Clinicopathologic and Molecular Characterization of Basal Cell Carcinoma Arising at Sun-protected Sites

Abstract

Basal cell carcinomas (BCC) are driven primarily by cumulative ultraviolet (UV) radiation exposure resulting in activation of the Hedgehog (Hh) signaling pathway, often as a result of UV-mediated Patched-1 ( PTCH1) gene inactivation. Accordingly, BCCs most commonly arise at sun-exposed sites such as the head and neck. Very rarely, BCCs can arise at sun-protected sites such as the genital skin and perianal area. This can pose significant diagnostic challenges not only due to the rarity of BCC at these sites but also due to the potential morphologic overlap with other entities such as basaloid squamous cell carcinoma, trichoblastic carcinoma, and even benign neoplasms such as trichoblastomas. Hh pathway alterations have not yet been described in BCCs arising at genital and perianal sites, and the role of UV radiation is uncertain at these anatomic locations. To address this ambiguity, we report the clinicopathologic features of a cohort of 14 BCCs arising at sun-protected sites (perianal n=7, vulva n=4, scrotum n=3). Furthermore, we use a next-generation DNA sequencing platform to investigate their pathogenesis and compare it to that of a cohort of 8 BCCs arising on sun-exposed skin. We find that BCCs arising on sun-protected sites display a spectrum of morphologic patterns, rarely recur, and do not metastasize. Both sun-protected and sun-exposed BCCs are characterized by recurrent PTCH1 alterations (93% and 100% of cases, respectively), supporting the classification of the tumors arising at sun-protected sites as bona fide BCCs. Notably, in contrast to conventional BCCs, none of the sun-protected BCCs harbored a UV mutation signature, suggesting an alternative mechanism of mutagenesis. Furthermore, the presence of upstream Hh pathway alterations in sun-protected BCCs supports their susceptibility to Hh pathway inhibitors such as vismodegib and sonidegib.

FIGURE 1.

Morphologic features of sun-protected BCC. A, Common architectural patterns of sun-protected BCC included nodular types as seen in this vulvar BCC. B, Infiltrative architecture was also seen. C, Typical morphologic features commonly found in sun-protected BCCs including peripheral palisading, mucin production and clefting were present. D, Tumors showed basaloid epithelial proliferations with scattered mitoses (arrow) and some areas of necrosis. E, Squamoid differentiation was present in 4 cases. F, Hedgehog pathway alterations were not identified in case 8, but it displayed classic morphologic features of BCC including a nodular proliferation of basaloid cells with clefting, mucin production and a fibromyxoid stroma.

FIGURE 2.

Summary of genomic landscape of sun-protected BCC. An Oncoprint illustrates the most significant alterations in the sun-protected BCC cases. The genes of interest are listed on the right-hand side, and the cases are arranged from left to right (case 1 to 14). The key to the right of the figure highlights the alterations as follows: in-frame mutation (brown box), missense mutation (light green or dark green box), splice mutation (orange box), truncating mutation (black box), amplification (red box), shallow deletion (turquoise box), loss of heterozygosity (yellow box), biallelic inactivation (purple outline), no alteration (gray box). For simplicity, low-level copy number alterations are not shown. The amplification events shown include: MYC amplification (30 copies), CCND2 amplification (42 copies), TERT amplification (13 copies), MDM2 amplification (13 copies).