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

Abstract

Naevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog (SHH) pathway and is characterised by early onset of multiple basal cell carcinomas (BCCs). Although skin tumours 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. A total of 140 skin tumours from NBCCS and 140 control BCC tumours 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 for immunohistochemical and molecular analysis. Thirty-three tumours among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were as follows: a small size (<1.5 mm), connection to a hair follicle, arborescent organoid architecture, lack of cytological atypia and 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 tumours to BCC. Our study confirms the high prevalence of BFH, representing up to 24% of skin tumours in NBCCS and potentially being BCC precursors.

Keywords: Gorlin syndrome; Sonic Hedgehog; basal cell carcinoma; basaloid follicular hamartoma; naevoid basal cell carcinoma syndrome.