Priyadharsini Nagarajan

Background: The standard‐of‐care for advanced periauricular cutaneous squamous cell carcinoma (pCSCC) is surgery and adjuvant radiation therapy. Neoadjuvant immunotherapy recently demonstrated high pathologic response rates in patients with resectable pCSCC. Methods: This retrospective review was conducted at a tertiary cancer center and included patients with pathologically confirmed pCSCC within the periauricular area treated with curative‐intent surgery with or without neoadjuvant immunotherapy from 2005 to 2025. Patients who received neoadjuvant immunotherapy followed by surgery were age‐ and stage‐matched to those who underwent upfront surgery. The primary outcomes were event‐free survival (EFS) and overall survival (OS), estimated using the Kaplan–Meier method. Results: The study included 85 patients. Twenty‐four (28.2%) of whom received neoadjuvant immunotherapy and 61 (71.7%) underwent upfront surgery. The two cohorts had no differences in staging or disease burden at presentation. Forty‐eight patients presented with recurrent disease, equally distributed among the groups (57% vs. 54%, p > 0.05). Patients receiving neoadjuvant immunotherapy had longer median EFS than those undergoing upfront surgery (5.9 vs. 3.4 years; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.13–0.84; p = 0.02). Specifically, EFS at 2 years was 87% in the neoadjuvant group compared with 55% in the upfront surgery group ( p < 0.05). Median OS was also longer in the neoadjuvant group (not met vs. 4.4 years; HR, 0.32; 95% CI, 0.11–0.90; p = 0.031). Conclusions: Neoadjuvant immunotherapy improved survival outcomes in patients with advanced resectable pCSCC. These findings underscore the importance of including this patient population in upcoming randomized trials.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types¹, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1^−/−) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Background: Digital 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.Methods: We 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.Results: Two 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.Conclusions: Our findings reveal novel fusions and validate altered replication pathways related to HPV42 in DPAC.

Digital papillary adenocarcinoma (DPA) is a rare malignant neoplasm which arises from the sweat glands and has metastatic potential. DPA exhibits a wide range of architectural features and exhibits low-grade to high-grade features, so distinguishing DPA from benign skin neoplasms, including acral hidradenoma, poses significant diagnostic challenges. The recent literature suggests a strong association between DPA and human papillomavirus (HPV) 42, a low-risk HPV (LR-HPV) subtype, and a possible association between DPA and BRAF p.V600E. To explore these associations, we assessed the utility of in situ hybridization (ISH) for LR-HPV (types 6, 11, 40, 42, 43, 44) and immunohistochemistry (IHC) for BRAF p.V600E in diagnosing DPA and distinguishing DPA from acral hidradenoma. With institutional review board approval, we retrospectively identified 15 specimens of DPA (from 13 patients) and 3 cases of acral hidradenoma. Of the 13 DPA cases, 6 were negative for LR-HPV and BRAF p.V600E; 6 were positive for only LR-HPV; and 1 was positive for only BRAF p.V600E but negative for LR-HPV. All three cases of acral hidradenoma were negative for LR-HPV and BRAF p.V600E. As our sample size is limited, larger studies are needed to assess the value of detecting LR-HPV and BRAF p.V600E in the distinction of DPA and acral hidradenoma. However, our findings indicate a stronger association of DPA with LR-HPV than with BRAF p.V600E.

Background: Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ.Methods: Two-hundred cases of non-melanocytic cutaneous neoplasm, including basal cell carcinomas (BCCs) (n = 41), SCCs (n = 35), Merkel cell carcinomas (MCCs) (n = 25), and adnexal neoplasms (n = 99), were tested for TRPS1 expression using a monoclonal anti- TRPS1 rabbit anti-human antibody.Results: TRPS1 expression was present in almost all cases of SCC (94%), with a median H-score of 200, while it was either absent or only focally present in most BCCs (90%), with a median H-score of 5. The difference between BCCs and SCCs in H-score was significant (p < .001). All MCCs (100%) lacked TRPS1 expression. TRPS1 expression was frequently seen in most adnexal neoplasms, benign and malignant, in variable intensity and proportion but was consistently absent in apocrine carcinomas. All endocrine mucin-producing sweat gland carcinomas (EMPSGCs) (100%, 6/6) showed diffuse and strong TRPS1 immunoreactivity, with a median H-score of 300, which was significantly different (p < .001) than that of BCCs.Conclusions: Our study shows that TRPS1 may be an effective discriminatory marker for BCCs and SCCs. It also has a role in distinguishing BCCs from EMPSGCs.

ALK‐fused Spitz melanocytic neoplasms are a distinct subgroup of melanocytic lesions exhibiting unique histopathologic characteristics. These lesions often manifest as exophytic or polypoid tumors, characterized by fusiform‐to‐epithelioid melanocytes arranged in a nested, fascicular, or plexiform growth pattern. Several fusion partners of the ALK gene have been identified in spitzoid melanocytic neoplasms, with TPM3 and DCTN1 being the most prevalent. Less common fusion partners include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, and EHBP1. The MLPH gene, which encodes melanophilin (MLPH), playing a crucial role in regulating skin pigmentation by acting as a linker between RAB27A and myosin Va during melanosome transport, has also recently been recognized as a rare fusion partner of ALK in Spitz melanocytic neoplasms. Currently, there exists a sparse documentation within English literature, illustrating a limited number of cases featuring MLPH::ALK fusion in Spitz melanocytic neoplasms. In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK‐fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), RORγT (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, RORγT < 10%, Foxp3 < 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted.