Squamous Cell Carcinoma of the Vulva: A Subclassification of 97 Cases by Clinicopathologic, Immunohistochemical, and Molecular Features (p16, p53, and EGFR)Dong, Fei MD*; Kojiro, Sakiko MD*; Borger, Darrell R. PhD*; Growdon, Whitfield B. MD†; Oliva, Esther MD*American Journal of Surgical Pathology: August 2015 - Volume 39 - Issue 8 - p 1045–1053 doi: 10.1097/PAS.0000000000000454 Original Articles Abstract Author Information Squamous cell carcinomas (SCCs) of the vulva develop through human papilloma virus (HPV)-associated or HPV-independent pathways, but the relationship between pathogenesis, classification, and prognosis of these tumors is controversial. Therefore, we review the morphology, immunophenotype, and select molecular features of a consecutive series of 97 patients with vulvar SCC with a median clinical follow-up of 3.6 years. Tumors were histologically classified as basaloid (13), warty (11), mixed basaloid and warty (1), keratinizing (68), nonkeratinizing (3), and sarcomatoid (1). Diffuse p16 expression was associated with younger age at presentation (P<0.0001), basaloid and warty carcinoma subtypes (P<0.0001), and usual vulvar intraepithelial neoplasia (P<0.0001) and was negatively associated with p53 immunopositivity (P=0.0008). Five keratinizing SCCs showed p16 and p53 coexpression, but only 1 was positive for high-risk HPV by in situ hybridization. Among 8 of 36 tumors with EGFR gene amplification, 4 were p53 positive but none p16 positive. In a Cox regression model, early clinical stage (P<0.006), p16 expression (P=0.002), and absent p53 expression (P=0.02) were independent predictors of improved overall survival. These findings utilize morphologic and immunohistochemical analysis to support HPV-associated and HPV-independent pathogenesis of vulvar SCCs and support p16 and p53 immunohistochemistry as markers of disease biology and clinical outcome. Departments of *Pathology †Obstetrics and Gynecology, Massachusetts General Hospital, Boston F.D. and S.K. contributed equally. 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: Esther Oliva, MD, Department of Anatomical Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: firstname.lastname@example.org). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.