Alessio Giubellino

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy that can arise through 2 oncogenic pathways: a Merkel cell polyomavirus–positive pathway and a virus-negative pathway driven by ultraviolet exposure. Cytokeratin 20 (CK20), expressed in a paranuclear dot-like pattern, is a cornerstone diagnostic marker for MCC, yet roughly 5% of cases are CK20 negative, an uncommon immunophenotype that can cause diagnostic difficulty. In this exploratory study, we asked whether CK20-negative tumors show a distinct nuclear phenotype on digital image analysis. Using the HALO artificial intelligence platform (Indica Labs), we performed artificial intelligence–assisted whole-slide image analysis of 5 CK20-negative and 36 CK20-positive MCC sections (from 30 patients), extracting nuclear and cytoplasmic metrics from manually annotated tumor regions. Because sections from the same patient are not independent, we repeated the primary comparison at the patient level across all 24 possible one-section-per-patient combinations. CK20-negative MCC showed lower average nucleus roundness than CK20-positive tumors; the difference was significant by the Welch t test in the section-level analysis (0.731 vs. 0.754; P = 0.012) and remained significant by the Welch t test across all 24 patient-level combinations ( P = 0.032 to 0.048), although the Mann–Whitney U test was no longer significant at the patient level. We also observed trends toward smaller nuclear area and perimeter, while cell, cytoplasmic, and tissue areas did not differ. Because Merkel cell polyomavirus status was unavailable, these differences cannot be attributed specifically to CK20 or viral status. These preliminary findings suggest that computational pathology can detect nuclear differences in this rare subset; larger, molecularly characterized cohorts from multiple institutions are needed for validation.

Primary cutaneous acral CD8 ⁺ T-cell lymphoproliferative disorder has been recognized by the World Health Organization as a distinct entity characterized by dermal-based, nonulcerated nodules typically involving the auricle and following an indolent course. By contrast, cytotoxic cutaneous lymphomas presenting with tumoral lesions of the auricle can follow a locally aggressive or metastatic course. In this study, we discuss the presentation, diagnosis, molecular characteristics, and treatment options for these under-recognized, aggressive cytotoxic lymphomas of the auricle. Six cases of cytotoxic lymphoma NOS and 4 cases of CD4 ⁺ primary cutaneous γδ T-cell lymphoma that presented as auricular tumors were included in this series. Patches at other sites resembling mycosis fungoides with variable immunophenotypes were observed in 7 cases. Despite multimodal therapy, 7 of 10 patients died within median 14 months of presentation. Necrotizing and locally progressive tumors of the auricle may represent an ominous sign of aggressive treatment-refractory cytotoxic lymphomas characterized by swift mortality.

Background/Objectives: Spitz nevus with architectural features of a Clark/dysplastic nevus (“SPARK nevus”) is an uncommon melanocytic lesion closely mimicking dysplastic nevus and melanoma, creating diagnostic challenges. This study aimed to delineate the clinical, histopathologic, and immunohistochemical features of SPARK-pattern lesions and to clarify their biologic behavior. Methods: A multi-institutional retrospective study across six academic centers identified 74 SPARK nevi. Candidate lesions were re-reviewed at each institution by board-certified dermatopathologists using predefined inclusion criteria requiring concurrent Spitzoid cytology and Clark-type architectural features. The demographic, clinical, histologic, immunohistochemical, and follow-up data were collected and reviewed. Results: The cohort showed a predominance of female patients (76%) with a mean age of 32.4 years (range 11-68), and lesions were small (mean diameter 5.8 mm, range 2-20 mm), most often on the proximal extremities and trunk. Histologically, lesions were mainly compound (70%) with Spitzoid cytology in Clark-type architecture; cytomorphology was mixed epithelioid–spindled (47%) or epithelioid (41%), Kamino bodies were infrequent (9%), inflammation was usually non-brisk (62%), and cytologic atypia often reached moderate to severe grades. Immunohistochemistry (performed in 55%) showed PRAME negativity, retained p16, and low MKI67 indices, and follow-up (available in 93%; median 18 months) revealed one local recurrence, two metachronous SPARK nevi, and no SPARK-related deaths. Conclusions: This largest series defines the clinicopathologic and immunohistochemical spectrum of SPARK-pattern lesions and demonstrates overall benign behavior despite morphologic overlap with dysplastic nevi and melanoma. SPARK is most appropriately interpreted as a morphologic pattern encompassing lesions arising from multiple melanocytic pathways.

Artificial intelligence (AI) has pervaded many fields of medicine in the last few years on the wave of similar changes in other disciplines. Adoption of AI-driven technologies will progress in pathology in the years to come and will also transform our subspecialty of dermatopathology. From the adoption of AI in teaching to its use in clinical practice and in advancing our field through improved research capabilities, we expect a great deal of changes that will hopefully improve our assessment of tissue sections for several cutaneous pathologies. In this review, we offer an overview of where the use of these tools currently stands in dermatopathology and the potential directions that will transform the way we practice and do research. We cover AI’s role in diagnosing various skin conditions, such as melanocytic lesions and other cutaneous skin cancers, and inflammatory dermatoses. The review further covers AI’s contributions to workflow automation, like mitotic figure detection and counting, predictive analytics (e.g., melanoma prognosis), and educational tools (e.g., AI-driven simulators). It also addresses critical technical aspects, including data curation, algorithm development, and model validation. We aim to provide a comprehensive overview of how AI is transforming dermatopathology, from diagnosis and prognosis to education and clinical integration.

Background/Objectives: Atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS)/pleomorphic dermal sarcoma (PDS) are related dermal neoplasms of uncertain histogenesis that occupy opposite ends of a shared clinical and histopathologic spectrum, with AFX displaying typically low-grade behavior and PDS representing its more aggressive counterpart. The recent literature has confirmed that AFX and PDS also overlap at the molecular and genomic levels; however, little is known about their gene-expression profiles. Methods: We performed gene-expression profiling using RNA sequencing with a Pan-Cancer RNA Panel on a small series of AFX and PDS samples. Results: Unsupervised cluster analysis showed a clear separation between the two groups. We confirmed a TP53 UV-radiation signature in both. However, while AFX and PDS share common DNA mutation profiles in our cohort, RNA sequencing reveals distinct gene-expression signatures that may aid in differentiating these related tumors. In particular, the MAPK pathway, cell adhesion, DNA repair, EMT-like signatures and inflammatory responses play key roles in distinguishing the two groups, at least in our limited cohort, consistent with their differing biological behavior. Differences in the expression of receptor tyrosine kinases were also observed. Conclusions: Gene-expression profiling have the potential to be a valuable tool for distinguishing AFX from PDS, clarifying their positions at opposite ends of a spectrum and providing deeper insight into the biology of these neoplasms.

Background: Myxoid glomus tumors (mGTs) are an uncommon histologic pattern of glomus tumors, characterized by prominent myxoid stromal changes that may mimic a wide range of soft tissue neoplasms. Recent reports of unexpected CD34 expression in some cases have further complicated their differential diagnosis. Objectives: This study aimed to characterize the histopathological, immunohistochemical, and clinical features of cutaneous mGTs, with particular emphasis on CD34 expression. Methods: We analyzed 8 histologically confirmed cases of cutaneous mGTs underwent to a comprehensive evaluation of morphological features and immunophenotypic profile, with available clinical data. The immunohistochemical panel included smooth muscle actin (SMA), CD34, and S100. Mast cell density was assessed by tryptase in 3 cases. As controls, 8 glomus tumors without myxoid features were also examined for CD34 expression. Results: The cohort consisted of 8 patients (2 males, 6 females; age range 23–71 years). All tumors were located on the distal phalanges of the digits and showed extensive myxoid stromal changes. Immunohistochemistry demonstrated SMA positivity and CD34 expression in all mGTs. In contrast, none of the control GTs without myxoid stroma expressed CD34. Mast cells were consistently identified in the tested cases, predominantly within the myxoid matrix, suggesting a possible role in stromal remodeling. Conclusions: mGTs represent a rare but distinct histological pattern within the glomus tumor spectrum; frequent CD34 expression and mast cell infiltration appear to be characteristic features, although their biological significance remains uncertain. Recognition of these findings is essential to avoid misdiagnosis with other CD34-positive perivascular neoplasms or myxoid soft tissue sarcomas.

The role of regional lymph nodes in melanoma metastasis has long been recognized. This review will detail the evolving role of sentinel lymph node biopsy (SLNB) in melanoma management in the era of adjuvant therapies. We analyze key themes and findings from recent publications, highlighting both areas of consensus and ongoing controversies. While the landscape of melanoma management continues to evolve with the advent of novel therapeutic combinations, SLNB remains a valuable tool for staging and potentially provides therapeutic benefit. However, optimal patient selection for SLNB requires careful consideration of individual risk factors and benefits of adjuvant therapy.

Melanoma is one of the most aggressive skin cancers, with increasing rates of occurrence. Although it has not traditionally been considered hormonally driven, recent evidence links androgen receptor (AR) signaling to important aspects of melanoma biology, including tumor growth, metastasis, immune evasion, and resistance to therapy. Mechanistically, AR promotes melanoma progression by activating a pro-metastatic gene program, suppressing anti-tumor immune responses, and altering the tumor microenvironment. Additionally, emerging data indicate AR’s involvement in resistance to chemotherapy and immune-based therapies. This review provides a comprehensive overview of AR’s intricate role in melanoma, focusing on its molecular mechanisms, its impact on immune evasion and therapy resistance, and its potential clinical applications. We also assess AR-targeted strategies, including androgen deprivation therapy and AR antagonists, to improve the effectiveness of chemotherapy, targeted therapy, and immunotherapy. Understanding AR’s role in melanoma could lead to new treatment options, particularly for sex-specific patient groups.

Melanoma is one of the most aggressive skin cancers, with increasing rates of occurrence. Although it has not traditionally been considered hormonally driven, recent evidence links androgen receptor (AR) signaling to important aspects of melanoma biology, including tumor growth, metastasis, immune evasion, and resistance to therapy. Mechanistically, AR promotes melanoma progression by activating a pro-metastatic gene program, suppressing anti-tumor immune responses, and altering the tumor microenvironment. Additionally, emerging data indicate AR's involvement in resistance to chemotherapy and immune-based therapies. This review provides a comprehensive overview of AR's intricate role in melanoma, focusing on its molecular mechanisms, its impact on immune evasion and therapy resistance, and its potential clinical applications. We also assess AR-targeted strategies, including androgen deprivation therapy and AR antagonists, to improve the effectiveness of chemotherapy, targeted therapy, and immunotherapy. Understanding AR’s role in melanoma could lead to new treatment options, particularly for sex-specific patient groups.

Congenital melanocytic nevi (CMN) are benign tumors present at birth or arising in the first few months of life. A small subset of these nevi present with mild atypical features and heterogeneous differentiation, including Schwannian differentiation. We present a case of a 3-week-old with a 7 cm red/purple scalp nodule consistent with CMN with mild atypical heterogeneous areas. On histology, there were dermal nests of spindle cells in a fibrillar matrix, with increased vessels and clusters of small round melanocytes interspersed between collagen bundles and around adnexal structures. The lesion also exhibited rare pagetoid ascent of melanocytes as single cells and nests. Overall, these features were consistent with a CMN with nodular proliferative neurocristic cutaneous hamartoma (NCH) with a component of a compound mild atypical melanocytic proliferation. Next generation sequencing (NGS) identified a novel SH2B1::BRAF fusion. This case highlights the diagnostic challenges of heterogeneous differentiation within CMN in young children.