Pediatric Atypical Melanocytic Proliferations: Single-Site Retrospective Cohort Assessment of Treatment and Long-Term Follow-Up.

Atypical and malignant cutaneous tumors are understudied in the pediatric population, with limited data on long-term follow-up. This study examines pediatric (0-18 years) atypical melanocytic proliferations over a twenty-year period (January 2002-December2022) using the EPIC SlicerDicer at our institution. Over a twenty-year period, there were 55 cases of pediatric melanoma (53 patients). The median follow-up time was 8 years, 11 months. A proportion of 96% were treated with wide local excision (WLE), and 47% had a sentinel lymph node biopsy (SLNB) (35% positive rate). There were 101 atypical Spitz tumor cases (85% atypical Spitz tumors, 15% Spitz melanoma), with a median follow-up duration of 9 years. A proportion of 77% were treated with WLE (with one patient dying of metastatic disease). There were 10 cases of atypical melanocytic proliferations not otherwise specified, including 5 pigmented epithelioid melanocytomas (PEM), 4 deep-penetrating nevi, and 1 atypical cellular blue nevus. This study adds to the growing body of knowledge on pediatric atypical cutaneous melanocytic proliferations, aligning with many described characteristics such as disease location and overall survival rates, with distinct exceptions (higher melanoma positive SLNB rate, lower atypical Spitz tumor WLE rate, and a case of fatal metastatic atypical Spitz tumor).

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.

A Case of Multiple Hemorrhagic Friable Nodules.

A man in his 50s with a history of mycosis fungoides presents with bleeding wounds and nodules on the bilateral hips and forearms. What is your diagnosis?

Spatial biology analysis reveals B cell follicles in secondary lymphoid structures may regulate anti-tumor responses at initial melanoma diagnosis.

Introduction: B cells are key regulators of immune responses in melanoma. We aimed to explore differences in the histologic location and activation status of B cell follicles in sentinel lymph nodes (SLN) of melanoma patients. Methods: Flow cytometry was performed on fresh tumor draining lymph nodes (LN). Paraffin slides from a separate cohort underwent NanoString Digital Spatial Profiling (DSP)®. After staining with fluorescent markers for CD20 (B cells), CD3 (T cells), CD11c (antigen presenting cells) and a nuclear marker (tumor) was performed, regions of interest (ROI) were selected based on the location of B cell regions (B cell follicles). A panel of 68 proteins was then analyzed from the ROIs. Results: B cell percentage trended higher in patients with tumor in LN (n=3) compared to patients with nSLN (n=10) by flow cytometry. B cell regions from a separate cohort of patients with tumor in the (pSLN) (n=8) vs. no tumor (nSLN) (n=16) were examined with DSP. Within B cell regions of the SLN, patients with pSLN had significantly higher expression of multiple activation markers including Ki-67 compared to nSLN patients. Among 4 patients with pSLN, we noted variability in arrangement of B cell follicles which were either surrounding the tumor deposit or appeared to be infiltrating the tumor. The B cell follicle infiltrative pattern was associated with prolonged recurrence free survival. Conclusion: These data suggest a role for B cell follicles in coordinating effective adaptive immune responses in melanoma when low volume metastatic disease is present in tumor draining LN.

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.

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.

BACKGROUND: We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response. METHODS: The following analyses were performed on tumor tissue (n=11): (1) flow cytometric assessment of immune cell density, (2) NanoString Digital Spatial profiling of protein and the transcriptome, and (3) bulk RNA sequencing. Immune cell phenotypes and responsiveness to in vitro stimulation, including in vitro lerapolturev challenge, were measured in peripheral blood (n=12). RESULTS: Three patients who received anti-PD-1 therapy within 30 days of lerapolturev have a current median progression-free survival (PFS) of 2.3 years and had higher CD8+T cell infiltrates in prelerapolturev tumor biopsies relative to that of 7 patients with median PFS of 1.6 months and lower CD8+T cell infiltrates in prelerapolturev tumor biopsies. In peripheral blood, four patients with PFS 2.3 years (including three that received anti-PD-1 therapy within 30 days before lerapolturev and had higher pretreatment tumor CD8+T cell infiltrates) had significantly higher effector memory (CD8+, CCR7-, CD45RA-) but lower CD8+PD-1+ and CD4+PD-1+ cells compared with eight patients with median PFS 1.6 months. In addition, pretreatment blood from the four patients with median PFS 2.3 years had more potent antiviral responses to in vitro lerapolturev challenge compared with eight patients with median PFS 1.6 months. CONCLUSION: An inflamed pretreatment tumor microenvironment, possibly induced by prior anti-PD-1 therapy and a proficient peripheral blood pretreatment innate immune response (antiviral/interferon signaling) to lerapolturev was associated with long term PFS after intratumoral lerapolturev in a small cohort of patients. These findings imply a link between intratumoral T cell inflammation and peripheral immune function. TRIAL REGISTRATION NUMBER: NCT03712358.

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.

Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.

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.

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.

Cutaneous Vascular Neoplasms of Uncertain Biological Behavior.

Neoplasms of uncertain biological behavior present physicians with a genuine conundrum in practice. Cutaneous vascular neoplasms within this category are exceedingly rare, possessing significant gaps and uncertainty in many facets of clinical practice. Firstly, lesions were selected for review based on their categorization as indeterminate behavior, indicating the potential for local recurrence and rarely metastasize. After identification of the target lesions, a comprehensive review of the literature using national databases produced several landmark studies and case series regarding these neoplasms. Limiting the review to only cutaneous limited tumors narrowed the pool of studies; however, quite a large sum of papers remained. Examination of each paper yielded beneficial results on diagnosing, effective treatments, follow-up findings, and prognosis for each indeterminate lesion discussed. Overall, the literature search combined the molecular, histologic, immunohistochemical, surgical strategies to develop an up-to-date and comprehensive framework to guide physicians when encountering such lesions. The tumors reviewed include: kaposiform hemangioendothelioma, endovascular papillary angioendothelioma, pseudomyogenic hemangioendothelioma, retiform hemangioendothelioma, epithelioid hemangioendothelioma, and composite hemangioendothelioma.

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 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.

Discordance in Diagnosis of Melanocytic Lesions and Its Impact on Clinical Management.

CONTEXT.­: Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management. OBJECTIVE.­: To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management. DESIGN.­: We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not. RESULTS.­: A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients. CONCLUSIONS.­: Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified, thus, resulting in critical changes in recommendations for clinical management.

The Utility of Perilipin in Liposarcomas: PLIN1 Differentiates Round Cell Liposarcoma From Other Round Cell Sarcomas.

Liposarcoma is the most common soft tissue sarcoma in adults; however, accurate diagnosis often depends on the use of ancillary molecular testing which can be time consuming and expensive. Myxoid/round cell liposarcoma may be a diagnostic challenge due to the morphologic similarities with other nonadipocytic sarcomas with round cell morphology. Immunohistochemistry may be a helpful adjunct to appropriately triage cases for molecular testing. Perilipin 1 (PLIN1) and perilipin 2 (adipophilin) (PLIN2) are intracellular proteins involved in lipid droplet formation, which we hypothesized may be useful as immunohistochemical markers for liposarcoma. Using archival tumor tissue, we assessed pattern of PLIN1 and PLIN2 expression in 46 adipocytic tumors and 36 nonadipocytic sarcomas. PLIN1 was expressed in 88% of liposarcomas, including 100% of myxoid/round cell liposarcomas, and did not have any expression in nonadipocytic sarcomas. PLIN1 was not expressed in dedifferentiated liposarcoma. Although PLIN2 demonstrates increased sensitivity for liposarcoma, including expression in dedifferentiated liposarcoma, it is not specific for adipocytic differentiation and is expressed in other nonadipocytic sarcomas. Furthermore, PLIN2 is not expressed in lipoma-like well-differentiated liposarcoma, and as such has limited diagnostic utility.

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.