Neoadjuvant immunotherapy (nIO) followed by a therapeutic lymph node dissection (TLND) for patients with clinically node-positive melanoma is supported by level 1 evidence. Our aim was to assess the association of pathologic response (PR) and nIO regimen with survival among patients with clinical stage III melanoma undergoing nIO and TLND. Our study included patients treated with nIO followed by a TLND from a large academic institution between 2016 and 2024. The pathologic response was assessed using established guidelines. Differences in extent of PR (PR) by nIO regimen were examined. Disease-free survival (DFS) and overall survival (OS) by PR and nIO regimen were assessed. The study included 121 patients (78.5

Melanoma arising in blue nevus (MBN) is a rare melanoma subtype with distinct molecular characteristics and biological behaviors compared to other cutaneous melanomas. However, limited data exists on the frequency of TERT promoter mutations (TPMs), tumor mutational burden (TMB), and molecular alterations beyond the well-known GNAQ, GNA11, SF3B1, and BAP1 mutations. Here, we provide a comprehensive clinicopathologic and molecular analysis of 11 MBNs from a single tertiary hospital. MBNs were consistently dermal-based with expansile vertical growth, exhibiting substantial Breslow thickness (median: 8.4 mm). At initial diagnosis, they frequently showed microscopic satellitosis (MS) (36

This article highlights current advances in melanocytic lesions and their impact on histopathologic diagnosis and patient management. Special emphasis is given to the concept of melanocytoma and the study of dysplastic nevi. Finally, the article describes the current status and possible future applications of immunohistochemistry, digital analysis, and artificial/augmented intelligence.

The scope of gene fusions in melanocytic neoplasms is broader than previously recognized, extending well beyond the Spitz-lineage neoplasms where kinase fusions involving ALK, ROS1, NTRK1/2/3, RET, MET, BRAF, and MAP3K8 define biologically and morphologically distinct tumors. Emerging studies demonstrate that a meaningful proportion of conventional non-Spitz lineage melanomas harbor oncogenic fusions. Such fusions may impact clinical behavior, histopathologic presentation and provide opportunities for targeted therapy. The World Health Organization classification of skin tumors, 5th edition, now incorporates fusion status into taxonomy and risk stratification, yet some important questions remain for further investigation: fusion-associated neoplasms can mimic non-melanocytic neoplasm; Spitz-type fusions appear in non-Spitz lesions; and melanocytic differentiation may occur in some other fusion-driven lesions. Broad-panel next-generation sequencing (including RNAseq), together with targeted fluorescence in situ hybridization and immunohistochemistry enhances detection of known and novel fusion partners. Early clinical evidence of TRK, ALK, and ROS1 inhibitor efficacy underscores the translational promise of fusion testing and opens avenues for personalized therapy. This review synthesizes current knowledge on the genomics, histopathology, diagnosis, and therapeutic implications of fusion-driven melanocytic neoplasms, highlighting consensus points and remaining controversies.

BACKGROUND:The mitogen-activated protein kinase (MAPK) pathway plays a key role in cell-cycle regulation and tumor progression in cancer. Dermatologic toxicities (DTs) to newer pan-RAS (RMC-6236) and pan-RAF (LXH254/naporafenib) inhibitors are emerging. Therefore, knowledge of the morphologic patterns of DTs from pan-RAS/RAF inhibitors will enable quick diagnosis and appropriate management. METHODS:The clinical and histologic features of patients treated with pan-RAS or pan-RAF inhibitors for advanced stage RAS mutated malignancies were retrospectively reviewed. RESULTS:Associated DTs were identified in eight patients treated with either pan-RAS (n = 4) or pan-RAF (n = 4) plus MEK/ERK inhibitors for RAS mutated tumors (colorectal, lung, pancreatic, thyroid, melanoma). The patients ranged from 37 to 72 years of age. Five patients had initial clinical presentation of an acneiform eruption complicated by ulceration, flaccid vesicles, or diffuse exfoliative erythroderma. Maculopapular eruption, purpuric patches and papules, and eruptive dark nevi were the other clinical presentations. Skin biopsies were primarily inflammatory with histopathologic features of suppurative folliculitis (n = 2), dermal hypersensitivity reaction (n = 2), subcorneal acantholytic dermatosis (n = 1), subcorneal pustules (n = 1), ulcer (n = 1), and eruptive nevi (n = 1). CONCLUSIONS:Treatment with novel pan-RAS/RAF inhibitors exhibits a spectrum of DTs that exhibit some overlap with small molecule inhibitors that target the MAPK pathway.

Lorigerlimab is a dual bispecific antibody (BsAb) targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 that is used for treatment of advanced solid cancers such as metastatic castration-resistant prostate carcinoma. Reported cutaneous immune-related adverse events (irAEs) of lorigerlimab, such as pruritus and rash, are mostly manageable. However, to the best of our knowledge, the clinical histopathologic features of irAEs of the skin to dual immune checkpoint blockade with BsAbs have not been characterized. We report herein on lorigerlimab-associated lichenoid and vacuolar interface dermatitis in two patients with metastatic castration-resistant prostate adenocarcinoma. Case 1 had a violaceous, papular eruption and a lichenoid, perivascular histopathologic reaction pattern that responded well to temporary withholding of lorigerlimab and to corticosteroids. Case 2 presented with a more severe rash characterized by mixed clinical features of psoriasiform, eczematous, and morbilliform eruption and a histopathologic pattern of vacuolar interface changes with superficial perivascular lymphocytic infiltrate, scattered dyskeratotic keratinocytes, and focal acantholysis. The eruption was refractory to treatment, despite the patient withholding lorigerlimab, leading to complete discontinuation of lorigerlimab. This report highlights the importance of histopathologic evaluation in guiding treatment decisions for lorigerlimab-associated irAEs and underscores the need for further research into its dermatologic irAEs.

BACKGROUND:Distinguishing melanoma cells from nevus cells remains a diagnostic challenge, particularly in cases where melanoma exhibits nevoid morphology or nevus cells display atypical or epithelioid features. Accurate identification is essential for proper measurement of Breslow depth in melanomas arising in association with nevi and for margin assessment, both of which are critical for patient prognosis. The dual multiplex immunohistochemical stain utilizing Melan-A (red chromogen) and Ki67 (brown chromogen) is a valuable tool for assessing the proliferative index of melanocytic populations, with melanoma cells typically showing a higher Ki67 index than nevus cells. METHODS:We identified 10 cases with invasive melanoma and associated nevus present on the same scanned histologic section for which the signing pathologist had ordered this dual multiplex immunohistochemical study. We annotated areas of melanoma versus nevus, then quantified the staining intensities. RESULTS:Melanoma cells often demonstrate more intense Melan-A red chromogen labeling than adjacent nevus cells (p = 0.008; Wilcoxon signed rank test). CONCLUSION:This differential labeling provides a helpful visual distinction between melanoma and nevus cells within the same histologic section, enhancing diagnostic confidence beyond the difference in Ki67 proliferation index.

Deep penetrating nevus (DPN)-like melanomas are believed to arise through sequential activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, followed by additional mutations. Due to their rarity and lack of standardized diagnostic criteria, their molecular landscape and clinical behavior remain still poorly understood. Here, we report the largest cohort to date of 14 DPN-like melanomas. These tumors predominantly affected middle-aged adults (median, 46 y), with the head and neck skin as the most common site. One rare case involved a mucosal site (epiglottis). DPN-like melanomas exhibited infiltrative growth, prominent vertical growth phase, severe nuclear atypia with occasional multinucleation, and increased mitotic activity (median, 3.5/mm 2 ). The median Breslow thickness was 3.3 mm (range: 1.2 to 9.2 mm), with all cases showing microscopic satellitosis, sentinel lymph node positivity, or synchronous metastasis. Most cases (93%) harbored MAPK pathway-activating mutations, predominantly in BRAF (77%), followed by NRAS and EGFR (an upstream regulator of the MAPK pathway). In addition, 79% of cases had mutations activating the canonical Wnt/β-catenin signaling pathway, mainly in CTNNB1 and APC . Two CTNNB1 / APC wild-type cases exhibited alternative mutations in genes indirectly modulating this pathway, such as ARID1A , EZH2 , FAT1 , and SETD2 , along with other mutations, including TERT promoter mutations (TPMs). TPMs were present in 56%, and the median tumor mutational burden was 30 mutations/Mb. After a median follow-up of 33.5 months, 36% of patients developed distant metastases, and 2 patients died of disease 8 and 32 months, respectively, after initial diagnosis. These findings expand the molecular diversity of DPN-like melanomas and provide valuable insights into their clinical outcomes.

The American Joint Committee on Cancer (AJCC) staging system for MCC defines pT1–pT3 disease by tumor size and pT4 disease as disease invading deep structures, including skeletal muscle. However, the prognostic significance of skeletal muscle invasion in MCC remains incompletely characterized, especially in the head and neck (H N), where the dermis and subcutis are often thin and even small tumors may invade skeletal muscle. We evaluated the clinicopathologic significance of skeletal muscle invasion in H N and non-H N MCC. MCCs diagnosed at a tertiary cancer center during 2002–2025 were stratified by anatomic site and presence of skeletal muscle invasion. Clinicopathologic features, Merkel cell polyomavirus (MCPyV) status, treatment parameters, and clinical outcomes were analyzed. The study included 65 cases: 23 H N skeletal-muscle-invasive, 18 H N non-skeletal-muscle-invasive, 4 non-H N skeletal-muscle-invasive, and 20 non-H N non-skeletal-muscle-invasive MCCs. Muscle-invasive tumors were significantly larger and thicker than non-muscle-invasive tumors and required more surgical procedures to achieve negative margins. In the H N, skeletal-muscle-invasive tumors had higher rates of vascular invasion and distant metastasis (3-year rate: 31

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.

ABSTRACTBackgroundMerkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell‐of‐origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.MethodsThe study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow‐up was 29.8 months (range, 2.7–234.1). We performed immunohistochemistry using antibodies against the α3, α5, and α7nAChR subunits.ResultsOur results show that the majority of MCC cases expressed α3, α5, and α7‐nAChR subunits. Of the 71 cases, 59 (83%) expressed α3‐nAChR, 71 (100%) expressed α5‐nAChR, and 63 (88%) expressed α7‐nAChR. Location of immunoreactivity differed between cases and included cytoplasmic only and nuclear/peri‐nuclear, with variation in the intensity of staining. There were significant correlations between the intensity or location of immunoreactivity and clinical and histopathologic parameters.ConclusionsThese findings seem to support that MCC displays the features of neural crest cells, and suggest the potential for nAChR‐targeted therapy.

Postradiation angiosarcoma of the breast is a secondary angiosarcoma in breast carcinoma patients who have undergone radiation therapy. Although postradiation angiosarcoma is rare, it is very aggressive and has an extremely poor prognosis. Previous studies have implicated matrix metalloproteinase 9 (MMP9) in some cancer development and progression and angiogenesis. In this study, we compared MMP9 expression in surgical specimens from breast cancer patients treated with radiation who did and did not develop breast angiosarcoma within 15 years. We also compared MMP expression in the breast angiosarcoma specimens from patients with postradiation angiosarcoma of the breast and patients with non-breast angiosarcoma not previously treated with radiation. Our results showed that MMP9 was expressed in the endothelial cells in the breast carcinoma specimens from patients who developed angiosarcoma after radiation therapy but not in the breast carcinoma specimens from patients without angiosarcoma. In addition, MMP9 expression was higher in patients with postradiation angiosarcoma of the breast than in patients with non-radiation-associated primary angiosarcomas at non-breast sites. These results suggest that MMP9 may be a risk factor for and play a significant role in the development of postradiation angiosarcoma of the breast.