Re-evaluation of the concept of basaloid follicular hamartoma associated with naevoid basal cell carcinoma syndrome: a morphological, immunohistochemical and molecular study

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog pathway (SHH) and characterized by early onset of multiple basal cell carcinoma (BCC). Although skin tumors with follicular differentiation notably basaloid follicular hamartoma (BFH) have been reported in NBCCS, their relations with BCC are poorly defined. In this context, the aim of this study was to clarify morphological, immunohistochemical and molecular features of BFH arising in a context of NBCCS.140 skin tumors from NBCCS and 140 control BCC tumors were reviewed blinded to clinical data and classified as BCC or BFH. The morphological characteristics of these two groups were then compared. Twenty cases were submitted to immunohistochemical and molecular analysis.Thirty-three tumors among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were: a small size (<1.5mm), connection to a hair follicle, arborescent organoid architecture, lack of cytologic atypia, infundibulocystic differentiation. Immunohistochemical analysis confirmed activation of the SHH pathway in these lesions. Targeted next-generation sequencing suggested that MYCN and GLI2/3 amplifications and TP53 mutations might be involved in progression of these follicular tumors to BCC.Our study confirms the high prevalence of BFH representing up to 24% of skin tumors in NBCCS and potentially being BCC precursors.