Automated Evaluation of p16/Ki-67 Dual-Stain Cytology as a Biomarker for Detection of Anal Precancer in Men Who Have Sex With Men and Are Living With Human Immunodeficiency Virus

Abstract

Background Human papillomavirus (HPV)-related biomarkers such as p16/Ki-67 “dual stain” (DS) cytology have shown promising clinical performance for anal cancer screening. Here, we assessed the performance of automated evaluation of DS cytology to detect anal precancer in men who have sex with men (MSM) living with human immunodeficiency virus (HIV). Methods We conducted a cross-sectional analysis of 320 MSM with HIV undergoing anal cancer screening and high-resolution anoscopy (HRA) between 2009-2010. We evaluated the performance of automated DS based on a deep-learning classifier compared to manual DS evaluation to detect anal intraepithelial neoplasia (AIN) grades 2 and 3 (AIN2+) and AIN3. We evaluated different DS-positive cell thresholds quantified by the automated approach and modeled its performance compared to other screening strategies in a hypothetical population of MSM with HIV. Results Automated DS had significantly higher specificity (50.9% vs. 42.2%, p=0.0004) and similar sensitivity (93.2% vs. 92.1%) for detection of AIN2+ compared to manual DS cytology. HPV testing with automated DS triage was significantly more specific (56.5% vs. 50.9%, p=0.0003) with the same sensitivity (93.2%) compared to automated DS alone. In a modeled analysis assuming a 20% AIN2+ prevalence, automated DS detected the most precancers compared to manual DS and anal cytology (186,184, and 162, respectively) and had the lowest HRA referral per AIN2+ detected (3.1,3.5, and 3.3, respectively). Conclusions Compared to manual evaluation, automated DS cytology detects the same number of precancers with lower HRA referral.

Anal Cancer and Anal Cancer Screening

“…The summary sensitivity and specificity performance estimates were 66% and 70%, respectively, with a high degree of variability observed across the 4 studies 53 . Reasons for differences in performance could include differences in the composition of study participants, differences in disease prevalence and outcome definitions, and/or differences in slide preparation and slide adequacy 69 …”

“…53 Reasons for differences in performance could include differences in the composition of study participants, differences in disease prevalence and outcome definitions, and/or differences in slide preparation and slide adequacy. 69 In one promising study in MSM LWH assessing automated evaluation of scanned dual stain cytology slides with a deep learning approach (not included in the systematic review), automation of dual stain cytology was able to detect anal precancer with high sensitivity and improved specificity compared with the manual reading of dual stain slides. Primary HPV testing with automated dual stain cytology triage further improved specificity.…”

“…Further research should prospectively evaluate automated dual stain cytology as a biomarker for anal cancer screening in different clinical populations. 69 HPV E6/E7 mRNA DETECTION HPV E6/E7 mRNA is an HPV-associated biomarker that has been evaluated for anal cancer screening. HPV E6/E7 mRNA assays target transcripts of the HPV oncogenes E6 and E7; expression of these genes increases in transforming infections associated with the development of cervical precancers.…”

“…In addition, automation provides fully quantitative results, so the positivity threshold can be shifted to meet the needs of the clinical setting (i.e., utilizing a higher threshold when HRA capacity is limited to optimize specificity). Further research should prospectively evaluate automated dual stain cytology as a biomarker for anal cancer screening in different clinical populations 69 …”

Infecciones transmisibles sexualmente que afectan colon, recto y ano.

“…Distintos biomarcadores se encuentran en investigación para definir su utilidad en la categorización de los pacientes en función de su riesgo de progresión a cáncer: test de hr-HPV, hr-HPV 16/18, la metilación del HPV, tinción dual p16/Ki-67, E6/E7 ARNm, integración del HPV y mutaciones somáticas. 37,42,57 Para definir su costo-efectividad debe considerarse el impacto que esta información tendrá en los pacientes, la dificultad en la implementación de nuevas tecnologías y la necesidad de una adecuada interpretación de sus resultados. La comprensión de la biología del CCE anal permitiría además personalizar el tratamiento.…”