Anal cancer is among the most prevalent neoplasias in HIV-infected MSM. Screening with anal citology results yields to high rates of false positive results and elevated burden of high-resolution anoscopies (HRA) with anal biopsies. High risk HPV up-regulate p16 expression and increase proliferation (Ki67 expression) in epithelial cells. We assessed the usefulness of P16/Ki-67 dual staining cytology for the diagnosis of precancerous anal lesions.
Prospective multi-center cohort study in 6 HIV clinics. Concomitant anal liquid cytology with p16/Ki-67 dual staining (CINtec® PLUS, Roche) and HRA with biopsy of acetowhite lugol-negative lesions was performed. We compared the diagnostic performance of an abnormal anal cytology (atypical squamous cells [ASC], LSIL or HSIL) and p16/Ki-67 dual positivity relative to HRA-guided biopsy. We calculated the independent predictive values of anal cytology and p16/Ki-67 positivity in multivariate logistic regression models adjusted by potential confounders.
A total of 328 HIV-infected MSM underwent 386 full examinations. Mean age was 39±10 years, median nadir CD4 367 (258-510) cells/uL, 57% had detectable plasma HIV RNA and 30% reported unprotected anal sex in the prior 3 months. Sixty-three % of anal cytologies were abnormal: 24(6.2%) ASC, 143(37%) LSIL and 74(19.2%) HSIL. HSIL was histologically diagnosed in 80 subjects (24.1%), and 2 (0.6%) were diagnosed with anal cancer, in whom the cytology had showed LSIL and HSIL, respectively. An abnormal citology showed the following statistics for the diagnosis of biopsy proven HSIL: sensitivity 95.6% (CI95%, 91.2-99.9), specificity 58.8% (CI95%, 52.2-65.4), positive predictive value 39.8% (CI95%, 33.2-46.4), negative predictive value 95.8% (CI95%, 91.6-99.9). P16/Ki67 dual positivity was not associated with higher rates of biopsy-proven HSIL (Table 1). After adjustment by potential confounders (age, nadir CD4, detectable HIV RNA, tobacco use), an abnormal anal citology, but not a positive P16/Ki67 stain, was an independent predictor of HSIL (OR, 12.1; CI95% 3.5-41.3 and OR, 1.2; CI95% 0.6-2.5, respectively).
P16/Ki67 dual staining does not improve the diagnostic accuracy of anal cytology, which shows a high sensitivity yet poor specificity. Other approaches aimed at improving the diagnostic accuracy of current techniques for the diagnostic of precancerous anal lesions are warranted.