Sun-Exposed vs. Non-Sun-Exposed Areas: Epidemiology and Pathogenesis of Non-Metastatic Merkel Cell Carcinoma

<b>Background:</b> Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy. The prognostic impact of sun exposure at the primary tumor site in localized and locally advanced MCC remains incompletely defined. We aimed to compare clinicopathologic characteristics and survival outcomes between sun-exposed and non-sun-exposed MCC in a large, multi-center Israeli cohort. <b>Methods:</b> We retrospectively identified 249 patients diagnosed with localized or locally advanced MCC between January 1985 and December 2020. Of these, 225 patients met eligibility criteria and were included in the analysis: 142 with sun-exposed primary tumors (cohort A) and 83 with non-sun-exposed tumors (cohort B). Baseline characteristics included age, sex, tumor size, lymph node (LN) involvement at diagnosis, disease-free survival (DFS), and overall survival (OS). <b>Results:</b> Median age at diagnosis was similar between cohorts (~73 years), with a male predominance in both groups. LN involvement was significantly more frequent in non-sun-exposed tumors compared with sun-exposed tumors (57.0% vs. 30.0%, <i>p</i> < 0.001), while tumor size distribution did not differ significantly. Median DFS was numerically longer in sun-exposed patients (58.0 vs. 47.8 months, <i>p</i> ≈ 0.18), whereas median OS favored non-sun-exposed patients (89.7 vs. 79.7 months, <i>p</i> ≈ 0.21), though neither difference reached statistical significance overall. Females demonstrated longer DFS and OS than males across both cohorts. Among LN-negative patients, non-sun-exposed tumors were associated with significantly improved OS (105.9 vs. 91.4 months, <i>p</i> ≈ 0.03), particularly in males. Primary tumor size further stratified outcomes: non-sun-exposed patients had significantly superior OS for tumors <2 cm and both improved DFS and OS for tumors ≥2 cm. <b>Conclusions:</b> In this large real-world MCC cohort, sun exposure status was associated with distinct patterns of nodal involvement and survival in clinically relevant subgroups. Non-sun-exposed MCC demonstrated favorable survival outcomes, particularly in LN-negative disease and across tumor size categories, suggesting underlying biological differences that merit further investigation.