Exploring Molecular Characteristics and Therapeutic Strategies for Primary Sinonasal Mucosal Melanoma with Distant Metastasis.

Sinonasal mucosal melanoma (SNMM) is a rare aggressive malignancy of the sinonasal tract. Due to its advanced clinical presentation and frequent late-stage diagnosis, the 5-year survival rate is less than 30%, with an even worse prognosis in patients with distant metastasis (SNMM-M). Therefore, characterizing the molecular landscape of SNMM may provide novel therapeutic targets for SNMM-M. This study aims to decipher the histopathological and molecular landscape of SNMM-M and yields novel insights into potential therapeutic approaches using targeted DNA and RNA next generation sequencing, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). SNMM-M cases were characterized by epithelioid-predominant morphology, frequent tumor necrosis, minimal pleomorphism and sparse tumor-infiltrating lymphocytes (TILs). A significant association between absence of brisk TILs and metastasis in SNMM was noted. Moreover, the presence of LVI and absence of brisk TILs were both significantly associated with poorer overall survival in SNMM patients. Both DNA and RNA sequencing identified no gene fusions, while DNA sequencing revealed 304 genomic alterations across 186 genes, including 9 multi-hit genes. Notably, missense mutations in structure-specific endonuclease subunit (SLX4), a key homologous recombination repair (HRR) scaffold protein, were exclusively detected in SNMM-M and patients with SLX4 mutations exhibited significantly worse survival (median: 9.9 vs. 41.2 months without SLX4 mutations, P < 0.0001). A comparative analysis of genomic alterations and copy number variations of clinically actionable genes between SNMM-M and SNMM-nM revealed that CDK4 gains/amplifications were commonly seen in SNMM-M cases, while receptor tyrosine kinase and HRR gene alterations were highly enriched in SNMM-nM cases. Additionally, PD-L1 was more commonly expressed in SNMM-nM. These exploratory findings suggest that SLX4 mutation may serve as a potential prognostic biomarker and that CDK4 inhibitors could represent promising therapeutic options for SNMM-M. However, given the limited sample size, further validation in larger studies is essential to confirm these findings.