Original ArticlesHPV-independent Precursors Mimicking High-grade Squamous Intraepithelial Lesions (HSIL) of the VulvaRakislova, Natalia MD, PhD*; Alemany, Laia MD, PhD†,‡; Clavero, Omar MD†,‡; del Pino, Marta MD, PhD§; Saco, Adela MD, PhD*; Marimon, Lorena BSc*; Quirós, Beatriz BSc†,‡; Lloveras, Belen MD, PhD∥; Ribera-Cortada, Inmaculada MD, PhD*; Alejo, Maria MD, PhD¶; Pawlita, Michael MD#; Quint, Wim MD, PhD**; de Sanjose, Silvia MD, PhD†,‡; Ordi, Jaume MD, PhD*,‡; On Behalf of VVAP Study GroupAuthor Information *Department of Pathology, Barcelona Institute of Global Health (ISGlobal), Hospital Clínic—University of Barcelona ‡Public Research Consortium of Epidemiology and Public Health (CIBER) §Institute of Gynecology, Obstetrics and Neonatology, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Faculty of Medicine, University of Barcelona ∥Department of Pathology, Hospital Mar, Barcelona †Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, IDIBELL ¶Department of Pathology, General Hospital of Hospitalet, L’Hospitalet de Llobregat, Spain #Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany **DDL Diagnostic Laboratory, Rijswijk, The Netherlands Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jaume Ordi, MD, PhD, Department of Pathology, ISGlobal, Hospital Clínic—Universitat de Barcelona, Barcelona 08036, Spain (e-mail: [email protected]). The American Journal of Surgical Pathology: November 2020 - Volume 44 - Issue 11 - p 1506-1514 doi: 10.1097/PAS.0000000000001540 Buy Metrics Abstract Two etiopathogenic types of vulvar squamous cell carcinoma (VSCC) have been described: human papillomavirus (HPV)-associated and HPV-independent. Precursor lesions, frequently identified in the adjacent skin, are also distinct in the 2 types of VSCC: high-grade squamous intraepithelial lesions (HSILs) in HPV-associated VSCC and differentiated vulvar intraepithelial neoplasia (dVIN) or vulvar acanthosis with altered differentiation in HPV-independent VSCC. Although HPV-independent precursors mimicking HSIL have been described in the vulva, their frequency and morphologic spectrum have not been completely characterized. We explored, in a large series of HPV-independent VSSC, the frequency and the histologic features of precursors mimicking HSIL. We included 779 DNA HPV-negative/p16-negative VSCC with at least 1 cm of adjacent skin. We evaluated the histologic and immunohistochemical (p16 and p53) characteristics of the intraepithelial lesions, focusing on precursors mimicking HPV-associated vulvar HSIL. A total of 254 tumors (33%) had adjacent premalignant lesions. Of them, 186 (73%) had dVIN, 22 (9%) had vulvar acanthosis with altered differentiation, and 46 (18%) had lesions that mimicked HSIL. The mean age of the patients with these HSIL-like lesions was 72±15 years. Twenty-six of these HSIL-like lesions had basaloid morphology, 13 warty, and 7 mixed basaloid/warty features. All the HSIL-like precursors were DNA HPV-negative/p16-negative; 74% of them showed p53 abnormal staining and 35% of them had areas of conventional dVIN. In conclusion, about one fifth of the HPV-independent precursors mimic HSIL, showing either basaloid or warty features. Older age and the presence of areas of typical HPV-independent intraepithelial lesions, together with p16 negativity, should raise suspicion of an HPV-independent etiology. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.