Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

Abstract

The objective of our study was to assess the performance of different triage strategies for high‐risk human papillomavirus (hrHPV)‐positive results utilizing either extended genotyping or a p16/Ki‐67 dual‐stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single‐genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)‐approved algorithm (HPV16/18 positive, or 12‐other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA‐approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV‐positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

DNA methylation markers as triage test for the early identification of cervical lesions in a Chinese population

“…But, HPV16/18 genotyping is useless for cervical cancer patients with hrHPV infections other than HPV16/18 subtypes. In our study, the sensitivity and specificity of HPV16/18 genotyping was 77% and 71%, respectively, to detect CIN2+, which is concordant with the data published by Bu et al from the Guangdong Province, China (sensitivity 65%, specificity 67%) 30 and other studies analyzing other populations 31,32 . Our study shows that the diagnostic performance of three methylation panels was noninferior to the HPV16/18 genotyping to triage hrHPV‐positive women.…”

“…and other studies analyzing other populations. 31,32 Our study shows that the diagnostic performance of three methylation panels was noninferior to the HPV16/18 genotyping to triage hrHPV-positive women. For triaging hrHPV-positive women in China, one might consider cotesting of HPV16/18 genotyping and methylation analysis, especially the potential application of methylation panels in hrHPV infections other than HPV16/18.…”

The effectiveness of HPV16 and HPV18 genotyping and cytology with different thresholds for the triage of human papillomavirus-based screening on self-collected samples

“…The high prevalence of hrHPV not only leads to unnecessary colposcopy or follow-up burden [9], but also might add to the mental burden of the HPV-positive women [17]. However, in HPVbased screening programs, there is still no consensus on the optimal management of HPVpositive women to maximize disease detection and minimize colposcopy rates [18,19]. Risk stratification has important implications for the personalized risk management of HPV positive women.…”

Accuracy of p16/Ki-67 dual staining for improved cervical cancer risk stratification in women aged ≤30 years with hr-HPV positive

“…Studies have shown that the most common screening method was high-risk HPV (hr-HPV) test. The superior sensitivity of clinically validated hr-HPV test and high repeatability with acceptable negative predictive value makes this method widely accepted as the most important strategy for the cervical cancer screening [6][7]. However, because of the unsatisfactory performance of hr-HPV test, the Preventive Services Task Force screening guidelines of the United States prefer primary hrHPV test every 5 years for screening [8].…”

“…Another important screening tool is cytology based on the Papanicolaou (Pap) smear, which was in largescale use and reduced the cervical cancer incidence and mortality in many regions [7]. However, because of its low sensitivity for detecting cervical intraepithelial neoplasia grade 2 (CIN2) or higher lesion [4], clinicians prone to nd other effective tools to screen the cervical cancer, one of whic was p16/Ki-67 dual staining.…”