Track

Clinical Studies

Abstract

Sebaceous carcinoma (SC) is a rare but aggressive malignancy commonly seen in the periocular region but also occurs extra-ocularly.  Surgery is the primary treatment; but effective systemic therapies are deficient due to poor understanding of molecular alterations driving SC. A retrospective review of pathology archives over three years identified seven patients with nine lesions of SC. Clinical, histopathological and immunohistochemical findings were documented. Molecular testing encompassed next-generation sequencing, copy-number and targeted analysis. The clinical presentation varied from localized-nodular to diffuse-infiltrative masses. Histopathology ranged from well-differentiated tumors with prominent sebaceous differentiation to poorly differentiated lesions. MMR protein identified loss of expression in a subset of cases, correlating with Muir-Torre syndrome on genetic testing. Recurrent mutations in NOTCH1 and NOTCH2 were observed, suggesting potential sensitivity to pan-NOTCH inhibitors. PIK3R1 and PIK3CA mutations implicated PI3K/AKT pathway dysregulation, offering a rationale for PI3K inhibitors in select cases. This study highlights unreported genes in SC, including ARID1A, SMARCA4, and KMT2D (MLL2), which are associated with other malignancies but may contribute to chromatin remodeling defects in SC. FLCN mutations, linked to Birt-Hogg-Dubé syndrome, were detected, implicating mTOR pathway dysregulation and potential therapeutic vulnerability to mTOR inhibitors. Furthermore, RNF43 alterations, known to activate WNT signaling, and BRCA2 mutations which confer sensitivity to PARP inhibitors were observed. Detection of AR and FGFR2 mutations expands the repertoire of actionable targets, including anti-androgen therapies and FGFR inhibitors. This study highlights clinical, histopathological, immunohistochemical, and molecular diversity of SC emphasizing the importance of a comprehensive diagnostic approach and