p16 Overexpression Identifies HPV-positive Vulvar Squamous Cell Carcinomas

Abstract

Two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are considered non-HPV-associated. Recently, immunohistochemical detection of p16 and p53 has been proposed to differentiate these 2 types of VSCCs. We conducted a histologic study with immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerase chain reaction using 2 different sets of primers in 92 cases of VSCCs to evaluate the usefulness of immunohistochemistry in the classification of VSCCs and to describe the clinico-pathologic characteristics of both types of VSCCs. HPV was detected in 16/92 (17.4%) specimens, HPV16 being identified in 75% of positive cases. A significant number of discrepancies between histology and HPV detection were observed, with 37.5% of HPV-positive tumors being keratinizing and 9.2% of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100% and 6.2% of HPV-positive tumors and in 2.3% and 64.5% of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and of p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8% HPV-positive tumors, including 3 keratinizing tumors. All these cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6% of HPV-negative cases; 90.8% of them were positive for p53 but all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and negative tumors. In summary, the current morphologic criteria to discriminate HPV-positive and negative VSCCs have a significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSSCs, which improves the results of histologic classification.

HPV-Related Squamous Cell Carcinoma Variants in the Head and Neck

“…Carcinomas with papillary growth pattern are known to occur in the uterine cervix and other genital sites, including the penis, vagina, and vulva [19][20][21][22]. Several morphologic patterns are described, including PSCC, warty (condylomatous) SCC, and VC.…”

Vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma: a clinicopathologic study of 18 cases

“…In addition, there is increase in the risk of squamous neoplasia, particularly of cervix and other parts of lower genital tract. The patients in this group appear to have a better prognosis than the group of patients with ISCC unrelated to HPV [1,2,9].…”

“…The first group is the type seen in young age groups (35-65 years old) and is associated with HPV, and the second group is the type seen mostly in older women (55-85 years old), is unrelated to HPV, and has different etiological factors [1,2,9].…”

“…The patients in this group typically develop a conventional (keratinizing) type ISCC associated with lichen sclerosis (LS) and squamous hyperplasia (SCH), and recent studies have shown the relationship with differentiated (simplex) VIN. Moreover, mutation in p53 tumor suppressing gene has often been observed [1,2,10,11].…”

“…Based on histological observations, approximately 90 % of all primary malign carcinomas of the vulvar tumors are invasive squamous cell carcinoma (ISCC) [1,2]. According to the currently popular classification system, vulvar invasive squamous cell carcinoma (ISCCV) is divided into 3 main histological groups; basaloid, warty and keratinizing ('conventional' or 'typical' keratinizing) types [1,3,4].…”