Time trends in prevalence of p16 positivity and combined HPV/p16 positivity in a large cohort of Danish vulvar cancer patients

Abstract

Vulvar cancer is rare, but causes substantial morbidity in affected patients. A subset of vulvar cancers is caused by high-risk human papillomavirus (hrHPV), which primarily exerts its oncogenic effect through upregulation of tumor suppressor protein p16.Tumors positive for both hrHPV and p16 (double positive) are assumed to be HPV-driven, but only few large studies have investigated the combined prevalence of hrHPV and p16 positivity in vulvar cancer over time. In this Danish cross-sectional study, we assessed the prevalence of p16 positivity and double positivity for hrHPV and p16 in a large sample of vulvar squamous cell carcinomas (VSCCs) diagnosed during 1990 to 2017. In a nationwide register, we identified VSCCs from 13 hospitals across Denmark, and collected archival tumor tissue for hrHPV testing with INNO-LiPA and immunohistochemical p16 staining. We calculated the prevalence of hrHPV, p16 positivity and double positivity according to time, age and histological Abbreviations: 4v, four-valent; 9v, nine-valent; EAPC, estimated annual percentage change; FFPE, formalin-fixed paraffin-embedded; H&E, hematoxylin and eosin; HPV, human papillomavirus; hrHPV, high-risk human papillomavirus; IHC, immunohistochemical; NOS, not otherwise specified; pRb, retinoblastoma protein; VSCC, vulvar squamous cell carcinoma.

Time trends in human papillomavirus prevalence and genotype distribution in vulvar carcinoma in Norway

“…As observed in our data, this increase was especially pronounced in younger women (>60 years of age). However, the authors recently investigated p16 mutational status in addition to HPV DNA detection in the same population, reporting an overall prevalence of 31% truly HPV‐driven (positive for both hrHPV and p16) vulvar carcinomas and an increase from 24.5% to 35.7% from 1990–1993 to 2014–2017 28 . The lack of p16 immunohistochemistry in our present study might have led to an overestimation of the true proportion of HPV‐driven cancers.…”

“…However, the authors recently investigated p16 mutational status in addition to HPV DNA detection in the same population, reporting an overall prevalence of 31% truly HPV-driven (positive for both hrHPV and p16) vulvar carcinomas and an increase from 24.5% to 35.7% from 1990-1993 to 2014-2017. 28 The lack of p16 immunohistochemistry in our present study might have led to an overestimation of the true proportion of HPV-driven cancers. Another recent report from New Zealand found a highly significant increase from 25.9% in 1990-1995 to 46.7% in 2011-2016.…”

PD‐L1 expression in vulvar cancer: a systematic review and meta‐analysis

“…Immunohistochemical p16 staining is a reliable surrogate marker for HPV 7 . However, combined assessment of both p16 and HPV DNA or RNA seems to be the optimal method for classifying vulvar SCC according to HPV, 7,8 and this was done by three studies 24,29,34 . Only one study used p53 wildtype immunohistochemical staining to identify HPV‐associated vulvar SCC 22 based on the rationale that p53 staining is a surrogate test for TP53 mutation and that TP53 mutations are rare in HPV‐associated VSSC 6 .…”

“…7 HPVassociated vulvar SCC accounts for 20-40% of vulvar SCC and most often arises in younger women. 8,9 HPV-negative vulvar SCC usually arises in older women with a history of lichen sclerosus and most cases harbour TP53 mutations. 6 The vulvar cancer prognosis is strongly associated with the stage of disease.…”

“…Although the characteristic morphology of the two types of vulvar SCC differs, the most recent WHO classification recommend that HPV status is confirmed using molecular analysis or p16 immunohistochemistry 7 . HPV‐associated vulvar SCC accounts for 20–40% of vulvar SCC and most often arises in younger women 8,9 . HPV‐negative vulvar SCC usually arises in older women with a history of lichen sclerosus and most cases harbour TP53 mutations 6 …”