A Novel Staging Model for Uveal Melanoma: Combining Tumor Volume, Clinical Factors, and Genetic Alterations in a Danish Cohort.

Importance: Uveal melanoma classification systems based on anatomical location show limitations in risk stratification and create ambiguities when tumors span multiple uveal regions.

Objective: To develop a comprehensive staging system for uveal melanoma integrating tumor volume, clinical factors, and genetic alterations that resolves classification challenges while improving risk stratification.

Design, setting, and participants: Nationwide retrospective cohort study of 3,696 patients diagnosed with uveal melanoma in Denmark from 1943 to 2022, including 3,062 choroidal melanomas, 245 ciliary body melanomas, and 389 iris melanomas.

Main outcomes and measures: Disease-specific survival was analyzed using volume-based tumor categories (T0-T5), clinical risk factors (ciliary body involvement and extraocular extension), and genetic alterations (chromosome 3 and 8q status) to develop an integrated staging system (S0-S6) with genetic enhancement (GS1-GS6).

Results: Tumor volume demonstrated strong risk stratification, with T0 tumors (<12 mm³) showing 0% mortality throughout follow-up while 20-year mortality progressively increased from T1 (23%) to T5 (63%). The integrated staging system (S0-S6) showed excellent discrimination with 5-year mortality ranging from 0% (S0) to 54% (S6). Iris melanomas demonstrated distinct survival patterns, with non-ring configurations showing minimal mortality (0.5% at 20 years) compared to ring melanomas (21%). Genetic analysis revealed that chromosome aberrations, particularly combined monosomy 3 and 8q-gain (HR 12.6, 95% CI 5.5-29.4), carried stronger prognostic weight than conventional staging parameters, with genetic-enhanced staging providing superior risk stratification (10-year mortality: 0% for GS1 to 77% for GS6).

Conclusions and relevance: Tumor volume represents a powerful risk stratifier for uveal melanoma that can be effectively integrated with clinical risk factors and genetic markers to create a refined staging system. The proposed unified approach incorporating volume-based categorization, clinical factors, and genetic status addresses current classification ambiguities and reflects the distinct natural histories of uveal melanoma subtypes. A practical scoring sheet is provided for clinical implementation of this staging system.