitively diagnose leprosy.7 If skin biopsy is nondiagnostic, PCR testing of a skin biopsy specimen may be helpful. PCR has a sensitivity of 34% to 80% for paucibacillary leprosy and greater than 90% sensitivity for multibacillary leprosy, with a specificity of up to 100% for both paucibacillary and multibacillary leprosy.9Early diagnosis and treatment are important to decrease disability and adverse psychosocial effects of leprosy and to reduce the risk of transmission.2,10 The WHO recommends a 6-month course of dapsone, rifampin, and clofazimine for paucibacillary leprosy and a 12-month course for multibacillary leprosy.2 Treatment with rifampin, moxifloxacin, and minocycline taken monthly for 12 to 24 months has similar efficacy, fewer adverse effects, and improved adherence compared with the WHO regimen but is 4 times more expensive.5Leprosy relapse rates after completion of WHO multidrug therapy are 0.77% for multibacillary leprosy and 1.07% for paucibacillary leprosy.8 Relapse rates appear similar after completing the regimen of rifampin, moxifloxacin, and minocycline.5 Risk factors for relapse include high mycobacterial load, increased number of skin lesions, insufficient treatment duration or regimen, and poor treatment adherence.4,8A skin biopsy sample from the patient’s arm sent to the US National Hansen’s Disease Program tested positive for M leprae using a quantitative PCR assay. The patient received prednisone (60 mg daily) for 5 days, then prednisone (5 mg daily) and methotrexate (20 mg weekly) to treat a leprosy reaction, which manifested as worsening paresthesia and erythema in existing skin plaques. Six days later, he started a monthly regimen of rifampin (600 mg), moxifloxacin (400 mg), and minocycline (100 mg) and received amitriptyline (10 mg) for neuropathic pain. Two months after initiation of antibiotics, the skin lesions and neuropathy symptoms had substantially improved. Eleven months after presentation, the patient underwent tendon transfer surgery with a fascia lata graft to the second through fifth fingers on his left hand, after which he completed 3 months of occupational therapy. At his most recent clinic visit, he had taken 9 of 12 planned months of rifampin, moxifloxacin, and minocycline and was taking prednisone (5 mg daily) and methotrexate (20 mg weekly).

General

A previously healthy individual in his 20s presented to the dermatology clinic for evaluation of annular skin lesions that appeared first on his right ankle and then on other areas of his body over a 3-month period. He reported numbness and paresthesia in the areas of affected skin and an inability to fully extend his fingers. The patient did not take any prescription medications or herbal supplements and had immigrated to the US from Samoa 4 years prior. Physical examination revealed multiple tattoos and annular erythematous plaques on his face, chest (Figure, left panel), back, arms, and legs. The patient had bilateral palpable thickened auricular and ulnar nerves, claw-hand deformity (Figure, right panel), foot drop bilaterally, and decreased sensation to temperature over the areas of skin plaque. Results of testing for rapid plasma reagin, antinuclear antibodies, and rheumatoid factor were negative. Examination of punch biopsy samples from 2 plaques on his back revealed granulomatous periadnexal and perivascular dermatitis with diffuse granulomatous infiltrate and foamy histiocytes. Findings on acid-fast bacilli stains and mycobacterial polymerase chain reaction (PCR) testing were negative. Repeat biopsy of a skin plaque revealed no fungal organisms, and Mycobacterium leprae was not identified on Fite Faraco stain.Trunk cutaneous lesions (left) and bilateral hand contractures (right) at initial presentation.Obtain serologic testing for M leprae phenolic glycolipid 1Send skin biopsy specimen to the US National Hansen’s Disease Program for PCR testing

what would you do next?

What would you do next?

Incubate skin biopsy specimen on chocolate agar

Obtain serologic testing for M leprae phenolic glycolipid 1

Treat with dapsone, rifampin, and clofazimine

Send skin biopsy specimen to the US National Hansen’s Disease Program for PCR testing

d

male

21-30

original

https://jamanetwork.com/journals/jama/fullarticle/2806639

A 60-year-old Black patient presented to the emergency department with a 2-month history of chest pain and shortness of breath with exertion, 3 months of toe numbness, and unintended weight loss of 8 kg over 6 months. The patient also had a history of lumbar spinal stenosis. On presentation, blood pressure was 104/73 mm Hg; heart rate, 91/min; respiratory rate, 16/min; and oxygen saturation, 96% on room air. Physical examination revealed edema to the mid-calf bilaterally, hypoesthesia below the knees, and ankle plantar flexion strength of 3 of 5 based on the Medical Research Council Scale for muscle strength. Laboratory testing revealed a high-sensitivity troponin level of 52 ng/L (reference, <34 ng/L); brain-type natriuretic peptide, 112 pmol/L (reference, <30 pmol/L); aspartate aminotransferase, 51 U/L (0.85 μkat/L) (reference, 0-35 U/L [0-0.58 μkat/L]); and alanine aminotransferase, 76 U/L (1.27 μkat/L) (reference, 0-45 U/L [0-0.75 μkat/L]). A chest radiograph showed cardiomegaly without pulmonary vascular redistribution or pulmonary edema.An electrocardiogram revealed normal sinus rhythm, left anterior fascicular block, and down-sloping anterolateral ST segments. The patient was admitted to the hospital, where electromyography results included reduced amplitude of peroneal nerve action potentials, consistent with axonal sensorimotor polyneuropathy of the bilateral lower extremities. Coronary angiography showed no coronary atherosclerosis, and cardiac magnetic resonance imaging demonstrated asymmetric left ventricular hypertrophy. Results of serum protein electrophoresis (SPEP) and serum free light chain testing were normal. A bone scintigraphy scan using technetium Tc 99m–labeled hydroxymethylene diphosphonate demonstrated increased cardiac uptake (Figure).Anterior (left) and posterior (right) bone scintigraphy scan of the patient. What Would You Do Next?

Perform bone marrow biopsy

Order genetic testing

Perform random skin biopsies

Order 24-hour urine testing for monoclonal proteins

Variant transthyretin amyloidosis

B

Order genetic testing

The key to the correct diagnosis is the increased cardiac uptake on bone scintigraphy in a patient with symptoms of heart failure, polyneuropathy, and spinal stenosis. Due to the normal SPEP result and absence of serum free light chains, a bone marrow biopsy (choice A) is not indicated. Tissue biopsy (choice C) is not necessary because the bone scintigraphy findings were diagnostic for transthyretin amyloidosis (ATTR) cardiomyopathy. Collecting a 24-hour urine sample to test for monoclonal proteins (choice D) would not establish the diagnosis of ATTR.Amyloidosis is caused by production of a misfolded protein that deposits extracellularly and is resistant to catabolism.1 ATTR amyloidosis is caused by transthyretin (TTR), a protein that is encoded by a single gene on chromosome 18 and binds thyroxine and retinol.2 TTR is primarily synthesized by hepatocytes, although approximately 5% is produced by retinal and choroid plexus epithelial cells.3ATTR amyloidosis presents as wild-type ATTR amyloidosis, caused by age-related instability of the TTR protein, or as variant ATTR amyloidosis (ATTRv), caused by abnormal TTR protein due to a genetic variant. ATTRv amyloidosis is inherited in an autosomal dominant pattern with variable penetrance, and up to 50% of patients with ATTRv have no family history of amyloidosis.3ATTR amyloidosis results in amyloid fibril accumulation in multiple organs, most commonly affecting the peripheral and autonomic nervous systems and the heart. Neurologic effects of ATTR amyloidosis include symmetric neuropathy, which may cause paresthesia, pain, weakness and imbalance, and autonomic dysfunction, such as orthostatic hypotension, early satiety, and erectile dysfunction. Patients with cardiac ATTR amyloidosis typically present with heart failure symptoms that appear similar to heart failure with preserved ejection fraction, and some develop atrial fibrillation and angina.2,3Clinical manifestations of ATTRv amyloidosis depend on the specific TTR gene variant, of which more than 140 have been reported.4 Sensorimotor peripheral neuropathy occurs in approximately 80% of patients with ATTRv amyloidosis but is present in more than 90% in patients with the most common variant, Val30Met.3 ATTR cardiomyopathy occurs in approximately 40% of patients with ATTRv amyloidosis but is the predominant feature in patients with the Val142Ile variant. Approximately 3% of Black individuals in the US are estimated to be carriers of the Val142Ile variant.5,6 Other manifestations of ATTRv amyloidosis include lumbar spinal stenosis7 and, less frequently, stroke, dementia, seizures, and headaches.3Underrecognition of ATTR amyloidosis is common,1 and the average diagnostic delay is approximately 4 years after symptom onset.4 Diagnosis of systemic amyloidosis typically requires tissue confirmation of Congo red extracellular deposits that show apple green birefringence under polarized light microscopy.3 However, the diagnosis of ATTR cardiac amyloidosis can be made based on increased cardiac uptake on radionuclide scanning in patients with symptoms suggestive of amyloidosis and a normal SPEP result. Radiotracer myocardial uptake on bone scintigraphy is more than 99% sensitive and 86% specific for the diagnosis of cardiac ATTR amyloidosis.8 Patients diagnosed with ATTR amyloidosis should undergo genetic testing to evaluate for an inherited variant of ATTR.1ATTR amyloidosis is a progressive disease. In untreated patients, life expectancy ranges from 2 to 10 years after symptom onset.4 Novel treatments have recently improved the prognosis. Tafamidis, an oral medication that binds to TTR and reduces its misfolding, decreased mortality by 30% and cardiovascular hospitalizations by 32% in patients with ATTR amyloidosis.9 For patients with peripheral neuropathy due to ATTRv amyloidosis, 2 US Food and Drug Administration–approved medications, inotersen and patisiran, slowed disease progression and improved quality of life.1,10 Liver transplant, which was previously the only potential therapy for ATTRv, is no longer commonly performed.Whole-exome sequencing and microarray testing for sequence variants demonstrated 2 heterozygous TTR gene variants: Val50Met and Val142Ile. The patient was treated with bumetanide, spironolactone, and patisiran. His first-degree family members were referred to a medical geneticist. At a clinic visit 1 year after initial presentation, the patient reported no further weight loss, chest pain, or shortness of breath but had persistent lower extremity weakness and numbness in his toes.

General

A 60-year-old Black patient presented to the emergency department with a 2-month history of chest pain and shortness of breath with exertion, 3 months of toe numbness, and unintended weight loss of 8 kg over 6 months. The patient also had a history of lumbar spinal stenosis. On presentation, blood pressure was 104/73 mm Hg; heart rate, 91/min; respiratory rate, 16/min; and oxygen saturation, 96% on room air. Physical examination revealed edema to the mid-calf bilaterally, hypoesthesia below the knees, and ankle plantar flexion strength of 3 of 5 based on the Medical Research Council Scale for muscle strength. Laboratory testing revealed a high-sensitivity troponin level of 52 ng/L (reference, <34 ng/L); brain-type natriuretic peptide, 112 pmol/L (reference, <30 pmol/L); aspartate aminotransferase, 51 U/L (0.85 μkat/L) (reference, 0-35 U/L [0-0.58 μkat/L]); and alanine aminotransferase, 76 U/L (1.27 μkat/L) (reference, 0-45 U/L [0-0.75 μkat/L]). A chest radiograph showed cardiomegaly without pulmonary vascular redistribution or pulmonary edema.An electrocardiogram revealed normal sinus rhythm, left anterior fascicular block, and down-sloping anterolateral ST segments. The patient was admitted to the hospital, where electromyography results included reduced amplitude of peroneal nerve action potentials, consistent with axonal sensorimotor polyneuropathy of the bilateral lower extremities. Coronary angiography showed no coronary atherosclerosis, and cardiac magnetic resonance imaging demonstrated asymmetric left ventricular hypertrophy. Results of serum protein electrophoresis (SPEP) and serum free light chain testing were normal. A bone scintigraphy scan using technetium Tc 99m–labeled hydroxymethylene diphosphonate demonstrated increased cardiac uptake (Figure).Anterior (left) and posterior (right) bone scintigraphy scan of the patient.

what would you do next?

What would you do next?

Perform random skin biopsies

Order 24-hour urine testing for monoclonal proteins

Order genetic testing

Perform bone marrow biopsy

c

neutral

51-60

Black

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2805070

A 64-year-old woman presented with diminution of vision, progressive redness, and dull aching pain in the right eye for 8 months. There was no history of trauma. Her medical history was unremarkable.On examination, her best-corrected visual acuity measured 20/60 OD and 20/25 OS. The anterior segment showed dilated corkscrew conjunctival vessels (Figure 1), a shallow anterior chamber in the right eye, and nuclear cataract in both eyes. Pupillary reaction and color vision were normal in both eyes. Intraocular pressure was 16 mm Hg by Goldman applanation tonometry in both eyes. Gonioscopy revealed an occludable angle in the right eye without evidence of blood in the Schlemm canal. Both eyes’ extraocular movements were full and free in all directions of gaze. Dilated fundus examination showed a clear vitreous cavity in the right eye, 360° serous choroidal detachment partly obscuring the optic disc nasally (Figure 1), and the fundus in the left eye was unremarkable.Slitlamp photograph of the right eye showing corkscrew episcleral vessels (A) and ultra-wide field imaging of the right eye showing a large choroidal detachment nasally and shallow detachment all around (B).Magnetic resonance imaging with magnetic resonance angiography or digital subtraction angiography What Would You Do Next?

Ultrasound biomicroscopy

Uveitis workup and steroids

Thyroid profile

Magnetic resonance imaging with magnetic resonance angiography or digital subtraction angiography

Low-flow carotid cavernous fistula

D

Magnetic resonance imaging with magnetic resonance angiography or digital subtraction angiography

Carotid cavernous fistula (CCF) is an abnormal communication between the carotid artery and its branches and the cavernous sinus (CS), causing high-pressure arterial blood flow within the low-pressure veins, sinuses, and cavernous sinus.1 Direct CCF (high-flow fistula) is a direct connection between the intracavernous segment of the internal carotid artery and CS, commonly caused by head injury. Presentations include blurred vision, pulsatile proptosis, orbital bruit, chemosis, corkscrew conjunctival vessels, raised intraocular pressure, and nerve palsies.1,2Indirect CCF (low-flow fistula) involves 1 or more meningeal branches of the internal carotid artery, external carotid artery, or both, communicating with CS. It can be spontaneous, associated with hypertension, older age, and female gender. Often asymptomatic, the most common presentation is conjunctival congestion misdiagnosed as conjunctivitis.1,3 This patient had corkscrew vessels with serous choroidal detachment (CD) and normal intraocular pressure.4,5 This may occur due to increased orbital venous pressure and intracapillary pressure in the choroid, resulting in transudation into the suprachoroidal space.5When CCF is suspected clinically, the patient requires neuroimaging (magnetic resonance imaging of the brain and orbit/magentic resonance angiography). Digital subtraction angiography is the gold standard for diagnosis1,6 (choice D). Magnetic resonance angiography in this case did not reveal dilatation of the superior ophthalmic vein or abnormal flow in CS. Due to strong clinical suspicion, the patient underwent digital subtraction angiography, which showed a small extremely low-flow type B CCF (dural shunts between the meningeal branches of the internal carotid artery and CS) on the right side. (Figure 2) Jamison et al7 described a patient with persistent red eye and glaucoma, later found to have CCF. The current case emphasizes the need to suspect CCF when a patient presents only with CD and red eye. In asymptomatic cases, close observation or ipsilateral manual carotid compression can achieve a success rate of 35%, with resolution occurring between 6 weeks and several months; 20% to 70% of these cases resolve spontaneously.1 Surgical options for closure include endovascular treatment (transarterial or transvenous) and stereotactic radiosurgery.1,6Digital subtraction angiographic image after transfemoral catheterization showing right-sided low flow type B carotid cavernous fistula (L marks the fistula). RT indicates right; INT, internal; CAR, carotid artery; LAT, lateral view.Choice A (ultrasound biomicroscopy ) is not the best option as there was no mass lesion, no sentinel conjunctival vessels (choroidal melanoma), severe pain, or inflammation (scleritis). Choice B (uveitis workup and steroids) is not an option as there was no evidence of inflammation. Choice C (thyroid profile) was not the best option because though chronic congestion can occur in thyroid eye disease, other features like eyelid retraction, proptosis, impaired extraocular movement, and systemic features of thyroid disease were absent. Low-flow CCF should be considered in cases of chronic red eye and CD. Prompt neuroimaging is essential to initiate appropriate management.The patient was advised to perform ipsilateral carotid compression with the contralateral hand for 30 seconds8 with 30-second release 6 to 7 times per hour in a sitting or supine posture, 40 to 50 times per day for 8 weeks. This resulted in resolution of the CD. Follow-up was advised every 4 to 6 weeks. Intermittent manual carotid compression is the initial choice of management for low-flow indirect CCF before more aggressive intervention.

Ophthalmology

A 64-year-old woman presented with diminution of vision, progressive redness, and dull aching pain in the right eye for 8 months. There was no history of trauma. Her medical history was unremarkable.On examination, her best-corrected visual acuity measured 20/60 OD and 20/25 OS. The anterior segment showed dilated corkscrew conjunctival vessels (Figure 1), a shallow anterior chamber in the right eye, and nuclear cataract in both eyes. Pupillary reaction and color vision were normal in both eyes. Intraocular pressure was 16 mm Hg by Goldman applanation tonometry in both eyes. Gonioscopy revealed an occludable angle in the right eye without evidence of blood in the Schlemm canal. Both eyes’ extraocular movements were full and free in all directions of gaze. Dilated fundus examination showed a clear vitreous cavity in the right eye, 360° serous choroidal detachment partly obscuring the optic disc nasally (Figure 1), and the fundus in the left eye was unremarkable.Slitlamp photograph of the right eye showing corkscrew episcleral vessels (A) and ultra-wide field imaging of the right eye showing a large choroidal detachment nasally and shallow detachment all around (B).Magnetic resonance imaging with magnetic resonance angiography or digital subtraction angiography

what would you do next?

What would you do next?

Uveitis workup and steroids

Thyroid profile

Ultrasound biomicroscopy

Magnetic resonance imaging with magnetic resonance angiography or digital subtraction angiography

d

female

61-70

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2805396

A 53-year-old woman presenting with a unilateral mild cortical and nuclear cataract associated with 20/32 visual acuity in her left eye was planning to undergo phacoemulsification. A few days before surgery, she noticed a sudden decrease in her left visual acuity measured at 20/80. Her eye specialist then observed a reverse pupillary block in her left eye and referred the patient to our department. At presentation, no other remarkable medical history was recorded and no precipitating factors identified. Slitlamp examination showed a unilateral deepening of the anterior chamber associated with signs of anterior uveitis (ie, keratic precipitates and severe aqueous flare, 3+) and posterior synechiae between the iris and the lens. In addition, fundus examination revealed an inferior retinal detachment without any associated visible tear. Intraocular pressure was 15 mm Hg in the right eye and 9 mm Hg in the left eye. Anterior segment optical coherence tomography images and fundus photographs of both eyes are shown in Figure 1.While anterior segment optical coherence tomography (AS-OCT) and fundus imaging were unremarkable for the right eye, the left anterior chamber was substantially deepened with a backbowing of the iris and an apposition to the lens, leading to a disappearance of the posterior chamber on AS-OCT scan. An inferior retinal detachment without any associated visible tear was present in the left eye (white arrowheads). What Would You Do Next?

Perform peripheral iridotomy

Perform full-thickness sclerectomy

Administer intravenous corticosteroids

Schedule combined phacoemulsification-vitrectomy surgery

Iris retraction syndrome

D

Schedule combined phacoemulsification-vitrectomy surgery

Iris retraction syndrome is a rare entity initially described by Campbell1 in 1984. The proposed pathogenesis is that the retinal pigment epithelium (RPE) excessively absorbs aqueous humor and acts as a pump in the posterior segment. This overabsorption could be secondary to exposure of RPE through a peripheral retinal tear, but retinal breaks, although present in most cases, are not always noted.2 The misdirected flow of aqueous humor can lead to an inversion of the pressure gradient between the anterior and posterior chambers. This in turn can lead to a reverse pupillary block and its associated proinflammatory consequences.3 The associated exudative retinal detachment could be related to the absorption of the aqueous humor by the RPE toward the suprachoroidal space and to inflammation.4 The aim of the treatment is, one the one hand, to lyse posterior synechiae between the iris and the lens and, on the other hand, to drain the subretinal fluid and to treat the tear—when found—through pars plana vitrectomy. In some cases, medical treatment alone with topical atropine and steroids may be sufficient.2 Peripheral iridotomy (choice A) might be a dangerous option, as the iris is wedged to the lens and would not modify the misdirection of the aqueous humor flow. Sclerotomy (choice B) to drain fluid likely would not be appropriate, as the initial mechanism is not related to uveal effusion. Corticosteroid therapy (choice C) typically would not be useful, as the primary cause is not inflammatory.1,4 Iris retraction syndrome requires surgical management (choice D) to stop misdirected flow of aqueous humor toward the posterior segment. A topical treatment combining atropine and corticosteroids can be prescribed while awaiting surgery.While awaiting surgery, topical atropine and topical corticosteroids were prescribed, but the retinal detachment progressed toward the posterior pole, confirming the necessity of vitrectomy. Combined phacoemulsification and vitrectomy were performed without complications. No retinal peripheral tears were identified. The accumulated subretinal fluid was aspirated through a punctate retinotomy, and sulfur hexafluoride was used as an internal tamponade at the end of the procedure. The outcome appeared favorable with complete retinal reattachment, while visual acuity returned to 20/20 in both eyes as shown in Figure 2.In 1-month postoperative anterior segment optical coherence tomography and fundus images of the left eye, anatomy of the anterior segment appeared normal, and the retinal detachment had resolved. Visual acuity had returned to 20/20.

Ophthalmology

A 53-year-old woman presenting with a unilateral mild cortical and nuclear cataract associated with 20/32 visual acuity in her left eye was planning to undergo phacoemulsification. A few days before surgery, she noticed a sudden decrease in her left visual acuity measured at 20/80. Her eye specialist then observed a reverse pupillary block in her left eye and referred the patient to our department. At presentation, no other remarkable medical history was recorded and no precipitating factors identified. Slitlamp examination showed a unilateral deepening of the anterior chamber associated with signs of anterior uveitis (ie, keratic precipitates and severe aqueous flare, 3+) and posterior synechiae between the iris and the lens. In addition, fundus examination revealed an inferior retinal detachment without any associated visible tear. Intraocular pressure was 15 mm Hg in the right eye and 9 mm Hg in the left eye. Anterior segment optical coherence tomography images and fundus photographs of both eyes are shown in Figure 1.While anterior segment optical coherence tomography (AS-OCT) and fundus imaging were unremarkable for the right eye, the left anterior chamber was substantially deepened with a backbowing of the iris and an apposition to the lens, leading to a disappearance of the posterior chamber on AS-OCT scan. An inferior retinal detachment without any associated visible tear was present in the left eye (white arrowheads).

what would you do next?

What would you do next?

Administer intravenous corticosteroids

Perform peripheral iridotomy

Schedule combined phacoemulsification-vitrectomy surgery

Perform full-thickness sclerectomy

c

female

51-60

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2805508

A 63-year-old man with no ocular history and a history of stage 3 cutaneous melanoma of the scalp and chronic lymphocytic leukemia was referred for kaleidoscope vision. He received nivolumab (anti–programmed cell death 1 checkpoint inhibitor) 9 months prior, obinutuzumab (B-cell lymphoma 2 inhibitor) 3 months later, and 5-mg oral prednisone daily. On presentation, nivolumab and obinutuzumab treatment was complete.His visual acuity was 20/125 OD and 20/50 OS. Ophthalmoscopy revealed bilateral panuveitis with diffuse pigmentary abnormalities. Fluorescein angiography showed diffuse retinal pigment epithelium loss and late staining of the retinal lesions. He received 60 mg of oral prednisone daily for 2 weeks with a planned 10-week taper. However, prednisone was discontinued due to positive Lyme disease exposure 6 weeks later. At this time, the active anterior and vitreous cells had resolved.However, 2 weeks later, visual acuity decreased to count fingers in his right eye and hand motions in the left eye. The anterior and vitreous chambers had grade +0.5 pigmented cells. The ophthalmoscopic examination showed a leopard-spot pattern (Figure 1), and optical coherence tomography showed substantial retinal pigment epithelium and outer retinal layer loss. Repeat testing for Treponema pallidum, Lyme disease, and HIV was negative. Results of magnetic resonance imaging of the brain and orbit were negative for leukemic infiltration.A, Ultra-widefield fundus photograph of the right eye showing pigmentary abnormalities (arrowhead) within and peripheral to the macula. This finding was similar in both eyes. A red-free image is depicted in the bottom left corner of the panel. B, Ultra-widefield fundus autofluorescence image of the right eye showing hypoautofluorescent (pink arrowhead) and hyperautofluorescent patches (blue arrowhead) within and peripheral to the macula. This finding was similar in both eyes.Immunomodulatory therapy with another course of oral steroidsPars plana vitrectomy for vitreous biopsy with or without chorioretinal biopsy for flow cytometry to assess for leukemic cells What Would You Do Next?

Immunomodulatory therapy with another course of oral steroids

Pars plana vitrectomy for vitreous biopsy with or without chorioretinal biopsy for flow cytometry to assess for leukemic cells

Intravitreal steroid injection

Observation

Immune checkpoint inhibitor–induced panuveitis of both eyes

C

Intravitreal steroid injection

The patient was referred for simultaneous panuveitis 6 months after receiving immune checkpoint inhibitor therapy. After the initial consultation, he started an oral steroid, which was stopped due to positive Lyme disease exposure. Despite negative Lyme disease serology results, immunomodulatory therapy was deferred due to his oncologic history. As such, option 1 would not be the best course of action. Given the patient’s oncologic history, there was a concern for a neoplastic masquerade syndrome. The utility of a pars plana vitreous biopsy with or without a chorioretinal biopsy to sample the subretinal lesions identified on optical coherence tomography (Figure 2) was discussed but ultimately deferred due to the likelihood of low yield in the setting of a relatively quiet vitreous segment (option 2). It is difficult to fully exclude the likelihood that the cells were not leukemic metastases in the absence of a vitreous biopsy. However, given a sustained resolution of active anterior and vitreous segment cells after steroid treatment, a complete blood cell count not suggestive of leukocytosis, negative bone marrow biopsy a month after presentation, and a negative magnetic resonance imaging result of the brain and orbits, the likelihood of a neoplastic masquerade syndrome was thought to be low. Instead, the patient received an injection of dexamethasone into the vitreous cavity (option 3).Spectral-domain optical coherence tomography of the right eye showing hyperreflective lesions (arrowhead) in the outer retina.Immune checkpoint inhibitors have gained popularity in recent years due to their ability to circumvent the protective signals that prevent the immune system from sensing and destroying malignant cells. While they have led to a decrease in the morbidity and mortality rates of individuals with cancers,1 their use has led to adverse reactions, including ocular sequelae like legal blindness, which presumably should be discussed with recipients of these treatments.A 2019 study identified all cases of ocular adverse effects that were reported to the US Food and Drug Administration Adverse Events Reporting System database from 2003 to 2018.2 They identified 131 adverse events ranging from uveitis, dry eye, ocular myasthenia, and eye inflammation. Nivolumab had the highest number of adverse events, accounting for 68 of 131 adverse events associated with immune checkpoint inhibitors.2 Here, we show that nivolumab can present with bilateral diffuse panuveitis.The precise mechanisms that mediate these events remain poorly understood. One study suggested that programmed cell death 1 inhibitors such as nivolumab produce pathologic autoantibodies that might be responsible for the high incidence of adverse effects with these drugs.3 Cytotoxic T-lymphocyte antigen 4 inhibitors are known to have a dose-dependent incidence of adverse effects leaving room for dose titration.4The patient’s visual acuity continued to decline (hand motions in both eyes). He received an intravitreal dexamethasone implant injection without a significant decline in the disease progression. Systemic immune modulatory therapy was deferred due to the patient’s poor response to local treatment.

Ophthalmology

A 63-year-old man with no ocular history and a history of stage 3 cutaneous melanoma of the scalp and chronic lymphocytic leukemia was referred for kaleidoscope vision. He received nivolumab (anti–programmed cell death 1 checkpoint inhibitor) 9 months prior, obinutuzumab (B-cell lymphoma 2 inhibitor) 3 months later, and 5-mg oral prednisone daily. On presentation, nivolumab and obinutuzumab treatment was complete.His visual acuity was 20/125 OD and 20/50 OS. Ophthalmoscopy revealed bilateral panuveitis with diffuse pigmentary abnormalities. Fluorescein angiography showed diffuse retinal pigment epithelium loss and late staining of the retinal lesions. He received 60 mg of oral prednisone daily for 2 weeks with a planned 10-week taper. However, prednisone was discontinued due to positive Lyme disease exposure 6 weeks later. At this time, the active anterior and vitreous cells had resolved.However, 2 weeks later, visual acuity decreased to count fingers in his right eye and hand motions in the left eye. The anterior and vitreous chambers had grade +0.5 pigmented cells. The ophthalmoscopic examination showed a leopard-spot pattern (Figure 1), and optical coherence tomography showed substantial retinal pigment epithelium and outer retinal layer loss. Repeat testing for Treponema pallidum, Lyme disease, and HIV was negative. Results of magnetic resonance imaging of the brain and orbit were negative for leukemic infiltration.A, Ultra-widefield fundus photograph of the right eye showing pigmentary abnormalities (arrowhead) within and peripheral to the macula. This finding was similar in both eyes. A red-free image is depicted in the bottom left corner of the panel. B, Ultra-widefield fundus autofluorescence image of the right eye showing hypoautofluorescent (pink arrowhead) and hyperautofluorescent patches (blue arrowhead) within and peripheral to the macula. This finding was similar in both eyes.Immunomodulatory therapy with another course of oral steroidsPars plana vitrectomy for vitreous biopsy with or without chorioretinal biopsy for flow cytometry to assess for leukemic cells

what would you do next?

What would you do next?

Observation

Pars plana vitrectomy for vitreous biopsy with or without chorioretinal biopsy for flow cytometry to assess for leukemic cells

Immunomodulatory therapy with another course of oral steroids

Intravitreal steroid injection

d

male

61-70

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2805263

A 71-year-old woman presented to the otolaryngology clinic for evaluation of a parapharyngeal space (PPS) mass that was incidentally found on magnetic resonance imaging (MRI) of the face. The patient experienced left jaw tightness, aural fullness, and facial discomfort. The MRI results demonstrated a well-circumscribed, ovoid mass in the left prestyloid PPS that measured 12 × 15 × 22 mm. The lesion was isointense on T1-weighted imaging, was hyperintense on T2-weighted imaging, and demonstrated heterogeneous enhancement following gadolinium administration (Figure 1). A computed tomography–guided fine-needle aspiration was performed, which demonstrated blood, fibrin, and rare mesenchymal cells. Given her ongoing symptoms, the patient requested surgical resection. The patient underwent transoral robotic surgery for resection of her PPS mass to achieve definitive diagnosis and treatment. Histopathologic evaluation demonstrated a well-circumscribed, 12-mm mass.Magnetic resonance imaging of the face. A, Coronal section from a T2-weighted image demonstrates a hyperintense mass in the left parapharyngeal space (PPS). B, Axial section from a postcontrast T1-weighted image shows a heterogeneously enhancing mass in the prestyloid PPS. What Is Your Diagnosis?

Schwannoma

Venous malformation

Pleomorphic adenoma

Paraganglioma

B. Venous malformation

B

Venous malformation

The PPS is often described as an inverted pyramid, with the base centered at the skull base and the apex at the greater cornu of the hyoid bone. Tumors of the PPS account for approximately 0.5% of head and neck neoplasms, and 80% are benign.1 The PPS is separated into prestyloid and poststyloid compartments by the tensor veli palatini muscle and the styloid process.1 Tumors in the PPS arise from structures that normally occupy the prestyloid and poststyloid compartments. The prestyloid space is composed of lymph nodes, adipose tissue, and a portion of the deep lobe of the parotid gland. Consequently, salivary gland neoplasms are the most common tumors found in the prestyloid PPS.2 The poststyloid PPS contains the internal carotid artery, the internal jugular vein, cranial nerves IX to XII, lymph nodes, and the sympathetic chain. As such, neurogenic tumors are the most commonly identified tumors in this compartment.2Vascular malformations develop uncommonly within the PPS, accounting for less than 0.01% of PPS tumors.1 The International Society for the Study of Vascular Anomalies separates vascular anomalies into 2 categories: vascular tumors and vascular malformations.3 Vascular tumors have a proliferative component, whereas vascular malformations are due to inborn errors in vascular morphogenesis.3 Vascular malformations are further characterized by the composition of their predominant vessel type, such as capillary, venous, lymphatic, arterial, or a combination of these. The patient in this report had a venous malformation (Figure 2), which is a slow-flow lesion. Venous malformations are benign and arise sporadically in more than 90% of cases.4 Small and asymptomatic venous malformations may be managed conservatively. However, surgical intervention may be warranted in patients with pain, bleeding, cosmetic deformities, or other symptoms related to the lesion.Hematoxylin-eosin–stained sections of the mass. A, A low-power view shows a relatively well-circumscribed mass with focal intermixing with surrounding adipose tissue at the periphery. B, Higher power highlights dilated, congested thin-walled vessels.Given the rarity of vascular malformations in the PPS, preoperative diagnosis can be exceedingly difficult. On ultrasonography, venous malformations are composed of small chambers and have characteristic phleboliths, which appear as a mass with acoustic shadowing.5However, MRI is the imaging modality of choice to diagnose venous malformations. These lesions are typically hyperintense on T2-weighted imaging and isointense on precontrast T1-weighted imaging.6 Venous malformations are highly variable in their pattern of enhancement on postcontrast imaging. In this case, the PPS mass was isointense on precontrast T1, heterogeneous on postcontrast T1, and hyperintense on T2 imaging.Similar to venous malformations, schwannomas are also isointense on T1-weighted images and hyperintense on T2-weighted images.7 Paragangliomas are hypointense on T1-weighted images, are isointense to hyperintense on T2-weighted images, and have homogeneous enhancement following contrast administration.8 Additionally, paragangliomas typically have a characteristic salt-and-pepper appearance due to vascular flow voids. Pleomorphic adenomas are classically hypointense on T1-weighted images, are hyperintense on T2-weighted images, and have homogeneous enhancement following contrast administration.9In this case, given the nondiagnostic fine-needle aspiration and MRI findings, surgical resection with microscopic tissue examination (Figure 2) was essential in making the diagnosis of a venous malformation. On histopathologic evaluation, venous malformations demonstrate enlarged venous channels that are lined by flattened endothelial cells and surrounded by sparse smooth muscle cells.10

General

A 71-year-old woman presented to the otolaryngology clinic for evaluation of a parapharyngeal space (PPS) mass that was incidentally found on magnetic resonance imaging (MRI) of the face. The patient experienced left jaw tightness, aural fullness, and facial discomfort. The MRI results demonstrated a well-circumscribed, ovoid mass in the left prestyloid PPS that measured 12 × 15 × 22 mm. The lesion was isointense on T1-weighted imaging, was hyperintense on T2-weighted imaging, and demonstrated heterogeneous enhancement following gadolinium administration (Figure 1). A computed tomography–guided fine-needle aspiration was performed, which demonstrated blood, fibrin, and rare mesenchymal cells. Given her ongoing symptoms, the patient requested surgical resection. The patient underwent transoral robotic surgery for resection of her PPS mass to achieve definitive diagnosis and treatment. Histopathologic evaluation demonstrated a well-circumscribed, 12-mm mass.Magnetic resonance imaging of the face. A, Coronal section from a T2-weighted image demonstrates a hyperintense mass in the left parapharyngeal space (PPS). B, Axial section from a postcontrast T1-weighted image shows a heterogeneously enhancing mass in the prestyloid PPS.

what is your diagnosis?

What is your diagnosis?

Venous malformation

Paraganglioma

Pleomorphic adenoma

Schwannoma

a

female

71-80

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2805264

A 47-year-old woman was seen with left-sided facial weakness and swelling for 2 months. She was diagnosed as having recurrent high-grade serous cystadenocarcinoma of the ovary and developed these symptoms after cycle 4 of chemotherapy. She was receiving oral antidiabetic agents, and her blood glucose level was 110 mg/dL (to convert to millimoles per liter, multiply by 0.0555). Physical examination findings were consistent with left lower-motor-neuron type of facial nerve palsy. She was conscious and well oriented, with no other relevant clinical signs or focal neurological deficits. There was no history of prior COVID-19 infection. Magnetic resonance imaging (MRI) of the brain was requested, with clinical suspicion of metastasis in view of mildly elevated CA125 levels.The results of MRI of the brain did not reveal any neuroparenchymal or meningeal lesions. However, both maxillary sinuses showed mucosal thickening, which was intermediate to hypointense on T2-weighted imaging and hypointense on T1-weighted imaging with postcontrast enhancement. Computed tomography sections confirmed bony destruction with foci of remodeling involving the walls of the maxillary sinuses (Figure 1).A, Axial T2-weighted magnetic resonance imaging (MRI) shows T2 heterogeneous soft tissue in the maxillary sinus with perimaxillary inflammatory changes (yellow arrowhead). B, In this axial contrast-enhanced, T1-weighted (T1 + C) image, linear enhancement corresponds to expected course of buccal branch of facial nerve (VII) (white arrow). The enhancement extends medially and involves the mandibular branch of the trigeminal nerve (V3). P indicates parotid gland, and the yellow dashed line outlines the edge of the parotid gland. B and C, The white arrow shows the intercommunication between the auriculotemporal branch of V3 and the intraparotid facial nerve (green marker). C, Additionally, involvement of enhanced thickening is seen up to the left foramen ovale, without involvement of the trigeminal ganglion. D, In oblique sagittal images, the thick enhancing branches of the facial nerves within the left parotid gland are seen (orange arrows). The enhancement of facial nerve extends up to the stylomastoid foramen (SMF) (blue arrow), and there is subtle enhancement along its mastoid segments (MSs). Iodinated contrast medium was used.Fat stranding and enhancing soft tissue was seen in the retroantral spaces bilaterally as well as the pterygopalatine fossae. Anteriorly, enhancing soft tissue was present in premaxillary space, from which contiguous linear enhancement was seen extending to left parotid gland—along the expected course of buccal branch of left facial nerve. The entire extracranial left facial nerve proximal to this showed diffuse enhancement and thickening. Associated stylomastoid foramen widening was present with subtle enhancement along its mastoid and tympanic segments. These features were compatible with perineural extension of disease (Figure 1A and B).Additionally, there was involvement of the mandibular branch of the trigeminal nerve via intercommunication between the auriculotemporal branch of trigeminal nerve and the intraparotid facial nerve. Diffuse enhancement and thickening was seen up to the left foramen ovale, without involvement of the trigeminal ganglion (Figure 1C and D). What Is Your Diagnosis?

Maxillary carcinoma with perineural spread

Schwannoma

Invasive fungal sinusitis (mucormycosis) with perineural spread

Metastases from ovarian primary

C. Invasive fungal sinusitis (mucormycosis) with perineural spread

C

Invasive fungal sinusitis (mucormycosis) with perineural spread

Overall, imaging features are highly suggestive of invasive fungal sinusitis with distinctive perineural spread of infection along the facial nerve and occult spread to the mandibular nerve via their intraparotid intercommunication. The patient started taking antifungal therapy (liposomal amphotericin B), and a biopsy was performed from the cheek lesion that yielded granulomatous inflammation. The strong clinicoradiological suspicion of fungal disease prompted a functional endoscopic sinus surgery exploration, which revealed cheesy, purulent discharge in both maxillary sinuses. The posterior wall of maxillary sinus, which was destroyed and sequestrum-like, was sampled. Histopathological examination with a fluorescent stain (Calcofluor White Stain) and Gomori methenamine silver stain (as shown in Figure 2) revealed aseptate fungal hyphae, highly suggestive of mucormycosis. Automated culture reports showed good sensitivity to voriconazole, to which the patient showed good clinical response. Although perineural spread is classically encountered with head and neck malignant tumors, the diffuse maxillary sinusitis bilaterally without any mass in the presence of a history of cancer chemotherapy strongly suggests an infectious cause.Histopathological image demonstrates nonpigmented aseptate/pauciseptate, broad ribbonlike hyphae with morphologic features suggestive of Mucorales genera (Gomori methenamine silver, original magnification ×200).Mucormycosis is a dreaded fungal infection, with a predilection to affect immunocompromised individuals. Risk factors include poorly controlled diabetes, neutropenia, corticosteroids or other immunosuppressive therapy, and iron overload states. A surge in the incidence of mucormycosis cases was noted in the aftermath of rampant corticosteroid use during the COVID-19 pandemic.1Rhino-orbital-cerebral mucormycosis usually begins as acute sinusitis with fever, progressing rapidly to pansinusitis with involvement of contiguous structures, skull base, orbit, and brain. Pathogenetically, angioinvasion and resultant thrombotic infarction of tissues are the hallmarks of rhino-orbital-cerebral mucormycosis. Perineural spread is being increasingly recognized as a critical pathway of intracranial extension.2 The favorable neurotropic factor-rich intraneural microenvironment is cited by some as the underlying reason.3The trigeminal and facial nerves are commonly involved by mucor disease. Radiological features of perineural spread of infection may go overlooked unless looked for actively. Signs of perineural spread of infection are best detected by contrast-enhanced MRI4 (which may be supplemented with computed tomography), and can be presumed to show patterns similar to the perineural spread of tumor. The direct signs may range from subtle neural enhancement to exuberant nerve thickening with phlegmon formation. Other signs include effacement or obliteration of fat pads, neural foraminal widening, and, occasionally, changes of denervation in the territory of the involved nerve. Rarely, the disease may spread to involve the cranial nerve nucleus and brainstem.5,6 In our experience, high-resolution T1-weighted and T1 postcontrast images are extremely helpful in accurate depiction.Radiological detection of perineural spread of infection is critical for the timely institution of aggressive medical and surgical therapy. Thus, familiarity with patterns of spread of perineural infection and its accurate recognition is imperative for therapeutic planning.

General

A 47-year-old woman was seen with left-sided facial weakness and swelling for 2 months. She was diagnosed as having recurrent high-grade serous cystadenocarcinoma of the ovary and developed these symptoms after cycle 4 of chemotherapy. She was receiving oral antidiabetic agents, and her blood glucose level was 110 mg/dL (to convert to millimoles per liter, multiply by 0.0555). Physical examination findings were consistent with left lower-motor-neuron type of facial nerve palsy. She was conscious and well oriented, with no other relevant clinical signs or focal neurological deficits. There was no history of prior COVID-19 infection. Magnetic resonance imaging (MRI) of the brain was requested, with clinical suspicion of metastasis in view of mildly elevated CA125 levels.The results of MRI of the brain did not reveal any neuroparenchymal or meningeal lesions. However, both maxillary sinuses showed mucosal thickening, which was intermediate to hypointense on T2-weighted imaging and hypointense on T1-weighted imaging with postcontrast enhancement. Computed tomography sections confirmed bony destruction with foci of remodeling involving the walls of the maxillary sinuses (Figure 1).A, Axial T2-weighted magnetic resonance imaging (MRI) shows T2 heterogeneous soft tissue in the maxillary sinus with perimaxillary inflammatory changes (yellow arrowhead). B, In this axial contrast-enhanced, T1-weighted (T1 + C) image, linear enhancement corresponds to expected course of buccal branch of facial nerve (VII) (white arrow). The enhancement extends medially and involves the mandibular branch of the trigeminal nerve (V3). P indicates parotid gland, and the yellow dashed line outlines the edge of the parotid gland. B and C, The white arrow shows the intercommunication between the auriculotemporal branch of V3 and the intraparotid facial nerve (green marker). C, Additionally, involvement of enhanced thickening is seen up to the left foramen ovale, without involvement of the trigeminal ganglion. D, In oblique sagittal images, the thick enhancing branches of the facial nerves within the left parotid gland are seen (orange arrows). The enhancement of facial nerve extends up to the stylomastoid foramen (SMF) (blue arrow), and there is subtle enhancement along its mastoid segments (MSs). Iodinated contrast medium was used.Fat stranding and enhancing soft tissue was seen in the retroantral spaces bilaterally as well as the pterygopalatine fossae. Anteriorly, enhancing soft tissue was present in premaxillary space, from which contiguous linear enhancement was seen extending to left parotid gland—along the expected course of buccal branch of left facial nerve. The entire extracranial left facial nerve proximal to this showed diffuse enhancement and thickening. Associated stylomastoid foramen widening was present with subtle enhancement along its mastoid and tympanic segments. These features were compatible with perineural extension of disease (Figure 1A and B).Additionally, there was involvement of the mandibular branch of the trigeminal nerve via intercommunication between the auriculotemporal branch of trigeminal nerve and the intraparotid facial nerve. Diffuse enhancement and thickening was seen up to the left foramen ovale, without involvement of the trigeminal ganglion (Figure 1C and D).

what is your diagnosis?

What is your diagnosis?

Schwannoma

Metastases from ovarian primary

Maxillary carcinoma with perineural spread

Invasive fungal sinusitis (mucormycosis) with perineural spread

d

female

41-50

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2805459

A 46-year-old man presented for an evaluation of a lesion on the dorsal tongue. The patient was asymptomatic and unaware of the lesion prior to it being discovered by his dentist. He underwent incisional biopsy at another institution and presented for a second opinion on the diagnosis. Overall, he was in good health with no underlying systemic diseases. Results of the most recent serologic analysis and urinalysis were also reportedly within normal limits.The extraoral examination was unremarkable, with no skin lesions, asymmetry, redness, swelling, or lymphadenopathy observed. The intraoral examination revealed an erythematous denuded area of the midline posterior dorsal tongue, with a central nodular component (Figure 1A). The nodule was firm to palpation and nontender. The remaining oral soft tissue was unremarkable. Because a biopsy specimen was already obtained, blank slides were requested from the aforementioned institution, and staining was performed in house.A, Clinical examination revealed a pink nodule in the midline dorsal tongue with surrounding atrophic papillae. B, Hematoxylin-eosin stain of the biopsy specimen showed acellular, amorphous, and eosinophilic material arranged in lobules.Histologic evaluation revealed a piece of soft tissue with normal overlying epithelium. In the connective tissue, acellular, amorphous, and eosinophilic material arranged in lobules was noted (Figure 1B). What Is Your Diagnosis?

Fibroma

Granular cell tumor

Median rhomboid glossitis (nodular variant)

Localized amyloidosis (amyloidoma)

D. Localized amyloidosis (amyloidoma)

D

Localized amyloidosis (amyloidoma)

The differential diagnoses for a tongue nodule typically include entities commonly occurring in the oral cavity such as granular cell tumors and fibromas. Granular cell tumors appear as solitary lesions that are yellow or pink in color, with a predilection for the dorsal tongue.1 Fibromas most frequently present on the gingiva or buccal mucosa as a well-circumscribed, smooth-surfaced nodule with a rubbery consistency.2 Grossly, granular cell tumors are submucosal (ie, growing under the mucosa), while fibromas are exophytic (ie, arising from the surface). Microscopically, granular cell tumors contain infiltrative, nonencapsulated nests, cords, or sheets of polygonal cells with abundant eosinophilic, finely granular cytoplasm.3 These cells stain positive for S-100, suggesting a neural origin.3 Fibromas, on the other hand, contain dense, fibrous connective tissue that can be arranged in radiating, circular, or haphazard bundles.2Median rhomboid glossitis is included as one of the differential diagnoses because there was a well-demarcated and depapillated area in the midline of dorsal tongue, surrounding the nodule. The tongue surface involved in median rhomboid glossitis is often smooth and denuded but can also be lobulated or nodular.4 Median rhomboid glossitis is a form of localized, chronic fungal infection by Candida albicans, and the diagnosis can be confirmed with a fungal smear. Treatment for oral candidiasis involves a course of antifungal medication, typically nystatin rinse or clotrimazole troches.In the present case, the fungal smear was negative, and the clinical appearance of the tongue remained unchanged after a preemptive course of antifungal medication, which ruled out median rhomboid glossitis. Microscopic examination revealed deposits of homogenous, eosinophilic, amorphous material, arranging in lobules or sheets, in the submucosal connective tissue. This histologic feature excluded granular cell tumor and fibroma from the diagnosis and raised the possibility of amyloidosis. Under Congo red stain, the described material appeared red orange to salmon pink under regular light (Figure 2), with apple green birefringence under polarized light microscopy, thus confirming the presence of amyloid.Results of a Congo red stain highlighted amyloid deposit as salmon pink under regular light microscopy (original magnification ×40).In general, amyloidosis is a process that involves deposition of insoluble aggregates of misfolded fibrillary proteins called amyloidogenic proteins in an extracellular matrix of various organs and tissues.5 The 3 major forms of amyloidosis include primary systemic amyloidosis, secondary systemic amyloidosis, and localized amyloidosis (also known as amyloidoma). Some of the commonly affected organs include the heart, lungs, gastrointestinal tract, kidneys, nerves, muscle, and skin.6 Amyloid deposit in the oral cavity, specifically the tongue, is almost always associated with underlying diseases such as primary amyloidosis, multiple myeloma, or rheumatoid arthritis.7 Amyloidosis isolated to the tongue without involvement of other organs is extremely rare.5 Tongue-localized amyloidosis often presents as a single nodule in the median of the dorsal tongue, surrounded by an area of atrophic papillae, which mimics the appearance of median rhomboid glossitis. The papillary atrophy is thought to be due to the effect of amyloid deposition.5 Patients with tongue amyloidoma are generally asymptomatic, but dysarthria and dysphasia have been reported sporadically due to enlargement of tongue.7,8 The appropriate diagnosis of localized amyloidosis, however, should only be rendered after the other 2 major forms are ruled out. The reason being is that localized amyloidosis is considered a benign process with minimal risk of advancing into systemic disease, while the prognosis for primary and secondary systemic amyloidosis is considerably guarded with mean survival of 5 to 15 months.7 As such, extensive investigations are compulsory once a diagnosis of amyloidosis is made. Evaluation for systemic amyloid includes, but is not limited to, biopsy of abdominal fat or rectal mucosa, urine and serum electrophoresis, liver function tests, echocardiogram, and dynamic magnetic resonance imaging.7 Based on his unremarkable test values and imaging, the present patient was diagnosed with localized amyloidosis of the tongue.In terms of management, there has yet to be a consensus among clinicians, and treatment is often based on a patient’s symptoms. For patients with functional impairment, surgical removal is recommended, but recurrence has been reported.6 In this case, the patient reported minimal discomfort, so he elected for continued observation. Still, little is known about the true prognosis of localized amyloidosis due to its rarity, and careful long-term follow-up is strongly advised regardless to monitor for disease progression.

General

A 46-year-old man presented for an evaluation of a lesion on the dorsal tongue. The patient was asymptomatic and unaware of the lesion prior to it being discovered by his dentist. He underwent incisional biopsy at another institution and presented for a second opinion on the diagnosis. Overall, he was in good health with no underlying systemic diseases. Results of the most recent serologic analysis and urinalysis were also reportedly within normal limits.The extraoral examination was unremarkable, with no skin lesions, asymmetry, redness, swelling, or lymphadenopathy observed. The intraoral examination revealed an erythematous denuded area of the midline posterior dorsal tongue, with a central nodular component (Figure 1A). The nodule was firm to palpation and nontender. The remaining oral soft tissue was unremarkable. Because a biopsy specimen was already obtained, blank slides were requested from the aforementioned institution, and staining was performed in house.A, Clinical examination revealed a pink nodule in the midline dorsal tongue with surrounding atrophic papillae. B, Hematoxylin-eosin stain of the biopsy specimen showed acellular, amorphous, and eosinophilic material arranged in lobules.Histologic evaluation revealed a piece of soft tissue with normal overlying epithelium. In the connective tissue, acellular, amorphous, and eosinophilic material arranged in lobules was noted (Figure 1B).

what is your diagnosis?

What is your diagnosis?

Localized amyloidosis (amyloidoma)

Median rhomboid glossitis (nodular variant)

Fibroma

Granular cell tumor

a

male

41-50

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2805464

A man in his 80s presented to the emergency department with a 4-week history of progressive weakness and fatigue, with associated development of purple bruiselike lesions on his head. He denied any history of trauma, falls, or occlusive headgear use. His medical history was significant for atrial fibrillation, receiving anticoagulation medication, and heart failure.On physical examination, numerous nontender violaceous plaques were seen on the forehead and scalp of the patient (Figure, A). On full skin examination, nonspecific skin-colored plaques were noted on the chest, and a 1.8 × 2.5-cm erythematous plaque was noted on the left lower back. There was no appreciable lymphadenopathy or hepatosplenomegaly. Peripheral blood test results revealed a hemoglobin level of 9.1 g/dL, a platelet count of 68 × 103/μL, a white blood cell count of 2800/μL, and an absolute neutrophil count of 1.0/μL. Lactate dehydrogenase level was 202 U/L. (To convert hemoglobin to g/L, multiply by 10.0; platelets to ×109/L, by 1; white blood cell and neutrophil counts to ×109/L, by 0.001; and lactate dehydrogenase to μkat/L, by 0.0167.) A 4-mm punch biopsy was performed on the erythematous plaque on the left lower back (Figure, B and C).A, Violaceous plaques on the scalp. B, Punch biopsy showing a grenz zone and infiltrate extending into deeper dermis (hematoxylin-eosin). C, Punch biopsy showing cellular infiltrate of basophilic blastoid cells (hematoxylin-eosin). D, Punch biopsy showing cellular infiltrate with CD123 staining. What Is Your Diagnosis?

Metastatic renal cell carcinoma

Blastic plasmacytoid dendritic cell neoplasm

Epithelioid angiosarcoma

Myeloid leukemia cutis

B. Blastic plasmacytoid dendritic cell neoplasm

B

Blastic plasmacytoid dendritic cell neoplasm

Histological assessment of skin biopsy revealed superficial and middermal infiltrate of small to medium basophilic blastoid cells, extending into the subcutaneous tissue and sparing epidermis with a grenz zone. Immunohistochemistry was positive for CD123 (Figure, D), CD4, CD56, CD7, and CD45, whereas myeloperoxidase was negative. The MIB-1 proliferation index was elevated at 70%. Overall, these findings were consistent with cutaneous blastic plasmacytoid dendritic cell neoplasm (BPDCN). A bone marrow biopsy was subsequently performed; this revealed hypercellular marrow for age, with estimated cellularity of 90%. Most cells were medium-large blasts that were positive for CD4, CD56, CD68, and CD123 and negative for CD34 and CD117. Hematologists noted the profile, occurring in the absence of myeloid and lymphoid lineage specific markers, as being effectively pathognomonic BPDCN.Following initial diagnosis, tagraxofusp was considered for management. This is a CD123-directed cytotoxin consisting of recombinant human interleukin 3 fused to a truncated diphtheria toxin. It comes from the breakthrough discovery that all BPDCNs overexpress CD123, subsequently leading to the first targeted and first approved therapy for BPDCN, tagraxofusp.1 Unfortunately, because of the patient’s significant comorbid status, this was not pursued.Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive hematological malignancy. Previously considered a subtype of acute myeloid leukemia in the 2008 revision of the World Health Organization classification, the 2022 update shows BPDCN reclassified as its own entity.2 It presents a diagnostic and therapeutic challenge, with poor prognosis regardless of diagnostic stage. Dermatologists may be the first physicians consulted, with cutaneous manifestations featuring as presenting signs in 90% of cases—predating dissemination by months.3 Median survival ranges from 9 to 23 months. Incidence is 3 times higher in men. Only those fit to undergo hematopoietic stem cell transplant obtain prolonged remission. Most patients are older adult and frail individuals, unsuitable for such therapies.3 For cutaneous-limited disease, excision and radiotherapy allow local resolution but fail to prevent systemic recurrences.4Pathogenesis of cutaneous tropism remains unknown. Hypotheses include expression of skin-migration molecules by neoplastic cells and chemokine receptors CXCR3 and CXCR4 with potent chemotactic activity for lymphocytes in the local cutaneous microenvironment.5,6 Skin manifestations are heterogeneous, and the trunk is frequently affected. Solitary or disseminated plaques and nodules are most common. Other presentations include morbilliform exanthem. Patients with bruiselike lesions (35% of cases) experience longer diagnostic delay secondary to misidentification of lesions.7 Mucosal involvement occurs in a minority of patients as purple macules, papules, or nodules. Extensive cutaneous involvement at diagnosis increases the likelihood of systemic involvement; however, survival does not correlate with the extent or morphologic features of skin disease. Skin biopsies are critical for diagnosis and should include deep dermis, as BPDCN often spares epidermis.5As exemplified in the present case, most patients are older adult men presenting with fatigue alongside new plaques, nodules, or bruiselike lesions. Two-thirds of patients display extracutaneous involvement at the time of diagnosis. This can manifest as lymphadenopathy, hepatosplenomegaly, and cytopenia. The differential diagnosis includes myeloid leukemia cutis. Similarities in both clinical and histopathological appearance preclude easy differentiation, and immunohistochemical staining is required. Positivity for CD4 and CD56 in combination with CD123 (diffuse staining), blood dendritic cell antigen 2, T-cell leukemia/lymphoma protein 1, and transcription factor 4 would support a diagnosis of BPDCN. Acute myeloid leukemia and myeloid sarcoma typically show positivity for CD34, CD117, and myeloperoxidase.8 Skin metastasis from renal cell carcinomas can present as similar rapidly growing lesions. Classic clear cell histological features would show neoplastic cells with ample lipid-rich cytoplasm arranged in nests with a delicate branching fibrovascular network.9 Epithelioid angiosarcoma is another possibility based on macroscopic appearance, but histological features would show poorly formed vascular channels with atypical endothelial cells with abundant eosinophilic to amphophilic cytoplasm and positivity for endothelial cell markers such as CD31 and ERG.10

Dermatology

A man in his 80s presented to the emergency department with a 4-week history of progressive weakness and fatigue, with associated development of purple bruiselike lesions on his head. He denied any history of trauma, falls, or occlusive headgear use. His medical history was significant for atrial fibrillation, receiving anticoagulation medication, and heart failure.On physical examination, numerous nontender violaceous plaques were seen on the forehead and scalp of the patient (Figure, A). On full skin examination, nonspecific skin-colored plaques were noted on the chest, and a 1.8 × 2.5-cm erythematous plaque was noted on the left lower back. There was no appreciable lymphadenopathy or hepatosplenomegaly. Peripheral blood test results revealed a hemoglobin level of 9.1 g/dL, a platelet count of 68 × 103/μL, a white blood cell count of 2800/μL, and an absolute neutrophil count of 1.0/μL. Lactate dehydrogenase level was 202 U/L. (To convert hemoglobin to g/L, multiply by 10.0; platelets to ×109/L, by 1; white blood cell and neutrophil counts to ×109/L, by 0.001; and lactate dehydrogenase to μkat/L, by 0.0167.) A 4-mm punch biopsy was performed on the erythematous plaque on the left lower back (Figure, B and C).A, Violaceous plaques on the scalp. B, Punch biopsy showing a grenz zone and infiltrate extending into deeper dermis (hematoxylin-eosin). C, Punch biopsy showing cellular infiltrate of basophilic blastoid cells (hematoxylin-eosin). D, Punch biopsy showing cellular infiltrate with CD123 staining.

what is your diagnosis?

What is your diagnosis?

Myeloid leukemia cutis

Blastic plasmacytoid dendritic cell neoplasm

Metastatic renal cell carcinoma

Epithelioid angiosarcoma

b

male

81-90

White

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2805527

A man in his late 60s was referred to the dermatologic clinic with a 10-day history of fever up to 38.5 °C and tender lesions on the neck and trunk. In the previous month, he had received the first cycle of a chemotherapeutic regimen of ixazomib, lenalidomide, and dexamethasone to treat a recurrence of IgG-κ multiple myeloma with a 10-year history. Physical examination showed annular erythematous plaques of up to 2 cm in diameter, with violaceous and crusted centers on the neck and trunk. On the right chest, an annular erythematous lesion with 2 zones of color—a central area of purpura and an outer erythematous and edematous ring—was present (Figure, A). Laboratory investigations found pancytopenia: a white blood cell count of 2.3 × 103/μL (reference range, 3.5-9.8 × 103/μL), hemoglobin levels of 12.1 g/dL (reference range, 13.5-17.6 g/dL), platelet count of 29 × 103/μL (reference range, 130-400 × 103μL), and elevated serum C-reactive protein levels of 3.31 mg/dL (reference range, <0.30 mg/dL). Blood culture results were negative. Granulocyte colony-stimulating factor analogs had not been prescribed to the patient. Skin biopsy from a lesion on the left chest was performed for histopathological and immunohistochemical analyses (Figure, B-D).A, Clinical image of annular erythematous plaques on the chest. B, A histopathologic image revealing inflammatory infiltrate of predominantly mononuclear cells in the superficial and mid dermis (hematoxylin-eosin stain). C, The predominantly infiltrated cells showing large, elongated, vesicular nuclei, single inconspicuous nucleoli, and scant, slightly eosinophilic cytoplasm (hematoxylin-eosin stain). D, An immunohistochemical image showing myeloperoxidase-positive cells. What Is Your Diagnosis?

Cutaneous involvement of multiple myeloma

Erythema multiforme

Histiocytoid Sweet syndrome

Cutaneous cryptococcosis

C. Histiocytoid Sweet syndrome

C

Histiocytoid Sweet syndrome

Skin biopsy revealed inflammatory infiltrate predominantly composed of mononuclear cells that showed large, elongated, vesicular nuclei, single inconspicuous nucleoli, and scant, slightly eosinophilic cytoplasm in the superficial and mid dermis. Nuclear dust was present, but there was no obvious leukocytoclastic vasculitis. Edema of the papillary dermis was not conspicuous (Figure, B and C). Immunohistochemical studies revealed that the mononuclear cells had positive results for CD68 and myeloperoxidase (Figure, D), but negative results for CD138. Histiocytoid Sweet syndrome (HSS) was diagnosed. Treatment with oral prednisolone at 0.3 mg/kg per day was initiated. The fever and cutaneous lesions subsided within 2 weeks. Treatment with another chemotherapeutic regimen of isatuximab, pomalidomide, and dexamethasone was initiated for the multiple myeloma. At 2-month follow-up, no recurrence of the skin lesions was seen, and the progression of multiple myeloma was controlled.Histiocytoid Sweet syndrome, an infrequent, histopathologic variant of Sweet syndrome, was first described by Requena et al1 in 2005. It is believed that the dermal infiltrates mainly consist of myeloperoxidase-positive immature myelomonocytic cells with a histiocytoid morphology. The clinical symptoms of HSS resemble those of classic neutrophilic Sweet syndrome, namely, acute-onset tender erythematous plaques, fever, and leukocytosis with neutrophilia. However, a few cases of HSS with atypical neutropenia have been reported, and these were associated with trimethoprim/sulfamethoxazole therapy or hematological malignant diseases.2 Both HSS and classic neutrophilic Sweet syndrome can be associated with upper respiratory tract infections, inflammatory bowel diseases, rheumatic arthritis, drugs, and hematologic disorders such as myelodysplastic syndrome, leukemia, and multiple myeloma.1,3 Compared with classical neutrophilic Sweet syndrome, it has been suggested that HSS may be more commonly associated with myelodysplastic syndrome and hematologic malignant diseases.3 Several drugs have been associated with HSS, such as trimethoprim/sulfamethoxazole, azacitidine, and piperacillin tazobactam, as well as proteasome inhibitors including bortezomib and ixazomib.3,4 In the only report of ixazomib-associated HSS that we could identify, HSS occurred after the first cycle of the chemotherapy as in this patient.4 Some case reports have suggested that lenalidomide may be associated with neutrophilic Sweet syndrome.5 However, to our knowledge, there is no reported case of lenalidomide-associated HSS. Because a challenge test could not be conducted, both factors—the recurrence of multiple myeloma and the drug (ixazomib or lenalidomide)—were still possible associated factors in the finding of HSS in the present case.The differentials in this case include cutaneous involvement of multiple myeloma, erythema multiforme, and cutaneous cryptococcosis. Cutaneous involvement of multiple myeloma occurs in approximately 1% of multiple myeloma cases, especially in cases with relapse or advance of multiple myeloma. Such involvement presents as erythematous, violaceous, or skin-colored plaques and nodules preferentially on the trunk and extremities. Immunohistochemical investigations for plasma cell markers including CD138 are required to rule out a cutaneous lesion of multiple myeloma.6 Erythema multiforme may be a likely differential diagnosis in this patient because of a targetoid lesion. In addition, lenalidomide has been reported as a possible factor in erythema multiforme, although only in rare cases.7 However, erythema multiforme presents with true target lesions with at least 3 zones of color, and the histopathologic findings of interface dermatitis help to confirm the diagnosis.8 Cutaneous cryptococcosis has been associated with HIV/AIDS and other sources of immunosuppression, including hematological malignant diseases and the administration of systemic immunosuppressive therapies. The lesions predominantly occur on the head, neck, and limbs, and have various clinical features, including acneiform papules, violaceous plaques, nodules, blisters, and ulcers.9 In addition to the clinical resemblance between Sweet syndrome and cutaneous cryptococcosis, the histologic findings of dermal infiltration of myeloperoxidase-positive myeloid cells with a surrounding halo, which are morphologically suggestive of cryptococcal organisms, have been described in cases of neutrophilic Sweet syndrome and HSS (cryptococcoid Sweet syndrome).10 Cryptococcus in biopsy specimens can be identified as fungal elements surrounded by a bright area (a polysaccharide capsule) with hematoxylin-eosin staining. Pathogens are stained by periodic acid-Schiff stain and Grocott methenamine silver stain, and their capsules are stained by mucicarmine. Tzanck smear (Giemsa stain) and India ink method from a skin lesion may show the encapsulated yeast form of Cryptococcus. Cultures should be performed to isolate and identify the pathogenic fungi.9Most cases of HSS have been successfully treated with oral corticosteroids.1 In cases of drug-induced HSS, the causative drug should be stopped.

Dermatology

A man in his late 60s was referred to the dermatologic clinic with a 10-day history of fever up to 38.5 °C and tender lesions on the neck and trunk. In the previous month, he had received the first cycle of a chemotherapeutic regimen of ixazomib, lenalidomide, and dexamethasone to treat a recurrence of IgG-κ multiple myeloma with a 10-year history. Physical examination showed annular erythematous plaques of up to 2 cm in diameter, with violaceous and crusted centers on the neck and trunk. On the right chest, an annular erythematous lesion with 2 zones of color—a central area of purpura and an outer erythematous and edematous ring—was present (Figure, A). Laboratory investigations found pancytopenia: a white blood cell count of 2.3 × 103/μL (reference range, 3.5-9.8 × 103/μL), hemoglobin levels of 12.1 g/dL (reference range, 13.5-17.6 g/dL), platelet count of 29 × 103/μL (reference range, 130-400 × 103μL), and elevated serum C-reactive protein levels of 3.31 mg/dL (reference range, <0.30 mg/dL). Blood culture results were negative. Granulocyte colony-stimulating factor analogs had not been prescribed to the patient. Skin biopsy from a lesion on the left chest was performed for histopathological and immunohistochemical analyses (Figure, B-D).A, Clinical image of annular erythematous plaques on the chest. B, A histopathologic image revealing inflammatory infiltrate of predominantly mononuclear cells in the superficial and mid dermis (hematoxylin-eosin stain). C, The predominantly infiltrated cells showing large, elongated, vesicular nuclei, single inconspicuous nucleoli, and scant, slightly eosinophilic cytoplasm (hematoxylin-eosin stain). D, An immunohistochemical image showing myeloperoxidase-positive cells.

what is your diagnosis?

What is your diagnosis?

Cutaneous involvement of multiple myeloma

Histiocytoid Sweet syndrome

Cutaneous cryptococcosis

Erythema multiforme

b

male

0-10

White

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2805562

A 6-year child presented with headache for 1 month and seizures followed by altered consciousness for 1 day. He had new-onset daily occipital headache for 1 month of mild to moderate severity and pulsating character. Occasionally, the headache became severe accompanied by vomiting, photophobia, and phonophobia. The child had 4 to 5 episodes of generalized tonic-clonic seizures 1 day prior to admission. He remained unconscious for several hours and spontaneously regained consciousness over 24 hours. There was no history of fever, weight loss, limb weakness, vision impairment, or any strokelike illness. His birth and developmental history were unremarkable.On examination, his pulse rate was 80 beats per minute (regular) with all peripheral pulses palpable without any radio-femoral delay. His blood pressure was 170/110 mm Hg with less than 10 mm Hg difference of systolic and diastolic blood pressure in other limbs. Abdominal examination revealed abdominal bruit. Fundus examination revealed papilledema with changes of hypertensive retinopathy. He was not oriented to place and time. The cranial nerves, motor, sensory, and autonomic system examination were unremarkable. Meningeal signs were absent. There was no evidence of neurocutaneous markers. His cranial magnetic resonance imaging revealed bilateral white matter hyperintensity that was more marked in the bilateral parieto-occipital region. Ultrasound of the abdomen revealed a small right kidney and renal Doppler was suggestive of right renal-artery stenosis. His computed tomography angiography revealed short segment (3 cm) and short circumferential thickening of the descending aorta with right renal artery narrowing (Figure 1). His repeat cranial magnetic resonance imaging showed significant reduction in the white matter hyperintensities.Maximum-intensity projection computed tomography (CT) angiography abdomen axial section (thickness 7 mm) (A) showing narrowing of whole length of right renal artery and thickened abdominal aortal wall (black arrowhead) and coronal section (B) showing small asymmetrical right kidney and compensatory enlarged left kidney. What Is Your Diagnosis?

Moyamoya disease with renovascular hypertension

Atherosclerotic disease

Fibromuscular dysplasia

Takayasu arteritis

D. Takayasu arteritis

D

Takayasu arteritis

The correct diagnosis is Takayasu arteritis. Takayasu arteritis is a chronic granulomatous vasculitis that affects the tunica media of medium/large arteries and produces narrowing, stenosis, and aneurysmal dilatation of aorta and its branches.1 In this patient, narrowing of whole length of the renal artery from its origin, involvement of ostia, and thickening of the wall of aorta favored the diagnosis of Takayasu arteritis. Atherosclerosis and fibromuscular dysplasia are the common causes of renovascular hypertension in adults and children, respectively.2 Atherosclerosis is characterized by presence of atheroma at the bifurcation of the renal artery and abdominal aorta. Absence of atheroma at origin of the renal artery and narrowing of its whole length is against atherosclerosis. Fibromuscular dysplasia is a nonatherosclerotic, noninflammatory vascular disease that mainly affects coronary and renal arteries. It rarely affects the aorta and involves the distal part of the renal artery and spares ostia.3 Moyamoya disease is a nonatherosclerotic cerebrovascular disease that presents with supraclinoid stenosis of internal carotid arteries and produces extensive collaterals. Children present with moyamoya disease with cerebral ischemic events whereas adults may present with cerebral ischemia or intracerebral hemorrhage. Moyamoya disease may present with renovascular hypertension in 5% to 8% children and 28.8% in adults.4 Moyamoya disease affects one-third of the length of the main renal artery and spares the ostia and rarely involves aorta.5Takayasu arteritis is rarely associated with posterior reversible encephalopathy syndrome. It presents with an early systemic phase characterized by malaise, myalgia, weight loss, and fever, and the late vaso-occlusive phase that manifests with stroke, syncope, limb claudication, pulselessness, hypertension, and vascular bruit. Early systemic manifestations are usually missed in children. Headache, cardiomyopathy, kidney failure, and systolic hypertension are significantly more common in children compared with adults.1 The markers of inflammation-like raised C-reactive protein, erythrocyte sedimentation rate, fibrinogen, β-2-microglobulin, haptoglobin, and orosomucoid are elevated. However, there are not diagnostic of Takayasu arteritis.1 Takayasu arteritis should be suspected in any child that presents with hypertension or its complications. Diagnosis is usually based on presence of hypertension, pulse deficit or claudication, blood pressure discrepancies in limbs, bruits, and angiographic abnormalities. The updated consensus criteria for diagnosis of Takayasu arteritis requires angiographic abnormality (aneurysm/dilatation, narrowing, occlusion, or thickened arterial wall) of the aorta or its main branches, coronaries, or pulmonary arteries not because of fibromuscular dysplasia or similar causes.6 Differential diagnosis of Takayasu arteritis includes giant-cell arteritis that involves large vessels in adults, medium-sized vasculitis with cross-symptomatology, like Kawasaki disease that involves coronaries, polyarteritis nodosa with mesenteric, and kidney involvement and systemic lupus erythematosus. The treatment of Takayasu arteritis includes control of hypertension, oral glucocorticoids, and immunosuppressants to control the disease activity, aspirin, and specific treatment of vaso-occlusive disease. This child showed recovery from headache and adequate control of hypertension while receiving amlodipine and an angiotensin-converting enzyme inhibitor. He was given oral corticosteroids and not offered kidney angioplasty due to poor function of the right kidney on diethylenetriamine pentaacetic acid scan.Posterior reversible encephalopathy syndrome is rare in children, mostly seen in the setting of acute lymphocytic leukemia during the induction phase of chemotherapy or rarely during hemopoietic stem cell transplantation. Cerebral autodysregulation due to hypertension produces vasodilatation and widening of endothelial tight junctions that produces vasogenic edema, predominantly in the occipital region due to relative lack of sympathetic fibers around arteries of posterior circulation. Headaches, seizures, and altered mental status are the main clinical features.7Takayasu arteritis frequently presents with hypertension in children, which makes it an ideal setting for the development of posterior reversible encephalopathy syndrome.

Neurology

A 6-year child presented with headache for 1 month and seizures followed by altered consciousness for 1 day. He had new-onset daily occipital headache for 1 month of mild to moderate severity and pulsating character. Occasionally, the headache became severe accompanied by vomiting, photophobia, and phonophobia. The child had 4 to 5 episodes of generalized tonic-clonic seizures 1 day prior to admission. He remained unconscious for several hours and spontaneously regained consciousness over 24 hours. There was no history of fever, weight loss, limb weakness, vision impairment, or any strokelike illness. His birth and developmental history were unremarkable.On examination, his pulse rate was 80 beats per minute (regular) with all peripheral pulses palpable without any radio-femoral delay. His blood pressure was 170/110 mm Hg with less than 10 mm Hg difference of systolic and diastolic blood pressure in other limbs. Abdominal examination revealed abdominal bruit. Fundus examination revealed papilledema with changes of hypertensive retinopathy. He was not oriented to place and time. The cranial nerves, motor, sensory, and autonomic system examination were unremarkable. Meningeal signs were absent. There was no evidence of neurocutaneous markers. His cranial magnetic resonance imaging revealed bilateral white matter hyperintensity that was more marked in the bilateral parieto-occipital region. Ultrasound of the abdomen revealed a small right kidney and renal Doppler was suggestive of right renal-artery stenosis. His computed tomography angiography revealed short segment (3 cm) and short circumferential thickening of the descending aorta with right renal artery narrowing (Figure 1). His repeat cranial magnetic resonance imaging showed significant reduction in the white matter hyperintensities.Maximum-intensity projection computed tomography (CT) angiography abdomen axial section (thickness 7 mm) (A) showing narrowing of whole length of right renal artery and thickened abdominal aortal wall (black arrowhead) and coronal section (B) showing small asymmetrical right kidney and compensatory enlarged left kidney.

what is your diagnosis?

What is your diagnosis?

Moyamoya disease with renovascular hypertension

Atherosclerotic disease

Takayasu arteritis

Fibromuscular dysplasia

c

male

0-10

White

original

https://jamanetwork.com/journals/jama/fullarticle/2806233

A 70-year-old man presented to the dermatology clinic for evaluation of a pruritic exanthem that began on his scalp and face and spread across most of his body over a 2-month period. The patient had no fever, night sweats, fatigue, recent unintentional weight loss, shortness of breath, chest pain, nausea, vomiting, or diarrhea. He reported no new prescription medications, over-the-counter drugs, or herbal supplements prior to the onset of the exanthem. He had no history of psoriasis, atopic dermatitis, or other skin disorder, and no recent viral or bacterial infection. On presentation, his temperature was 37.1 °C (98.7 °F); blood pressure, 128/86 mm Hg; heart rate, 110/min; and respiratory rate, 30/min. Physical examination revealed confluent salmon-colored plaques composed of folliculocentric scaly papules across his body with several patches of unaffected skin on his trunk. The patient had waxy, exfoliative scale on the volar aspect of his hands and feet and thickened, onycholytic nails. Severe ectropion prevented complete eyelid closure (Figure). He was referred to the emergency department, where laboratory testing revealed a normal complete blood cell count and normal lactate dehydrogenase level. The patient was admitted to the hospital and was treated with intravenous fluids and daily wet-wrap therapy with topical triamcinolone ointment (0.1%) applied to his trunk, arms, and legs, followed by a layer of warm, damp gauze and dry, cotton pajamas.Clinical examination at the time of presentation revealed generalized and coalescing salmon-colored plaques with “islands of sparing” on the abdomen (far left); waxy, exfoliative scale on the palms (center left) and soles (center right); and ectropion (far right). What Would You Do Next?

Order a myositis-specific autoantibody panel

Obtain skin biopsy with T-cell clonality studies

Order testing for anti–double-stranded DNA (dsDNA) antibody

Order testing for HLA-B27

Erythrodermic pityriasis rubra pilaris

B

Obtain skin biopsy with T-cell clonality studies

The key to the correct diagnosis is recognition that generalized salmon-colored plaques with areas of unaffected skin (“islands of sparing”) and waxy palmoplantar keratoderma are characteristic of pityriasis rubra pilaris (PRP).1 Testing for myositis-specific autoantibodies (choice A), anti-dsDNA (choice C), and HLA-B27 (choice D) is incorrect because the patient’s skin findings were not typical of dermatomyositis, systemic lupus erythematosus, or reactive arthritis, respectively.Erythroderma, also known as exfoliative dermatitis, is diffuse dermal erythema and scaling involving more than 90% of the body surface area.1 Erythroderma is a dermatologic emergency because it may cause excessive loss of fluid and heat, which can lead to hypothermia and rigors, dehydration, hypotension, and high-output cardiac failure.2 Due to disruption of the skin barrier, erythroderma is also associated with increased risk of cellulitis. Erythroderma is most commonly associated with psoriasis or atopic dermatitis but can occur in patients with infections (eg, HIV, scabies), malignancy (eg, cutaneous T-cell lymphoma), medications (eg, antibiotics, anticonvulsants), and congenital skin diseases.1PRP is a rare, inflammatory disorder that may cause erythroderma, especially in adults.3 Of the 6 clinical subtypes of PRP, type I (classic adult) is the most common, accounting for 55% of cases.3,4 Patients with type I PRP have waxy palmoplantar keratoderma and salmon-colored plaques with sharply-demarcated areas of spared skin that typically start on the upper half of the body and spread downward. Hyperkeratotic nail changes, nonscarring hair loss, and ectropion are also common findings in type I PRP.3,4 The other PRP subtypes are type II (atypical adult), type III (classical juvenile), type IV (circumscribed juvenile), type V (atypical juvenile), and type VI (HIV-related).3PRP affects males and females of all ages, and incidence peaks in children at age 1 to 10 years and in adults at age 50 to 60 years.3,4 The US Health and Human Services Genetic and Rare Diseases Information Center estimates that fewer than 5000 people in the US currently have PRP.5 Although the pathophysiology of PRP is unknown, some cases may be precipitated by bacterial or viral infections.3 Some patients with PRP type V have an autosomal dominantly–acquired or sporadic genetic variant of caspase recruitment domain family, member 14 (CARD14), which is an activator of a signaling pathway involved in inflammation.3,4The differential diagnosis of erythrodermic PRP includes psoriasis, atopic dermatitis, cutaneous T-cell lymphoma, generalized hypersensitivity reactions, immunobullous diseases, acquired ichthyoses, and erythrokeratoderma variabilis.4 The diagnosis of PRP is made based on clinical findings and histopathological characteristics on skin biopsy.3,4 T-cell clonality studies should be obtained for patients with erythroderma and ectropion and/or palmoplantar keratoderma to evaluate for Sezary syndrome, a distinctive form of erythrodermic cutaneous T-cell lymphoma with leukemic involvement of malignant T cells. The prognosis of PRP varies among subtypes.1Although no evidence-based guidelines exist for treatment of PRP, common treatments include topical corticosteroids, methotrexate, systemic retinoids, phototherapy, and cyclosporine.3,4,6 Improvement or resolution of PRP has been reported with use of biologic therapies (such as tumor necrosis factor inhibitors and anti–IL-17 or anti–IL-12/IL-23 biologics) in case reports and small case series.3,7-9A skin biopsy sample from the patient’s upper back revealed acanthosis with broad rete ridges, confluent hypergranulosis, and alternating orthokeratosis and parakeratosis, consistent with the diagnosis of PRP. Flow cytometry and T-cell clonality studies did not reveal findings characteristic of Sezary syndrome, and results of HIV testing were negative. During his hospitalization, the patient was treated with acitretin (50 mg daily), methotrexate (25 mg weekly), infliximab (10 mg/kg every 4 weeks), and topical triamcinolone ointment (0.1%). Six months later, his erythroderma had resolved, and he underwent oculoplastic surgery for repair of his ectropion. At his most recent clinic visit, 3 years after initial presentation, the patient was taking infliximab (5 mg/kg every 6 weeks) and methotrexate (12.5 mg weekly), and findings on skin examination were normal.

General

A 70-year-old man presented to the dermatology clinic for evaluation of a pruritic exanthem that began on his scalp and face and spread across most of his body over a 2-month period. The patient had no fever, night sweats, fatigue, recent unintentional weight loss, shortness of breath, chest pain, nausea, vomiting, or diarrhea. He reported no new prescription medications, over-the-counter drugs, or herbal supplements prior to the onset of the exanthem. He had no history of psoriasis, atopic dermatitis, or other skin disorder, and no recent viral or bacterial infection. On presentation, his temperature was 37.1 °C (98.7 °F); blood pressure, 128/86 mm Hg; heart rate, 110/min; and respiratory rate, 30/min. Physical examination revealed confluent salmon-colored plaques composed of folliculocentric scaly papules across his body with several patches of unaffected skin on his trunk. The patient had waxy, exfoliative scale on the volar aspect of his hands and feet and thickened, onycholytic nails. Severe ectropion prevented complete eyelid closure (Figure). He was referred to the emergency department, where laboratory testing revealed a normal complete blood cell count and normal lactate dehydrogenase level. The patient was admitted to the hospital and was treated with intravenous fluids and daily wet-wrap therapy with topical triamcinolone ointment (0.1%) applied to his trunk, arms, and legs, followed by a layer of warm, damp gauze and dry, cotton pajamas.Clinical examination at the time of presentation revealed generalized and coalescing salmon-colored plaques with “islands of sparing” on the abdomen (far left); waxy, exfoliative scale on the palms (center left) and soles (center right); and ectropion (far right).

what would you do next?

What would you do next?

Order testing for anti–double-stranded DNA (dsDNA) antibody

Order testing for HLA-B27

Order a myositis-specific autoantibody panel

Obtain skin biopsy with T-cell clonality studies

d

male

61-70

original

https://jamanetwork.com/journals/jama/fullarticle/2805120

An 80-year-old man presented to the emergency department with a 5-day history of fever and right shoulder pain. His temperature was 37.9 °C (100.2 °F); heart rate, 74/min; and blood pressure, 90/49 mm Hg. He had tenderness to palpation and decreased range of motion of his right shoulder. Laboratory testing showed a white blood cell count of 9.6 ×  109/L (reference, 4.0-9.0 × 109/L); C-reactive protein level, 35.6 mg/dL (reference, <0.3 mg/dL), and creatine kinase level, 1036 U/L (17.30 μkat/L) (reference, 60-270 U/L [1.00-4.51 μkat/L]). Magnetic resonance imaging revealed an effusion and synovial thickening with enhancement in the right shoulder joint and inflammation in the right subscapularis muscle. Gram stain of the synovial fluid revealed gram-positive cocci in clusters. Intravenous cefazolin therapy was initiated, and he underwent right shoulder joint arthroscopic irrigation, synovectomy, and surgical drainage for subscapularis pyomyositis. Blood and synovial fluid cultures grew methicillin-susceptible Staphylococcus aureus, and intravenous cefazolin was continued. One week after hospitalization, the patient developed asymptomatic black discoloration of the dorsal surface of his tongue (Figure). He reported no prior lingual discoloration and did not smoke cigarettes, use chewing tobacco or illicit drugs, or drink alcohol.Elongated filiform papillae and black discoloration of patient’s tongue. What Would You Do Next?

Measure serum cortisol level

Perform a tongue biopsy

Provide reassurance and prescribe oral care

Stop cefazolin

Black hairy tongue (lingua villosa nigra)

C

Provide reassurance and prescribe oral care

The key to the correct diagnosis is recognizing that black tongue discoloration in an older male patient undergoing treatment with antimicrobial therapy is characteristic of black hairy tongue. Choice A is incorrect because the patient did not have physical signs or symptoms consistent with Addison disease. A tongue biopsy (choice B) is an invasive procedure not typically needed to make the diagnosis of black hairy tongue. Discontinuing cefazolin (choice D) is not recommended because this antibiotic is the preferred treatment for methicillin-susceptible S aureus bacteremia and septic arthritis of the shoulder.Black hairy tongue, also known as lingua villosa nigra, is characterized by discoloration of the dorsal surface of the tongue and hypertrophied, filiform papillae that are longer than 3 mm and wider than 2 mm and that appear like hair growth on the tongue.1,2 Although patients typically have a black-colored tongue, the tongue may appear brown or, less commonly, yellow, green, or blue.3 Most patients with black hairy tongue are asymptomatic, but some may present with halitosis, dysgeusia, gagging, nausea, xerostomia, and pain or burning of the tongue.1,4 The diagnosis of black hairy tongue is typically made by visual inspection, but dermoscopy is sometimes used to evaluate the filiform papillae.1-3The exact pathophysiology of black hairy tongue remains unclear, but the condition may be caused by defective desquamation of the dorsal tongue, leading to accumulation of keratinized layers that elongate the filiform papillae.1 These papillae accumulate bacteria, fungi, and residue from food, coffee, tea, and tobacco.1,4 Discoloration of the tongue may also be caused by porphyrin-producing chromogenic bacteria or yeast, although no specific bacteria or yeast have been identified as causing black hairy tongue.1,2Factors associated with black hairy tongue include certain behaviors, such as smoking or chewing tobacco, alcohol use, heavy black tea consumption, illicit drug use, poor dental hygiene, and excessive use of oxidizing mouth washes that contain sodium perborate, sodium peroxide, and hydrogen peroxide.1 Medications associated with black hairy tongue include many antibiotics, antipsychotic drugs that cause xerostomia (eg, olanzapine and chlorpromazine), and some chemotherapeutic agents (eg, erlotinib).1-3,5 Patients who are edentulous or who have HIV, advanced cancer, graft-vs-host disease, trigeminal neuralgia, amyotrophic lateral sclerosis, or chronic xerostomia, or who have received recent radiation therapy to the head or neck, are at increased risk of black hairy tongue.1,2,4 Black hairy tongue has also been reported in patients with COVID-19.6Although the exact prevalence of black hairy tongue is unknown and varies among populations, studies of dental and oral medicine outpatients have reported a prevalence of 1.2% to 11.3%.4,7-9 Black hairy tongue is 3 times more common in males than females, which may be due to higher rates of cigarette smoking and poor oral hygiene among men.1 The prevalence of black hairy tongue also increases with advancing age, especially after age 60 years.1Black hairy tongue should be differentiated from pseudo–black hairy tongue, a condition in which the tongue is darkly stained due to medications (eg, bismuth subsalicylate or minocycline), chemicals, or food coloring, but the filiform papillae are not enlongated.2,4 The differential diagnosis of black hairy tongue includes pigmented fungiform papillae of the tongue, acanthosis nigricans, congenital lingual melanotic macules, oral hairy leukoplakia, congenital melanocytic nevi, premalignant leukoplakia, squamous cell carcinoma, and hypertrophic herpes simplex virus infection.2Aside from cosmetic concerns, black hairy tongue is benign. Treatment consists of providing reassurance to the patient, removing possible causative factors, gentle debridement with a toothbrush or tongue scraper, and improved oral hygiene.4 Application of topical baking soda or diluted hydrogen peroxide helps with desquamation of the hyperkeratotic papillae.1 Black hairy tongue generally resolves within days to weeks after mechanical debridement and removal of precipitating factors. Patients who do not respond to these treatments may undergo papillae clipping or removal by carbon dioxide laser or electrodessication.1The patient was instructed to brush his tongue twice daily with a soft toothbrush. Within 2 weeks, black hairy tongue resolved without interruption of intravenous cefazolin therapy. He had no recurrence of black hairy tongue within 6 months after initial hospitalization and has since been lost to follow-up.

General

An 80-year-old man presented to the emergency department with a 5-day history of fever and right shoulder pain. His temperature was 37.9 °C (100.2 °F); heart rate, 74/min; and blood pressure, 90/49 mm Hg. He had tenderness to palpation and decreased range of motion of his right shoulder. Laboratory testing showed a white blood cell count of 9.6 ×  109/L (reference, 4.0-9.0 × 109/L); C-reactive protein level, 35.6 mg/dL (reference, <0.3 mg/dL), and creatine kinase level, 1036 U/L (17.30 μkat/L) (reference, 60-270 U/L [1.00-4.51 μkat/L]). Magnetic resonance imaging revealed an effusion and synovial thickening with enhancement in the right shoulder joint and inflammation in the right subscapularis muscle. Gram stain of the synovial fluid revealed gram-positive cocci in clusters. Intravenous cefazolin therapy was initiated, and he underwent right shoulder joint arthroscopic irrigation, synovectomy, and surgical drainage for subscapularis pyomyositis. Blood and synovial fluid cultures grew methicillin-susceptible Staphylococcus aureus, and intravenous cefazolin was continued. One week after hospitalization, the patient developed asymptomatic black discoloration of the dorsal surface of his tongue (Figure). He reported no prior lingual discoloration and did not smoke cigarettes, use chewing tobacco or illicit drugs, or drink alcohol.Elongated filiform papillae and black discoloration of patient’s tongue.

what would you do next?

What would you do next?

Measure serum cortisol level

Perform a tongue biopsy

Provide reassurance and prescribe oral care

Stop cefazolin

c

male

71-80

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2803833

A 7-year-old girl was referred to the otolaryngology clinic by her pediatrician for a left pharyngeal lesion. Her parents noted the lesion 18 months prior. It remained stable in size and was asymptomatic. She denied sore throat, dysphagia, and dyspnea. She was otherwise healthy with no history of recurrent pharyngitis.On examination, her vital signs were within normal limits. She was comfortable with no noted stridor and tolerated her oral secretions. Her oropharyngeal examination was notable for size 2+ palatine tonsils without exudate and a white mass on the posterior tonsillar pillar. She did not tolerate palpation of the lesion. There was no palpable cervical adenopathy, and her lungs were clear to auscultation. No laboratory work or imaging were performed.The patient was taken to the operating room for an excisional biopsy. There, a more thorough gross examination of the lesion was notable for a pedunculated, white rubbery mass arising from the left posterior tonsillar pillar with a narrow mucosal stalk (Figure, A).A, Pedunculated, white rubbery mass arising from the left posterior tonsillar pillar with a narrow mucosal stalk. B and C, A keratinizing squamous epithelium with Actinomyces colonization was found overlying pilosebaceous units including hair follicles, arrector pili muscles, and sebaceous glands (hematoxylin-eosin stains).Gross examination revealed a 2.2 × 1.1 × 0.7-cm, pink-tan to purple, rubbery lesion. Histologic examination demonstrated both ectodermal and mesodermal components. A keratinizing squamous epithelium with Actinomyces colonization was found overlying pilosebaceous units including hair follicles, arrector pili muscles, and sebaceous glands (Figure, B and C). The core of the lesion comprised adipose and fibrous tissue. The stalk was covered with acanthotic squamous epithelium, and the base contained embedded salivary glands. What Is Your Diagnosis?

Teratoma

Dermoid cyst

Hairy pharyngeal polyp

Squamous papilloma

C. Hairy pharyngeal polyp

C

Hairy pharyngeal polyp

First reported in 1784, hairy polyps are benign masses that can occur anywhere in the body.1,2 They are examples of bigerminal choristomas and considered the most common congenital tumor of the nasopharynx and oropharynx with an incidence of 1 in 40 000.1,3 Hairy polyps have a 3.5- to 5-times higher incidence in females, and nearly 80% of cases have been reported in children younger than 1 year. Hairy polyps are characteristically found on the left (6.5:1), lateral nasopharyngeal wall with less common locations including the tonsil/tonsillar pillar, palate, eustachian tube, and middle ear.1,3From a histologic perspective, hairy polyps are malformations of bigerminal origin characterized by both mesodermal constituents such as adipose and ectodermal components, including sebaceous glands and hair follicles,3 as were present in this patient (Figure, B and C). While teratomas are frequently contrasted with hairy polyps, they contain elements from all 3 germinal layers.4 Additional distinctions between these 2 lesions include the malignant potential of teratomas and a nearly equal ratio of morbidity between males and females.4,5 Although similar histologically to dermoid cysts, hairy polyps lack ectodermal inclusion cysts within the mesoderm and are more characteristically polypoid than cystic.6 Another possible diagnosis includes squamous papilloma. However, these masses exhibit fingerlike projections with squamous epithelium on a fibrovascular core lacking pilosebaceous units or adipose tissue.The pathogenesis of hairy polyps remains unclear. Several different theories have been proposed. A common theme among these theories is an inciting factor that interrupts normal tissue morphogenesis or migration resulting in heterotopic tissue.1 A more recent theory is that hairy polyps are related to pharyngeal arch development. There is an association described between hairy polyps and first and second pharyngeal arch malformations.3,6 However, the incidence of these lesions in patients with pharyngeal arch anomalies is not determined.1,3 Alternative explanations for this association include the potential for the hairy polyp to cause the malformation by mass effect during embryogenesis or as a result of genetic factors.3,7Clinically, hairy pharyngeal polyps manifest as soft, pedunculated polypoidal lesions potentially harboring hair-bearing areas. Symptoms associated with hairy polyps are related to their location and size. Large polyps can produce symptoms secondary to mass effect.8 Interestingly, smaller polyps (<3.0 cm) have an increased likelihood of causing respiratory distress and feeding difficulties in part due to evasion of diagnosis.9 For this reason, establishing a diagnosis becomes especially important because smaller polyps can remain undetected and have an increased propensity to cause airway obstruction.3 Nasal and oral endoscopy are a mainstay in diagnosis, although computed tomography and magnetic resonance imaging can be of use. Hairy polyps are treated with complete resection. Recurrence has been reported in only 1 case after surgical excision.3,5 Nevertheless, postoperative care is of utmost importance considering the risk of postoperative hemorrhage and edema in infants.10The present patient had an uncomplicated postoperative course. Her excision site completely healed, and there was no evidence of recurrence at her last examination.

General

A 7-year-old girl was referred to the otolaryngology clinic by her pediatrician for a left pharyngeal lesion. Her parents noted the lesion 18 months prior. It remained stable in size and was asymptomatic. She denied sore throat, dysphagia, and dyspnea. She was otherwise healthy with no history of recurrent pharyngitis.On examination, her vital signs were within normal limits. She was comfortable with no noted stridor and tolerated her oral secretions. Her oropharyngeal examination was notable for size 2+ palatine tonsils without exudate and a white mass on the posterior tonsillar pillar. She did not tolerate palpation of the lesion. There was no palpable cervical adenopathy, and her lungs were clear to auscultation. No laboratory work or imaging were performed.The patient was taken to the operating room for an excisional biopsy. There, a more thorough gross examination of the lesion was notable for a pedunculated, white rubbery mass arising from the left posterior tonsillar pillar with a narrow mucosal stalk (Figure, A).A, Pedunculated, white rubbery mass arising from the left posterior tonsillar pillar with a narrow mucosal stalk. B and C, A keratinizing squamous epithelium with Actinomyces colonization was found overlying pilosebaceous units including hair follicles, arrector pili muscles, and sebaceous glands (hematoxylin-eosin stains).Gross examination revealed a 2.2 × 1.1 × 0.7-cm, pink-tan to purple, rubbery lesion. Histologic examination demonstrated both ectodermal and mesodermal components. A keratinizing squamous epithelium with Actinomyces colonization was found overlying pilosebaceous units including hair follicles, arrector pili muscles, and sebaceous glands (Figure, B and C). The core of the lesion comprised adipose and fibrous tissue. The stalk was covered with acanthotic squamous epithelium, and the base contained embedded salivary glands.

what is your diagnosis?

What is your diagnosis?

Hairy pharyngeal polyp

Squamous papilloma

Teratoma

Dermoid cyst

a

female

0-10

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2803851

A 28-year-old woman presented to the emergency department with a 5-day history of bilateral blurry vision, eye redness, discharge, photophobia, and pain. She also reported rhinorrhea and lethargy. Her medical history included Leber congenital amaurosis treated with voretigene neparvovec (Luxturna; Spark Therapeutics) 8 years ago, and acute myeloid leukemia (AML) diagnosed 6 months prior to presentation treated with cytarabine and idarubicin. Her latest chemotherapy was 3 weeks before presentation, and a peripherally inserted central catheter (PICC) was removed 2 weeks ago. A complete blood cell count was ordered, revealing anemia, neutropenia, lymphocytopenia, and monocytopenia in the setting of recent chemotherapy. Blood cultures were drawn, and results were pending at the time of presentation.Her ophthalmic examination showed visual acuity of 20/800 OD and 20/400 OS, decreased from her baseline of 20/200 OU. Intraocular pressures were 37 mm Hg OD and 31 mm Hg OS. Slitlamp examination revealed chemosis, conjunctival hyperemia, and microcystic corneal edema bilaterally. There were more than 20 cells per high-power field of 1 mm × 1 mm beam, with fibrin bilaterally and 2.5-mm hypopyon in the right eye and 2.7-mm hypopyon in the left eye (Figure 1). Posterior segment examination was limited because of corneal edema and anterior inflammation, but there were no vitreous opacities on B-scan ultrasonography.A 2.5-mm pseudohypopyon in the right eye due to leukemic infiltrate.Observe, as this is expected inflammation after voretigene neparvovec gene therapyObtain a sample of the hypopyon through anterior chamber paracentesis and inject intravitreal antibioticsAwait results from systemic laboratory tests and blood culture What Would You Do Next?

Observe, as this is expected inflammation after voretigene neparvovec gene therapy

Perform pars plana vitrectomy

Obtain a sample of the hypopyon through anterior chamber paracentesis and inject intravitreal antibiotics

Await results from systemic laboratory tests and blood culture

Bilateral anterior uveitis with pseudohypopyon in the setting of AML infiltration

C

Obtain a sample of the hypopyon through anterior chamber paracentesis and inject intravitreal antibiotics

This is a case of AML relapse with bilateral pseudohypopyon. A hypopyon forms when white exudate collects in the inferior aspect of the anterior chamber (AC). When a hypopyon consists of neoplastic cells, the term pseudohypopyon is used. However, the appearance is identical to a hypopyon resulting from suppurative infection or inflammation.1 In this patient, AC aspiration was done and showed malignant cells (Figure 2), confirming AML relapse with monocytic differentiation.Cytology of anterior chamber aspirate showing malignant cells confirming intraocular relapse of acute myeloid leukemia (Giemsa stain, original magnification ×40).Leukemia accounts for 34.8% of ocular metastases affecting the retina, choroid, optic nerve, vitreous, iris, and AC.2 Acute leukemias present more frequently with ocular manifestations than in chronic leukemias,3 with ocular involvement ranging from 32% to 35.5%.4 Ocular involvement of the anterior segment specifically due to acute lymphocytic leukemia relapse ranges from 2.5% to 18%, while anterior involvement in AML relapse is very rare.1The differential diagnosis for hypopyon includes 4 broad categories: noninfectious inflammation, infectious, neoplastic, and corneal etiologies.1 Noninfectious causes include uveitis, most commonly HLA B-27–associated or Behçet disease–associated inflammation, and postsurgical or medical-induced inflammation, such as with rifabutin.5 Infectious causes can be exogenous with postsurgical or traumatic inoculation or endogenous, such as endogenous endophthalmitis from hematological spread. Hypopyon due to neoplasia can be caused by leukemia, lymphoma, retinoblastoma, melanoma, or metastases. Finally, corneal etiologies include microbial keratitis or noninfectious chemical or traumatic injuries. Recognition on physical examination and proper investigation is crucial for correct diagnosis and treatment, as hypopyon usually occurs with specific conditions rather than as a universal ocular inflammatory response.1Option C, perform AC aspiration (as this can detect neoplastic cells) and inject intravitreal antibiotics, is the correct next step.6-8 Although rare, given this patient’s history of AML, suspicion for infiltrative pseudohypopyon as a mimicker of reactive intraocular inflammation should be raised. However, this patient is immunocompromised with a recent PICC, so an infectious process must be kept on the differential. Broad-spectrum intravitreal antibiotics, such as vancomycin and ceftazidime, should be injected until AC aspiration results return, as the consequences of untreated endophthalmitis are severe.8Option A is incorrect. A 2022 study has shown that ocular inflammation can occur in the weeks following subretinal administration of voretigene neparvovec gene therapy9; however, this patient underwent treatment years ago. Option B, perform vitrectomy, is incorrect as there is not evidence of posterior segment inflammation, the patient’s vision does not meet criteria by the Endophthalmitis Vitrectomy Study, and there are less invasive methods for specimen evaluation. Endophthalmitis can occur in the setting of a blood-borne infection, but awaiting systemic laboratory tests and blood culture results, option D, would not help distinguish between AML pseudohypopyon vs endophthalmitis and would delay endophthalmitis treatment. Additionally, it has been suggested that leukemic pseudohypopyon can be associated with relapse even if leukemia is not systemically detected.10The patient was admitted and started venetoclax combined with fludarabine, cytarabine, and idarubicin chemotherapy and received low-dose 1400 cGy involved-field radiotherapy to the eyes for 1 week. Over a few days of radiotherapy, the hypopyon fully resolved along with improved pain and visual acuity to 20/400 OD and 20/200 OS.

Ophthalmology

A 28-year-old woman presented to the emergency department with a 5-day history of bilateral blurry vision, eye redness, discharge, photophobia, and pain. She also reported rhinorrhea and lethargy. Her medical history included Leber congenital amaurosis treated with voretigene neparvovec (Luxturna; Spark Therapeutics) 8 years ago, and acute myeloid leukemia (AML) diagnosed 6 months prior to presentation treated with cytarabine and idarubicin. Her latest chemotherapy was 3 weeks before presentation, and a peripherally inserted central catheter (PICC) was removed 2 weeks ago. A complete blood cell count was ordered, revealing anemia, neutropenia, lymphocytopenia, and monocytopenia in the setting of recent chemotherapy. Blood cultures were drawn, and results were pending at the time of presentation.Her ophthalmic examination showed visual acuity of 20/800 OD and 20/400 OS, decreased from her baseline of 20/200 OU. Intraocular pressures were 37 mm Hg OD and 31 mm Hg OS. Slitlamp examination revealed chemosis, conjunctival hyperemia, and microcystic corneal edema bilaterally. There were more than 20 cells per high-power field of 1 mm × 1 mm beam, with fibrin bilaterally and 2.5-mm hypopyon in the right eye and 2.7-mm hypopyon in the left eye (Figure 1). Posterior segment examination was limited because of corneal edema and anterior inflammation, but there were no vitreous opacities on B-scan ultrasonography.A 2.5-mm pseudohypopyon in the right eye due to leukemic infiltrate.Observe, as this is expected inflammation after voretigene neparvovec gene therapyObtain a sample of the hypopyon through anterior chamber paracentesis and inject intravitreal antibioticsAwait results from systemic laboratory tests and blood culture

what would you do next?

What would you do next?

Perform pars plana vitrectomy

Await results from systemic laboratory tests and blood culture

Obtain a sample of the hypopyon through anterior chamber paracentesis and inject intravitreal antibiotics

Observe, as this is expected inflammation after voretigene neparvovec gene therapy

c

female

21-30

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2804363

A 5-year-old girl was referred to ophthalmology care for evaluation of nystagmus. Her medical history included esophageal atresia, small bowel obstruction, mild cognitive impairment, low tone, and increased reflexes. Prenatal history was complicated by insulin-controlled gestational diabetes and polyhydramnios. Her ocular history was notable for eye movement abnormalities since birth. She had no family history of ocular disease.On examination, her visual acuity was 20/150 OU and did not improve with correction (right eye, −1.50 [2.00] × 180; left eye, −1.00 [1.50] × 180). Pupillary responses were normal. Alternating vertical and torsional nystagmus was noted (Figure 1). Specifically, 1 eye was noted to rise and intort while the other would fall and extort, followed by reversal of the vertical and torsional components in the opposite eye (Video). The optic nerve and foveal reflexes were normal in both eyes. Flash visual evoked potential (VEP) demonstrated strong ipsilateral activity of the occipital lobe. Results of a previously obtained brain magnetic resonance imaging (MRI) scan were reported as normal. What Would You Do Next?

Review brain MRI and order electroretinogram

Refer for strabismus surgery

Order genetic workup

Treat with clonazepam

Achiasma with seesaw nystagmus

A

Review brain MRI and order electroretinogram

Seesaw nystagmus (SSN) is a rare pendular nystagmus characterized by elevation and intorsion of 1 eye and synchronous depression and extorsion of the other eye for a half cycle with reversal of these movements constituting the second half cycle to form seesawlike movements, as seen in this patient. Etiologies can include achiasma, septo-optic dysplasia,1 albinism, retinal dystrophies, and Chiari malformation.2 Acquired forms can result from pituitary adenoma, head trauma, brain stem infarction, whole brain radiation, and intrathecal methotrexate.2 Achiasma is the absence of the optic chiasm when nasal optic nerve fibers fail to decussate to the contralateral hemisphere and is associated with nystagmus, strabismus, and decreased visual acuity.1 Diagnosis is made by absent optic chiasm and nonsegregation of the visual pathway on MRI.Choice A, review brain MRI and order an electroretinogram (ERG), is the correct next step. MRI reads may miss achiasma, especially if thick sections are evaluated or if the optic pathway is not carefully assessed.1 The VEP in this patient showed the right eye projecting to the right ocular cortex and the left eye to the left cortex (thus each cortex was receiving complete but monocular visual field). Therefore, achiasma should be suspected despite the initially normal MRI results. These VEP findings contrast with albinism, in which VEP shows interocular contralateral asymmetry.3 An ERG is useful to rule out SSN due to retinal dystrophies. Regardless of waveform, in the workup of infantile nystagmus, an ERG is of high diagnostic yield, whereas MRI is more useful when neurological abnormalities or an unusual nystagmus pattern is present.4,5 This case illustrates that an MRI scan may be erroneously interpreted as normal if the imaging protocol and assessment are not specific for the suspected ophthalmic pathology.Strabismus surgery (choice B) is incorrect as surgery for SSN is not well established.6 Genetic testing can be an important step in the general workup of nystagmus in children5; however, the genetic mechanisms of achiasma are not understood,7 therefore, genetic workup (choice C) would not guide management. Achiasma can be associated with craniofacial defects, heart defects, agenesis of the corpus callosum, and vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, kidney anomalies, and limb abnormalities (VACTERL) syndrome.8 Similar to this patient, an association with esophageal atresia has been reported.9 Clonazepam may be effective in acquired SSN,10 but there is a lack of evidence for congenital SSN; therefore, option D is incorrect.A second read with guidance regarding clinical suspicion of achiasma was ordered and found normal contour, caliber, and signal intensity of the optic nerves with a normal course into the suprasellar cistern, but no chiasm was identified. The optic tracts deviated in the expected lateral direction and superolateral plane without neural or fibrous connections between the optic nerves (Figure 2). When suspecting achiasma, 3-T imaging with thin-slice T2 fast imaging employing steady-state acquisition or constructive interference into steady state, or T1-weighted 3-dimentional spoiled gradient recalled echo through the basal cisterns (to illustrate absence of connection between optic nerves) and ideally with high-resolution diffusion tensor imaging (to review the course and distribution of the optic tracts) are the preferred imaging protocols for diagnosis. The results of the ERG were normal. Although rare, achiasma should be considered in the differential diagnosis of congenital nystagmus. Thorough imaging evaluation is important to avoid misdiagnosis.Oblique axial image from 3-dimensional spoiled gradient recalled echo (SPGR) sequence along the right (white arrowhead) and left (blue arrowhead) optic nerves shows no meeting of the nerves to form a chiasm, but each nerve coursing laterally to form optic tracts (pink arrowheads). Inset shows coronal image from the same 3-dimensional SPGR sequence at level of pituitary stalk and gland (yellow arrowhead) shows separate white matter bundles (green arrowheads) where a chiasm is normally evident.

Ophthalmology

A 5-year-old girl was referred to ophthalmology care for evaluation of nystagmus. Her medical history included esophageal atresia, small bowel obstruction, mild cognitive impairment, low tone, and increased reflexes. Prenatal history was complicated by insulin-controlled gestational diabetes and polyhydramnios. Her ocular history was notable for eye movement abnormalities since birth. She had no family history of ocular disease.On examination, her visual acuity was 20/150 OU and did not improve with correction (right eye, −1.50 [2.00] × 180; left eye, −1.00 [1.50] × 180). Pupillary responses were normal. Alternating vertical and torsional nystagmus was noted (Figure 1). Specifically, 1 eye was noted to rise and intort while the other would fall and extort, followed by reversal of the vertical and torsional components in the opposite eye (Video). The optic nerve and foveal reflexes were normal in both eyes. Flash visual evoked potential (VEP) demonstrated strong ipsilateral activity of the occipital lobe. Results of a previously obtained brain magnetic resonance imaging (MRI) scan were reported as normal.

what would you do next?

What would you do next?

Refer for strabismus surgery

Review brain MRI and order electroretinogram

Order genetic workup

Treat with clonazepam

b

female

0-10

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2803624

A 75-year-old man with myelodysplastic syndrome (MDS) with isolated deletion 5q (del5q) presented with multiple nonhealing skin ulcers on the chest and upper extremities. Four years earlier, he started taking lenalidomide, 10 mg/d (28-day cycle), to treat worsening anemia; after 2 cycles of treatment, he became transfusion independent. Since then, he has remained stable with the same dose and schedule of lenalidomide without significant adverse effects. The presenting skin lesions developed 1 month before presentation and began as small pustules that rapidly transformed into painful ulcers. He was treated with valacyclovir for a presumed diagnosis of shingles, but the lesions did not improve. Because of suspected necrotizing fasciitis, he underwent incision and drainage of the lesions. Cultures from the surgical specimen grew methicillin-resistant Staphylococcus hemolyticus. However, the lesions continued to worsen despite vancomycin and additional debridement. Thus, he was transferred to our facility.Physical examination showed multiple cutaneous ulcers with gray undermined borders and red papules of varying depths involving the chest, back, and upper extremity; lesions were as large as 9 × 15 cm. A complete blood cell count showed a white blood cell count of 16.2 × 103/μL (to convert to 109/L, multiply by 1.0) with an absolute neutrophil count of 12.7 × 103/μL, hemoglobin level of 9.4 g/dL (to convert to g/L, multiply by 10.0), and platelet count of 262 × 103/μL with no circulating blasts. Results of additional laboratory studies, including blood culture and tests for herpes zoster virus (via polymerase chain reaction), antinuclear antibody, rheumatoid factor, and antineutrophil cytoplasmic antibody were all negative. Additionally, the patient also had hypertension and hypercholesterolemia for which he was taking lisinopril and simvastatin, respectively. Pathologic sampling from skin lesions demonstrated a dense dermal infiltrate with predominantly neutrophils along with reactive histiocytes, fibroblasts, and angioplasia (Figure, A). Immunohistochemical staining showed myeloperoxidase-positive neutrophils (Figure, B), histiocytic markers (CD43, CD63, CD168), and CD117-positive mast cells, but no immature myeloid precursors. Results of Grocott-Gomori methenamine silver staining were unremarkable.A, Hematoxylin-eosin staining shows polymorphonuclear neutrophils admixed with scattered histiocytes and vasculatures with a prominent endothelial lining. B, Immunohistochemical staining shows myeloperoxidase-positive neutrophils peripherally and in aggregates. What Is Your Diagnosis?

Leukemia cutis

Pyoderma gangrenosum

Leukocytoclastic vasculitis

Lymphomatoid papulosis

B. Pyoderma gangrenosum

B

Pyoderma gangrenosum

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis (ND) characterized by painful erythematous or inflammatory papules that often progress to ulcers with a violaceous border.1 A large cohort study showed that PG is commonly associated with other systemic disorders, such as inflammatory bowel disease (41% of participants), inflammatory arthropathies (21%), hematological malignancies (11%), and solid tumors (7%),2 with an overall incidence of 0.63 per 100 000 person-years.3 It frequently occurs in young or middle-aged adults (median age, 51.6 years) and it is more common in women.2Cutaneous lesions in PG mimic lesions of other skin disorders, and no finding is pathognomonic for PG. Therefore, diagnosis of PG depends largely on clinical history, histological findings, and exclusion of other inflammatory or ulcerative cutaneous diseases.1,2 While early-stage PG shows intradermal neutrophils and perifollicular inflammation, ulcerative PG at later stages typically demonstrates epidermal or dermal necrosis, infiltration of inflammatory cells, and abscess formation.1 Deposition of IgM, C3, and fibrin can be observed in PG, but these findings are nonspecific.4 There are 4 morphologic subtypes of PG. Ulcerative PG is characterized by rapid progression of inflammatory papules, pustules, or vesicles to ulcerative lesions. Bullous PG is characterized by rapid development of inflammatory bullae. Pustular PG commonly occurs in patients with inflammatory bowel disease during an acute exacerbation. Vegetative PG is characterized by localized and superficial lesions with an indolent disease course.1The pathogenesis of PG depends primarily on immune dysregulation and genetic factors. Previous studies have shown that gene expression levels of proinflammatory cytokines (eg, tumor necrosis factor α and interleukins [ILs] IL-1α, IL-1β, IL-8, IL-12, IL-15, IL-17, IL-23, and IL-36) and levels of pattern recognition receptors are increased in the cutaneous lesions of PG, leading to activation of inflammasomes and dysregulation of innate and adaptive immunities.1 Furthermore, several reports from familial cases of PG suggest that genetic factors can play important roles in PG pathogenesis,5 and variants in PTSTPIP1/CD2BP1, MEFV, NLRP3, NLRP12, NOD2, and LPIN2 have been reported in PG.1Among hematological cancers associated with PG, 10% to 20% of patients with MDS develop autoimmune manifestations that include NDs, systemic lupus erythematosus, Behçet disease, and vasculitis.6 Chromosomal abnormalities commonly identified in patients with MDS and their autoimmune manifestations include del5q (22.6% of participants in one study),7 in which haploinsufficiency of RPS14 from del5q upregulates S100A9, a DAMP (damage-associated molecular pattern) protein, that plays essential roles in chronic inflammation and innate immunity.8 Notably, ND was associated with significantly adverse survival outcomes in patients with MDS in multivariate analyses (hazard ratio, 1.79; 95% CI, 1.03-3.09; P = .04),7 although other studies found that overall prognosis was more closely related to the IPSS (International Prognostic Scoring System) category than to the underlying autoimmune process.9 In addition, PG has been reported to be associated with lenalidomide, an immunomodulatory drug that is commonly used to treat MDS, multiple myeloma, and lymphomas,10 although the exact frequency of PG associated with lenalidomide remains to be determined.Treatment of PG varies depending on severity and extent of involved cutaneous lesions. First-line treatment for limited disease includes topical corticosteroid or tacrolimus.1 For patients with extensive or rapidly progressing disease, a systemic steroid (0.5-1.5 mg/kg/d of prednisone or its equivalent, then taper over 4-6 weeks) or cyclosporin (in patients who cannot tolerate systemic steroids) is recommended as the first-line treatment, and adjunctive agents (eg, infliximab, azathioprine, mycophenolate) can be added to prevent disease flare during steroid taper.1 In cases of refractory disease, intravenous immunoglobulin or alkylating agents (eg, cyclophosphamide, chlorambucil) could be an option, although many other agents (eg, melphalan, thalidomide, canakinumab, tocilizumab) have been reported to be effective.1In this patient, lenalidomide was discontinued and he was treated with methylprednisolone, 1 mg/kg/d, and infliximab, 5 mg/kg. Skin lesions improved considerably and there has been no recurrence.

Oncology

A 75-year-old man with myelodysplastic syndrome (MDS) with isolated deletion 5q (del5q) presented with multiple nonhealing skin ulcers on the chest and upper extremities. Four years earlier, he started taking lenalidomide, 10 mg/d (28-day cycle), to treat worsening anemia; after 2 cycles of treatment, he became transfusion independent. Since then, he has remained stable with the same dose and schedule of lenalidomide without significant adverse effects. The presenting skin lesions developed 1 month before presentation and began as small pustules that rapidly transformed into painful ulcers. He was treated with valacyclovir for a presumed diagnosis of shingles, but the lesions did not improve. Because of suspected necrotizing fasciitis, he underwent incision and drainage of the lesions. Cultures from the surgical specimen grew methicillin-resistant Staphylococcus hemolyticus. However, the lesions continued to worsen despite vancomycin and additional debridement. Thus, he was transferred to our facility.Physical examination showed multiple cutaneous ulcers with gray undermined borders and red papules of varying depths involving the chest, back, and upper extremity; lesions were as large as 9 × 15 cm. A complete blood cell count showed a white blood cell count of 16.2 × 103/μL (to convert to 109/L, multiply by 1.0) with an absolute neutrophil count of 12.7 × 103/μL, hemoglobin level of 9.4 g/dL (to convert to g/L, multiply by 10.0), and platelet count of 262 × 103/μL with no circulating blasts. Results of additional laboratory studies, including blood culture and tests for herpes zoster virus (via polymerase chain reaction), antinuclear antibody, rheumatoid factor, and antineutrophil cytoplasmic antibody were all negative. Additionally, the patient also had hypertension and hypercholesterolemia for which he was taking lisinopril and simvastatin, respectively. Pathologic sampling from skin lesions demonstrated a dense dermal infiltrate with predominantly neutrophils along with reactive histiocytes, fibroblasts, and angioplasia (Figure, A). Immunohistochemical staining showed myeloperoxidase-positive neutrophils (Figure, B), histiocytic markers (CD43, CD63, CD168), and CD117-positive mast cells, but no immature myeloid precursors. Results of Grocott-Gomori methenamine silver staining were unremarkable.A, Hematoxylin-eosin staining shows polymorphonuclear neutrophils admixed with scattered histiocytes and vasculatures with a prominent endothelial lining. B, Immunohistochemical staining shows myeloperoxidase-positive neutrophils peripherally and in aggregates.

what is your diagnosis?

What is your diagnosis?

Lymphomatoid papulosis

Leukemia cutis

Pyoderma gangrenosum

Leukocytoclastic vasculitis

c

male

71-80

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2804447

A 72-year-old woman was referred for an eye examination because of visual changes in the left eye. Her medical history was notable for end-stage kidney disease requiring a kidney transplant at age 50 years and a second transplant at age 65 years. She had received her medical care at outside facilities, the records of which were not available. She could not recall being given any precise diagnosis but reported having proteinuria since age 7 years. Her other medical conditions included hyperlipidemia, arterial hypertension, and pulmonary Mycobacterium avium complex infection. She was taking tacrolimus, amlodipine, atorvastatin, ethambutol, rifampin, and clarithromycin. Her family history was unremarkable. She had 2 healthy adult children.One year after the first kidney transplant, she noted an inferior visual field defect in the left eye and was diagnosed with nonarteritic anterior ischemic optic neuropathy. Several years later, she underwent uncomplicated bilateral cataract procedures.Visual acuity with distance correction was 20/25 OD and 20/30 OS. Color vision was 14/14 plates for each eye. There was a left relative afferent pupillary defect. Confrontation visual field was full for the right eye and demonstrated an inferior defect for the left eye. External and slitlamp examinations were notable only for bilateral pseudophakia. Both optic discs were anomalous in appearance, with central excavation in the left eye greater than the right eye (Figure). The remainder of the posterior pole examination, including the retinal vessels, appeared normal in both eyes.The right optic disc is dysplastic, with a subtle appearance of the peripheral location of blood vessels emanating from the central disc. There is a central excavation of the left optic disc, with peripherally located blood vessels and the absence of central vessels. What Would You Do Next?

Cranial magnetic resonance imaging

Genetic testing

Vasculitis serological evaluation

Positron emission tomography

Papillorenal syndrome due to a PAX2 gene variant

B

Genetic testing

The appearance of the patient’s optic discs (particularly of the left eye) is consistent with a vacant optic disc associated with the autosomal dominant papillorenal syndrome (PAPRS; OMIM 120330). Sequence analysis identified a heterogeneous pathological variant (c.335G>A) in the PAX2 gene, confirming the clinical diagnosis (choice B). Cranial magnetic resonance imaging is not indicated, as this is not a morning glory disc anomaly (MGDA) that can be associated with a basal encephalocele or moyamoya disease (choice A). There are no historical or examination findings to suggest an underlying vasculitic condition; therefore, serological testing is not indicated (choice C). A vacant optic disc is not associated with an underlying malignancy, and for that reason, positron emission tomography is not needed (choice D).PAPRS—also known as renal-coloboma syndrome, coloboma-ureteral-renal syndrome, optic nerve coloboma with renal disease, coloboma of the optic nerve with renal disease, and optic coloboma-vesicoureteral reflux-renal anomalies—was first reported by Reiger1 in 1977, with a more extensive clinical description by Weaver et al2 in 1998. In 1995, Sanyanusin and colleagues3 discovered a variant of the PAX2 gene as the cause of PAPRS. Because of the phenotypic heterogeneity of PAPRS, experts have suggested it be termed PAX2-related disorders.4 However, not all patients with PAPRS have a known PAX2 variant.5Clinically, the syndrome is characterized by kidney and eye (one or both) abnormalities. Approximately 70% of patients will have optic disc abnormalities and approximately 10% will have retinal findings.4 A forme fruste of the disease may present with only 1 of these conditions. Kidney dysfunction resulting in end-stage kidney disease can occur at any age and can be manifested by a variety of pathology, including kidney hypoplasia or dysplasia, multicystic dysplastic kidney, oligomeganephronia, vesicoureteral reflux, focal segmental glomerulosclerosis, and uric acid nephrolithiasis.4 Systemic manifestations include hearing loss, growth retardation, microcephaly, developmental delay, gout, joint laxity, and soft skin.4The hallmark eye finding is an anomalous optic disc, which was initially termed a coloboma, but vacant optic disc is a more appropriate term, given the clinical features and proposed embryogenesis.6 In some cases, retinal coloboma, scleral staphyloma, optic nerve cyst, foveal hypoplasia, macular changes, and microphthalmia have been reported in conjunction with PAPRS.7Excavated or cavitary optic disc anomalies comprise a group of congenital, morphologically distinct conditions, which include vacant optic disc, MGDA, optic disc coloboma, megallopapilla, optic disc pit, and peripapillary staphyloma. However, some have considered these anomalies to be along a spectrum because certain optic discs do not conform to any one particular entity.8Located on chromosome 10, the PAX2 gene is within the PAX family of genes that includes 8 other members. The PAX2 gene encodes a transcriptional factor that is important in the development of the eye, kidneys, and central nervous system.9 Parsa and colleagues5 have hypothesized that the vacant optic disc arises from deficiency in vascular development during embryogenesis, resulting in the absence of central retinal vessels within the excavated optic disc, with the peripheral vasculature representing cilioretinal vessels. In comparison, an optic disc coloboma demonstrates an absence of tissue in the inferonasal quadrant of the disc and the central retinal vessels emerge superotemporally from the unaffected portion of the disc. Recognizing a vacant optic disc and differentiating it from MGDA and optic disc coloboma is essential, as it can lead to early recognition and treatment of unrecognized kidney disease.10The patient was evaluated by a geneticist to discuss the implications of the PAX2 gene variant and was explained the 50% risk of transmitting the genetic variant to her children.

Ophthalmology

A 72-year-old woman was referred for an eye examination because of visual changes in the left eye. Her medical history was notable for end-stage kidney disease requiring a kidney transplant at age 50 years and a second transplant at age 65 years. She had received her medical care at outside facilities, the records of which were not available. She could not recall being given any precise diagnosis but reported having proteinuria since age 7 years. Her other medical conditions included hyperlipidemia, arterial hypertension, and pulmonary Mycobacterium avium complex infection. She was taking tacrolimus, amlodipine, atorvastatin, ethambutol, rifampin, and clarithromycin. Her family history was unremarkable. She had 2 healthy adult children.One year after the first kidney transplant, she noted an inferior visual field defect in the left eye and was diagnosed with nonarteritic anterior ischemic optic neuropathy. Several years later, she underwent uncomplicated bilateral cataract procedures.Visual acuity with distance correction was 20/25 OD and 20/30 OS. Color vision was 14/14 plates for each eye. There was a left relative afferent pupillary defect. Confrontation visual field was full for the right eye and demonstrated an inferior defect for the left eye. External and slitlamp examinations were notable only for bilateral pseudophakia. Both optic discs were anomalous in appearance, with central excavation in the left eye greater than the right eye (Figure). The remainder of the posterior pole examination, including the retinal vessels, appeared normal in both eyes.The right optic disc is dysplastic, with a subtle appearance of the peripheral location of blood vessels emanating from the central disc. There is a central excavation of the left optic disc, with peripherally located blood vessels and the absence of central vessels.

what would you do next?

What would you do next?

Vasculitis serological evaluation

Cranial magnetic resonance imaging

Positron emission tomography

Genetic testing

d

female

71-80

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2803777

A 74-year-old man with a history of multiple squamous cell carcinomas that were treated with Mohs micrographic surgery presented with a tender, enlarging scalp lesion of 6 months’ duration. Skin examination revealed a 5-mm bright pink, dome-shaped papule with overlying vessels located at the crown of the scalp (Figure, A). There was no purulent discharge or overlying skin changes. A shave skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, Bright pink, dome-shaped papule of the scalp crown with overlying vessels measuring 5 mm. B, Hematoxylin-eosin staining of the lesion from biopsy. Scanning magnification demonstrates dermal-based tumor cells arranged in a vague nodular configuration. C, Proliferation of tumor cells is present around small vessels with scattered mitoses (black arrowhead) and necrosis (yellow arrowheads) (hematoxylin-eosin). D, Smooth muscle actin stain. What Is Your Diagnosis?

Symplastic glomus tumor

Angioleiomyoma

Solitary fibrous tumor

Malignant myopericytoma

D. Malignant myopericytoma

D

Malignant myopericytoma

Hematoxylin-eosin staining of the lesion demonstrated concentric proliferation of ovoid tumor cells present around small vessels over a hyalinized background stroma. The cells were hyperchromatic and variable in nuclear size, with scattered mitoses and necrosis. Smooth muscle actin (SMA) was diffusely positive in the tumor cells, and a CD31 immunostain highlighted many endothelial-lined vascular channels. Additional immunohistochemical staining for smooth muscle myosin, h-caldesmon, calponin, desmin, Kaposi sarcoma–associated herpesvirus, SOX10, human melanoma black, S-100, and STAT6 was negative.This patient received a diagnosis of malignant myopericytoma (MMPCT) given the (1) histopathologic evidence of concentric perivascular growth of spindle to ovoid cells with a myoid appearance, (2) nuclear atypia and scattered single-cell necrosis, (3) high mitotic index score (17/10 high-power field), and (4) uniform immunoreactivity for SMA. Because of the small tumor size and superficial location, treatment involved wide local excision of the tumor with 1-cm margins. The final pathology results confirmed MMPCT, 0.8 cm wide, with a depth of invasion of 1.8 mm. Positron emission tomography scan results 6 months postdiagnosis revealed no metastases. Surveillance for recurrence/metastasis includes follow-up with a dermatology department every 3 months and head/neck/chest computed tomography every 6 months for 5 years.Myopericytomas are tumors with differentiation toward perivascular myoid cells, distinguished histologically by the presence of concentric perivascular proliferation of spindle cells. McMenamin and Fletcher1 described 5 cases of MMPCT, tumors that exhibited myopericytic differentiation in addition to malignant features of high cellularity, frequent mitotic figures, pleomorphism, and necrosis. Fourteen cases of MMPCT have been documented in the PubMed database.2 Patients had a median age of 52 years (range, 19-81 years). Five of 15 cases (33.3%) of MMPCT occurred in the setting of HIV-related immunosuppression.Clinically, MMPCT usually present as a painless, slowly growing, deeply seated nodule. Tumor size ranges from 1.5 to 13 cm (median 5.6 cm). Malignant myopericytomas classically affect subcutaneous tissues of the extremities.1 Other locations include the neck, axilla, mediastinum, spine, and intracranial fossa.1,2 Contrastingly, the current case of MMPCT was uncharacteristically located superficially in sun-exposed skin of the scalp. A case of MMPCT occurring in sun-exposed skin of the forearm in an elderly patient was reported.1 Immunophenotypically, MMPCT demonstrates uniform positivity for SMA. Smooth muscle markers, including desmin and h-caldesmon, are variable.1,3 Epstein-Barr virus–positive cases have been reported in patients with immunosuppression.2,4Histopathologic mimickers of MMPCT include glomus tumor, angioleiomyoma, and solitary fibrous tumor, among others. These neoplasms either exhibit a prominent vascular component or nested growth pattern similar to MMPCT; however, the striking concentric perivascular growth pattern characteristic of MMPCT is not present. The cells of symplastic glomus tumor have high-grade nuclear pleomorphism in the absence of other malignant features and distinct cellular borders, unlike the spindle, to ovoid, fusiform tumor cells in MMPCT.5,6 Angioleiomyomas show smooth muscle differentiation and diffuse immunoreactivity for desmin and h-caldesmon. The cells in solitary fibrous tumors appear patternless and have positive stain results for STAT6.7Malignant myopericytoma metastasizes to distant organs in more than 50% of cases within 1 year of diagnosis.2 Most metastatic MMPCT involves the liver. Brain, lung, subcutaneous skin, muscle, lymph node, and spine metastases have also been reported.2,4,8 Imaging with ultrasonography, computed tomography, and magnetic resonance imaging of the head, thorax, abdomen, and pelvis may aid in identifying metastases.2,4,9 With an estimated mortality rate of at least 25% within 1 year,2 prompt initiation of therapy is warranted. Previous cases of MMPCT were managed surgically. Adjuvant chemotherapy and radiation therapy offer limited efficacy, although 1 case of intracranial MMPCT was successfully treated with adjuvant bevacizumab.9 Several cases of Epstein-Barr virus–positive MMPCT in patients with HIV were treated with simultaneous highly active antiretroviral therapy.2,4,8 Given the rapid potential for metastasis and high rate of mortality, surveillance with imaging studies for patients with MMPCT is recommended.

Dermatology

A 74-year-old man with a history of multiple squamous cell carcinomas that were treated with Mohs micrographic surgery presented with a tender, enlarging scalp lesion of 6 months’ duration. Skin examination revealed a 5-mm bright pink, dome-shaped papule with overlying vessels located at the crown of the scalp (Figure, A). There was no purulent discharge or overlying skin changes. A shave skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, Bright pink, dome-shaped papule of the scalp crown with overlying vessels measuring 5 mm. B, Hematoxylin-eosin staining of the lesion from biopsy. Scanning magnification demonstrates dermal-based tumor cells arranged in a vague nodular configuration. C, Proliferation of tumor cells is present around small vessels with scattered mitoses (black arrowhead) and necrosis (yellow arrowheads) (hematoxylin-eosin). D, Smooth muscle actin stain.

what is your diagnosis?

What is your diagnosis?

Solitary fibrous tumor

Symplastic glomus tumor

Angioleiomyoma

Malignant myopericytoma

d

male

71-80

Black

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2804571

An otherwise healthy female patient in her late 20s was seen with a 2-year history of multiple, slowly growing, infiltrated erythematous-violaceous patches and plaques, with occasional slight pain extending from her left upper arm to the left side of her chest. No triggers, such as local infection, insect bite, or trauma, occurred before the appearance of the lesions. She denied fever, weight loss, or fatigue. Physical examination showed multiple firm, nonscaly, purple erythematous patches and plaques with irregular borders on her left axilla, medial upper arm, and lateral thoracic region (Figure, A). No extracutaneous involvement was observed. A skin biopsy specimen was obtained from the left side of her chest for histopathological examination (Figure, B and C).A, Multiple nonscaly, erythematous-violaceous patches and plaques with irregular borders on the patient’s left axilla, medial upper arm, and lateral thoracic region. B, Irregularly branched, thin-walled blood vessels dissecting through collagen bundles within the superficial to mid dermis (hematoxylin-eosin). C, Irregularly branched, thin-walled blood vessels with plump endothelial cells dispersed between thickened collagen bundles without signs of atypia (hematoxylin-eosin). D, Endothelial cells positive for cluster of differentiation (CD) 31 (CD31). What Is Your Diagnosis?

Patch-stage Kaposi sarcoma

Interstitial granulomatous dermatitis

Acquired progressive lymphangioma

Microvenular hemangioma

D. Microvenular hemangioma

D

Microvenular hemangioma

Histopathological examination showed thin-walled, irregularly branched blood vessels dispersed between thickened collagen bundles (Figure, B and C). The endothelial cells were plump but displayed no significant cytologic atypia. Immunohistochemically, the neoplastic endothelial cells were positive for cluster of differentiation (CD) 31 (Figure, D), CD34, and Ki-67 (<1%) and negative for podoplanin (D2-40) and human herpesvirus 8 (HHV-8). A diagnosis of microvenular hemangioma (MVH) was made.Microvenular hemangioma is a rare, acquired, benign vascular proliferation with unknown etiology. It is hypothesized that changing levels of hormones due to oral contraceptive drugs or pregnancy may be associated with the pathogenesis of MVH,1 as well as the individual susceptibility of patients with systemic immunosuppression.2,3 However, most patients with MVH have not reported any coincidental events or underlying comorbidities, and the factors that predispose, trigger, or facilitate the development of MVH require further research.3Microvenular hemangioma is typically characterized by a solitary, slowly enlarging, asymptomatic or slightly tender violaceous or reddish blue nodule.4 Papules or plaques are less frequent morphological features, followed by macules or patches.3 To our knowledge, 12 cases of multiple MVH have been reported, but those lesions ranged in diameter from 0.5 to 1.8 cm.4,5 Multiple and large plaques and patches with linear distribution, as with the patient described here, are rare. In most cases, MVH occurs in young to middle-aged adults, with a slight predominance for women.3 Microvenular hemangioma has a predilection for the trunk and/or extremities, and only a few cases are seen involving the face and neck. Histopathological features show the proliferation of irregularly branched, thin-walled small blood vessels lined by normal to plump endothelial cells with inconspicuous lumina in the dermis.3,4 There are also variable degrees of fibrosis or desmoplasia but no extravasation of erythrocytes or cellular atypia. Immunohistochemical examination shows that vascular endothelial cells are positive for CD31, CD34, and Wilms tumor 1 and negative for D2-40 and HHV-8.3 Pericytes are positive for smooth muscle actin.Differential diagnoses include Kaposi sarcoma, interstitial granulomatous dermatitis, and acquired progressive lymphangioma. Kaposi sarcoma shares similar clinical features of MVH, which are slowly growing pink to red-violet macules, plaques, and nodules, but it usually is seen in elderly men or patients with HIV infection or iatrogenic immunosuppression. Besides small, angulated vessels between collagen bundles, histopathological features of Kaposi sarcoma also include cellular atypia, eosinophilic hyaline globules, extravasated erythrocytes, hemosiderin deposits, spindle-cell fascicles, and perivascular plasma cells, with positive HHV-8 staining. Interstitial granulomatous dermatitis may also manifest as erythematous to violaceous patches or plaques with a symmetrical distribution pattern in the lateral upper trunk and proximal inner arms.6 Its distinctive histopathological features include foci of degenerated collagen surrounded by variably dense histiocytes, which may be confused with epithelial cells.6 However, different from the branching collapsed-looking vessels in MVH, histiocytes in interstitial granulomatous dermatitis may form small granulomas, and they are positive for CD68 but negative for CD31 and CD34. Acquired progressive lymphangioma typically is seen as a slowly progressive, infiltrative, reddish to violaceous plaque at any site of the body, usually affecting children and young adolescents.7 Histopathological features may show thin-walled interconnecting vascular channels that are arranged horizontally in the upper dermis and “dissect” the dermal collagen bundles, with a smaller, more irregular and angular appearance in the deep dermis or subcutis.7 In immunohistochemistry results, lymphatic endothelial marker D2-40 is strongly positive in acquired progressive lymphangioma, but negative in MVH.Microvenular hemangioma has a relatively benign nature, and the therapy is based on the size of the lesions. The smaller lesions can be resected surgically, usually with no recurrence. Treatment with a pulsed dye laser has been tried with slight improvement.8 For untreated larger or multiple skin lesions, most cases have shown persistence, growth, and/or an increase in the number of lesions,3 and regular follow-up observation should be performed because of possible regression after biopsy.9

Dermatology

An otherwise healthy female patient in her late 20s was seen with a 2-year history of multiple, slowly growing, infiltrated erythematous-violaceous patches and plaques, with occasional slight pain extending from her left upper arm to the left side of her chest. No triggers, such as local infection, insect bite, or trauma, occurred before the appearance of the lesions. She denied fever, weight loss, or fatigue. Physical examination showed multiple firm, nonscaly, purple erythematous patches and plaques with irregular borders on her left axilla, medial upper arm, and lateral thoracic region (Figure, A). No extracutaneous involvement was observed. A skin biopsy specimen was obtained from the left side of her chest for histopathological examination (Figure, B and C).A, Multiple nonscaly, erythematous-violaceous patches and plaques with irregular borders on the patient’s left axilla, medial upper arm, and lateral thoracic region. B, Irregularly branched, thin-walled blood vessels dissecting through collagen bundles within the superficial to mid dermis (hematoxylin-eosin). C, Irregularly branched, thin-walled blood vessels with plump endothelial cells dispersed between thickened collagen bundles without signs of atypia (hematoxylin-eosin). D, Endothelial cells positive for cluster of differentiation (CD) 31 (CD31).

what is your diagnosis?

What is your diagnosis?

Acquired progressive lymphangioma

Patch-stage Kaposi sarcoma

Interstitial granulomatous dermatitis

Microvenular hemangioma

d

female

0-10

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2803934

A man in his late 50s was released from a tertiary hospital with an anterior ST-elevation myocardial infarction and cardiogenic shock with onset 6 days before admission. On admission, vital signs showed blood pressure as 98/66 mm Hg while receiving dobutamine and norepinephrine from the referral hospital, a regular heart rate of 90 beats per minute, a respiratory rate of 22 breaths per minute, peripheral oxygen saturation 96% nasal oxygen at 3 L per minute, and a temperature of 36.7° C. Echocardiography showed reduced left ventricle systolic function (estimated ejection fraction, 34%) and hypokinesia of the anteroseptal, anterior, anterolateral, and septal walls. Lung ultrasound demonstrated multiple B-lines in both lung fields. Diagnostic coronary angiography revealed a total occlusion in the left main coronary artery. Percutaneous coronary intervention (PCI) was successful in opening the osteal left main and drug-eluting stents were placed in the left main and left anterior descending arteries.Following PCI, the patient had episodes of supraventricular tachycardia and atrial fibrillation with a rapid ventricular response. Electrical cardioversion was performed and a loading dose of amiodarone was administered. Chest radiography during the loading dose of amiodarone showed infiltrates in both lung fields (Figure 1A). While in the intensive cardiovascular care unit, maintenance doses of amiodarone were continued because of episodes of paroxysmal supraventricular tachycardia, ventricular tachycardia, and torsaded de pointes. On the third day of hospitalization, despite adequate diuresis, the chest radiography showed persistent pulmonary edema. Chest computed tomography showed a reticular pattern predominantly in the perihilar area with consolidation and diffuse ground-glass opacity in both lung fields (Figure 1B). In addition, hemodynamic evaluation and lung ultrasound showed no congestion and laboratory markers, including a procalcitonin level of 0.01 ng/mL, and ruled out an infectious etiology. What Would You Do Next?

Perform a lung biopsy

Discontinue amiodarone and administer a corticosteroid

Perform bronchoalveolar lavage

Check amiodarone plasma level

Acute amiodarone-induced pulmonary toxicity

B

Discontinue amiodarone and administer a corticosteroid

As one of the antiarrhythmic drugs commonly used to treat ventricular and supraventricular arrhythmias, amiodarone has complex pharmacology and has potential for significant adverse reactions. This drug has been associated with a variety of adverse events since it tends to accumulate in several organs, including the lungs, which could induce amiodarone pulmonary toxicity. 1,2 Many systemic adverse effects are related to pharmacokinetic properties and resulting tissue accumulation. Amiodarone organ toxicity usually occurs after long-term oral therapy and is rarely found in short-term intravenous therapy, especially during loading doses. Although the incidence of acute amiodarone-induced pulmonary toxicity (AIPT) is rare, the onset of its clinical manifestations is highly variable and can be an aggressive form of pulmonary disease.Acute respiratory distress syndrome (ARDS) is the most common pattern of AIPT, usually represented by diffuse alveolar damage with hyaline membranes.2 The diagnosis of ARDS is based on the following clinical criteria: acute onset of symptoms (less than 1 week), absence of cardiac failure or fluid overload, moderate to severe impairment of oxygenation, and bilateral opacities consistent with pulmonary edema on chest computed tomography. The alternative forms of interstitial lung disease and relevant alternative causes of ARDS should also be considered. The workup for acute AIPT should focus on ruling out sepsis, cardiogenic pulmonary edema, and pulmonary embolism as alternative causes.All clinicians should be vigilant of this possibility since amiodarone is widely used. Discontinuation or dose reduction may resolve most of its adverse effects and the prognosis is good if there is early detection of AIPT. Lung biopsy could be an option, but is not recommended for severe cases.3 It is associated with increased mortality and morbidity and this procedure does not contribute to the presumed diagnosis since there are no noticeable histopathological differences between suspected acute AIPT-associated ARDS and ARDS of alternative origins.4 Although the total bronchoalveolar cell count may be increased in AIPT, no difference in the number of absolute lymphocytes was observed in patients without toxicity compared with other causes of interstitial pneumonitis.5 In addition, testing plasma amiodarone levels is not helpful because amiodarone levels are not predictive nor diagnostic of pulmonary toxicity.6Improvement in symptoms after amiodarone cessation helps to support the diagnosis.7 Most diagnosed patients respond well to discontinuation of amiodarone and administration of a corticosteroid (usually for up to 4 to 12 months). Several case reports suggest that glucocorticoid therapy is associated with substantial improvement, even in severe cases.8 Glucocorticoid therapy must be tapered over 2 to 6 months after the clinical response is evident unless there are signs and symptoms of recurrence.9Chest radiography on the third day after discontinuation of amiodarone and corticosteroid treatment showed improvement in the lung pattern, thus supporting the diagnosis of interstitial pneumonitis. Treatment was continued with oral prednisone (1 mg per kilogram of body weight) for a week and then the dose was decreased by 10 mg weekly. A chest radiography at the end of corticosteroid treatment showed a normal lung pattern without pulmonary infiltrates (Figure 2).Chest radiography at the end of corticosteroid treatment.

Cardiology

A man in his late 50s was released from a tertiary hospital with an anterior ST-elevation myocardial infarction and cardiogenic shock with onset 6 days before admission. On admission, vital signs showed blood pressure as 98/66 mm Hg while receiving dobutamine and norepinephrine from the referral hospital, a regular heart rate of 90 beats per minute, a respiratory rate of 22 breaths per minute, peripheral oxygen saturation 96% nasal oxygen at 3 L per minute, and a temperature of 36.7° C. Echocardiography showed reduced left ventricle systolic function (estimated ejection fraction, 34%) and hypokinesia of the anteroseptal, anterior, anterolateral, and septal walls. Lung ultrasound demonstrated multiple B-lines in both lung fields. Diagnostic coronary angiography revealed a total occlusion in the left main coronary artery. Percutaneous coronary intervention (PCI) was successful in opening the osteal left main and drug-eluting stents were placed in the left main and left anterior descending arteries.Following PCI, the patient had episodes of supraventricular tachycardia and atrial fibrillation with a rapid ventricular response. Electrical cardioversion was performed and a loading dose of amiodarone was administered. Chest radiography during the loading dose of amiodarone showed infiltrates in both lung fields (Figure 1A). While in the intensive cardiovascular care unit, maintenance doses of amiodarone were continued because of episodes of paroxysmal supraventricular tachycardia, ventricular tachycardia, and torsaded de pointes. On the third day of hospitalization, despite adequate diuresis, the chest radiography showed persistent pulmonary edema. Chest computed tomography showed a reticular pattern predominantly in the perihilar area with consolidation and diffuse ground-glass opacity in both lung fields (Figure 1B). In addition, hemodynamic evaluation and lung ultrasound showed no congestion and laboratory markers, including a procalcitonin level of 0.01 ng/mL, and ruled out an infectious etiology.

what would you do next?

What would you do next?

Check amiodarone plasma level

Perform a lung biopsy

Perform bronchoalveolar lavage

Discontinue amiodarone and administer a corticosteroid

d

male

51-60

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2805065

A woman in her late 60s presented to the emergency department after an episode of syncope. She described several other episodes occurring at rest over the past several weeks. She denied palpitations, chest pain, and shortness of breath. She was otherwise in excellent health and not taking any medications. She had no family history of syncope or sudden death. Her vital signs and physical examination were unremarkable. The initial electrocardiogram (ECG) results were normal, but premature ventricular contractions (PVCs) were noted on telemetry. Shortly thereafter, 2 episodes of fast polymorphic ventricular tachycardia (PVT), 30 minutes apart, were recorded, both lasting less than 4 seconds (Figure 1A). A repeat ECG showed PVCs (Figure 1B). Laboratory test results including serum potassium and magnesium as well as 3 serial troponin levels were normal. Echocardiography showed normal left ventricular systolic function without wall motion abnormalities or valvular abnormalities. Coronary angiography showed a 50% stenosis of the left circumflex artery. Instant wave-free ratio across the stenosis was 1.0.A, A continuous rhythm strip showing a short episode of polymorphic ventricular tachycardia (PVT), which is initiated by a short-coupled premature ventricular contraction (PVC) identical in morphology and coupling interval to the PVC occurring a few beats earlier. B, A subsequent electrocardiogram (ECG) showed frequent short-coupled premature ventricular contractions. What Would You Do Next?

Implant a defibrillator

Perform provocative drug testing with procainamide

Start nadolol

Ablate PVCs

Short-coupled PVCs initiating PVT

A

Implant a defibrillator

The ECG in Figure 1B shows normal sinus rhythm with a normal axis, sinus arrhythmia, nonspecific P wave abnormality, and minor nonspecific T wave changes. There are frequent uniform PVCs with a right bundle branch block morphology and a right superior axis. Retrograde P waves following the PVCs are noted. The PVCs are superimposed on the T waves, most notably in lead aVF (the PVCs start after the peak of the T wave), consistent with the R-on-T phenomenon, with a short coupling interval of approximately 330 milliseconds.PVCs with short coupling intervals have been shown to trigger PVT and ventricular fibrillation in patients with structurally normal hearts, which can lead to syncope and sudden cardiac death. The episodes of PVT shown in Figure 1A are initiated with a PVC that has an identical morphology and coupling interval to the PVC occurring few beats earlier. The QT interval is not prolonged. There is no coved ST-segment elevation in V1 through V2 to suggest Brugada syndrome. No ST-segment elevation precedes runs of PVT, ruling out coronary spasm as the etiology.Provocative drug testing is not helpful since there is no suspicion of Brugada syndrome or prolonged QT interval. Options C is therapy for long QT syndrome. Option D, PVC ablation, can be a complimentary treatment, but placement of a defibrillator is required to reduce the risk of sudden cardiac death.The first mention of the association of the R-on-T phenomenon with malignant ventricular arrhythmias was by Fastier and Smirk1 in 1948 (Figure 2). R waves interrupting T waves were described again in 17 patients by Smirk2 in 1949, with several patients dying suddenly. Two more cases of Adams-Stocks attacks due to ventricular fibrillation in patients with apparently normal hearts were reported around the same time.3,4Polymorphic ventricular tachycardia reported in 1948.1 Reprinted with permission from Copyright Clearance Center.PVCs are ubiquitous in the general population. In the Framingham Heart Study, PVCs or more complex ventricular arrhythmias were observed in 12% of participants without coronary artery disease monitored for just 1 hour.5 Initially, it was thought that the prognosis of PVCs, in the absence of evident structural heart disease, was excellent. Later, the likelihood of cardiac mortality was reportedly double in patients with ventricular ectopy followed up for 10 years.6 A PVC grading system, from 0 to 5, was introduced by Lown and Wolf7 in 1971. An early PVC (R-on-T PVC) was graded at 5, denoting the highest risk. Lown and Wolf referenced the earlier work by Smirk,2 but the grading system was gauged to assess the risk after myocardial infarction. Grade 2 to 4 A&B per the Lown and Wolf system are frequent PVCs, multiform PVCs, ventricular couplets and 3 or more PVCs in a row. High burden of PVCs and interpolated ones have been linked to cardiomyopathy in the absence of coronary artery disease.Idiopathic ventricular fibrillation was coined to describe the arrhythmia in an otherwise normal heart and is responsible for approximately 5% to 7% of cases of aborted cardiac arrest.8 Short-coupled idiopathic ventricular fibrillation (SCIVF) is diagnosed in the presence of PVCs initiating PVT and fibrillation. A review of 86 patients with SCIVF showed the mean (SD) PVC coupling interval was 293 (50.5) milliseconds and less than 300 milliseconds in 48 patients.8 As is likely in this case, the majority of PVC triggers of SCIVF originate from the Purkinje system. Long-term suppression of arrhythmias with oral medications was highest with quinidine (83.3%) followed by verapamil (50%). Ablation of PVC trigger was attempted in 55.8% and was successful in the acute phase in 83.3%.8An implanted cardioverter/defibrillator was placed. Verapamil was started for suppression of PVCs. Ablation was planned if the patient had recurrence of arrhythmias. This patient had 1 episode of nonsustained ventricular tachycardia 3 months after initial presentation; it terminated without a shock. She had no other episodes over the ensuing 5 years.

Cardiology

A woman in her late 60s presented to the emergency department after an episode of syncope. She described several other episodes occurring at rest over the past several weeks. She denied palpitations, chest pain, and shortness of breath. She was otherwise in excellent health and not taking any medications. She had no family history of syncope or sudden death. Her vital signs and physical examination were unremarkable. The initial electrocardiogram (ECG) results were normal, but premature ventricular contractions (PVCs) were noted on telemetry. Shortly thereafter, 2 episodes of fast polymorphic ventricular tachycardia (PVT), 30 minutes apart, were recorded, both lasting less than 4 seconds (Figure 1A). A repeat ECG showed PVCs (Figure 1B). Laboratory test results including serum potassium and magnesium as well as 3 serial troponin levels were normal. Echocardiography showed normal left ventricular systolic function without wall motion abnormalities or valvular abnormalities. Coronary angiography showed a 50% stenosis of the left circumflex artery. Instant wave-free ratio across the stenosis was 1.0.A, A continuous rhythm strip showing a short episode of polymorphic ventricular tachycardia (PVT), which is initiated by a short-coupled premature ventricular contraction (PVC) identical in morphology and coupling interval to the PVC occurring a few beats earlier. B, A subsequent electrocardiogram (ECG) showed frequent short-coupled premature ventricular contractions.

what would you do next?

What would you do next?

Start nadolol

Implant a defibrillator

Ablate PVCs

Perform provocative drug testing with procainamide

b

female

61-70

original

https://jamanetwork.com/journals/jama/fullarticle/2804367

A 70-year-old woman with hypertension, atrial fibrillation, congestive heart failure, and gallstones presented to the emergency department with 3 days of nausea, vomiting, and abdominal pain. She reported no hematemesis, hematochezia, or melena and had no history of abdominal surgery. On admission to the emergency department, she was afebrile, her blood pressure was 80/60 mm Hg, and heart rate was 122/min. On physical examination, her abdomen was distended, tympanic, and slightly tender to palpation diffusely. Blood testing showed a white blood cell count of 10 450/μL (84.1% neutrophils); C-reactive protein level, 9.5 mg/dL; potassium level, 3.0 mEq/L (reference, 3.6-5.2 mEq/L); and creatinine level, 5.57 mg/dL (429.39 μmol/L, up from a baseline level of 0.80 mg/dL [70.72 μmol/L]). Sodium and liver function values were normal.In the emergency department, she received a 500-mL bolus of intravenous crystalloid fluid and 1 g of intravenous ceftriaxone. A nasogastric tube was placed and initially drained 300 mL of biliary fluid.A non–contrast-enhanced abdominal computed tomography (CT) scan was performed (Figure 1).Left, Abdominal computed tomography scan showing a thickened gallbladder with air and gallstones adherent to the duodenum, with a suspected fistula tract. Right, Axial section showing a 2.7-cm gallstone in the middle ileum and proximal bowel distension.Administer barium through the nasogastric tube to evaluate for bowel obstructionPlan for surgical intervention after intravenous fluid resuscitation in the intensive care unit (ICU) What Would You Do Next?

Administer barium through the nasogastric tube to evaluate for bowel obstruction

Order magnetic resonance cholangiopancreatography

Perform an emergency explorative laparotomy

Plan for surgical intervention after intravenous fluid resuscitation in the intensive care unit (ICU)

Gallstone ileus

D

Plan for surgical intervention after intravenous fluid resuscitation in the intensive care unit (ICU)

The key to the correct diagnosis is recognition that the combination of an ectopic gallstone in the small bowel and a thickened gallbladder wall with intraluminal air adherent to the duodenum is characteristic of a cholecystoenteric fistula. Choice A is incorrect because administration of barium could worsen bowel obstruction and can induce barium peritonitis in the setting of bowel perforation.1 Ordering magnetic resonance cholangiopancreatography (choice B) is not recommended because the abdominal CT scan findings confirmed the diagnosis of gallstone ileus. Emergency exploratory laparotomy (choice C) is not indicated because the patient was hemodynamically unstable and would need a large amount of intravenous fluid to stabilize her blood pressure prior to surgery.Gallstone ileus is a mechanical obstruction caused by migration of a gallstone from the gallbladder through a biliary-enteric fistula into the gastrointestinal tract. A fistula typically occurs when inflammation from recurrent episodes of cholecystitis cause gallbladder adhesion to surrounding organs.2 In 85% of patients with gallstone ileus, gallstones travel through a cholecystoduodenal fistula into the duodenum, and 15% have a fistula that involves the stomach, small bowel, or transverse colon.1,2 Once in the gastrointestinal tract, gallstones typically advance distally and are expelled through the rectum, if they are small. Gallstones with diameter of 2 cm or greater may cause intestinal obstruction,1 which occurs most commonly in the ileum (50% to 60.5%) and less frequently in the jejunum, duodenum, colon, or stomach.2,3Patients with gallstone ileus typically present with nausea, vomiting, abdominal pain, and distension, which may be intermittent as gallstones pass along the gastrointestinal tract.4,5 Rarely, an impacted gallstone can cause intestinal perforation.2Gallstone ileus represents 1% to 4% of all cases of mechanical gastrointestinal obstruction but accounts for up to 25% of bowel obstruction in patients older than 65 years.5 Gallstone ileus occurs most commonly in older patients (mean age, 74 years),6 and 80% to 90% have multiple medical conditions,2 including hypertension, diabetes, and ischemic heart disease.7 Between 72% and 90% of patients with gallstone ileus are women,2 and approximately 50% of patients have no history of gallbladder disease.1 An abdominal CT scan has a sensitivity of 93% and specificity of 100% for the diagnosis of gallstone ileus and is recommended for diagnostic imaging.8Surgical treatment is typically recommended for patients with gallstone ileus because spontaneous resolution of intestinal obstruction is rare.1 Potential surgical procedures, performed using an open or laparoscopic approach, include extraction of the gallstone through an enterotomy (enterolithotomy) or enterolithotomy plus cholecystectomy and fistula closure performed in a single operation (1-step procedure) or in sequential operations (2-step procedure).2,8,9 Although no randomized clinical trials currently exist to support a preferred surgical treatment,7 enterolithotomy alone is the most commonly performed surgical procedure for gallstone ileus and has been associated with lower mortality rates and fewer immediate postoperative complications than alternative surgical options.2,8,9 However, a 1-step procedure may be considered for patients at low risk of surgical complications to decrease the likelihood of gallstone recurrence, retrograde cholecystitis, and gallbladder cancer.6Recurrent gallstone ileus occurs in approximately 5% of patients treated with enterolithotomy, with 85% of recurrences occurring within 6 months of surgery.5 Despite surgical treatment, gallstone ileus is associated with a mortality rate of 7% to 30%, in part due to the advanced age and multiple medical comorbidities of most patients.6The patient was admitted to the ICU and received 3 L of intravenous fluid resuscitation over 12 hours. The following day, her vital signs were within normal range and she underwent a midline laparotomy and enterolithotomy (Video), with removal of a 2.7-cm gallstone (Figure 2) that was obstructing the middle ileum. A 3-cm ileal resection with a hand-sewn side-to-side anastomosis was performed due to evidence of mild ischemic changes in the posterior wall of the ileum. The patient was monitored in the ICU for 3 days and discharged from the hospital on postoperative day 8. At a clinic visit 1 month later, she was asymptomatic, and her serum creatinine level was normal. She was referred to a hepatobiliary surgical specialist for follow-up and management of care.Intraoperative image of a 2.7-cm gallstone surgically removed from the middle ileum.

General

A 70-year-old woman with hypertension, atrial fibrillation, congestive heart failure, and gallstones presented to the emergency department with 3 days of nausea, vomiting, and abdominal pain. She reported no hematemesis, hematochezia, or melena and had no history of abdominal surgery. On admission to the emergency department, she was afebrile, her blood pressure was 80/60 mm Hg, and heart rate was 122/min. On physical examination, her abdomen was distended, tympanic, and slightly tender to palpation diffusely. Blood testing showed a white blood cell count of 10 450/μL (84.1% neutrophils); C-reactive protein level, 9.5 mg/dL; potassium level, 3.0 mEq/L (reference, 3.6-5.2 mEq/L); and creatinine level, 5.57 mg/dL (429.39 μmol/L, up from a baseline level of 0.80 mg/dL [70.72 μmol/L]). Sodium and liver function values were normal.In the emergency department, she received a 500-mL bolus of intravenous crystalloid fluid and 1 g of intravenous ceftriaxone. A nasogastric tube was placed and initially drained 300 mL of biliary fluid.A non–contrast-enhanced abdominal computed tomography (CT) scan was performed (Figure 1).Left, Abdominal computed tomography scan showing a thickened gallbladder with air and gallstones adherent to the duodenum, with a suspected fistula tract. Right, Axial section showing a 2.7-cm gallstone in the middle ileum and proximal bowel distension.Administer barium through the nasogastric tube to evaluate for bowel obstructionPlan for surgical intervention after intravenous fluid resuscitation in the intensive care unit (ICU)

what would you do next?

What would you do next?

Plan for surgical intervention after intravenous fluid resuscitation in the intensive care unit (ICU)

Administer barium through the nasogastric tube to evaluate for bowel obstruction

Order magnetic resonance cholangiopancreatography

Perform an emergency explorative laparotomy

a

female

61-70

White

original

https://jamanetwork.com/journals/jama/fullarticle/2804051

A 95-year-old woman presented to the emergency department with 24 hours of abdominal pain, 2 weeks of diarrhea, and 3 months of intermittent abdominal bloating and anorexia. She was a farmer in rural Japan who did not drink alcohol and had been diagnosed with bullous pemphigoid 8 months prior, initially treated with prednisolone (15 mg daily). Her medications at presentation were prednisolone (8 mg daily) and lansoprazole. She had experienced 1 episode of dyspnea on exertion 2 weeks before presentation but reported no fevers, cough, wheeze, nausea or vomiting, hematochezia, or melena. In the emergency department, her temperature was 37.7 °C (99.9 °F); blood pressure, 110/56 mm Hg; heart rate, 125/min; and oxygen saturation, 95% on room air. On physical examination her lungs were clear to auscultation, and her abdomen was diffusely tender to palpation without rebound. Skin examination revealed purpuric macules and small thumbprint-like patches on the upper abdomen and central chest (Figure 1).Purpuric macules and thumbprint-like patches (arrowheads) on patient’s upper abdomen and central chest.Laboratory testing showed white blood cell count, 13 600/μL (89.9% neutrophils, 0.2% eosinophils); hemoglobin, 10.9 g/dL; serum sodium, 130 mEq/L (reference, 138-145 mEq/L); creatinine, 0.82 mg/dL (72.49 μmol/L); aspartate aminotransferase, 55 U/L (0.92 μkat/L) (reference, 13-30 U/L [0.22-0.50 μkat/L]); alanine aminotransferase, 54 U/L (0.90 μkat/L) (reference, 7-23 U/L [0.12-0.38 μkat/L]); and erythrocyte sedimentation rate, 31 mm/h (reference, 3-15 mm/h). Platelet count and prothrombin time were normal. Abdominal computed tomography with intravenous contrast revealed inflammation of the small intestine.The patient was treated with ampicillin/sulbactam, and her blood cultures grew Klebsiella pneumoniae after hospital admission.Obtain a polymerase chain reaction (PCR) panel for gastrointestinal pathogensOrder measurement of antineutrophil cytoplasmic antibody (ANCA) level What Would You Do Next?

Check stool for ova and parasites

Obtain a polymerase chain reaction (PCR) panel for gastrointestinal pathogens

Order measurement of antineutrophil cytoplasmic antibody (ANCA) level

Send blood for fungal culture

Disseminated strongyloidiasis

A

Check stool for ova and parasites

The key to the correct diagnosis is recognition that chronic abdominal symptoms, abdominal purpuric macules and patches, and bacteremia in an immunosuppressed agricultural worker are characteristic findings of disseminated strongyloidiasis. A PCR panel for gastrointestinal pathogens (choice B) is useful to evaluate acute but not chronic diarrhea. Ordering measurement of ANCA level (choice C) is not indicated because the patient did not have typical signs of ANCA-associated vasculitis. Choice D is incorrect because fungal infection does not typically cause purpura.Strongyloidiasis is caused by Strongyloides stercoralis, an intestinal helminth, and affects approximately 370 million people worldwide, with a prevalence of 10% to 40% in people living in tropical and subtropical regions.1 In the US, strongyloidiasis is most commonly diagnosed in people who have immigrated or in travelers returning from high-prevalence regions; however, S stercoralis is endemic in the southeastern US.2,3Infection with S stercoralis typically occurs when filariform larvae in soil penetrate the skin of individuals who walk barefoot on contaminated soil. The larvae migrate through the venous circulation to the lungs and ascend the trachea to the oropharynx, where they are swallowed.1 After ingestion, the larvae lodge in the small intestine and produce eggs that become rhabditiform larvae that are excreted in stool.3,4 Some larvae mature into filariform larvae, which penetrate the colonic wall or perianal skin, leading to reinfection of the host (autoinfection).1 This process results in persistent S stercoralis infection.Chronic strongyloidiasis develops when acute strongyloidiasis is not treated and is perpetuated by autoinfection via the gastrointestinal tract, peritoneum, and lungs, which are directly involved in the life cycle of S stercoralis.1 Immunocompetent patients with chronic strongyloidiasis are often asymptomatic or have only mild abdominal symptoms, minor skin manifestations, and eosinophilia ranging from 5% to 15%.1Hyperinfection syndrome, defined by an accelerated rate of autoinfection, typically occurs when patients with chronic strongyloidiasis develop impaired cell-mediated immunity due to corticosteroids, human T-cell leukemia virus type 1 (HTLV-1), chemotherapy, solid organ transplant, or malnutrition.3 Disseminated strongyloidiasis can develop after hyperinfection and involves propagation of S stercoralis to organs outside the typical autoinfection cycle, such as the skin, brain, heart, liver, gallbladder, pancreas, kidneys, ovaries, and skeletal muscle.1,5Patients with hyperinfection syndrome and disseminated strongyloidiasis may experience small bowel obstruction due to the large quantity of intestinal larvae, and gastrointestinal bleeding from intestinal invasion, in addition to abdominal pain, diarrhea, constipation, nausea, and vomiting.6 Pulmonary symptoms may include cough, shortness of breath, wheeze, and hemorrhagic pneumonitis.3 Periumbilical purpura in the pattern of a thumbprint results from larval invasion into the umbilical vein; this is rare but pathognomonic for disseminated strongyloidiasis.6,7 Eosinophilia is often absent in hyperinfection syndrome and disseminated strongyloidiasis.3,4Patients with hyperinfection syndrome and disseminated strongyloidiasis have abundant larvae, which can be easily detected on examination of stool, sputum, and pleural or cerebrospinal fluid.5 Although no evidence-based guidelines exist for treatment of severe strongyloidiasis, daily ivermectin (200 μg/kg) is typically prescribed for a minimum of 2 weeks and until stool examination is negative for 2 weeks.6,8 Despite treatment, mortality associated with hyperinfection syndrome and disseminated strongyloidiasis has been reported as 69% to 85%,1,5 due to complications such as peritonitis, respiratory failure, meningitis, and bacteremia caused by enteric bacterial translocation that accompanies larval invasion of the intestines.3,5,6,9Strongyloides stercoralis larvae were detected in the patient’s stool and induced sputum (Figure 2). She was treated with ivermectin (9 mg orally daily for 14 days). Antibody testing for HTLV-1 was negative. The patient’s mental status declined, and a lumbar puncture was performed on hospital day 10. Enterococcus faecium was identified in cerebrospinal fluid culture, and her antibiotics were changed to vancomycin and meropenem. Four weeks after hospital admission, the patient died of upper gastrointestinal bleeding.Filariform Strongyloides stercoralis larva on an unstained wet mount of patient’s induced sputum.

General

A 95-year-old woman presented to the emergency department with 24 hours of abdominal pain, 2 weeks of diarrhea, and 3 months of intermittent abdominal bloating and anorexia. She was a farmer in rural Japan who did not drink alcohol and had been diagnosed with bullous pemphigoid 8 months prior, initially treated with prednisolone (15 mg daily). Her medications at presentation were prednisolone (8 mg daily) and lansoprazole. She had experienced 1 episode of dyspnea on exertion 2 weeks before presentation but reported no fevers, cough, wheeze, nausea or vomiting, hematochezia, or melena. In the emergency department, her temperature was 37.7 °C (99.9 °F); blood pressure, 110/56 mm Hg; heart rate, 125/min; and oxygen saturation, 95% on room air. On physical examination her lungs were clear to auscultation, and her abdomen was diffusely tender to palpation without rebound. Skin examination revealed purpuric macules and small thumbprint-like patches on the upper abdomen and central chest (Figure 1).Purpuric macules and thumbprint-like patches (arrowheads) on patient’s upper abdomen and central chest.Laboratory testing showed white blood cell count, 13 600/μL (89.9% neutrophils, 0.2% eosinophils); hemoglobin, 10.9 g/dL; serum sodium, 130 mEq/L (reference, 138-145 mEq/L); creatinine, 0.82 mg/dL (72.49 μmol/L); aspartate aminotransferase, 55 U/L (0.92 μkat/L) (reference, 13-30 U/L [0.22-0.50 μkat/L]); alanine aminotransferase, 54 U/L (0.90 μkat/L) (reference, 7-23 U/L [0.12-0.38 μkat/L]); and erythrocyte sedimentation rate, 31 mm/h (reference, 3-15 mm/h). Platelet count and prothrombin time were normal. Abdominal computed tomography with intravenous contrast revealed inflammation of the small intestine.The patient was treated with ampicillin/sulbactam, and her blood cultures grew Klebsiella pneumoniae after hospital admission.Obtain a polymerase chain reaction (PCR) panel for gastrointestinal pathogensOrder measurement of antineutrophil cytoplasmic antibody (ANCA) level

what would you do next?

What would you do next?

Order measurement of antineutrophil cytoplasmic antibody (ANCA) level

Check stool for ova and parasites

Obtain a polymerase chain reaction (PCR) panel for gastrointestinal pathogens

Send blood for fungal culture

b

female

91-100

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2803658

A patient in their mid-30s with a medical history of deceased donor kidney transplant, cytomegalovirus (CMV) colitis, and CMV viremia with documented resistance to foscarnet and ganciclovir (UL97 and UL54 gene mutations) presented with new-onset floaters in both eyes. The patient was taking systemic immunosuppression but recently stopped taking maribavir because of concerns about resistance and was transitioned to cidofovir and CMV immune globulin. On clinical examination, the visual acuity measured 20/25 OD and 20/20 OS. Motility, visual fields, and anterior segment examination were normal. Dilated fundus examination revealed tortuous vasculature, multiple cotton wool spots along the arcades and periphery, and granular, hypopigmented retinal lesions without hemorrhage in the macula and temporal periphery in both eyes (Figure 1A). Optical coherence tomography showed localized areas of full-thickness retinitis (Figure 1B). CMV titers indicated viremia at 2.24 million IU/mL. Despite the patient’s documented UL97 and UL54 mutations, a series of 5 biweekly intravitreal injections of foscarnet and ganciclovir were performed given their vision-threatening lesions. Retinal pathology failed to improve, and the patient eventually refused additional intravitreal therapy because of pain and transiently decreased vision after each injection.Ultra-widefield fundus photograph and optical coherence tomography of a necrotic retinal lesion in the right eye demonstrating (A) multiple cotton wool spots along the arcades with retinal lesions in the temporal periphery (arrowheads) and (B) a cross-section through a temporal lesion along the superior arcade showing full thickness retinitis (arrow).Observation with systemic cidofovir and CMV immune globulin What Would You Do Next?

Observation with systemic cidofovir and CMV immune globulin

Multivirus-specific cytotoxic T lymphocytes (CTLs)

Continued foscarnet and ganciclovir intravitreal injections

Leflunomide initiation

UL97- and UL54-resistant CMV retinitis

B

Multivirus-specific cytotoxic T lymphocytes (CTLs)

Treatment of CMV retinitis is a challenging situation in patients who have undergone transplant because they require long-term immunosuppression and therefore must also receive ongoing antiviral therapy for an increasingly resistant virus. The option of systemic cidofovir and CMV immune globulin or continued treatment with intravitreal ganciclovir and foscarnet would be suboptimal, as no significant improvement was seen using these medications in the context of documented mutations in the UL97 and UL54 genes. A mutation in the UL97 gene confers resistance to ganciclovir and valganciclovir, while mutation in the UL54 gene confers resistance to ganciclovir, valganciclovir, foscarnet, and cidofovir.1-3 Furthermore, the patient did not tolerate biweekly intravitreal injections because of pain and transient vision changes. Leflunomide would be an option; however, in the context of the patient’s high viral load, resistance would likely develop quickly, resulting in only a transient effect.4Cytotoxic T lymphocytes are a novel therapy for CMV retinitis that is refractory to available therapies. A type of immunotherapy, CTLs involve adoptive transfer of donor T cells to provide a virus-specific immune response to clear infection.5 This patient received posoleucel, a multivirus-specific T-cell therapy, with dramatic improvement in both retinal findings (Figure 2) and CMV titers (2.24 million IU/mL to 14 700 IU/mL) 1 month after the first infusion. There was complete resolution of active retinitis with residual scarring. Visual acuity remained stable at 20/20 OD and 20/25 OS.Ultra-widefield fundus photograph of the right eye after multivirus-specific cytotoxic T-lymphocyte therapy demonstrates resolution of active cytomegalovirus retinitis and cotton wool spots with residual areas of partially pigmented scarring (arrowheads).There have been a handful of cases in the literature on outcomes of CMV retinitis treated with CTL therapy.5-7 Gupta et al5 presented a series of 7 patients treated with CMV-specific T cells in which 90% of eyes achieved disease resolution and 80% had stable or improved visual acuity. Prior to CTL therapy, all patients had progressive retinitis despite systemic and intravitreal antiviral therapy. Three patients had UL97 mutations, and 1 patient had a UL54 mutation. Underlying immunosuppression was secondary to stem cell transplant in 4 patients, AIDS in 2 patients, and kidney transplant in 1 patient.5 Treatment was well tolerated in the limited sample size with no cases of immune recovery uveitis, 1 case of cystoid macular edema, and 2 cases of retinal detachment.5 In addition to ocular adverse effects, systemic adverse effects of CTL therapy described in the oncology literature can include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias.8 Compared with the series from Gupta et al,5 we used multivirus-specific T-cell therapy rather than CMV-specific T cells.The patient returned 8 weeks after their initial diagnosis (6 weeks after the first infusion) with decreased vision. Best-corrected visual acuity was 20/70 OD and 20/60 OS. Optical coherence tomography showed new subretinal fluid under the fovea in both eyes, and retinal thickness had increased (right eye: 273 to 336 μm; left eye: 273 to 324 μm). CMV lesions in both eyes remained inactive. Unfortunately, before any additional testing could occur, the patient rapidly declined from complications of posttransplant lymphoproliferative disorder and transitioned to hospice. The patient’s decreased vision could represent an adverse effect of CTL therapy or cidofovir, but the critically ill status of the patient precluded definitive diagnosis. Overall, CTL therapy is a promising novel therapy that requires further investigation, ideally with prospective trials, to evaluate its role in the treatment for CMV retinitis.

Ophthalmology

A patient in their mid-30s with a medical history of deceased donor kidney transplant, cytomegalovirus (CMV) colitis, and CMV viremia with documented resistance to foscarnet and ganciclovir (UL97 and UL54 gene mutations) presented with new-onset floaters in both eyes. The patient was taking systemic immunosuppression but recently stopped taking maribavir because of concerns about resistance and was transitioned to cidofovir and CMV immune globulin. On clinical examination, the visual acuity measured 20/25 OD and 20/20 OS. Motility, visual fields, and anterior segment examination were normal. Dilated fundus examination revealed tortuous vasculature, multiple cotton wool spots along the arcades and periphery, and granular, hypopigmented retinal lesions without hemorrhage in the macula and temporal periphery in both eyes (Figure 1A). Optical coherence tomography showed localized areas of full-thickness retinitis (Figure 1B). CMV titers indicated viremia at 2.24 million IU/mL. Despite the patient’s documented UL97 and UL54 mutations, a series of 5 biweekly intravitreal injections of foscarnet and ganciclovir were performed given their vision-threatening lesions. Retinal pathology failed to improve, and the patient eventually refused additional intravitreal therapy because of pain and transiently decreased vision after each injection.Ultra-widefield fundus photograph and optical coherence tomography of a necrotic retinal lesion in the right eye demonstrating (A) multiple cotton wool spots along the arcades with retinal lesions in the temporal periphery (arrowheads) and (B) a cross-section through a temporal lesion along the superior arcade showing full thickness retinitis (arrow).Observation with systemic cidofovir and CMV immune globulin

what would you do next?

What would you do next?

Observation with systemic cidofovir and CMV immune globulin

Multivirus-specific cytotoxic T lymphocytes (CTLs)

Leflunomide initiation

Continued foscarnet and ganciclovir intravitreal injections

b

neutral

31-40

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2802569

A 76-year-old woman presented with a palpable left axillary mass. When she was 36 years old, she underwent a hysterectomy due to abnormal uterine bleeding and was taking estradiol to control postmenopausal vasomotor symptoms for the past 20 years. Bilateral diagnostic mammography revealed a high-density irregular mass in the left axilla with no nodules, architectural distortions, or microcalcifications in the breasts. Ultrasonography of the left breast showed a 4.6-cm lobulated mixed cystic and solid left axillary mass. Contrast-enhanced magnetic resonance imaging showed an enhancing 5.2-cm left axillary mass with no breast lesions (Figure 1A). The biopsy examination indicated high-grade adenocarcinoma with papillary features (estrogen receptor– and progesterone receptor–positive, ERBB2 [formerly HER2]–negative, and a high Ki67 index). Positron emission tomography/computed tomography revealed only high uptake in the left axilla region. The patient was treated at an outside hospital with neoadjuvant dose-dense doxorubicin and cyclophosphamide, followed by weekly paclitaxel for 10 weeks. She then transferred her care to our center for surgical management. We requested the pathology slides for review at our laboratory and additional immunostaining was performed, which revealed high-grade adenocarcinoma with tumor cells positive for PAX8 (Figure 1B), p53, and WT1 and negative for GATA3.A, Magnetic resonance image of the breasts shows an enhancing 5.2-cm left axillary mass (arrowhead) but no breast lesions. B, Immunohistochemical staining revealed tumor cells positive for PAX8 (original magnification ×100).High-grade carcinoma of the breast with occult primary What Is Your Diagnosis?

Papillary carcinoma of the thyroid

High-grade serous carcinoma of gynecological origin

High-grade carcinoma of the breast with occult primary

High-grade papillary carcinoma of unknown primary

B. High-grade serous carcinoma of gynecological origin

B

High-grade serous carcinoma of gynecological origin

This patient underwent left axillary excisional lymph node biopsy, peritoneal washings, laparoscopic bilateral salpingo-oophorectomy, omental biopsy, and bilateral ureterolysis. Laparoscopy revealed that both ovaries were affixed to the pelvic peritoneum with adhesions, requiring bilateral ureterolysis. The uterus, cervix, and proximal fallopian tubes were surgically absent. On gross examination the distal fallopian tubes appeared unremarkable, and the left ovary appeared nodular. Given the clinical scenario, the fimbrial ends of the fallopian tubes were entirely excised and submitted for microscopic examination along with both ovaries. Microscopic examination revealed a residual 2.1-mm focus of high-grade serous carcinoma (Figure 2) involving the fimbrial end of the left fallopian tube. No omental involvement was seen. The immunostaining pattern was similar to that seen in the axillary metastasis prior to therapy. No residual carcinoma was identified in the left axillary lymph node. The patient’s cancer antigen 125 level was 13 U/mL before the surgery. Disease was staged as FIGO (International Federation of Gynecology and Obstetrics) stage IVB, and the patient received additional platinum-based adjuvant chemotherapy. Test results were negative for germline pathogenic sequence variants, including BRCA1 and BRCA2.Hematoxylin-eosin–stained biopsy specimen of the left fallopian tube fimbria at low power (A) and high power (B) shows residual high-grade adenocarcinoma invading into the stroma (arrowheads).Although metastatic ovarian or tubal serous carcinoma typically first spreads locally within the abdomen or peritoneum, distal extra-abdominal involvement is well established.1 An isolated axillary mass rarely presents as the initial sign of ovarian or tubal serous carcinoma, and there are few cases reported.2-4 Unlike other patients, this patient was initially treated with neoadjuvant chemotherapy with a presumptive diagnosis of an occult breast cancer with axillary metastasis. After histopathologic reassessment and additional immunostaining at our institution, the treatment plan was adjusted accordingly. Her initial diagnostic evaluation included clinical history, radiography, and pathologic examination. Given the pathologic findings, location of the malignant neoplasm, and positive hormone receptor expression, this case was misdiagnosed as breast cancer at the outside institution. Immunohistochemical staining was key to reaching the correct diagnosis.Clinical management of axillary nodal metastases of carcinoma of unknown primary (CUPAx) is challenging. A systematic review reported that 72% of the patients with CUPAx treated with prophylactic mastectomy had an occult primary cancer of the breast,5 which implied that a thorough investigation of breast origin might be appropriate and could avoid unnecessary surgeries. In these situations, immunostaining can offer more insight but only to a limited extent. Greco et al6 evaluated diagnoses based on molecular profile, immunostaining (median of 6 stains), and clinical findings, and reported that diagnoses among all 3 modalities were consistent for only 34% of the patients. Some markers may provide evidence implying the primary site; for example, TTF-1 and thyroglobulin are relatively specific for thyroid cancer, CK7 and GATA3 are highly suggestive of breast cancer, and CK7, WT1, and PAX8 are indicative of gynecological adenocarcinoma.7,8 While estrogen and progesterone receptors are frequently evaluated in breast cancers, they can also be expressed in ovarian cancer, and some evidence supports their prognostic value.9,10 Thus, infradiaphragmatic primary malignant neoplasm should not be completely excluded when positive hormone profiles are present.Ovarian serous papillary adenocarcinoma initially presenting as axillary lymph node metastasis is rare. When managing CUPAx, primary sites other than the breast should be explored. Thorough clinical history, physical examination, and histopathologic evaluation of the biopsy specimen in conjunction with immunostaining is invaluable in establishing a diagnosis.

Oncology

A 76-year-old woman presented with a palpable left axillary mass. When she was 36 years old, she underwent a hysterectomy due to abnormal uterine bleeding and was taking estradiol to control postmenopausal vasomotor symptoms for the past 20 years. Bilateral diagnostic mammography revealed a high-density irregular mass in the left axilla with no nodules, architectural distortions, or microcalcifications in the breasts. Ultrasonography of the left breast showed a 4.6-cm lobulated mixed cystic and solid left axillary mass. Contrast-enhanced magnetic resonance imaging showed an enhancing 5.2-cm left axillary mass with no breast lesions (Figure 1A). The biopsy examination indicated high-grade adenocarcinoma with papillary features (estrogen receptor– and progesterone receptor–positive, ERBB2 [formerly HER2]–negative, and a high Ki67 index). Positron emission tomography/computed tomography revealed only high uptake in the left axilla region. The patient was treated at an outside hospital with neoadjuvant dose-dense doxorubicin and cyclophosphamide, followed by weekly paclitaxel for 10 weeks. She then transferred her care to our center for surgical management. We requested the pathology slides for review at our laboratory and additional immunostaining was performed, which revealed high-grade adenocarcinoma with tumor cells positive for PAX8 (Figure 1B), p53, and WT1 and negative for GATA3.A, Magnetic resonance image of the breasts shows an enhancing 5.2-cm left axillary mass (arrowhead) but no breast lesions. B, Immunohistochemical staining revealed tumor cells positive for PAX8 (original magnification ×100).High-grade carcinoma of the breast with occult primary

what is your diagnosis?

What is your diagnosis?

High-grade serous carcinoma of gynecological origin

High-grade papillary carcinoma of unknown primary

Papillary carcinoma of the thyroid

High-grade carcinoma of the breast with occult primary

a

female

71-80

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2801610

A 7-year-old boy presented with a slowly growing, asymptomatic lump on his left lower neck since birth. His parents denied any medical history of trauma, infection, or surgery. Physical examination showed a 1.3 × 0.7 × 0.6 cm, yellowish, hump-like mass with hairy surface and cartilage-like consistency on the anterior border of the lower third of the left sternocleidomastoid muscle (SCM) (Figure, A). No other anomalies were observed. Ultrasonography revealed a 1.2 × 1.0 × 0.9 cm, hypoechoic, avascular, bulging nodule with an anechoic tubular structure extending to the subcutaneous fat and reaching the surface of the muscular layer. Magnetic resonance imaging (MRI) demonstrated a protuberant nodule with diffuse, slight hyperintensity on T1WI; and 2 mild hyperintense foci surrounded by hypointense tissue on fat-suppressed T2WI (Figure, B). The neck mass was completely excised under general anesthesia in the department of pediatric surgery. Intraoperatively, the mass extended into the anteromedial fascia of the left SCM and did not involve the deeper neck structures. Postoperative histopathologic analysis showed normal-appearing epidermis, multiple pilosebaceous follicles, abundant adipose tissue, and 2 centrally circumscribed segments of cartilage in the subcutis (Figure, C). Van Gieson stain highlighted elastic fibers surrounding individual chondrocytes.A, A yellowish hump-like mass with hairy surface on the anterior-inferior third border of the left sternocleidomastoid muscle (SCM). B, Transverse T2-weighted, fat-suppressed magnetic resonance image (MRI) revealed a nodular bulge with 2 mild hyperintense foci (arrowheads) surrounded by hypointense tissue. C, Whole-slide hematoxylin-eosin stain showed normal-appearing epidermis, multiple pilosebaceous follicles, abundant adipose tissue, and 2 centrally circumscribed segments of cartilage (arrowheads) in the subcutis (original magnification ×10). What Is Your Diagnosis?

Branchial cleft cyst

Epidermoid cyst

Cervical chondrocutaneous branchial remnant

Hair follicle nevus

C. Cervical chondrocutaneous branchial remnant

C

Cervical chondrocutaneous branchial remnant

Cervical chondrocutaneous branchial remnant (CCBR) was termed by Altan et al1 in 1997. It is also known as congenital cartilaginous rest of the neck, wattle, cervical auricle, or accessory tragus, and represents an uncommon, congenital, cartilaginous choristoma on the cervical area.2-4 To date more than 136 cases have been reported, of which male sex is predominant (male vs female, 1.67:1), and unilateral CCBR (87.5%; left vs right, 1.64:1) is more common than bilateral CCBR (12.5%).2 It may originate from the remnant of the second or lower branchial arch or pluripotent cell rests.2,3 Generally, CCBR presents as an asymptomatic skin-colored protuberant mass with soft or cartilage-like texture and hairy surface, and involves the inferior third of the lateral neck, particularly along the anterior border of the SCM.1-5 The incidence of associated anomalies is 11.8%-76.5% of patients with CCBR, with genitourinary, digestive, auditory, and cardiovascular anomalies being more common.2 There is no correlation between associated anomalies and unilateral vs bilateral CCBR.3Ultrasonography and computed tomography (CT) have been used for preoperative evaluation of CCBR. These and other imaging studies may also be useful in assessing for associated anomalies, in addition to a detailed physical examination.3,4,6 The cartilage core manifests as a tubular hypoechoic core on ultrasonography or a central intermediate attenuation on CT findings, which extends to the underlying SCM.3,6 Findings on MRI showed a nodular bulge with 2 mild hyperintense foci surrounded by hypointense tissue on fat-suppressed T2WI in this case (Figure, C).Clinical and imaging findings are helpful in the diagnosis of CCBR, but its definite diagnosis is dependent on histopathologic findings. The histopathologic features of CCBR are cartilage cores in abundant adipose tissue with numerous overlying vellus hair follicles.7 The cartilage is primarily elastic and occasionally hyaline.2-4Main differential diagnoses include branchial cleft cyst, epidermoid cyst, hair follicle nevus, and fibroepithelial polyp, which can be easy to distinguish from CCBR in histopathologic diagnosis due to their absence of cartilage structure.4,8 Branchial cleft cyst is characterized clinically by a pit or sinus tract in the lateral neck and pathologically by upper respiratory epithelium with seromucinous glands.4 Hair follicle nevus is a rare congenital follicular hamartoma that resembles CCBR clinicopathologically except for lack of cartilaginous component; both may belong to a spectrum of the same entity.7Because CCBR is connected to the neck musculature or fascia, simple excision extending no deeper than the superficial neck musculature is recommended.1,3,4 This patient underwent en bloc resection of the neck lump without complications or recurrence at 4-month follow-up.

General

A 7-year-old boy presented with a slowly growing, asymptomatic lump on his left lower neck since birth. His parents denied any medical history of trauma, infection, or surgery. Physical examination showed a 1.3 × 0.7 × 0.6 cm, yellowish, hump-like mass with hairy surface and cartilage-like consistency on the anterior border of the lower third of the left sternocleidomastoid muscle (SCM) (Figure, A). No other anomalies were observed. Ultrasonography revealed a 1.2 × 1.0 × 0.9 cm, hypoechoic, avascular, bulging nodule with an anechoic tubular structure extending to the subcutaneous fat and reaching the surface of the muscular layer. Magnetic resonance imaging (MRI) demonstrated a protuberant nodule with diffuse, slight hyperintensity on T1WI; and 2 mild hyperintense foci surrounded by hypointense tissue on fat-suppressed T2WI (Figure, B). The neck mass was completely excised under general anesthesia in the department of pediatric surgery. Intraoperatively, the mass extended into the anteromedial fascia of the left SCM and did not involve the deeper neck structures. Postoperative histopathologic analysis showed normal-appearing epidermis, multiple pilosebaceous follicles, abundant adipose tissue, and 2 centrally circumscribed segments of cartilage in the subcutis (Figure, C). Van Gieson stain highlighted elastic fibers surrounding individual chondrocytes.A, A yellowish hump-like mass with hairy surface on the anterior-inferior third border of the left sternocleidomastoid muscle (SCM). B, Transverse T2-weighted, fat-suppressed magnetic resonance image (MRI) revealed a nodular bulge with 2 mild hyperintense foci (arrowheads) surrounded by hypointense tissue. C, Whole-slide hematoxylin-eosin stain showed normal-appearing epidermis, multiple pilosebaceous follicles, abundant adipose tissue, and 2 centrally circumscribed segments of cartilage (arrowheads) in the subcutis (original magnification ×10).

what is your diagnosis?

What is your diagnosis?

Branchial cleft cyst

Epidermoid cyst

Hair follicle nevus

Cervical chondrocutaneous branchial remnant

d

male

0-10

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2801970

An 11-year-old girl with no significant medical history was referred to the pediatric otolaryngology department for a painless, left-sided neck mass that had been slowly enlarging for 8 months. On examination, there was an easily palpable 3-cm firm, fixed, well-circumscribed left supraclavicular mass without overlying skin changes or cutaneous involvement. She had no other masses, cervical lymphadenopathy, or systemic symptoms. In workup for this mass, she initially underwent ultrasound imaging, which demonstrated a hypoechoic mass. Findings from fine-needle aspiration and core-needle biopsy were inconclusive, demonstrating histiocytes. Magnetic resonance imaging demonstrated a well-circumscribed mass of mainly soft tissue density with contrast enhancement (Figure 1).Magnetic resonance imaging of the left-sided supraclavicular mass. T2 sequencing with contrast demonstrates strong enhancement of the mass.Given persistence of the lesion, and inconclusive biopsies, the decision was made to pursue surgical excision. In the operating room, a well-defined 5.5-cm left level V mass was excised. The mass was found to attach deep to the middle scalene and was fed by several unnamed vessels; however, there was no involvement of the clavicle. Pathology confirmed complete excision of a well-circumscribed lesion with peripheral casing of bone, cyst-like spaces filled with serous fluid, walls of spindle-shaped fibroblasts, osteoclast-type giant cells, thin trabeculae of woven bone surfaced with osteoblasts, and scattered macrophages. There was local infiltration into surrounding skeletal muscle, but no atypical mitoses or pleomorphic cells were identified. The lesion was positive for USP6 locus rearrangement (17p13.2) on florescence in situ hybridization. What Is Your Diagnosis?

Soft tissue giant cell tumor

Ossifying fibromyxoid tumor

Soft tissue aneurysmal bone cyst

Soft tissue osteosarcoma

C. Soft tissue aneurysmal bone cyst

C

Soft tissue aneurysmal bone cyst

The gross and microscopic findings were characteristic of a soft tissue (extraosseous) aneurysmal bone cyst (ABC) with USP6 locus rearrangement, confirming the diagnosis (Figure 2). Aneurysmal bone cysts are benign but locally aggressive tumors most commonly found in association with the long bones and spines of children and young adults.1,2 Extraosseous or soft tissue ABCs pathologically and genetically resemble those associated with bone but lack a bony attachment.2 Soft tissue ABCs are a rare phenomenon with approximately 40 cases reported in the literature.3 Extraosseous ABCs were first described in 1972 by Salm and Sissons as soft tissue lesions with identical histopathological findings as ABCs.4 Aneurysmal bone cysts are classically described as bony-shelled, blood-filled cysts with fibrous septa, which contain giant cells, woven bone, fibroblasts, and histiocytes.5-7 In 1999, Dal Cin et al described chromosomal rearrangement of 17p13 in all ABCs, including those associated only with soft tissue, confirming similar neoplastic pathogenesis.8 Furthermore, USP6 locus rearrangement has been determined to be sensitive for ABCs in a more recent study by Li et al.9 Magnetic resonance imaging is identical to osseous ABCs, demonstrating an expansile lesion, T2-weighted intense, with strong contrast enhancement and fluid levels.2,6,7,10 These lesions tend to occur within the first 2 decades of life, and of cases reported there is no sex predominance.2,10 Aneurysmal bone cysts, including the soft tissue variety, are difficult to diagnose given their rarity and similar presentation, clinically and radiographically, to other more common tumors such as giant cell tumors, extraskeletal osteosarcomas, ossifying fibromyxoid tumors, and myositis ossificans.2,3,6,7A, Gross pathology of the left-sided supraclavicular mass demonstrates a cystic lesion with fibrous septae. B, Microscopic findings show staining of spindle-shaped fibroblasts, osteoclast-type giant cells, woven bone surfaced with osteoblasts, and scattered macrophages.Extraosseous ABCs are rare in the head and neck. In 1993, Petrik et al described a 3-cm left common carotid mass in a 7-year-old boy, excised completely with no intracranial or bony component.4 Of other reported cases, most have occurred within the soft tissue of the limbs.2,4 Definitive treatment for these tumors, regardless of anatomical site, is complete surgical excision.2-7 Recurrence risk is reported as low in the literature, with a 2019 review citing 5% after incomplete excision.3The present case represents a classic presentation of a soft tissue ABC of the head and neck. Imaging and pathology represent the characteristic findings of this entity, and the diagnosis was able to be confirmed with gene rearrangement. The patient did well with surgical excision and has returned to normal activities with no concern for recurrence. Soft tissue ABCs should be considered on the differential for any slowly enlarging mass of the head and neck in the pediatric population.

General

An 11-year-old girl with no significant medical history was referred to the pediatric otolaryngology department for a painless, left-sided neck mass that had been slowly enlarging for 8 months. On examination, there was an easily palpable 3-cm firm, fixed, well-circumscribed left supraclavicular mass without overlying skin changes or cutaneous involvement. She had no other masses, cervical lymphadenopathy, or systemic symptoms. In workup for this mass, she initially underwent ultrasound imaging, which demonstrated a hypoechoic mass. Findings from fine-needle aspiration and core-needle biopsy were inconclusive, demonstrating histiocytes. Magnetic resonance imaging demonstrated a well-circumscribed mass of mainly soft tissue density with contrast enhancement (Figure 1).Magnetic resonance imaging of the left-sided supraclavicular mass. T2 sequencing with contrast demonstrates strong enhancement of the mass.Given persistence of the lesion, and inconclusive biopsies, the decision was made to pursue surgical excision. In the operating room, a well-defined 5.5-cm left level V mass was excised. The mass was found to attach deep to the middle scalene and was fed by several unnamed vessels; however, there was no involvement of the clavicle. Pathology confirmed complete excision of a well-circumscribed lesion with peripheral casing of bone, cyst-like spaces filled with serous fluid, walls of spindle-shaped fibroblasts, osteoclast-type giant cells, thin trabeculae of woven bone surfaced with osteoblasts, and scattered macrophages. There was local infiltration into surrounding skeletal muscle, but no atypical mitoses or pleomorphic cells were identified. The lesion was positive for USP6 locus rearrangement (17p13.2) on florescence in situ hybridization.

what is your diagnosis?

What is your diagnosis?

Ossifying fibromyxoid tumor

Soft tissue osteosarcoma

Soft tissue aneurysmal bone cyst

Soft tissue giant cell tumor

c

female

11-20

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2802781

A healthy, uncircumcised man in his 30s presented with a 14-year history of dyspareunia and recurrent, purulent discharge from his penis. He had undergone multiple evaluations by dermatologists and urologists and had not responded to systemic antibiotics and topical corticosteroids. Physical examination revealed an erythematous, pinpoint orifice on his glans penis, with peripheral telangiectasias and a linear bluish structure on dermoscopy (Figure, A and B). Ultrasonography revealed a hypoechoic focal zone on the right side of the glans, with multiple hyperechoic bilaminar structures (Figure, C). A biopsy was performed (Figure, D).A, Clinical image of glans penis with a pinpoint orifice. B, Dermoscopy reveals an orifice surrounded by peripheral telangiectasias and an extending bluish linear structure. C, Ultrasonography of the glans penis demonstrates a hypoechoic focal zone in the parenchyma on the right containing multiple hyperechoic bilaminar tracts (arrowheads) (18 MHz; longitudinal view). D, Hematoxlyin-eosin stain with original magnification ×100. What Is Your Diagnosis?

Pilonidal sinus

Cutaneous larva migrans

Median raphe cyst

Vellus hair cyst

A. Pilonidal sinus

A

Pilonidal sinus

Surgical incision revealed multiple protruding hairs. The lesion was excised and sent for histopathological analysis, which revealed a sinus tract in the dermis lined by stratified epithelium and filled with hair shafts, surrounded by a lymphoplasmacytic inflammatory infiltrate (Figure, D). The wound healed by secondary intention, and the patient had a successful recovery with no signs of recurrence at 6-month follow-up.A pilonidal sinus is a benign tract that contains hair fragments and extends from a skin-lined opening into the subcutaneous tissue. It is a chronic inflammatory condition most frequently located in the natal or gluteal cleft; this is why the condition was initially thought to be congenital. However, there is now consensus that pilonidal sinus is an acquired lesion.1 Some authors propose that local trauma and friction produce subcutaneous trapping of hair, leading to the formation of a cyst and then a sinus to drain the suppuration.1,2 However, more current reports suggest that these lesions may be localized forms of hidradenitis suppurativa.3-5 Pilonidal sinuses in unusual locations have been reported, including the scalp, neck, abdomen, groin, axilla, and even amputation stumps; these locations correlate with the classic sites of hidradenitis suppurativa. However, penile involvement is considered rare.6,7 The few reported cases all occur in uncircumcised men, suggesting that the prepuce plays a role in the mechanical forces needed for the implantation of hair; other factors, such as shaving, high body mass index, and hirsutism, have also been proposed as contributory. Clinical presentation varies and includes penile papules and swelling; in complicated cases, there may be abscess formation, coinfection, and even ulceration mimicking sexually transmitted infections and penile carcinoma.8 Additional findings that may point to the diagnosis are hair protruding from the cavity and a central orifice on dermoscopy.9 Treatment is surgical with excision of the tract and healing by secondary intention.Clinical features and histopathology are crucial for making the differential diagnosis. Cutaneous larva migrans of the penis is very rare and has been attributed to the habit of not wearing underwear at the beach. Its presentation varies from a nonspecific dermatitis to the typical creeping eruption; however, the condition is itchy and usually self-limiting. Median raphe cysts are lined by urothelial, epidermoid, glandular, or mixed epithelium and present as movable nodules on the median line of the ventral male genital region. Vellus hair cysts may resemble pilonidal sinuses histologically since they have an epidermal lining and contain multiple hair shafts; however, the hairs are vellus and thus typically nonpigmented, and they may present as multiple papules.Pilonidal sinus of the penis is an entity that dermatologists must be familiar with, because given its rarity in this location, it can easily be misdiagnosed and mistreated.

Dermatology

A healthy, uncircumcised man in his 30s presented with a 14-year history of dyspareunia and recurrent, purulent discharge from his penis. He had undergone multiple evaluations by dermatologists and urologists and had not responded to systemic antibiotics and topical corticosteroids. Physical examination revealed an erythematous, pinpoint orifice on his glans penis, with peripheral telangiectasias and a linear bluish structure on dermoscopy (Figure, A and B). Ultrasonography revealed a hypoechoic focal zone on the right side of the glans, with multiple hyperechoic bilaminar structures (Figure, C). A biopsy was performed (Figure, D).A, Clinical image of glans penis with a pinpoint orifice. B, Dermoscopy reveals an orifice surrounded by peripheral telangiectasias and an extending bluish linear structure. C, Ultrasonography of the glans penis demonstrates a hypoechoic focal zone in the parenchyma on the right containing multiple hyperechoic bilaminar tracts (arrowheads) (18 MHz; longitudinal view). D, Hematoxlyin-eosin stain with original magnification ×100.

what is your diagnosis?

What is your diagnosis?

Pilonidal sinus

Median raphe cyst

Vellus hair cyst

Cutaneous larva migrans

a

male

11-20

original

https://jamanetwork.com/journals/jama/fullarticle/2803025

A 42-year-old man with hypertension, type 2 diabetes diagnosed at age 25 years, and gastroparesis presented to the emergency department with right lower extremity blisters that had developed spontaneously over the prior 36 hours. He reported a tingling sensation in the affected area but no pruritus or pain. He had no history of leg trauma and no chemical or extreme temperature exposure. Medications included insulin lispro (sliding scale 3 times daily) and insulin glargine (20 units nightly). On physical examination, he was afebrile and had normal vital signs. His extremities were warm with palpable distal pulses. Hyperpigmented macules were present on the anterior lower legs below the knees, and tense bullae were present on the anterior aspect of the right lower extremity, dorsal foot surface, and toes (Figure). There was no surrounding erythema or edema, and findings on the remainder of the skin and mucocutaneous examination were unremarkable. Laboratory testing revealed a blood glucose level of 375 mg/dL (20.81 mmol/L) and hemoglobin A1c level of 9.8%. Results of a basic metabolic panel and complete blood cell count were within reference range except for mild anemia (hemoglobin level, 10.9 g/dL).Patient's right lower extremity with bullae and hyperpigmented macules and patches, characteristic of diabetic dermopathy (left). Bullae on patient’s right toes, anterior foot, and ankle (right).Aspirate the bullae with a sterile needle and cover with a clean dressingPerform a skin biopsy for histopathology and direct immunofluorescence What Would You Do Next?

Aspirate the bullae with a sterile needle and cover with a clean dressing

Perform a skin biopsy for histopathology and direct immunofluorescence

Start oral prednisone (1 mg/kg/d)

Treat with oral cephalexin for 7 days

Bullosis diabeticorum

A

Aspirate the bullae with a sterile needle and cover with a clean dressing

The key to the correct diagnosis was recognition of spontaneous blistering on noninflamed skin in a patient with diabetes. The long-standing nature of the patient’s diabetes was supported by the incidental finding of diabetic dermopathy, characterized by hyperpigmented macules and patches on the anterior lower legs. A skin biopsy (choice B) is not needed to make the diagnosis in the appropriate clinical context and would likely show nonspecific features, such as subepidermal blister formation with minimal inflammation and negative direct immunofluorescence.1,2 Oral prednisone (choice C) is not recommended because the diagnosis of bullous pemphigoid is unlikely with bullae on a single distal extremity, and prednisone might worsen the patient’s hyperglycemia. Choice D (oral cephalexin) is incorrect because the lack of surrounding erythema, warmth, tenderness, and serous crusting make infection unlikely.Bullosis diabeticorum, also known as diabetic bullae, is a rare complication of type 1 or 2 diabetes that results in spontaneous, noninflammatory blistering, most often affecting the lower extremities. Although the prevalence of bullosis diabeticorum is unknown, in small retrospective studies the annual incidence among patients with diabetes has been estimated at 0.16% to 0.5%.3 It is more common in males and often associated with long-standing peripheral neuropathy.4The pathophysiology of bullosis diabeticorum is unclear and may be multifactorial. Microangiopathy may contribute to premature connective tissue aging.5 Patients with diabetes may also have increased susceptibility to the formation of cutaneous blisters. In one study, the time to development of suction blisters was significantly shorter in patients with insulin-dependent diabetes compared with controls when suction mechanical force was applied to the skin.6 Given the typical acral location of bullosis diabeticorum, trauma has also been implicated; however, in the majority of reported cases, blisters occurred spontaneously.7 Although many reports of bullosis diabeticorum in the medical literature involve patients with long-standing or poorly controlled diabetes, bullosis diabeticorum can precede the diagnosis of diabetes7 or occur in patients with adequate glycemic control.8Bullosis diabeticorum typically presents with the sudden onset of 1 or more tense, painless blisters on otherwise normal-appearing skin. Lesions can range in size from a few millimeters up to 10 cm or more and generally contain sterile fluid, which may be clear or blood-tinged. Until they heal, these blisters are at risk of secondary bacterial infection.4 Most cases of bullosis diabeticorum resolve spontaneously within 2 to 6 weeks.7The differential diagnosis of cutaneous blisters is broad and includes bullous pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa aquisita, porphyria cutanea tarda, bullous impetigo, bullous cellulitis, and blisters resulting from edema or friction.1,8 Recent case reports have described the development of bullous pemphigoid after initiation of dipeptidyl peptidase 4 inhibitors, such as sitagliptin and saxagliptin, in patients with diabetes, with improvement after the gliptin medication was discontinued.9Treatment of bullosis diabeticorum involves gentle wound care and prevention of infection. Because bullae on the feet and lower legs can limit mobility and may be associated with an increased risk of unintentional rupture, potentially resulting in large areas of denuded skin, a sterile needle can be used to aspirate large bullae. Clean, nonstick dressings should be used to cover the blister site, and gentle compression can be helpful to prevent fluid reaccumulation. Although some authors have proposed more invasive treatment strategies, including early deroofing and other surgical intervention,4,10 there is no evidence supporting these interventions in the absence of infection. Patients with bullosis diabeticorum need careful monitoring of their affected skin and should follow up with their primary care clinician or endocrinologist to optimize glycemic control and screen for other complications of diabetes.The patient’s bullae were aspirated with a sterile needle and covered with a nonstick petrolatum dressing. His right foot and leg were wrapped with gauze, and an elastic bandage was placed for gentle compression. After receiving this treatment, the patient was discharged from the emergency department. Approximately 12 months after presentation, the patient reported by telephone that his bullae had healed, with no subsequent recurrence.

General

A 42-year-old man with hypertension, type 2 diabetes diagnosed at age 25 years, and gastroparesis presented to the emergency department with right lower extremity blisters that had developed spontaneously over the prior 36 hours. He reported a tingling sensation in the affected area but no pruritus or pain. He had no history of leg trauma and no chemical or extreme temperature exposure. Medications included insulin lispro (sliding scale 3 times daily) and insulin glargine (20 units nightly). On physical examination, he was afebrile and had normal vital signs. His extremities were warm with palpable distal pulses. Hyperpigmented macules were present on the anterior lower legs below the knees, and tense bullae were present on the anterior aspect of the right lower extremity, dorsal foot surface, and toes (Figure). There was no surrounding erythema or edema, and findings on the remainder of the skin and mucocutaneous examination were unremarkable. Laboratory testing revealed a blood glucose level of 375 mg/dL (20.81 mmol/L) and hemoglobin A1c level of 9.8%. Results of a basic metabolic panel and complete blood cell count were within reference range except for mild anemia (hemoglobin level, 10.9 g/dL).Patient's right lower extremity with bullae and hyperpigmented macules and patches, characteristic of diabetic dermopathy (left). Bullae on patient’s right toes, anterior foot, and ankle (right).Aspirate the bullae with a sterile needle and cover with a clean dressingPerform a skin biopsy for histopathology and direct immunofluorescence

what would you do next?

What would you do next?

Perform a skin biopsy for histopathology and direct immunofluorescence

Aspirate the bullae with a sterile needle and cover with a clean dressing

Treat with oral cephalexin for 7 days

Start oral prednisone (1 mg/kg/d)

b

male

41-50

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2802378

A 62-year-old patient presented to the ophthalmology department with sudden painless vision loss in her right eye that occurred 24 hours ago. She also reported a 4-week history of right ear pain and fullness, discomfort over her frontal and maxillary sinuses, and nasal congestion without discharge. Over the past 2 weeks, she had experienced drenching night sweats, cramps in her quadriceps, and weight loss of 3 kg. She denied respiratory symptoms, headaches, scalp tenderness, or jaw claudication. She took no regular medication and did not smoke.At presentation, her visual acuities were perception of light OD and 20/20 OS. There was a right relative afferent pupillary defect. Dilated fundus examination showed a cherry red spot in the right macula with hyperreflectivity and thickening of the inner retinal layers on optical coherence tomography (Figure 1A and B). External eye examination results and ocular motility were normal. Examination by an otolaryngologist revealed normal tympanic membranes and a dry but otherwise normal nasal mucosa on flexible endoscopy. Blood tests showed leukocytosis (white blood cell count, 15 000 /µL; to convert to 109 per liter, multiply by 0.001) with neutrophilia (white blood cell count, 12 500 /µL), elevated C-reactive protein (19.4 mg/dL; to convert to milligrams per liter, multiply by 10), elevated plasma viscosity (2.06 mPas), and thrombocytosis (467 ×103/µL; to convert to ×109 per liter, multiply by 1). Kidney function was within normal limits. Chest radiograph results were unremarkable.False-color and red-free (inset) fundus photograph of the right eye shows retinal pallor (white arrowheads) with a cherry red spot (yellow arrowhead) in the macula (A). Optical coherence tomography of the right macula shows hyperreflectivity and thickening of the inner retinal layers (yellow arrowheads) and hyporeflectivity of the outer retinal layers (blue arrowheads), except for increased signal intensity in the outer retinal layers of the fovea (white arrowhead) (B).Request a magnetic resonance image of orbits and sinuses What Would You Do Next?

Request a magnetic resonance image of orbits and sinuses

Commence high-dose corticosteroids

Commence broad-spectrum antibiotics

Request urgent stroke consult

Granulomatosis with polyangiitis

B

Commence high-dose corticosteroids

The presence of a central retinal artery occlusion (CRAO) in the context of sinonasal symptoms and elevated inflammatory markers in a middle-aged patient should raise suspicion of a vasculitic process. Granulomatosis with polyangiitis (GPA), previously known as Wegener granulomatosis, is a necrotizing vasculitis that typically affects patients older than 50 years and is characterized by the presence of antineutrophil cytoplasmic antibodies against proteinase 3.1,2 The condition has a predilection for small- and medium-sized vessels of the upper and lower respiratory tract, frequently mimicking infective sinusitis, mastoiditis, or otitis.2 Almost 50% of patients with GPA will develop ocular or orbital involvement.3 Vision loss may occur due to compressive optic neuropathy from granulomatous inflammation at the orbital apex or, rarely, as a result of an occlusive retinal vasculitis or CRAO.3,4 Magnetic resonance imaging of the orbits and sinuses (choice A) may show granulomatous orbital inflammation, sinonasal mucosa thickening, or osseous destruction in advanced disease.5 However, these features are not specific for GPA and need to be correlated with clinical signs and laboratory tests.3,5 Imaging or further blood tests (eg, neutrophil cytoplasmic antibodies) should not delay the commencement of high-dose corticosteroids (choice B) if a vasculitic process is suspected as immediate immunomodulatory treatment reduces morbidity, mortality, and relapses of GPA and other vasculitides.6 The mainstay of treatment for organ-threatening GPA remains high-dose intravenous methylprednisolone, followed by oral corticosteroids and steroid-sparing agents such as cyclophosphamide or rituximab.6-8The combination of elevated inflammatory markers, neutrophils, and upper respiratory tract symptoms may be suggestive of an infective process. Bacterial or fungal sinusitis can result in sight-threatening septic thrombophlebitis or cavernous sinus thrombosis, but vision loss due to an isolated CRAO is rare.9 Importantly, this patient did not have proptosis or limited eye movements indicative of an orbital pathology. In this situation, starting broad-spectrum antibiotics (choice C) without confirming an orbital infection on computed tomography is not recommended.Patients with a nonarteritic CRAO should have an urgent stroke consult (choice D) for consideration of intravenous tissue plasminogen activator, usually if presenting within 4.5 hours of vision loss.10 This patient had no vascular risk factors and no visible embolus on fundus examination (Figure 1) and elevated inflammatory markers, thus making an inflammatory etiology more likely. Arteritic CRAO is most often due to giant cell arteritis but can be caused by other vasculitides.10 In these circumstances, referral to a stroke specialist should not delay further inflammatory workup alongside administration of high-dose corticosteroids to reduce the risk of further sight loss.This patient had a positive anti–proteinase 3 antineutrophil cytoplasmic antibodies and pulmonary nodules on computed tomography imaging of the chest (Figure 2), confirming a diagnosis of GPA. Treatment with intravenous methylprednisolone improved her constitutional and sinus symptoms and her visual acuity from perception of light to 20/125 OD. She subsequently developed a large pulmonary embolism, which was successfully thrombolyzed. Currently, she is receiving cyclophosphamide infusions for GPA and takes apixaban for ongoing anticoagulation.Postcontrast computed tomography image of the chest and lung window (8-mm maximum intensity projection slice) demonstrates multiple small bilateral lung nodules involving multiple lobes (yellow arrowheads). A larger, more focal nodule (blue arrowhead) is seen anteriorly within the right upper lobe.

Ophthalmology

A 62-year-old patient presented to the ophthalmology department with sudden painless vision loss in her right eye that occurred 24 hours ago. She also reported a 4-week history of right ear pain and fullness, discomfort over her frontal and maxillary sinuses, and nasal congestion without discharge. Over the past 2 weeks, she had experienced drenching night sweats, cramps in her quadriceps, and weight loss of 3 kg. She denied respiratory symptoms, headaches, scalp tenderness, or jaw claudication. She took no regular medication and did not smoke.At presentation, her visual acuities were perception of light OD and 20/20 OS. There was a right relative afferent pupillary defect. Dilated fundus examination showed a cherry red spot in the right macula with hyperreflectivity and thickening of the inner retinal layers on optical coherence tomography (Figure 1A and B). External eye examination results and ocular motility were normal. Examination by an otolaryngologist revealed normal tympanic membranes and a dry but otherwise normal nasal mucosa on flexible endoscopy. Blood tests showed leukocytosis (white blood cell count, 15 000 /µL; to convert to 109 per liter, multiply by 0.001) with neutrophilia (white blood cell count, 12 500 /µL), elevated C-reactive protein (19.4 mg/dL; to convert to milligrams per liter, multiply by 10), elevated plasma viscosity (2.06 mPas), and thrombocytosis (467 ×103/µL; to convert to ×109 per liter, multiply by 1). Kidney function was within normal limits. Chest radiograph results were unremarkable.False-color and red-free (inset) fundus photograph of the right eye shows retinal pallor (white arrowheads) with a cherry red spot (yellow arrowhead) in the macula (A). Optical coherence tomography of the right macula shows hyperreflectivity and thickening of the inner retinal layers (yellow arrowheads) and hyporeflectivity of the outer retinal layers (blue arrowheads), except for increased signal intensity in the outer retinal layers of the fovea (white arrowhead) (B).Request a magnetic resonance image of orbits and sinuses

what would you do next?

What would you do next?

Commence high-dose corticosteroids

Commence broad-spectrum antibiotics

Request a magnetic resonance image of orbits and sinuses

Request urgent stroke consult

a

female

61-70

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2802123

A 72-year-old male patient presented with 2 days of conjunctival injection in the right eye, chemosis, eyelid edema, and pain with eye movements. His medical history included hypothyroidism, psoriasis, and recent diagnosis of multiple myeloma, and he was taking daratumumab and zoledronic acid. He denied eye trauma, dental surgery, or sinus disease. Examination of the right eye was notable for visual acuity of 20/50, reduced ocular motility in all gazes, proptosis, and chemosis. There was no afferent pupillary defect. Examination of the left eye was unremarkable. Computed tomography of the orbits with contrast demonstrated right preseptal edema and intraorbital fat stranding of the extraconal and intraconal fat without sinus disease. Nasal endoscopy performed by the otolaryngology service showed no evidence of invasive fungal sinusitis. The patient received a single dose of intravenous vancomycin and ceftriaxone, then was transitioned to ampicillin-sulbactam for presumed orbital cellulitis. After 48 hours, motility, proptosis, and chemosis worsened (Figure 1A).A, External photograph of the right eye demonstrating periocular edema, conjunctival injection, and chemosis. B, Axial T1 fat-suppressed postcontrast magnetic resonance imaging (MRI) demonstrating proptosis of the right eye with optic nerve straightening, diffuse enhancement of the right intraconal and extraconal fat, and periorbital tissues.Magnetic resonance imaging of the orbits with and without contrast (Figure 1B) was remarkable for proptosis with optic nerve straightening, enhancement of the intraconal and extraconal fat, edema and enhancement of the right extraocular muscles, new thickening of the left sphenoid sinus with internal air-fluid level, and new inflammation of the left masticator space. A follow-up computed tomography of the sinus with contrast showed no evidence of osseous structure destruction to suggest invasive fungal sinusitis. Under guidance from the infectious disease service, antibiotics were broadened back to vancomycin and ceftriaxone with continued worsening. What Would You Do Next?

Start antifungal therapy

Sinus biopsies

Start corticosteroids

Orbital biopsy

Zoledronic acid-induced orbital inflammation

C

Start corticosteroids

This patient with multiple myeloma presented with acute unilateral orbital congestion and ophthalmoplegia and was initially treated for presumed orbital cellulitis. His condition worsened despite treatment with broad-spectrum intravenous antibiotics, thus raising suspicion for an alternative etiology. Although invasive fungal sinusitis was considered on the differential diagnosis due to his immunocompromised state, neither bedside nasal endoscopy nor computed tomography of the sinus was suggestive of the disease. Therefore, antifungals were not started (choice A), and sinus biopsies were not pursued (choice B).An inflammatory etiology was considered, given the multifocal involvement observed on imaging (right orbit, left sphenoid sinus, masticator space). On further probing, the patient reported he received his first infusion of zoledronic acid, a bisphosphonate, as part of his treatment for multiple myeloma 3 days prior to presentation. Given the acute onset of symptoms within 72 hours of the first zoledronic acid infusion, a diagnosis of orbital inflammatory disease due to bisphosphonate infusion was suspected. Treatment with intravenous pulse methylprednisolone was initiated (choice C). Due to the suspected etiology and the acute nature of the presentation, an orbital biopsy would not be the best next option (choice D).Bisphosphonates are commonly used in osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, bone metastases, hypercalcemia of malignancy, and multiple myeloma.1 Bisphosphonate-induced orbital and ocular inflammation is uncommon and has been described in both case reports and case series. With widespread use of bisphosphonates, orbital and sinus inflammation is becoming an increasingly recognized adverse effect.2 Ocular adverse effects include anterior uveitis, scleritis, and optic neuritis.3 Orbital inflammation can be severe and occurs acutely, usually within 72 hours of medication administration when given intravenously and within 2 to 3 weeks when given orally.2,4-7The close temporal association between the infusion of zoledronate and the onset of orbital inflammation in this patient is consistent with prior reports. Prompt administration of corticosteroids was associated with good response.2,4-7 Corticosteroids are the mainstay of therapy, but the ideal dosing strategy and taper schedule is unclear. Discontinuation of bisphosphonates is recommended; in most reported cases, the bisphosphonate was discontinued. There is 1 report of a patient who continued monthly bisphosphonate therapy without recurrence of orbital inflammation.5 Further studies are needed to clarify the likelihood of recurrence if patients continue taking bisphosphonates.This patient received intravenous solumedrol, 500 mg, daily for 2 days with immediate marked clinical improvement (Figure 2). He received 1 more dose of intravenous solumedrol, 250 mg, and was transitioned to an oral prednisone taper. He was examined 2 weeks after discharge with complete resolution of all orbital symptoms: he had no chemosis, conjunctival injection, proptosis, or double vision. The oncologist discontinued zoledronate and prescribed denosumab. At 3-month follow-up, none of the presenting symptoms had recurred and uncorrected visual acuity in the right eye had improved to 20/25 OD.External photograph after 2 days of intravenous methylprednisolone demonstrating clinical improvement in orbital congestion.

Ophthalmology

A 72-year-old male patient presented with 2 days of conjunctival injection in the right eye, chemosis, eyelid edema, and pain with eye movements. His medical history included hypothyroidism, psoriasis, and recent diagnosis of multiple myeloma, and he was taking daratumumab and zoledronic acid. He denied eye trauma, dental surgery, or sinus disease. Examination of the right eye was notable for visual acuity of 20/50, reduced ocular motility in all gazes, proptosis, and chemosis. There was no afferent pupillary defect. Examination of the left eye was unremarkable. Computed tomography of the orbits with contrast demonstrated right preseptal edema and intraorbital fat stranding of the extraconal and intraconal fat without sinus disease. Nasal endoscopy performed by the otolaryngology service showed no evidence of invasive fungal sinusitis. The patient received a single dose of intravenous vancomycin and ceftriaxone, then was transitioned to ampicillin-sulbactam for presumed orbital cellulitis. After 48 hours, motility, proptosis, and chemosis worsened (Figure 1A).A, External photograph of the right eye demonstrating periocular edema, conjunctival injection, and chemosis. B, Axial T1 fat-suppressed postcontrast magnetic resonance imaging (MRI) demonstrating proptosis of the right eye with optic nerve straightening, diffuse enhancement of the right intraconal and extraconal fat, and periorbital tissues.Magnetic resonance imaging of the orbits with and without contrast (Figure 1B) was remarkable for proptosis with optic nerve straightening, enhancement of the intraconal and extraconal fat, edema and enhancement of the right extraocular muscles, new thickening of the left sphenoid sinus with internal air-fluid level, and new inflammation of the left masticator space. A follow-up computed tomography of the sinus with contrast showed no evidence of osseous structure destruction to suggest invasive fungal sinusitis. Under guidance from the infectious disease service, antibiotics were broadened back to vancomycin and ceftriaxone with continued worsening.

what would you do next?

What would you do next?

Start antifungal therapy

Start corticosteroids

Orbital biopsy

Sinus biopsies

b

male

71-80

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2802694

A 61-year-old Black man with hypertension and diabetes presented with decreased vision 3 months after uneventful cataract surgery in his left eye. He had undergone laser retinopexy for retinal tears in his right eye and a scleral buckle and vitrectomy for a retinal detachment in his left eye 1 year earlier. Best-corrected visual acuity (BCVA) was 20/40 OD and counting fingers OS. Intraocular pressure (IOP) was 14 mm Hg in the right eye and 44 mm Hg in the left eye. Anterior segment examination of the right eye was unremarkable, while ophthalmoscopic examination showed vascular attenuation and treated retinal breaks. In the left eye, microcystic corneal edema and Descemet membrane folds limited examination, but no residual lenticular fragments or neovascularization of the iris or angle were seen. The patient was discharged taking timolol, dorzolamide, brimonidine, and prednisolone. Twelve days later, the cornea had cleared and IOP in the left eye improved to 32 mm Hg. Gonioscopy revealed 360° of anterior synechiae and complete angle closure, which was documented on ultrasound biomicroscopy (Figure 1). The patient started treatment with 500 mg of acetazolamide daily and referred to the glaucoma service for surgical evaluation.Ultrasound biomicroscopy of the left eye demonstrating angle closure (arrowheads).When the patient returned for his glaucoma evaluation 3 days later, he was noted to have loss of appetite, drowsiness, nausea, and malaise. The patient’s intraocular examination was stable bilaterally. During this visit, the patient developed acute chest pain and respiratory insufficiency requiring immediate transfer to the emergency department. He was found to have a hemoglobin level of 8.5 g/dL (to convert to grams per liter, multiply by 10.0) and a hematocrit level of 22.1% (to convert to a proportion of 1.0, multiply by 0.01).Obtain blood cultures, perform vitreous tap, and inject antibiotics What Would You Do Next?

Obtain blood cultures, perform vitreous tap, and inject antibiotics

Perform laser iridotomy

Observation

Perform hemoglobin electrophoresis

Acute chest syndrome induced by acetazolamide in a patient with previously undiagnosed sickle cell disease.

D

Perform hemoglobin electrophoresis

Obtaining blood cultures, performing a vitreous tap, and injecting antibiotics (choice A) would be an appropriate choice of action in suspected endogenous endophthalmitis. However, while this patient had systemic symptoms, the examination did not demonstrate findings consistent with endophthalmitis, such as vitritis, chorioretinal infiltration, fibrin, a hypopyon, or conjunctival hyperemia. Laser iridotomy (choice B) would be useful if the patient demonstrated acute angle closure. While acute angle closure can cause nausea and vomiting, it would not be expected to cause acute chest pain or respiratory distress. Additionally, pupillary block was not found on examination. Finally, observation (choice C) is inappropriate in this systemically unstable patient.Hemoglobin electrophoresis (choice D) is the correct answer in this patient who presented with symptoms of an acute sickling crisis (chest pain, respiratory distress) and decreased hemoglobin level after the initiation of acetazolamide, which is a carbonic anhydrase inhibitor (CAI). The results of the hemoglobin electrophoresis test were consistent with hemoglobin SC disease.Sickle cell disease (SCD) is a hemoglobinopathy that affects 9.3 per 100 000 people worldwide,1 disproportionately affecting those of African descent such as this patient. The reported incidence of SCD is 1 in 365 Black individuals in the United States.2 In patients with traumatic hyphema, a high index of suspicion is required to avoid oral CAI medications, which can induce sickling.3,4 However, at-risk populations with glaucoma are not typically screened for SCD prior to initiation of treatment despite the potential for systemic complications. This patient harbored occult SCD that was exacerbated with the initiation of an oral CAI.There are currently no management recommendations for populations at risk of SCD who require treatment for glaucoma. Acetazolamide increases hemoconcentration and blood viscosity, causing systemic acidosis that may induce sickling.3 Methazolamide reduces the secretion of aqueous humor without altering the kidney secretion of bicarbonate, thus avoiding systemic acidosis and making it more appropriate for use by patients with SCD.5 As shown in this patient who developed acute chest syndrome, consideration of hematologic screening or methazolamide use instead of acetazolamide may be appropriate in patients with a high risk of SCD. However, there is currently insufficient information, including whom to screen, to recommend this approach. More research on the medical management of glaucoma in patients at risk of SCD is warranted, including a cost-benefit analysis of routine screening prior to treatment.Results of the workup for myocardial infarction, thrombosis, and occult blood loss were unremarkable. Hemoglobin electrophoresis testing revealed a hemoglobin S level of 49.5% [to convert to the proportion of total hemoglobin, multiply by 0.01] and hemoglobin C level of 42.3%. The patient was treated with blood transfusion and supportive care. After discharge, the patient returned to the glaucoma service with 20/400 BCVA and an IOP of 38 mm Hg in the left eye. Examination demonstrated microcystic corneal edema, neovascularization of the iris, and a 3-mm hyphema consistent with neovascular glaucoma. Widefield fluorescein angiography revealed extensive peripheral retinal ischemia that was worse in the left eye (Figure 2) than in the right eye, without clear neovascularization. The patient underwent intravitreal bevacizumab injection, implantation of a glaucoma drainage device, and panretinal photocoagulation. After 6 months of follow-up, the patient remained stable with a BCVA of 20/200 and IOP of 15 mm Hg in the left eye and had discontinued all glaucoma medications.Ultrawidefield fluorescein angiography of the left eye demonstrating significant vascular nonperfusion (asterisks).

Ophthalmology

A 61-year-old Black man with hypertension and diabetes presented with decreased vision 3 months after uneventful cataract surgery in his left eye. He had undergone laser retinopexy for retinal tears in his right eye and a scleral buckle and vitrectomy for a retinal detachment in his left eye 1 year earlier. Best-corrected visual acuity (BCVA) was 20/40 OD and counting fingers OS. Intraocular pressure (IOP) was 14 mm Hg in the right eye and 44 mm Hg in the left eye. Anterior segment examination of the right eye was unremarkable, while ophthalmoscopic examination showed vascular attenuation and treated retinal breaks. In the left eye, microcystic corneal edema and Descemet membrane folds limited examination, but no residual lenticular fragments or neovascularization of the iris or angle were seen. The patient was discharged taking timolol, dorzolamide, brimonidine, and prednisolone. Twelve days later, the cornea had cleared and IOP in the left eye improved to 32 mm Hg. Gonioscopy revealed 360° of anterior synechiae and complete angle closure, which was documented on ultrasound biomicroscopy (Figure 1). The patient started treatment with 500 mg of acetazolamide daily and referred to the glaucoma service for surgical evaluation.Ultrasound biomicroscopy of the left eye demonstrating angle closure (arrowheads).When the patient returned for his glaucoma evaluation 3 days later, he was noted to have loss of appetite, drowsiness, nausea, and malaise. The patient’s intraocular examination was stable bilaterally. During this visit, the patient developed acute chest pain and respiratory insufficiency requiring immediate transfer to the emergency department. He was found to have a hemoglobin level of 8.5 g/dL (to convert to grams per liter, multiply by 10.0) and a hematocrit level of 22.1% (to convert to a proportion of 1.0, multiply by 0.01).Obtain blood cultures, perform vitreous tap, and inject antibiotics

what would you do next?

What would you do next?

Observation

Obtain blood cultures, perform vitreous tap, and inject antibiotics

Perform hemoglobin electrophoresis

Perform laser iridotomy

c

male

61-70

Black

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2801593

A 56-year-old woman presented at the clinic for follow-up of metastatic hormone receptor–positive, ERBB2-negative breast cancer. She had locally advanced disease that was invading the skin overlying her right breast and metastatic disease to the thoracic and lumbar spine, liver, and mediastinal, axillary, and retroperitoneal lymph nodes. Her disease had progressed after receiving first-line therapy with palbociclib and anastrozole. Subsequent treatments with fulvestrant and paclitaxel were also followed by progressive disease. She received treatment with capecitabine; after 6 weeks of treatment, she developed some redness on her hands and feet that resolved on its own.She then presented to the clinic with pruritic, erythematous, scaly macules and papules on her forearms, faces, chest, and upper back (Figure). The rash had been present for 3 weeks and had recently worsened. Her palms and soles were spared. The rash did not respond to treatment with topical clindamycin, oral solumedrol, or doxycycline. She had a history of substantial sun exposure but no history of skin cancer. What Is Your Diagnosis?

Cutaneous deposits of metastatic breast cancer

Inflammation of actinic keratoses

Medication hypersensitivity reaction

Discoid lupus erythematosus

B. Inflammation of actinic keratoses

B

Inflammation of actinic keratoses

Capecitabine is an orally bioavailable prodrug of fluorouracil that was initially approved by the US Food and Drug Administration for treating breast and colorectal cancer and has since gained additional indications for various solid tumor cancers. After metabolism to active fluorouracil in the target tissue, the drug exhibits a cytotoxic effect through incorporation within the DNA, which is followed by strand breaks, inhibition of RNA synthesis, and inhibition of thymidylate synthase.1,2 There are several cutaneous adverse effects associated with capecitabine, such as palmar-plantar erythrodysesthesia, vitiligo, pruritus, dermatitis, alopecia, onycholysis, and the inflammation of preexisting actinic keratoses (AKs).Actinic keratoses result from atypical proliferation of keratinocytes, with the potential for malignant transformation. They occur predominantly on chronic sun-exposed skin areas, such as the balding scalp, face, and dorsal forearms and hands, and are the most common premalignant skin condition in elderly individuals.2 Many treatments exist for AKs, of which one of the most used and successful is topical fluorouracil.3Shortly after US Food and Drug Administration approval, cases describing inflammation of AKs in patients undergoing treatment with capecitabine were published.2-6 In 2020, a systemic review described the available evidence for the use of capecitabine for preventing and treating AKs, as well as its use for chemoprevention of cutaneous squamous cell carcinomas in solid organ transplant recipients.7 The review comprised 8 case reports of AK inflammation, with the onset of dermatologic changes ranging from 4 days to 6 weeks after receiving treatment with capecitabine. After initial inflammation of the AK lesions, the typical course includes gradual healing and disappearance during the coming days to weeks. In described cases, some patients were prescribed topical corticosteroids for symptomatic relief, but its use was not universal. Antoniolli and colleagues8 published a similar literature review and described a tendency for older studies to have included discontinuation of the drug, with a trend toward a treat through approach more recently. In all cases that reported outcomes, there was a partial or complete resolution of the inflammation of the AKs. Thus, this effect should potentially be considered therapeutic, and treatment with capecitabine should not necessarily be discontinued.The underlying mechanism for the inflammation of AKs with capecitabine is similar to the direct cytotoxic effect seen in any cancer treated with fluorouracil. The interference of DNA and RNA synthesis via inhibition of thymidylate synthase that causes double-stranded DNA breaks is key to its cytotoxic mechanism of action.1,9 When administered systemically, capecitabine exhibits preferential accumulation in areas of active cell proliferation.8 This is associated with amplified responses in the skin and the resultant inflammation of AKs, while sparing normal skin.A pathologically distinct yet phenotypically similar phenomenon has been described in radiation recall dermatitis. It is defined as the recalling of an effect that is similar to an acute radiation reaction in an area of previous irradiation.10 Capecitabine has been a medication recently implicated in this phenomenon.10 The underlying pathophysiology is poorly understood, but it is theorized that upregulation of thymidine phosphorylase plays a role in the neoangiogenesis and preferential accumulation of capecitabine in previously irradiated tissue.The current patient was prescribed triamcinolone, 0.1%, cream for symptomatic relief. She did not experience further episodes of inflammation with subsequent treatment cycles of capecitabine, and the skin lesions eventually resolved.

Oncology

A 56-year-old woman presented at the clinic for follow-up of metastatic hormone receptor–positive, ERBB2-negative breast cancer. She had locally advanced disease that was invading the skin overlying her right breast and metastatic disease to the thoracic and lumbar spine, liver, and mediastinal, axillary, and retroperitoneal lymph nodes. Her disease had progressed after receiving first-line therapy with palbociclib and anastrozole. Subsequent treatments with fulvestrant and paclitaxel were also followed by progressive disease. She received treatment with capecitabine; after 6 weeks of treatment, she developed some redness on her hands and feet that resolved on its own.She then presented to the clinic with pruritic, erythematous, scaly macules and papules on her forearms, faces, chest, and upper back (Figure). The rash had been present for 3 weeks and had recently worsened. Her palms and soles were spared. The rash did not respond to treatment with topical clindamycin, oral solumedrol, or doxycycline. She had a history of substantial sun exposure but no history of skin cancer.

what is your diagnosis?

What is your diagnosis?

Discoid lupus erythematosus

Medication hypersensitivity reaction

Inflammation of actinic keratoses

Cutaneous deposits of metastatic breast cancer

c

female

51-60

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2801145

A 12-year-old girl presented to the clinic with a 3-month history of intermittent stridor. Her symptoms were initially most prominent while playing sports and were suspected to be due to asthma or seasonal allergies. However, medical management with albuterol, intranasal fluticasone, and cetirizine failed to provide relief. More recently, the patient’s parents noted that she developed stridor while sleeping and while at rest, prompting the family to present for medical attention.Previous workup, including pulmonary function testing, was concerning for an upper airway obstructive process, for which she was referred to otolaryngology. In-office flexible videostroboscopy revealed a mass in the distal cervical trachea that appeared nearly obstructive. Chest radiography confirmed the presence of an approximately 1.5-cm, well-circumscribed soft tissue mass within the cervical trachea.Direct laryngoscopy and bronchoscopy were performed in the operating room under general anesthesia. This demonstrated an exophytic, pedunculated mass that emanated from the anterior wall of the cervical trachea (Figure 1A and B). The patient was intubated via Seldinger technique to bypass the mass, with a 4.0-mm cuffed endotracheal tube loaded over a 0-degree Hopkins endoscope (Figure 1C). With the airway secured, attention was turned to excision of the mass. Lidocaine, 1%, with epinephrine 1:100 000 was injected in a submucosal plane, and laryngeal scissors were used to excise the attachment of the mass from the tracheal wall. The mass was then resected en bloc and removed with laryngeal cupped forceps. The attachment site was then ablated with the Coblator (Figure 1D).Intraoperative photographs demonstrating supraglottic view of intratracheal mass (A); exophytic, pedunculated mass emanating from the anterior wall of the cervical trachea (B); endotracheal intubation via Seldinger technique bypassing the mass (C); and cervical trachea following ablation of attachment site (D). What Is Your Diagnosis?

Chondroma

Glomus tumor

Schwannoma

Granular cell tumor

C. Schwannoma

C

Schwannoma

Intratracheal schwannomas are very rare neurogenic tumors that are generally benign and have a predilection for adult females.1 Only approximately 20% of reported cases have occurred in pediatric patients.2 Diagnosis is often delayed or misdiagnosed as asthma due to the insidious presentation of tracheal schwannomas. More obvious signs such as stridor, coughing, and wheezing typically only become more apparent when the tumor enlarges and obstructs more than half of the tracheal lumen.1,3,4Pulmonary function testing is useful for early diagnosis of such intratracheal masses and may demonstrate an obstructive ventilatory defect with no considerable bronchodilator response.5 Radiography and computed tomography scans can help define tumor size, location, and potential extratracheal extension. Ultimately, bronchoscopy with biopsy is the most effective way to diagnose intratracheal schwannomas. Reported bronchoscopic manifestations of intratracheal schwannomas include (1) a broad base with a round or oval protrusion into the tracheal lumen; (2) a pedicled tumor with polyplike growth into the lumen; and (3) a dumbbell-shaped mass growing into the lumen.3 Definitive diagnosis depends on histopathologic analysis. Key findings on histopathology include an intact envelope and Antoni A and B architectural patterns. Positive S-100 and negative beta-catenin and SMA immunohistochemical staining also help confirm the diagnosis. In the present patient, histologic section analysis showed a benign spindle cell lesion with focal nuclear palisading (Figure 2A). Immunohistochemical stains of the specimen were positive for S-100 (Figure 2B) and negative for beta-catenin and SMA.A, Histologic section analysis demonstrating benign spindle cell lesion with focal nuclear palisading. B, Immunohistochemical stain positive for S-100.Reported treatments for pedunculated and completely intraluminal tumors include endoscopic excision with or without a carbon dioxide laser, electronic snaring, and cryotherapy.6 Continued postoperative monitoring is advised because local recurrence has been previously reported, albeit rarely.2 Patients with recurrent disease, cancer, or extratracheal tumor extension may benefit from limited tracheal resection with primary anastomosis.2,6 Fortunately, this patient had no evidence of recurrence on follow-up direct laryngoscopy and bronchoscopy 3 months later.Careful consideration of airway management is essential prior to surgical intervention on obstructive tracheal masses. Obtaining a secure airway, distal to the mass, is paramount. In this case, a thoughtful plan for airway management was devised in conjunction with the anesthesia team prior to the procedure. The preoperative plan included the induction of anesthesia while maintaining spontaneous ventilation in the event that the mass could not be bypassed. Fortunately, bag-mask ventilation was achieved, thus allowing for a deepened plane of anesthesia necessary for direct laryngoscopy and bronchoscopy. Palpation of the mass confirmed its compressible nature, suggesting it could be bypassed. The endoscope was loaded with a 4.0-mm cuffed endotracheal tube, which was easily inserted distal to the mass via Seldinger technique.Obtaining a secure airway can be difficult in the case of obstructive tracheal masses. Maintaining spontaneous ventilation is useful to preserve patients’ preoperative ability to ventilate. The use of bag-mask ventilation should be confirmed early in the management of a difficult airway, as this, if nothing else, provides reassurance of the ability to maintain oxygenation and ventilation over a period of time. Certainly, intubation with a cuffed endotracheal tube distal to the lesion is ideal. However, alternative options can be used in cases of near-complete tracheal obstruction. For example, the Cooke catheter and Hunsaker Mon-Jet ventilation tube are both narrow-caliber tubes that allow for oxygenation and ventilation. An open approach with displacement of the mass into a mainstem bronchus is a less ideal, yet possibly lifesaving, option. An open tracheotomy approach with appropriate neck extension was discussed prior to this procedure and could have been performed if the aforementioned techniques had all been unsuccessful. Ultimately, a carefully coordinated, algorithmic, team-based approach to the management of such difficult airways allows for the highest chance of successfully securing the airway.

General

A 12-year-old girl presented to the clinic with a 3-month history of intermittent stridor. Her symptoms were initially most prominent while playing sports and were suspected to be due to asthma or seasonal allergies. However, medical management with albuterol, intranasal fluticasone, and cetirizine failed to provide relief. More recently, the patient’s parents noted that she developed stridor while sleeping and while at rest, prompting the family to present for medical attention.Previous workup, including pulmonary function testing, was concerning for an upper airway obstructive process, for which she was referred to otolaryngology. In-office flexible videostroboscopy revealed a mass in the distal cervical trachea that appeared nearly obstructive. Chest radiography confirmed the presence of an approximately 1.5-cm, well-circumscribed soft tissue mass within the cervical trachea.Direct laryngoscopy and bronchoscopy were performed in the operating room under general anesthesia. This demonstrated an exophytic, pedunculated mass that emanated from the anterior wall of the cervical trachea (Figure 1A and B). The patient was intubated via Seldinger technique to bypass the mass, with a 4.0-mm cuffed endotracheal tube loaded over a 0-degree Hopkins endoscope (Figure 1C). With the airway secured, attention was turned to excision of the mass. Lidocaine, 1%, with epinephrine 1:100 000 was injected in a submucosal plane, and laryngeal scissors were used to excise the attachment of the mass from the tracheal wall. The mass was then resected en bloc and removed with laryngeal cupped forceps. The attachment site was then ablated with the Coblator (Figure 1D).Intraoperative photographs demonstrating supraglottic view of intratracheal mass (A); exophytic, pedunculated mass emanating from the anterior wall of the cervical trachea (B); endotracheal intubation via Seldinger technique bypassing the mass (C); and cervical trachea following ablation of attachment site (D).

what is your diagnosis?

What is your diagnosis?

Granular cell tumor

Glomus tumor

Chondroma

Schwannoma

d

female

11-20

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2801952

A 25-month-old child with unilateral hearing loss was referred to a pediatric ear, nose, and throat surgeon in a secondary care hospital. Clinical findings suggested unilateral right middle ear effusion associated with ipsilateral conductive hearing loss. After an initial observation period, a right tympanostomy tube was inserted. During the procedure, a clear liquid pulsating from the middle ear was noted, and samples were sent for β-2-transferrine analysis. This confirmed the presence of a cerebrospinal fluid (CSF) leak.The patient was referred to our tertiary referral center hospital. The leak settled with conservative management, and imaging of the brain and skull base was performed. A high-resolution computed tomography scan of the temporal bone showed a lytic aspect of the right temporal bone extending to the petrous apex and the petrous bone, sparing the otic capsule (Figure 1A). There was soft tissue opacification of the right mastoid air cells. Magnetic resonance imaging of the skull base with contrast was performed (Figure 1B). It showed a hyperintense T2 signal in the petrous apex and mastoid air cells. There was a suspected communication into the soft tissues of the right neck in the posterior triangle. Magnetic resonance imaging also showed signs of Chiari malformation type 1. After a skull base multidisciplinary discussion, the patient underwent a bone biopsy through a transmastoid approach.A, Axial high-resolution computed tomography scan of the temporal bones at the level of the basal turn of the cochlea showed osteolysis involving the petrous part of the right temporal bone. There was associated soft tissue partial opacification of the right mastoid air cells. The destructive process did not involve the otic capsule. B, Coronal magnetic resonance imaging of the brain and skull base, T2-weighted images showed a hypersignal in the right mastoid and middle ear with suspected communication through the tegmen. There was also a hypersignal in the soft tissues of the right neck in keeping with extravasation of cerebrospinal fluid in cervical lymphatics. What Is Your Diagnosis?

Gorham-Stout disease

Langerhans cell histiocytosis

Cholesteatoma

Sarcoma

A. Gorham-Stout disease

A

Gorham-Stout disease

Gorham-Stout disease (GSD), also known as disappearing bone disease or bony lymphangiomatosis, was first described in 1838 by Jackson, before being formally defined by Gorham et al in 1954.1 It is caused by a proliferation of endothelial-lined lymphatic vessels and replacement of the bone by fibrous tissue.2 This results in a massive osteolysis of the bone involved with cortical resorption. It most commonly affects children and young adults, with more than 300 cases in the literature. Most common sites are the cranium, mandible, shoulder, and pelvis. Less than 10% of cases affect the skull base.2 Presenting symptoms include pain, soft tissue swelling, or fractures.A common presentation of GSD with temporal bone involvement is CSF leak, which may present initially as nonspecific middle ear effusion, as in the present case. In more severe forms of the disease, CSF may diffuse in the soft tissues of the neck.2 It is hypothesized that newly formed lymphatic vessels in the skull base connect to existing lymphatic channels in the neck and may be responsible for this rare presentation. A similar phenomenon can occur in thoracic lymphangiomatosis leading to chylothorax.Cerebrospinal fluid leak increases the risk of meningitis and may cause intracranial hypotension.3 Association with Chiari malformation type 1 has been previously described and should be systematically searched for in GSD.2,4 Investigations include high-resolution imaging of the skull base and whole-body imaging. Most cases require tissue sampling and histopathological confirmation. Computed tomography scan usually shows intramedullary or subcortical bony erosion, which gradually leads to cortical resorption.2 The otic capsule is usually spared in GSD. If the otic capsule is involved, it should raise suspicion for neoplasm (giant cell tumor), infections (otosyphilis), or genetic conditions (osteogenesis imperfecta, otosclerosis). Magnetic resonance imaging can demonstrate variable signal patterns and degree of enhancement depending on the stage of the disease. Histologic staining shows fibrous tissue with dilated endothelial-lined vessels expressing lymphatic markers replacing normal bone (Figure 2). In the absence of complications (CSF leak, meningitis), long-term prognosis remains favorable.Hematoxylin-eosin stain (original magnification ×20) showed dilated lymphatic endothelial-lined channels (yellow arrowheads) disrupting normal bone architecture (black arrowhead).Differential diagnosis includes other lymphatic malformations (lymphangiomas, hemangiomas as well as malignant neoplasms, including angiosarcoma), infections (mastoiditis), and inflammatory conditions, such as Langerhans cell histiocytosis. Langerhans cell histiocytosis typically presents with a more discrete solid mass enhancement on imaging and well-defined margins.2Current management includes medical treatments and surgical management of complications.5 Gorham-Stout disease with skull base involvement should be discussed in a skull base multidisciplinary team meeting involving a pediatrician, anterior skull base and lateral skull base ear, nose, and throat surgeon, neurosurgeon, and head and neck radiologist.First-line management includes vitamin D, calcium supplementation, and pamidronate. Some cases can resolve spontaneously with supportive treatment. Pegylated interferon alfa has been described in some cases with stabilization of the lesions.6 Sirolimus, a mammalian target of rapamycin inhibitor, has been used with success in a small number of lymphatic abnormalities.7,8 It has been trialed as a promising treatment for GSD.Surgical treatment may be discussed in some cases. Skull base defects may be eligible for CSF closure surgery. This often necessitates an obliteration of the middle ear with eustachian tube ligation.9 Simon et al6 reported on 6 cases of skull base GSD. They observed that CSF leak surgery was inefficient if the disease was not stabilized, as leakage reoccurred around the operated site. They suggested surgery only in life-threatening situations (recurrent meningitis) or to fix residual CSF leak in patients with stable GSD lesions. A 2021 publication identified a somatic variant in KRAS that may induce a hyperactive lymphatic development.10 A targeted therapy with trametinib may be a promising treatment for GSD.

General

A 25-month-old child with unilateral hearing loss was referred to a pediatric ear, nose, and throat surgeon in a secondary care hospital. Clinical findings suggested unilateral right middle ear effusion associated with ipsilateral conductive hearing loss. After an initial observation period, a right tympanostomy tube was inserted. During the procedure, a clear liquid pulsating from the middle ear was noted, and samples were sent for β-2-transferrine analysis. This confirmed the presence of a cerebrospinal fluid (CSF) leak.The patient was referred to our tertiary referral center hospital. The leak settled with conservative management, and imaging of the brain and skull base was performed. A high-resolution computed tomography scan of the temporal bone showed a lytic aspect of the right temporal bone extending to the petrous apex and the petrous bone, sparing the otic capsule (Figure 1A). There was soft tissue opacification of the right mastoid air cells. Magnetic resonance imaging of the skull base with contrast was performed (Figure 1B). It showed a hyperintense T2 signal in the petrous apex and mastoid air cells. There was a suspected communication into the soft tissues of the right neck in the posterior triangle. Magnetic resonance imaging also showed signs of Chiari malformation type 1. After a skull base multidisciplinary discussion, the patient underwent a bone biopsy through a transmastoid approach.A, Axial high-resolution computed tomography scan of the temporal bones at the level of the basal turn of the cochlea showed osteolysis involving the petrous part of the right temporal bone. There was associated soft tissue partial opacification of the right mastoid air cells. The destructive process did not involve the otic capsule. B, Coronal magnetic resonance imaging of the brain and skull base, T2-weighted images showed a hypersignal in the right mastoid and middle ear with suspected communication through the tegmen. There was also a hypersignal in the soft tissues of the right neck in keeping with extravasation of cerebrospinal fluid in cervical lymphatics.

what is your diagnosis?

What is your diagnosis?

Langerhans cell histiocytosis

Gorham-Stout disease

Cholesteatoma

Sarcoma

b

neutral

0-10

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2801445

A woman in her 80s initially presented with numerous, primarily photodistributed, crusted, and ulcerated plaques of the trunk and extremities. She had a medical history of essential thrombocytosis (ET), which was treated with hydroxyurea for 14 years, with a total cumulative dose of approximately 2500 g. She was otherwise reasonably well and denied any other constitutional symptoms. The ulcerations had slowly increased in number and size over several years and were quite painful (Figure, A-C). She did have a medical history of nonmelanoma skin cancer (NMSCa), which had previously been treated surgically. Several tangential shave biopsies were performed to help clarify the patient’s diagnosis.A-C, Clinical findings including widespread photodistributed ulcerated pink papules and plaques on the extremities. D, Histopathologic findings (hematoxylin-eosin stain). What Is Your Diagnosis?

Hydroxyurea-induced ulcerations

Hydroxyurea-induced squamous dysplasia

Hydroxyurea-induced phototoxic eruption

Iatrogenic epidermodysplasia verruciformis