Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma

Abstract

<jats:p>Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.</jats:p>

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

“…In this study, we also investigated the molecular profile of a subset of dVIN and de-VIL, with a view to facilitate the identification of other potential diagnostic markers. In dVIN, TP53 and CDKN2A mutations were detected most frequently, in line with previous reports [ 47 , 54 , 55 , 56 , 57 , 58 , 59 ]. Interestingly, TP53 mutations were also detected in de-VIL, and dVIN that showed wild-type-expression on p53-IHC.…”

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging—observations from a bi-national ring-study

“…In this study, we also correlated the histological consensus diagnoses with the immunohistochemical expression of p53, as this marker is commonly used to aid the diagnosis of dVIN. p53-mutant patterns have been reported to accurately reflect underlying TP53 mutations, which characterize dVIN [ 19 , 20 , 32 ]. Substantial concordance of p53-IHC patterns with the histological consensus diagnoses was recorded, which confirms that routine use of this marker can improve the diagnostic accuracy for dVIN.…”

Molecular Landscape of Vulvar Squamous Cell Carcinoma

“…One study evaluated the molecular profiles in primary and metastatic VSCC in a subset of cases [29]. Eight studies (57%) analyzed only somatic mutations [25,28,[30][31][32][33][34][35], two studies (14%) focused only on copy number alterations [36,37], and four (28%) included both somatic mutation profiling and analysis of copy number alterations [27,29,38,39]. Twelve studies (86%) applied NGS.…”

“…Three series [28,33,38] have identified statistical differences in TP53 alterations depending on the HPV status and four [25,29,31,39] have shown a tendency in TP53 enrichment in HPV-independent VSCC, often combined with CDKN2A alterations. Two studies, both conducted by the same group [30,34], have not shown any differences for TP53 or CDKN2A mutations based on HPV status. In 2017, Watkins et al [27] showed a significant increase of PIK3CA mutations in DEVIL lesions, described as an HPV-negative precursor.…”