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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Semin Diagn Pathol. 2020 Sep 25;38(1):50–61. doi: 10.1053/j.semdp.2020.09.010

Figure 2.

Figure 2.

Overview of the multistage, stepwise evolution of HPV-unrelated vulvar squamous cell carcinoma (VSCC). The HPV-independent pathway often, but not always, starts with lichen sclerosus, which can develop into differentiated vulvar intraepithelial neoplasia (dVIN), which is thought to be the precursor of HPV-unrelated VSCC. Genome-wide analysis has provided genetic and epigenetic evidence for a clonal relationship between lichen sclerosus, dVIN, and HPV-unrelated VSCC. TP53 somatic mutation and CDKN2A promoter methylation have been observed in all three lesions. Additional genetic (for example, somatic mutations of CDKN2A, NOTCH1, and HRAS) and epigenetic alterations (for example, promoter methylation of MGMT, RASSF2A, RARβ and IRF6) acquired in the each step facilitate the oncogenic process.