Immunohistochemical and molecular profiling of uveal melanoma: clinicopathological correlations from an Italian cohort

Objective. Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, characterized by distinct histopathological and molecular features and often associated with poor prognosis due to its high metastatic potential. While histology, BAP1 status, and chromosomal changes are established prognostic markers, integration of morphological, immunophenotypic, and molecular data is evolving. Methods. We retrospectively analyzed 84 UM cases from a single institution using an integrated approach combining histological classification, immunohistochemical profiling, and targeted next-generation sequencing with a 63-gene panel. Tissue microarrays were used for immunophenotyping, and mutation data were stratified by prognostic outcomes. Results. Most tumors were localized to the choroid and predominantly exhibited spindle-cell morphology. Mutations in GNAQ or GNA11 were identified in 83% of sequenced cases. Loss of BAP1 expression correlated with epithelioid histology and denser T-cell infiltration yet lacked PD-L1 expression. Aberrant p53 staining was more frequent in spindle-cell tumors, though TP53 mutations were rare, suggesting functional inactivation through other mechanisms. Notably, mutations typically associated with cutaneous melanomas (e.g., BRAF, KIT, CDKN2A) were also detected, particularly in a single iris melanoma, suggesting site-specific molecular convergence. Additional recurrent alterations were found in NOTCH1, PTEN, PIK3CA, and KDR, implicating the mTOR and VEGF signaling pathways. A high mutational burden, along with mutations in genes such as H3F3A, IDH2, JAK3, and ESR1, was more frequent in tumors with poorer prognosis, supporting their potential role in disease aggressiveness. Conclusions. This study highlights the heterogeneous molecular landscape of UM and underscores the importance of integrating histopathological and molecular data for improved prognostic stratification. The identification of potential therapeutic targets and atypical mutations typically associated with other melanoma subtypes suggests avenues for future research and tailored therapeutic strategies.