Merkel cell carcinoma in Taiwan: a subset is chronic arsenicism-related, and the Merkel cell polyomavirus-negative cases are pathologically distinct from virus-related cases with a poorer outcome.

Merkel cell carcinoma (MCC) is a rare primary neuroendocrine carcinoma of the skin, more frequent in the West than in the East. The pathogenesis is complex, with Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) light being reported to play important roles. In this retrospective study of MCC cases from Taiwan, we analysed the prognostic significance of pathological features and the status of MCPyV and retinoblastoma (Rb) expression. We retrospectively collected MCC cases from five hospitals in Taiwan from 1994 to 2022. We examined the clinical and pathological features, performed immunohistochemical studies for the large T antigen of MCPyV and Rb, and reviewed medical records from electronic data. Disease-specific survival was estimated by using the Kaplan-Meier estimate and compared between subgroups using log-rank test. The clinical and pathological features and the immunohistochemical profiles between subgroups were compared using the Fisher exact test for categorical variables. The 38 patients were mostly (71%) males, with a median age of 79. In 22 (58%) patients, the tumours occurred in sun-exposed areas. Clinically, five (13%) patients had chronic arsenicism. Histopathologically, 11 (29%) cases showed combined tumours (MCC with squamous cell carcinoma or Bowen disease/squamous carcinoma in situ). Seventeen (45%) cases were positive for MCPyV, whereas all combined tumours were negative. MCPyV-negative MCC displayed distinctive pathological features, including epidermal changes, presence of an intraepidermal MCC component, linear or single-file growth pattern, and pleomorphic nuclei. Immunohistochemically, 59% (22/37) MCC cases showed complete loss of Rb protein expression, more frequent in MCPyV-unrelated (p<0.001) and combined (p=0.014) cases, ​but without statistical significance among patients with chronic arsenicism, sun exposure, or disease-specific survival. MCPyV-negative cases exhibited a shorter disease-specific survival than MCPyV-positive cases (median overall survival 13 months vs not reached; p=0.041). MCPyV-negative or combined MCCs were associated with a higher disease-specific mortality and poorer prognosis. MCCs occurring in sun-shielded sites, MCPyV-negativity, and combined tumours correlated with a higher disease-specific mortality and a poorer prognosis by multivariable Cox proportional hazard model. The occurrence of MCCs with arsenic exposure was also identified. Our study showed that MCPyV-negative MCC cases in Taiwan exhibited distinctive pathological features and a poorer outcome than MCPyV-related cases. We also confirmed an association of chronic arsenicism with MCC, which might be considered as the third pathogenetic factor after MCPyV and UV light. Further studies including epidemiological and genetic investigations are warranted to elucidate the pathogenesis of MCC in Taiwan, particularly the significance of chronic arsenicism.