BAP1 inactivated melanocytic tumors (BIMTs) are recognized for their potential for significant morphologic atypia including nuclear atypia, expansile growth, and mitotic activity, making it difficult to form firm morphologic criteria for malignancy. Next generation sequencing (NGS) is becoming increasingly utilized in melanocytic pathology. We conducted a two-phase survey with 26 dermatopathologists from the International Melanoma Pathology Study Group to assess the impact of NGS on diagnostic accuracy and interobserver agreement in 31 BIMTs. After NGS results, interobserver agreement improved from fair on Survey 1 (κ = 0.348) to moderate on Survey 2 (κ = 0.441). Respondents were 1.7 times more likely to be correct on Survey 2 after NGS results (OR = 1.67, 95% CI [1.16-2.44], p = 0.005). When accounting for case variability and difficulty, respondents were 8.7 times more likely to provide a correct diagnosis for a given case (CMH OR = 8.69, 95% CI [4.89-15.44], p < 0.001). Among the 8 BAP1 inactivated melanomas in this study, 3 transitioned from a majority of votes for benign/intermediate grade BIMT to a majority of votes for melanoma after seeing NGS data. Genomic aberrations exclusive to malignant cases included pathogenic variants in TERT-p, CDKN2A, PTEN, and amplification of MYC. Our study suggests NGS has the potential to improve diagnostic accuracy and interobserver agreement for BAP1 inactivated melanocytic tumors. With the advent of increasingly effective therapies for melanoma, there is value in forming a definitive diagnosis of melanoma when appropriate. Additional studies with greater case numbers and follow-up are needed to further validate these findings.

ABSTRACTBackgroundDigital papillary adenocarcinoma (DPAC) is a rare but aggressive cutaneous malignant sweat gland neoplasm that occurs on acral sites. Despite its clinical significance, the cellular and genetic characteristics of DPAC remain incompletely understood.MethodsWe conducted a comprehensive genomic and transcriptomic analysis of DPAC (n = 14) using targeted next‐generation DNA and RNA sequencing, along with gene expression profiling employing the Nanostring Technologies nCounter IO 360 Panel. Gene expression in DPAC was compared to that in hidradenoma (n = 10). Immunohistochemistry was employed to validate gene expression.ResultsTwo out of eight DPACs showed fusion gene rearrangements (CRTC3::MAML2 and TRPS1::PLAG1). No uniform mutational signature was detected in DPAC. Comparative gene expression analysis revealed an enrichment of genes related to matrix remodeling, metabolism, and DNA damage repair. Hallmark pathway analysis demonstrated significant upregulation of E2F target genes in DPAC compared to hidradenoma (p = 0.00710). Human papillomavirus‐42 was found to be positive in all of our tested DPAC cases. Immunohistochemistry confirmed increased protein expression of CD56, CDC20, and SOX10 in DPAC. Notably, most DPAC tumors also exhibited B‐cell infiltration, as indicated by CD20 staining.ConclusionsOur findings reveal novel fusions and validate altered replication pathways related to HPV42 in DPAC.

BACKGROUND:Primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP) are indolent CD30-positive lymphoproliferative disorders that rarely express TCR-γδ. However, primary cutaneous gamma-delta T-cell lymphoma (pcGDTCL), characterized by TCR-γδ expression on neoplastic cells, is a rare, aggressive cutaneous T-cell lymphoma with a poor prognosis. Accurate differentiation is essential due to distinct clinical behavior and treatment. METHODS:We identified 11 TCR-γδ-positive pcALCL cases from internal and consultation files, verified by two cutaneous lymphoma experts, with clinicopathologic data recorded. RESULTS:The median age was 68 years (range 38-95). Most cases presented as a single dermal lesion on the upper extremities. All were ALK-negative, CD30-positive (> 90% tumor cells), TCR-βF1-negative, and diffusely TCR-γδ-positive. CD4-/CD8- (54.5%) and CD4+/CD8- (45.5%) immunophenotypes were observed. CD2 (63.6%) and CD3 (54.5%) were the most common T-cell antigens. Ulceration, inflammation (both 45.5%), and necrosis (36.4%) were frequent. Angiotropism, angiocentricity, and myxoid stroma appeared in one case; epidermotropism in two. Four of ten tested were DUSP22-rearranged, and TP63 was negative in all eight tested. CONCLUSIONS:Most ALK-negative TCR-γδ-positive pcALCL were CD4-/CD8-, followed by CD4+/CD8-. DUSP22 rearrangement occurred in 40% of cases, similar to reports in typical pcALCL. Its prognosis and the role of DUSP22 are yet to be clarified.

Immune checkpoint blockade (ICB) has revolutionized outcomes for patients with melanoma across multiple disease settings. In patients with advanced, unresectable disease, the ICB combination of nivolumab (anti-PD1) and relatlimab (anti-LAG-3) has demonstrated improved clinical outcomes compared with nivolumab monotherapy. There exists an unmet need to identify biomarkers that predict response to this combination regimen and rational therapeutic strategies to overcome resistance. We previously reported the initial results of a phase II clinical trial (ClinicalTrials.gov identifier: NCT02519322) of neoadjuvant systemic treatment (NST) followed by adjuvant treatment with nivolumab and relatlimab, which achieved a major pathologic response (MPR; ≤10% viable tumor) rate of 63% in patients with stage III/IV, surgically resectable melanoma. Our updated clinical follow-up (median 47 months) for these patients demonstrates that at 4 years from the start of NST, 80% of patients remain event-free, including 95% of patients who achieved a MPR. Gene expression analysis of longitudinally collected biospecimens from the trial identifies baseline upregulation of several immune modulatory pathways associated with MPR; by contrast, increased B7-H3 expression was associated with resistance. This work demonstrates the long-term benefit of neoadjuvant nivolumab and relatlimab and identifies a potentially targetable predictor of resistance to this combination therapy.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous T-cell lymphoma with adipotropism characterized by infiltration of CD8 + T cells exhibiting a cytotoxic and αβ phenotype. Although SPTCL is typically indolent, distinguishing it from more aggressive cutaneous lymphomas such as primary cutaneous γδ T-cell lymphoma is critical for accurate prognosis. We present a case of SPTCL in a 26-year-old Asian woman with a history of hemophagocytic lymphohistiocytosis, who presented with nonulcerated, erythematous patches and hyperpigmented nodules on her extremities and trunk persisting for 5 months. Biopsy specimens revealed an atypical lymphoid infiltrate with prominent adipotropism, predominantly comprising atypical medium-sized lymphocytes rimming the adipocytes. Immunophenotypically, the lesional lymphocytes were CD3+/CD4−/CD8+/CD7+ T cells expressing TIA1, granzyme B, and TCR βF1, while lacking CD30 and Epstein–Barr virus-encoded small RNA expression. Intriguingly, there was a markedly increased density of T cells expressing TCR δ, some surrounding adipocytes and appearing neoplastic. CD123 failed to reveal aggregates of plasmacytoid dendritic cells. Molecular analysis revealed monoclonal TCR β and γ gene rearrangements. Despite the elevated γδ T-cell population (20%–50% of the T cells), the overall clinical, histopathologic, and molecular findings, along with the absence of rapid disease progression, supported a diagnosis of SPTCL. Although increased densities of reactive γδ T-cells or γδ T-cell phenotypes in neoplastic cells are observed in various benign and malignant dermatologic conditions, the literature on this phenomenon—particularly in SPTCL—remains scarce. Our case highlights the importance of recognizing an increased γδ T-cell population in SPTCL to prevent misdiagnosis as a more aggressive lymphoma such as primary cutaneous γδ T-cell lymphoma, underscoring the need for thorough clinicopathologic correlation.

B-Raf Proto-Oncogene (BRAF) fusions are rare in melanomas. We present a case of cutaneous melanoma with a Ring Finger Protein 11 (RNF11)::BRAF fusion in a 63-year-old man with a history of stage IB melanoma on the right upper back (pT2apN0cM0; nonulcerated with a Breslow thickness of 1.2 mm). Despite initial treatment, the melanoma progressed to multiple metastases. Histopathologically, the tumor cells exhibited epithelioid and rhabdoid morphologies, with occasional giant pleomorphic cells and multinucleation, and were positive for antimelanocytic cocktail (HMB45, Melan-A, tyrosinase) and S100. Next-generation sequencing of a metastatic specimen identified an RNF11::BRAF fusion and TERT promoter mutation, but no other somatic mutations (eg, BRAF, NRAS, KIT) or copy number variations were detected. The patient died to melanoma approximately 58 months after initial diagnosis, despite several lines of systemic therapy, including immunotherapies and a mitogen-activated protein kinases 1 and 2 inhibitor. RNF11::BRAF fusions are known oncogenic drivers in histiocytic disorders such as Erdheim-Chester disease and non-Langerhans cell histiocytosis. Although BRAF fusions are commonly observed in Spitz melanocytic neoplasms, the discovery of the RNF11::BRAF fusion in melanomas is unprecedented. Our case represents a triple wild-type, clinically aggressive melanoma of possibly non-Spitz lineage with an ultraviolet signature and a rare BRAF fusion, contributing to the expanding body of literature on BRAF-fused melanomas.

Trophoblast cell surface antigen 2 (TROP2) has emerged as a promising therapeutic target in oncology. TROP2-directed antibody-drug conjugates (ADCs) are now approved for treating advanced malignancies such as breast carcinomas by the Food and Drug Administration. However, the expression patterns and potential therapeutic relevance of TROP2 in cutaneous neoplasms remain largely unexplored. In this study, we evaluated TROP2 expression by immunohistochemistry in 198 cutaneous tumors, including squamous cell carcinomas (SCCs; n = 44), basal cell carcinomas (BCCs; n = 27), Merkel cell carcinomas (MCCs; n = 12), melanomas (n = 25), atypical fibroxanthomas/pleomorphic dermal sarcomas (AFXs/PDSs; n = 17), and various adnexal (n = 58) and mesenchymal (n = 15) neoplasms. H-scores were calculated to quantify expression levels. TROP2 was consistently expressed in all SCCs (100 %; median H-score: 272.5) and in nearly all adnexal tumors (98 %; 57/58). In contrast, TROP2 expression was minimal or absent in BCCs, MCCs, melanomas, AFXs/PDSs, and mesenchymal neoplasms. Among adnexal tumors, at least moderately positive (H-score >100) TROP2 expression was observed in endocrine mucin-producing sweat gland carcinomas (n = 6; median: 170), sebaceous carcinomas (n = 6; median: 140), trichilemmal carcinomas (n = 2; median: 220), and individual cases of porocarcinoma, hidradenocarcinoma, pilomatrical carcinoma, and squamoid eccrine ductal carcinoma (H-scores: 280-295). Statistical analysis revealed significant differences in TROP2 expression among five major tumor groups (p < 0.001). Our study suggests that TROP2 immunohistochemical expression may have diagnostic utility and that TROP2-directed ADCs could offer therapeutic benefit to patients with advanced cutaneous SCCs and select adnexal carcinomas.

Detection of Merkel cell carcinoma (MCC) micrometastases in sentinel lymph nodes (SLNs) often necessitates immunohistochemical studies like pancytokeratin (panCK) or CK20. However, panCK can label non-epithelial cells, particularly dendritic reticulum cells, complicating interpretation, while CK20 is absent in up to 24 % of MCCs, leading to potential false negatives. Recent evidence suggests SOX11 and INSM1 as sensitive nuclear neuroendocrine markers, though their comparative performance in this setting remains unclear. We assessed the expression of panCK (AE1/AE3, CK8/18, Cam5.2, and MNF116), CK20, SOX11, and INSM1 in 25 primary MCCs and 8 nodal metastases. SOX11 and INSM1 demonstrated the highest median H-scores (both 297), significantly outperforming panCK and CK20 (both 255) (p < 0.001). Although median H-scores for SOX11 and INSM1 were similar, 9 % (3/33) of cases lacked SOX11 expression. Direct comparison revealed significant differences in proportion and median H-score between SOX11 and INSM1 (p = 0.020 and p = 0.012, respectively), while intensity did not differ significantly (p = 0.317). When used alongside panCK, INSM1 yielded the highest combined sensitivity (100 %), surpassing panCK/CK20 and panCK/SOX11 combinations. These findings support the use of a panCK/INSM1 panel as a highly sensitive approach for detecting MCC micrometastases in SLNs. While INSM1 demonstrates robust performance, interpretation must account for background immunoreactivity in hematolymphoid elements, a possible and important diagnostic pitfall when using this marker in clinical practice. Further prospective studies with larger and more diverse cohorts may be needed to confirm these results and refine the optimal immunohistochemical strategy for MCC detection in SLNs.

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions.

BACKGROUND:Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities.METHODS:We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis.RESULTS:Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs.CONCLUSIONS:Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."