Tumor of Follicular Infundibulum Is Molecularly Distinct From Basal Cell Carcinoma

Tumor of follicular infundibulum (TFI) is a rare cutaneous lesion of unclear histogenesis. Various benign and malignant cutaneous neoplasms have been reported in association with TFI, including most commonly basal cell carcinoma (BCC). Indeed, some authors have suggested that TFI may represent a variant of BCC. Because BCC are well established to be driven by alterations in the Hedgehog signaling pathway, most often secondary to ultraviolet (UV)-induced mutagenesis, we undertook next-generation DNA sequencing of a cohort of TFI to determine their molecular relatedness to BCC. Four TFI cases were successfully sequenced, with 3 of the 4 patients being men, and a mean age at diagnosis of 57.8 years (range: 46-68 years). All 4 tumors were located on the face and showed typical histologic features of TFI, including a plate-like proliferation of bland keratinocytes with peripheral palisading and multiple points of connection to the epidermis. Two of the lesions were solitary and 2 occurred as part of eruptive TFI. No recurrences were reported. Molecular profiling failed to reveal Hedgehog pathway alterations, TP53 mutations, or a UV mutation signature in any case. In contrast, 3 cases demonstrated recurrent SLX4 mutations. In total, 18 unique mutations in 15 genes spanning an array of cellular functions including DNA repair and cell signaling were identified. Overall, the histomorphologic, clinical, and molecular features of TFI support its classification as a distinct and benign entity from BCC. In addition, the presence of recurrent SLX4 alterations suggests that TFI are likely not reactive but rather may represent a true neoplasm.