Chronic ulcer in a patient with essential thrombocythemia taking hydroxyurea.

Chronic skin ulcers in patients with suspected pyoderma gangrenosum can, on closer inspection and further workup, have a different cause. Recognition of key features on clinical examination such as the presence of atrophie blanche is key to avoid misdiagnosis of pyoderma gangrenosum and its subsequent treatment with high-dose corticosteroids and other immunosuppressive medications.

Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020.

BACKGROUND: Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020. PATIENTS AND METHODS: Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference. RESULTS: Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: ß = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: ß = $3810, 95%CI $365-$7260; pembrolizumab: ß = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days. CONCLUSIONS: Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

Comparison of clinicopathologic features, survival, and demographics in sebaceous carcinoma patients with and without Muir-Torre syndrome.

BACKGROUND: Visceral malignancies in patients with Lynch syndrome behave less aggressively than in those without Lynch syndrome. The behavior of sebaceous carcinoma (SC) in Muir-Torre syndrome (MTS), a variant of Lynch syndrome, is incompletely investigated. OBJECTIVE: To investigate features and survival of SC patients with and without MTS. METHODS: Retrospective cohort study in the Surveillance, Epidemiology, and End Results 17 database from 2000 to 2019 of patients with SC. Patients were classified as MTS or non-MTS cases based on a threshold score of 2 on the Mayo MTS risk score. RESULTS: We identified 105 (2.8%) MTS cases and 3677 (97.2%) non-MTS cases. On univariate analysis, MTS patients were younger, had a higher proportion of tumors outside the head/neck, and had fewer high-grade tumors. On Kaplan-Meier analysis, MTS patients trended toward having better SC-specific survival. On multivariate Cox proportional hazards analysis adjusting for other covariates, MTS status was an independent predictor of worse overall survival. However, there was no association between MTS status and SC-specific survival. LIMITATIONS: Given relatively high disease-specific survival in SC, our study may have been underpowered to detect a difference on Kaplan-Meier analysis. CONCLUSIONS: Our study suggests SC does not behave more aggressively in patients with MTS.

Dedifferentiated chondrosarcoma with minimal or small dedifferentiated component.

Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone sarcoma characterized by low-intermediate grade cartilage component with abrupt transition to a high-grade non-chondrosarcomatous component. Generally, the dedifferentiated (DD) component is large. However, rare cases have minimal (<1 cm) or small (1-2 cm) areas of DD. We describe the clinicopathologic features of such tumors and evaluate the prognostic significance of this finding compared to cases with large DD (>2 cm). Available slides were re-reviewed for assessment of histologic features. The medical record was reviewed for imaging studies and clinical characteristics. Thirty-five cases were included. Six patients had minimal DD, four had small DD and 25 had large DD. None of the minimal DD showed definitive imaging evidence of DD. Two minimal DD (33%) locally recurred and 2 (33%) developed distant metastases. None of the small DD cases showed definitive imaging evidence of DD. None of the small DD locally recurred and at least 1 (25%) developed distant metastases. There was no significant difference in age, gender, pelvic site, tumor size >8 cm, tumor necrosis or undifferentiated pleomorphic sarcoma-like morphology between minimal or small DD compared to large DD, though osteosarcomatous differentiation was significantly more common in large DD. There was no significant difference in overall survival between minimal or small DD compared to large DD (p = 0.81 and p = 0.17, respectively), or in progression-free survival (p = 0.47 and 0.29, respectively), or metastasis-free survival (p = 0.06 and 0.62, respectively). DDCS with minimal or small DD show similar demographic distribution, anatomic localization and histologic features to large DD. DD in these cases is unlikely to be detected on imaging. Furthermore, at least a subset of these tumors is extremely aggressive despite the limited extent of DD. This highlights the need for thorough gross and histologic examination and sampling.

Pigmented PRRX1::NCOA1-rearranged fibroblastic tumor: A rare morphologic variant of an emerging mesenchymal tumor.

PRRX::NCOAx-rearranged fibroblastic tumor is a recently described, morphologically distinctive subcutaneous fibroblastic tumor with benign behavior. To date, 12 cases have been reported. Here, we report a new case of PRRX::NCOAx-rearranged fibroblastic tumor showing a prominent pigmented component. The lesion occurred on the shoulder of a 23-year-old male. It was an at least 2.5 cm subcutaneous tumor with a multinodular and plexiform appearance. Morphologically, the tumor was characterized by a variably cellular proliferation of uniform oval to spindle cells arranged in fascicles and cords within a myxocollagenous stroma. Irregular, elongated, dilated vessels were prominent at the periphery of tumor nodules. In addition, nests and clusters of pigment-laden epithelioid and dendritic cells were present. Immunohistochemically, the non-pigmented tumor cells showed patchy positivity for factor XIIIa and focal positivity for S100 protein. The pigmented cells were positive for S100 protein, SOX10, MITF, and a pan-melanocytic cocktail (Melan-A, HMB-45, and tyrosinase). Next-generation RNA sequencing identified an in-frame PRRX1::NCOA1 fusion. In summary, this case highlights a rare pigmented variant of PRRX::NCOAx-rearranged fibroblastic tumor, expanding the morphologic spectrum of this newly described mesenchymal tumor.

Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review.

PURPOSE: Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). METHODS: To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. RESULTS: We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10 days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. CONCLUSION: Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

Sweet syndrome as an adverse reaction to tyrosine kinase inhibitors: A review.

Tyrosine kinase inhibitors are a class of targeted anticancer drugs that inhibit cancer cell proliferation by inactivating proteins involved in signal transduction cascades. Various cutaneous adverse events have been observed after tyrosine kinase inhibitor administration, including Sweet syndrome. We queried the PubMed database to identify 14 cases of Sweet syndrome thought to be secondary to tyrosine kinase inhibitors. Tyrosine kinase inhibitor-induced Sweet syndrome had a median of 2 months latency following drug administration. All cases but one had morphologic features classic for Sweet syndrome (erythematous and tender papules, plaques, or nodules). All cases also had classic histopathologic findings (dermal neutrophilic infiltrate without vasculitis or necrosis). Using diagnostic criteria for drug-induced Sweet syndrome and the Naranjo Drug Reaction Probability Scale for a drug-induced cutaneous eruption, we found that six cases favored a drug-induced etiology over malignancy, two cases favored a malignancy-associated Sweet syndrome, and the remaining eight met drug-induced Sweet syndrome criteria but had low Naranjo scores. Nine cases resulted in medication discontinuation, while five cases continued anticancer therapy and were treated only with corticosteroids with quick resolution of skin lesions. Dermatologists should be aware of this adverse cutaneous reaction to tyrosine kinase inhibitors and should treat on a case-by-case basis, though limited evidence in this review suggests that oncologic therapy may safely be continued with prompt corticosteroid treatment.

Competing risks analysis of Merkel cell carcinoma with concurrent chronic lymphocytic leukemia and non-Hodgkin lymphoma.

BACKGROUND: Although hematogenous malignancy is a risk factor for poorer prognosis in Merkel cell carcinoma (MCC), current guidelines make no specific recommendations for surveillance. OBJECTIVE: We aim to characterize MCC-specific mortality compared to other causes of death for patients with hematologic malignancy in MCC, which will guide workup and surveillance strategies. METHODS: The Surveillance, Epidemiology, and End Results-18 registry was queried for MCC patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL). RESULTS: Of 8519 patients with MCC, 146 (1.7%) had CLL and 234 (2.8%) had NHL. Chronic lymphocytic leukemia patients had 5-year cumulative incidence of MCC-specific mortality of 38.4% versus 28.4% in patients without CLL/NHL. For both cohorts, oncologic risk was highest within the first three years of diagnosis with competing risks favored thereafter. On competing risk regression, a history of CLL trended toward statistical significance with poorer MCC-specific mortality (subdistribution hazard ratio: 1.33, 95% CI: 0.963-1.834, P=0.084), while NHL was not prognostic. CONCLUSIONS: Merkel cell carcinoma patients with CLL may benefit from more aggressive initial management. Surveillance for similar length in CLL patients with MCC may be appropriate; this co-morbidity did not affect the timeframe by which the risk of competing causes of death exceeded oncologic risks.

Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1.

Spinal muscular atrophy is a neurodegenerative disease resulting from irreversible loss of anterior horn cells owing to biallelic deletions/mutations in the survival motor neuron (SMN) 1 gene. Gene replacement therapy using an adeno-associated virus vector containing the SMN gene was approved by the US Food and Drug Administration in May 2019. We report 2 cases of transient, drug-induced liver failure after this therapy.

A concise review of angiofibroma of soft tissue: A rare newly described entity that can be encountered by dermatopathologists.

Angiofibroma of soft tissue (AFST) is a newly described, rare mesenchymal neoplasm with fibroblastic and vascular components; it can be seen in both sexes and in a broad age range. It presents as a slowly enlarging mass, most often in the deep tissues of the upper and lower extremities, but occasionally in a superficial location where it may be encountered by dermatopathologists. It has a benign clinical course with a very low probability of recurrence after complete excision. This lesion has a prominent vasculature and may have an infiltrative growth pattern. These features could lead to a misdiagnosis, such as malignant vascular tumor, by an unwary dermatopathologist. The diagnosis of AFST initially relied solely on morphology and immunohistochemistry but, more recently, molecular studies have begun to play a role. Because of the potential for misdiagnosis, we present this review to raise awareness.

Expanding the differential of superficial tumors with round-cell morphology: Report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity.

Among sarcomas with a round-cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC-rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC-rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under-recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC-rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology.

Alopecia areata as an immune-related adverse event of immune checkpoint inhibitors: A review.

Immune checkpoint inhibitors (ICI) improve the ability of the immune system to target cancer cells by blocking signaling through either the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD-1) receptor, or its ligand (PD-L1). They have been found to cause a variety of immune-related adverse events (irAEs) including a form of nonscarring alopecia that resembles alopecia areata (AA) in presentation and histology. Clinical features of ICI-induced AA are poorly described. We queried the Pubmed database for cases of AA secondary to ICI use reporting on extent of hair loss, treatments attempted, alopecia outcome, and time of follow-up with 13 cases identified. Although most patients had localized hair loss with subsequent regrowth, four of them experienced extensive and persistent AA, lasting up to a year. All but one patient continued ICI after the onset of hair loss. Many used topical corticosteroids with varying outcomes. Possible prognostic factors for severe and persistent disease may include young age and male sex. However, the low number of reported cases limits the generalizability of these findings. Tumor response was positive in every case of immune-induced AA where it was reported. Further investigation will be needed to better characterize clinical features of this irAE, risk factors for persistent disease, and determine its optimal management.

Papillary Hemangioma: An Under-Recognized Entity Not to Be Confused With Glomeruloid Hemangioma.

Papillary hemangioma is a recently described benign hemangioma that typically presents on the head and neck of otherwise healthy individuals. It comprises branching papillary structures that protrude into the lumen of ectatic thin-walled vessels. Glomeruloid hemangioma (GH) is a similar, but unique, entity that occurs in patients with POEMS syndrome. The additional clinical implications of GH make distinction from papillary hemangioma critical. An additional case is herein presented and the literature on the subject reviewed. Potential differential diagnoses are discussed, with particular emphasis on the distinction from GH.

A novel MAP3K7CL-ERG fusion in a molecularly confirmed case of dermatofibrosarcoma protuberans with fibrosarcomatous transformation.

Dermatofibrosarcoma protuberans (DFSP) is a translocation-associated, low-grade sarcoma with fibroblastic differentiation. It is the most common superficial sarcoma, almost exclusively arising within the dermis. In a minority of cases, there is a transition from the conventional morphology to a fibrosarcomatous pattern, known as a fibrosarcomatous DFSP (FS-DFSP). Although a number of different molecular alterations have been described to account for this transformation, it remains poorly understood. Herein we report the first case of a FS-DFSP with a fusion between ERG, an ETS family transcription factor, and MAP3K7CL, a kinase gene rarely observed in fusion gene events.

Neutrophilic dermatoses as adverse effects of checkpoint inhibitors: A review.

Checkpoint inhibitors are a new class of drugs that enhance the immune system's intrinsic ability to destroy tumor cells by blocking signaling through the programmed cell death (PD-1) receptor, its ligand (PD-L1), and the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). The resulting increase in immunologic activity is responsible for a variety of adverse cutaneous reactions, which sometimes include neutrophilic dermatoses. We queried the PubMed database for existing cases of checkpoint inhibitors causing neutrophilic dermatoses. The literature search identified four cases of Sweet syndrome, four cases of pustular eruptions, two cases of pyoderma gangrenosum, and one case of bullous lupus erythematosus secondary to checkpoint inhibitors. All neutrophilic dermatoses were treated with topical or systemic steroids and most (9 of 11) completely resolved. Dermatologists should be aware of these rare, adverse cutaneous reactions to checkpoint inhibitors and how to approach their treatment, especially as their use increases.

Superficial Nodular Fasciitis With Atypical Presentations: Report of 3 Cases and Review of Recent Molecular Genetics.

Nodular fasciitis is a benign proliferation of fibroblasts/myofibroblasts that can be mistaken for an aggressive neoplasm because of its spectrum of appearances and anatomical locations, rapid growth, infiltrative growth pattern, and high mitotic rate. The presence of fusions involving USP6 gene in most cases provides a useful tool for diagnostic confirmation. Nodular fasciitis is often deep, in association with fascia, but less commonly, it arises superficially and can be biopsied by dermatologists. We present herein 3 such cases with confirmed USP6 rearrangement by fluorescence in situ hybridization (FISH) in which the diagnosis of nodular fasciitis was not initially obvious because of atypical morphologic and clinical features. These cases illustrate that in cutaneous myofibroblastic proliferations, nodular fasciitis should be given consideration even when encountered in unusual locations.

Dupilumab in Dermatology: Potential for Uses Beyond Atopic Dermatitis

Dupilumab inhibits the interleukin-4 receptor subunit α and is FDA approved for treatment of moderate-to-severe atopic dermatitis. It is a relatively new drug, and whether it is efficacious for other diseases in dermatology is an area of increasing interest. We searched the literature and ClinicalTrials.gov database for uses of dupilumab beyond atopic dermatitis in dermatology and for ongoing studies on new uses for dupilumab. Off-label reports identified described use of dupilumab for several different dermatologic conditions, including allergic contact dermatitis, hand dermatitis, chronic spontaneous urticaria, prurigo nodularis, and alopecia areata. Overall, there is limited but promising data for dupilumab use beyond atopic dermatitis in dermatology. The relatively safe adverse effect profile of dupilumab may make it an option for certain recalcitrant diseases in dermatology, but further studies will be needed to assess its efficacy and determine its best possible use. J Drugs Dermatol. 2019;18(10):1053-1055.