Most human papillomavirus (HPV)-associated vulvar squamous cell
carcinomas (VSCCs) originate from high-grade squamous
intraepithelial lesions, also named usual type vulvar
intraepithelial neoplasia. However, growing evidence suggests
that morphologic studies have limitations in predicting HPV
status in vulvar lesions. We aimed to evaluate adjacent
intraepithelial lesions in a series of DNA HPV-positive VSCCs,
focusing on unusual histologic patterns mimicking differentiated
vulvar intraepithelial neoplasia (dVIN) or lichen sclerosus
(LS). We identified 326 DNA HPV-positive VSCC with at least 1 cm
of skin adjacent to the invasive tumor and analyzed HPV typing,
HPV E6*I mRNA, and p16 immunohistochemistry in all cases. A
careful histologic evaluation was conducted. A conclusive
association with HPV was based on a positive p16 or HPV E6*I
mRNA result or both in addition to the HPV DNA, whereas cases
negative for both markers were classified as nonconclusively
associated with HPV. One hundred twenty-one tumors (37.1%) had
normal adjacent skin, 191 (58.6%) had only high-grade squamous
intraepithelial lesions, also named usual type vulvar
intraepithelial neoplasia, and unusual intraepithelial lesions
were identified in 14 (4.3%) tumors. Seven cases showed
dVIN-like features, 5 showed adjacent LS-like lesion, and in 2
cases dVIN-like and LS-like lesions were identified
simultaneously. Six of them were conclusively associated with
HPV (3 dVIN-like, 2 LS-like, 1 with combined dVIN/LS-like
features). All 6 tumors were associated with HPV16 and were
positive for both p16 and HPV mRNA, and p16 was also positive in
the dVIN-like and LS-like lesions. In summary, a small subset of
VSCCs conclusively associated with HPV may arise on
intraepithelial lesions, mimicking precursors of HPV-independent
VSCC