Update in the Molecular Pathogenesis of Sebaceous Carcinoma

Sebaceous carcinoma is an uncommon but potentially aggressive adnexal malignancy whose molecular pathogenesis has been substantially clarified in recent years. Rather than representing a single molecular entity, sebaceous carcinoma is now understood as a biologically heterogeneous group of tumors arising through distinct yet sometimes overlapping oncogenic pathways. Recent genomic and multi-omics studies have identified several major molecular subsets, including mismatch repair-deficient (dMMR)/microsatellite instability (MSI)-associated tumors, ultraviolet (UV) radiation-driven tumors, and pauci-mutational tumors characterized predominantly by alterations in cell-cycle and epithelial differentiation regulators such as TP53, RB1, and ZNF750. These findings have also reinforced biologically relevant differences between ocular and extraocular sebaceous carcinoma, with periocular tumors more often enriched for TP53/RB1/ZNF750-driven mechanisms and extraocular tumors more frequently showing UV-related and dMMR signatures. In addition to these core pathways, recent evidence has highlighted the contribution of NOTCH signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway alterations, copy-number changes including MYC amplification, rare human papillomavirus (HPV)-associated cases, and emerging transcriptomic abnormalities involving cholesterol metabolism and sebaceous differentiation programs. These advances not only deepen current understanding of sebaceous carcinoma biology but also have important diagnostic, prognostic, and therapeutic implications, particularly in relation to Lynch/Muir–Torre syndrome screening, molecular subclassification, and the potential use of immune checkpoint inhibitors and other targeted strategies in selected patients. This review provides an updated overview of the molecular pathogenesis of sebaceous carcinoma, focusing on the main genomic, transcriptomic, and biologically actionable alterations described to date, and discusses their implications for tumor classification, pathogenesis, and future translational research.