EWSR1::NR4A3 gene fusion in a cutaneous atypical myoepithelial neoplasm.

Myoepithelial neoplasms of the skin and soft tissue are rare and share histopathologic features with their salivary gland counterpart. We present a case of an atypical myoepithelial neoplasm from the back of a 72-year-old female. This lesion harbored an EWSR1::NR4A3 gene fusion, a genetic signature characteristically seen in extraskeletal myxoid chondrosarcoma. To our knowledge, this is a unique case of an atypical cutaneous myoepithelial neoplasm harboring EWSR1::NR4A3 fusion.

Application of immunohistochemical studies in diagnosing emerging superficial mesenchymal neoplasms.

Molecular diagnostics, with the subsequent development of novel immunohistochemical markers, continues to advance and expand the field of soft tissue pathology. As such, the ever-evolving molecular diagnostic landscape will continue to shape and refine our understanding and classification of neoplasms. This article reviews the current literature on various tumors of mesenchymal origin, including fibroblastic/fibrohistiocytic, adipocytic, vascular, and tumors of uncertain origin. We aim to give the reader a detailed understanding and pragmatic approach to various new and established immunohistochemical stains in diagnosing these neoplasms and also discuss various pitfalls with significant repercussions.

Giant cell tumor of bone in the pediatric population: a retrospective study highlighting cases of metaphyseal only location and increased local recurrence rates in skeletally immature patients.

OBJECTIVE: To describe the presentation of giant cell tumors (GCT) of the bone in the pediatric population to (1) improve the differential diagnosis of pediatric bone tumors and (2) identify the origin of GCT. Understanding the origin of bone tumors assists in establishing appropriate diagnoses and recommending treatment options. This is particularly important in children, where evaluating the need for invasive procedures is balanced with the desire to avoid overtreatment. GCT have historically been considered epiphyseal lesions with potential metaphyseal extension. Therefore, GCT may be inappropriately excluded from the differential diagnosis of metaphyseal lesions in the skeletally immature. MATERIALS AND METHODS: We identified 14 patients from 1981 to 2021 at a single institution who had histologic confirmation of GCT and were less than 18 years old at diagnosis. Patient characteristics, tumor location, surgical treatment, and local recurrence rates were collected. RESULTS AND CONCLUSIONS: Ten (71%) patients were female. Eleven (78.6%) were epiphysiometaphyseal (1 epiphyseal, 4 metaphyseal, 6 epiphysiometaphyseal). Five patients had an open adjacent physis, of which three (60%) had tumors confined solely to the metaphysis. Of the five patients with open physis, four (80%) developed local recurrence while only one patient (11%) with a closed physis had local recurrence (p value = 0.0023). Our results illustrate that for the skeletally immature, GCT can (and in our results more commonly did) occur in the metaphyseal location. These findings suggest that GCT should be included in the differential diagnosis of primary metaphyseal-only lesions in the skeletally immature.

Clinical and direct immunofluorescence characteristics of cutaneous toxicity associated with enfortumab vedotin.

Enfortumab vedotin (EV), a novel antibody-drug conjugate approved for metastatic urothelial carcinoma, causes a variety of cutaneous adverse reactions. We present two cases of bullous eruptions following treatment with EV, both demonstrating IgG deposition on direct immunofluorescence (DIF) correlating to the location of nectin-4 in the epidermis. This suggests that the IgG component of EV binding to nectin-4 in keratinocytes is likely a primary contributor to the high rates of cutaneous toxicity.

The Role of T Helper Type 2 (Th2) Cytokines in the Pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (eGPA): an Illustrative Case and Discussion.

PURPOSEOF REVIEW: The pathogenesis of eosinophilic granulomatosis with polyangiitis (eGPA) is driven largely by CD4 + type 2 helper T cells (Th2), B cells, and eosinophils. Interleukin (IL)-4 and IL-13 are critical cytokines in Th2 cell-mediated inflammation; however, inhibition of IL-4 and IL-13 does not reduce serum eosinophil counts and has even been associated with hypereosinophilia. This review explores the role of IL-4, IL-5, and IL-13 in Th2-mediated inflammation to consider the potential clinical consequences of inhibiting these individual cytokines in eGPA. RECENT FINDINGS: Treatments for eosinophilic granulomatosis with polyangiitis (eGPA) are rapidly evolving through using biologic therapies to modulate the Th2 inflammatory response via eosinophil inhibition. While IL-4, IL-5, IL-13, and IL-25 can all affect eosinophils, only IL-5 inhibition has demonstrated therapeutic benefit to-date. In this review, we report a clinical vignette of a patient with adult-onset asthma who developed severe manifestations of eGPA after switching from mepolizumab (an IL-5 inhibitor) to dupilumab (an inhibitor of IL-4 and IL-13). By understanding the role of IL-4, IL-5, and IL-13 in Th2-mediated vasculitis, we can start to understand how eGPA might respond differently to focused cytokine inhibition.

Cutaneous inflammatory myofibroblastic tumor with CARS-ALK fusion: Case report and literature review.

Cutaneous inflammatory myofibroblastic tumors (IMT) constitute a rare entity, generating a diagnostic pitfall when diagnosing spindle cell proliferation within the dermis. Raising awareness of this tumor among dermatopathologists remains vital in differentiating it from common cutaneous tumors such as fibrous histiocytoma, atypical fibroxanthoma, melanoma, poorly differentiated carcinoma, and other more aggressive tumors. Accurate diagnosis of IMT aids in ensuring appropriate management and follow-up for patients while preventing unnecessary harm and overtreatment. Here we report a case of a 38-year-old female with a painless, slow-growing nodule of the left posterior scalp initially diagnosed as a dermatofibroma. The histopathological examination revealed an ill-defined dermal nodule of spindled cells without connection or infiltration of the epidermis. At high power, the cells were arranged in fascicles with a prominent background of lymphocytic infiltrate. Immunohistochemical analysis showed strong diffuse immunoreactivity for anaplastic lymphoma kinase (ALK), and targeted RNA sequencing identified a CARS-ALK fusion ultimately confirming the accurate diagnosis of a cutaneous IMT.

A Case of Congenital Syphilis-Focus on Histopathology and Literature Review.

ABSTRACT: Although a rare disease, the incidence of congenital syphilis is on the rise in the US. We report a case of early congenital syphilis in a 1-day-old premature boy with positive Rapid plasma reagin titer, respiratory insufficiency, disseminated intravascular coagulation, and encephalopathy, born to a mother with known syphilis infection. Skin examination showed diffuse truncal petechiae, desquamation of the distal extremities, and violaceous, retiform plaques on the buttocks and lower extremities. A biopsy was performed to rule out an infectious etiology or vasculitis. Histopathologic examination revealed irregular epidermal acanthosis with orthokeratosis and parakeratosis. There were foci of neutrophilic infiltrate forming rare pustules within the stratum corneum and focal intraepidermal eosinophils, neutrophils, and rare dyskeratotic keratinocytes. In the dermis, there was some minimal endothelial swelling with a perivascular, interstitial, and periadnexal infiltrate of lymphocytes, eosinophils, and rare plasma cells. A Treponema pallidum immunostain highlighted spirochetes present within the epidermis and within the eccrine ducts. Penicillin G therapy was administered for 10 days. The infant's Rapid plasma reagin titer trended downward until it was negative 6 months after birth. Literature review reveals 8 case reports within the last 20 years describing the histopathology of rashes in congenital syphilis. Herein we summarize the reported histopathology of rashes in congenital syphilis and compare it to the histopathology of rashes in secondary syphilis in adults.

An Atypical Myelomonocytic Cell Infiltrate: Use of Next-Generation Sequencing to Diagnose Indeterminate Cell Histiocytosis.

ABSTRACT: Indeterminant cell histiocytosis (ICH) is a rare lymphoproliferative disorder that demonstrates features of Langerhans and non-Langerhans cell histiocytoses and diagnosis can be challenging. We present a case of a 62 year old woman with a generalized eruption of erythematous papules on the face, trunk and extremities. Skin biopsies demonstrated a dermal mononuclear cell infiltrate with monocytic (CD4, CD33), histiocytic (CD68, CD163), and dendritic cell (CD1a) immunophenotype but negative for Langerhans' cell marker (CD207). The differential diagnosis included leukemia cutis and ICH, and further workup revealed a normal bone marrow biopsy. To confirm the diagnosis of ICH, next generation sequencing with ETV3-NCOA2 gene fusion was performed and was positive. The patient's condition improved with methotrexate and narrow band UVB phototherapy. Our case adds to the existing literature supporting the use of next-generation sequencing to test for ETV3-NCOA2 gene fusion in suspected cases of ICH.

Dissecting the immune landscape of tumor draining lymph nodes in melanoma with high-plex spatially resolved protein detection.

BACKGROUND: In melanoma patients, microscopic tumor in the sentinel lymph-node biopsy (SLN) increases the risk of distant metastases, but the transition from tumor in the SLN to metastatic disease remains poorly understood. METHODS: Fluorescent staining for CD3, CD20, CD11c, and DNA was performed on SLN tissue and matching primary tumors. Regions of interest (ROI) were then chosen geometrically (e.g., tumor) or by fluorescent cell subset markers (e.g., CD11c). Each ROI was further analyzed using NanoString Digital Spatial Profiling high-resolution multiplex profiling. Digital counts for 59-panel immune-related proteins were collected and normalized to account for system variation and ROI area. RESULTS: Tumor regions of SLNs had variable infiltration of CD3 cells among patients. The patient with overall survival (OS) > 8 years had the most CD11c- and CD3-expressing cells infiltrating the SLN tumor region. All patients had CD11c (dendritic cell, DC) infiltration into the SLN tumor region. Selecting ROI by specific cell subtype, we compared protein expression of CD11c cells between tumor and non-tumor/normal tissue SLN regions. Known markers of DC activation such as CD86, HLA-DR, and OX40L were lowest on CD11c cells within SLN tumor for the patient with OS < 1 year and highest on the patient with OS > 8 years. CONCLUSION: We demonstrate the feasibility of profiling the protein expression of CD11c cells within the SLN tumor. Identifying early regulators of melanoma control when the disease is microscopically detected in the SLN is beneficial and requires follow-up studies in a larger cohort of patients.

Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma.

BACKGROUND: Although sentinel lymph node (SLN) biopsy is a standard procedure used to identify patients at risk for melanoma recurrence, it fails to risk-stratify certain patients accurately. Because processes in SLNs regulate anti-tumor immune responses, the authors hypothesized that SLN gene expression may be used for risk stratification. METHODS: The Nanostring nCounter PanCancer Immune Profiling Panel was used to quantify expression of 730 immune-related genes in 60 SLN specimens (31 positive [pSLNs], 29 negative [nSLNs]) from a retrospective melanoma cohort. A multivariate prediction model for recurrence-free survival (RFS) was created by applying stepwise variable selection to Cox regression models. Risk scores calculated on the basis of the model were used to stratify patients into low- and high-risk groups. The predictive power of the model was assessed using the Kaplan-Meier and log-rank tests. RESULTS: During a median follow-up period of 6.3 years, 20 patients (33.3%) experienced recurrence (pSLN, 45.2% [14/31] vs nSLN, 20.7% [6/29]; p = 0.0445). A fitted Cox regression model incorporating 12 genes accurately predicted RFS (C-index, 0.9919). Improved RFS was associated with increased expression of TIGIT (p = 0.0326), an immune checkpoint, and decreased expression of CXCL16 (p = 0.0273), a cytokine important in promoting dendritic and T cell interactions. Independent of SLN status, the model in this study was able to stratify patients into cohorts at high and low risk for recurrence (p < 0.001, log-rank). CONCLUSIONS: Expression profiles of the SLN gene are associated with melanoma recurrence and may be able to identify patients as high or low risk regardless of SLN status, potentially enhancing patient selection for adjuvant therapy.

Cutaneous involvement by T-cell prolymphocytic leukemia presenting as livedoid vasculopathy.

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T-cells. Patients are typically middle aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.

Diagnosis of melanoma by imaging mass spectrometry: Development and validation of a melanoma prediction model.

BACKGROUND: The definitive diagnosis of melanocytic neoplasia using solely histopathologic evaluation can be challenging. Novel techniques that objectively confirm diagnoses are needed. This study details the development and validation of a melanoma prediction model from spatially resolved multivariate protein expression profiles generated by imaging mass spectrometry (IMS). METHODS: Three board-certified dermatopathologists blindly evaluated 333 samples. Samples with triply concordant diagnoses were included in this study, divided into a training set (n = 241) and a test set (n = 92). Both the training and test sets included various representative subclasses of unambiguous nevi and melanomas. A prediction model was developed from the training set using a linear support vector machine classification model. RESULTS: We validated the prediction model on the independent test set of 92 specimens (75 classified correctly, 2 misclassified, and 15 indeterminate). IMS detects melanoma with a sensitivity of 97.6% and a specificity of 96.4% when evaluating each unique spot. IMS predicts melanoma at the sample level with a sensitivity of 97.3% and a specificity of 97.5%. Indeterminate results were excluded from sensitivity and specificity calculations. CONCLUSION: This study provides evidence that IMS-based proteomics results are highly concordant to diagnostic results obtained by careful histopathologic evaluation from a panel of expert dermatopathologists.

Cutaneous metastasis of SMARCA4-deficient thoracic sarcoma: A diagnostic dilemma with therapeutic implications.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently recognized entity with undifferentiated rhabdoid morphology and mutations in the switch/sucrose nonfermenting BRG1-associated factors complex. Patients are typically males in their fifth decade with a history of smoking who present with rapidly progressive intrathoracic disease and follow an aggressive clinical course. Metastatic disease is reported in up to 77% of cases; however, to our knowledge, cutaneous metastasis has not been reported nor has it been reported as the initial manifestation of the disease. Recognizing SMARCA4-DTS from other types of epithelioid tumors that involve the skin is clinically relevant, as targeted therapies for SMARC-deficient tumors are currently being investigated and early clinical trial data show therapeutic benefit.

Trichoblastic carcinosarcoma: A case report and literature review.

Trichoblastic carcinosarcoma is a rare biphasic adnexal neoplasm. This case report chronicals the eighth occurrence of this tumor published in the English literature and provides a review of the prior publications. Clinically, this tumor presents as an isolated, rapidly growing lesion in elderly patients and is usually cured by complete surgical excision, with no evidence of recurrence or metastasis at follow-up (7/8 cases). Histopathologically, trichoblastic carcinosarcoma is dermal-based, with an epithelial component of basal cells and a mesenchymal component of spindle cells, both of which display malignant features. In addition to a morphologic description of trichoblastic carcinosarcoma, a discussion of the differential diagnoses, including other biphasic neoplasms, is also included. The small number of cases of trichoblastic carcinosarcoma is most likely secondary to under-recognition and underreporting and a larger case volume is needed to more accurately assess the clinical course and treatment strategies.

Successful Treatment of Painful Cutaneous Vasculopathy With Rivaroxaban in a Patient With Systemic Lupus Erythematosus.

Novel oral anticoagulant (NOAC) medications have revolutionized hematology and cardiology. Recently, NOACs have demonstrated additional promise in dermatology. Specifically, rivaroxaban, a direct factor Xa inhibitor NOAC, has been shown to be successful in the treatment of livedoid vasculopathy. Herein, we describe a patient with systemic lupus erythematosus who presented with painful cutaneous vasculopathy, demonstrated on biopsy with occlusive microvascular fibrin thrombi without evidence of concurrent vasculitis. Interestingly, imaging and laboratory studies did not show evidence of hypercoagulability, arterial disease, or embolic disease. The patient’s vasculopathy and pain progressed despite antiplatelet therapy, often considered first-line in cases of microvascular occlusive disease. However, with rivaroxaban therapy, the patient experienced complete regression of her painful lesions, thereby supporting a further role for NOACs in cutaneous vasculopathy treatment. J Drugs Dermatol. 2020;19(5) doi:10.36849/JDD.2020.4684.

BCAT1 and miR-2504: novel methylome signature distinguishes spindle/desmoplastic melanoma from superficial malignant peripheral nerve sheath tumor.

Superficial/cutaneous malignant peripheral nerve sheath tumor is a rare soft tissue neoplasm that shares morphological, immunohistochemical, and molecular features with spindle/desmoplastic melanoma. We aimed to identify a methylome signature to distinguish these two entities. We analyzed 15 cases of spindle/desmoplastic melanoma and 15 cases of cutaneous malignant peripheral nerve sheath tumor in 23 men and 7 women. DNA from formalin-fixed, paraffin-embedded tissues was extracted and processed using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. Using a home-grown informatics pipeline, we identified differentially methylated positions between the two entities. Functional network analysis for enrichment signatures was performed using DAVID tools. Identified differentially methylated positions were compared with the Cancer Genome Atlas's cutaneous melanoma dataset and a recently published malignant peripheral nerve sheath tumor dataset to assess the specificity of the identified signature. Unsupervised hierarchical clustering showed different patterns of methylation in cutaneous malignant peripheral nerve sheath tumor and spindle/desmoplastic melanoma. Two probes, cg20783223 and cg13332552, colocalized in the promoter region of BCAT1 and miR-2504. Pathway analysis highlighted enrichment in a subset of genes involved in breast and gastric cancer centered on BCAT1 and downstream activated genes in the mTOR pathway. Our study identifies BCAT1 as a novel methylome signature distinguishing spindle/desmoplastic melanoma from cutaneous malignant peripheral nerve sheath tumor.

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas.

Superficial malignant peripheral nerve sheath tumour (MPNST) is a rare, soft tissue neoplasm that shares morphological features and some molecular events with spindle/desmoplastic melanoma (SDM). Herein, we sought to identify molecular targets for therapy by using targeted RNA/DNA sequencing and gene expression of key immunological players. DNA and RNA from formalin-fixed paraffin-embedded tissue were extracted and processed. Massive high-throughput deep parallel sequencing was performed with the Oncomine comprehensive panel, enabling detection of relevant single-nucleotide variants, copy number variations, gene fusions and indels for 143 unique genes on the Ion torrent sequencer for clinical trial research programmes. Gene expression analysis was carried out with a customized 770-gene expression panel combining markers for 24 different immune cell types and 30 common cancer antigens, including key checkpoint blockade genes analysed with the Ncounter system. Fifty-one patients (SDM, 16/11; MPNST, 24; male, n = 37; female, n = 16) had sufficient DNA and RNA for testing. NF1 deleterious mutations and/or deep/homozygous deletions were identified in 73% of MPNSTs and 67% of SDMs, with 50% of the mutations involving the RAS-binding domain. Inactivating/deleterious mutations of TSC1/TSC2 were identified in 40% and 41% of MPNSTs and SDMs, respectively. Activating mutations affecting the EGFR-like and the negative regulatory domains of NOTCH1 and KDR (VEGFR2) were identified in 45% and 40% of SDMs and in 30% and 8% of MPNSTs, respectively. Differential gene expression and gene clustering analysis showed significantly perturbed immune pathway components, including nuclear factor-κB (NF-κB), JAK-STAT, and CXCL12-CXCR4, and differentially expressed CD274 and CTLA4, in both SDM and MPNST. Angiogenesis (KDR and NOTCH1) and mammalian target of rapamycin complex (mTORC) pathways offer a rationale for anti-angiogenic and selective mTORC inhibition as treatment strategies for MPNST and SDM. Cytokines and the JAK-STAT, TNF and NF-κB axes were perturbed in both SDM and MPNST. These pathways have been targeted in haematological malignancies and present promising targets for these tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Low-grade fibromyxoid sarcoma of acral sites: Case report and literature review.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue sarcoma that usually presents as a deep-seated tumor in young adults; however, they can occur on superficial sites, mostly documented in pediatric age groups. LGFMS presenting on acral sites is not highly emphasized in the general pathology or dermatopathology literature. The case presented is that of a 30-year-old man with a foot mass that was removed 15 years earlier and subsequently recurred as two masses, the first occurring between the third and fourth toes/metatarsal region and the second over the lateral tarsal region. An excisional biopsy showed a relatively circumscribed, bland spindle cell proliferation with hypocellular and hypercellular zones. The cells showed minimal pleomorphism and lacked mitotic activity. Immunohistochemical analysis showed immunoreactivity for MUC4 and break-apart fluorescence in situ hybridization was positive for FUS rearrangement, confirming the diagnosis of LGFMS. There are multiple spindle cell tumors that occur on acral sites which usually generates a list of differential diagnoses; however, LGFMS is not usually discussed in that anatomic location. Awareness of the occurrence of LGFMS on acral sites is important to avoid misdiagnosis of this deceptively benign-appearing tumor.

Post-irradiation morphoea of the breast: a case report and review of the literature.

We describe a 44-year-old female with triple-negative breast cancer who developed skin erythaema, sclerosis and contracture of her entire right breast 15 months after completion of post-lumpectomy chemotherapy and radiotherapy, consistent with post-irradiation morphoea (PIM). PIM is a rare complication of breast irradiation that impairs a patient's quality of life. PIM is located usually at the radiation port or in the surrounding tissue. Clinically, PIM is misdiagnosed commonly as lymphoedema and cellulitis in the early inflammatory phase, and recurrent breast cancer, chronic radiodermatitis (CRD), radiation-induced fibrosis (RIF), post-irradiation pseudosclerodermatous panniculitis (PIPP), atypical vascular lesions (AVL) or angiosarcoma (AS) in the late burnout phase. Arriving at the correct diagnosis typically requires a multidisciplinary approach, including a skin biopsy for confirmation. To date, satisfactory treatment of this condition has been challenging. and the clinical outcome after therapy is often unsatisfactory.

Dermal xanthomatous infiltrates after brentuximab vedotin therapy in mycosis fungoides with large-cell transformation: A novel histologic finding.

Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphomas. Large-cell transformation of MF has been associated with disease progression and overall poor outcome. The expression of CD30, which defines anaplastic large cell lymphoma (ALCL) and lymphomatoid papulosis, might also occur in a subset of patients with MF, with or without large-cell transformation. Brentuximab vedotin is an anti-CD30 monoclonal antibody which has been proven to be a safe and effective therapeutic agent in the treatment of CD30-positive lymphomas, such as Hodgkin lymphoma and ALCL. Recently, brentuximab vedotin has been shown to have a significant clinical activity in treatment-refractory or advanced MF or Sezary syndrome with a wide-range of CD30 expression levels. We report a patient with MF tumor stage with large-cell transformation and low CD30 expression with good response to brentuximab vedotin and unusual extensive xanthomatous changes in the follow-up biopsy.