BackgroundPap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing.MethodsA total of 27349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined.ResultsThe p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001).ConclusionsThe p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.

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Two distinct types of vulvar squamous cell carcinomas and their precursors, vulvar intraepithelial neoplasias (VIN), which differ in terms of clinical presentation and behavior, have been delineated. Human papillomavirus (HPV)-associated carcinomas are of basaloid or warty type, whereas tumors unrelated to HPV are usually keratinizing and differentiated. Thus, the major stratifying factor for vulvar carcinomas and VIN is their etiopathogenetic relationship with HPV. However, because of technical difficulties in confidently detecting HPV in tissues, this diagnosis is usually based on purely morphologic criteria, even though some overlap exists between these histologic types. Recently, the tumor suppressor protein p16 has been shown to be specifically overexpressed in HPV-related carcinomas and premalignant lesions of the uterine cervix, oral cavity, and anus, but the presence of p16 vulvar squamous lesions has not been examined. We have evaluated the immunohistochemical expression of p16 in a series of formalin-fixed, paraffin-embedded vulvar carcinomas and their putative precursors. p16 was strongly positive in all cases of basaloid/condylomatous VIN3 (30/30) and basaloid (7/7) and warty (3/3) carcinomas. In contrast, p16 was almost consistently negative in normal skin, squamous cell hyperplasia (0/20), lichen sclerosus (0/19), differentiated (simplex) VIN3 (0/11), verrucous carcinoma (0/2), and keratinizing squamous cell carcinoma (3/33, 9%). One of the keratinizing squamous cell carcinomas positive for p16 occurred in a 25-year-old woman and the other two were associated with small foci of basaloid VIN3 adjacent to the tumor, suggesting a probable relationship with HPV. p16 was positive in 6 of 10 of basal cell carcinomas. In conclusion, p16 immunostaining is a good discriminator between HPV-associated and HPV-unrelated vulvar carcinomas and VIN, although it cannot differentiate basaloid squamous and basal cell carcinoma.