Improved screening for anal neoplasia by immunocytochemical detection of minichromosome maintenance proteins.

PURPOSE: Early detection of anal intraepithelial neoplasia (AIN) and anal squamous cell carcinoma (SCC) by screening will improve clinical outcome. Assessment of anal cytology samples using routine Papanicolaou testing suffers from shortcomings in sensitivity and/or specificity, suggesting that screening tests based on biomarkers may be of value. We tested the suitability in this context of minichromosome maintenance (MCM) proteins, accurate markers of the deregulated cell cycle entry that characterizes malignancy and premalignancy. EXPERIMENTAL DESIGN: We undertook an initial immunohistochemical study of 54 anal tissue samples and validated our findings using an independent prospective cohort study of 235 anal cytology samples from 144 subjects. RESULTS: In the progression from normal anal epithelium through AIN to SCC, there was increasing expression of MCM2 and MCM5, including in the superficial epithelial third, the source of the majority of cells collected by anal swab. The median labeling indices (LI) for MCM2 and MCM5 in the superficial third of AIN2/3 and SCCs combined were 90.2% and 84.0%, respectively. MCM LIs in the superficial layers were significantly greater than LIs for Ki67, an alternative marker of cell cycle entry (P<0.0001). By immunocytochemistry using a mixture of anti-MCM2 and anti-MCM5 antibodies, immunopositive cells were readily identified in anal cytology samples, even at low magnification. MCM testing showed sensitivity for AIN2/3 of 84% (95% confidence interval, 75,93) and for AIN1/viral changes of 76% (68, 84), with overall specificity (for any lesion) of 77% (64, 90). CONCLUSIONS: MCMs are promising biomarkers for improving detection of AIN and SCC in anal cytology samples.

Multifocal intraepithelial neoplasia and the psychological consequence of vulvectomy.

A 41-year-old female with significant psychiatric history presented with persistent vulvar lesions that were refractory to common clinic and home based wart therapies. Vulvoscopy directed biopsies confirmed invasive vulvar squamous cell carcinoma and further investigation revealed cervical and anal intraepithelial neoplasia in a patient who remained HIV negative with no other cause of immunosuppression detected other than smoking. Vulvectomy following cancer diagnosis lead to a relapse of her psychiatric illness and excessive alcohol intake. Her psychiatric illness in turn affected her further management and follow-up. This case highlights the need for the case based, medical, surgical, psychological and social considerations when managing persistent anogenital warts and anogenital neoplasia as well as the psychological impact of vulvectomy.

Performance of anal cytology in a clinical setting when measured against histology and high-resolution anoscopy findings.

OBJECTIVES: The success of cervical cytology in screening for cervical neoplasia has led to the concept of anal cytology screening for anal neoplasia. Our objective is to study the performance of anal cytology as a screening tool. DESIGN: We assessed anal cytology against histology and high-resolution anoscopy in a clinical setting. METHODS: Anal pap test was obtained prior to high-resolution anoscopy examinations and biopsies. The results were analysed against a number of patient variables. RESULTS: From 395 individuals (93% men), 584 anal pap tests were obtained. HIV status was positive in 212 (54%) and negative in 156 (39%) individuals. On the basis of 288 histology results, the sensitivity of anal cytology to detect disease was 70% [95% confidence interval (CI) 64-75], whereas the specificity was 67% (95% CI 38-88). For high-grade disease (anal intraepithelial neoplasia 2/3), sensitivity of anal cytology was 81% (95% CI 70-90), and the negative predictive value was 85% (95% CI 76-92). Sensitivity was dependent on the area of disease (86% for two or more quadrants vs. 69% for one or more quadrants, P = 0.002) and HIV positivity (76% in HIV positive vs. 59% in HIV negative, P = 0.009). Amongst HIV-positive patients, the sensitivity was 90% when CD4 cell count was 400 cells/microl or less compared with 67% when CD4 cell count was above 400 cells/microl (P = 0.005). CONCLUSION: Anal cytology performs similar to cervical cytology in a clinical setting. Sensitivity of anal smear is dependent on the area (quadrants) of disease present. Sensitivity of anal cytology is enhanced when CD4 cell count is less than 400 cells/microl in HIV-positive men. Our results may explain the variable sensitivity reported in the literature.