{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:08:33Z","timestamp":1779167313356,"version":"3.51.4"},"reference-count":81,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence for the further separation of HPV-independent into p53 abnormal and p53 wild-type cancers. Although the diagnosis and subclassification of VSCC is often straightforward, using immunohistochemical markers such as p16 and p53 as surrogate markers for high-risk HPV infection and TP53 mutation respectively, rare and unusual scenarios exist that can complicate VSCC classification. Herein we discuss these challenging scenarios in VSCC classification, as well as emerging VSCC prognostic biomarkers such as cyclin D1. In addition, the pathologic diagnosis of VSCC precursor lesions, particularly those of HPV-independent type, are frequently challenging to distinguish from benign conditions of the vulva. We discuss the recent literature describing the added diagnostic value of immunohistochemical biomarkers p53, CK17, CK13, SOX2, GATA3, GLUT1 and others, which may be particularly helpful when morphology is inconclusive. It is anticipated that with improved VSCC classification and precursor recognition, avenues for more tailored therapeutic strategies and earlier therapeutic intervention can be achieved.<\/jats:p>","DOI":"10.3390\/cancers18101518","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:14:16Z","timestamp":1778530456000},"page":"1518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Squamous Cancers and Precancers of the Vulva: Emerging Diagnostic, Prognostic and Predictive Biomarkers in Pathology"],"prefix":"10.3390","volume":"18","author":[{"given":"Somayah","family":"Alsolami","sequence":"first","affiliation":[{"name":"Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Laboratory Medicine, Department of Pathology, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Ji","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC V5Z 1M9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn","family":"Hoang","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC V5Z 1M9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. 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