PCR-reverse dot blot human papillomavirus genotyping as a primary screening test for cervical cancer in a hospital-based cohort

Abstract

Objective: To evaluate the polymerase chain reaction (PCR)-reverse-dot-blot (RDB) human papillomavirus (HPV) genotyping test as a feasible assay for the cervical cancer primary screening.

Methods: In a hospital-based cohort, a total of 21,568 women were voluntarily enrolled from March 2009 to November 2016 for evaluating the 3 current cervical cancer screening strategies: co-test, cytology primary and high-risk HPV (HR-HPV) primary by using PCR-RDB HPV genotyping and liquid-based cytology (thinprep cytologic test [TCT]). Women with HR-HPV infection and/or abnormal cytology were referred for colposcopy, and the biopsy or conization was performed according to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.

Results: Overall, 18.20% (3,935/21,568) of the women were detected as HR-HPV-positive, 5.04% (1,088/21,568) were diagnosed with cervical intraepithelial neoplasia 2 or higher (CIN2+), and 3.43% (739/21,568) with CIN3+. The cumulative incidence rates for CIN2+/CIN3+ in patients with HPV-16/18-positive were 48.28%/37.20%, while they were 0.86%/0.38%, 0.30%/0.15% and 0.18%/0.09% in cytology-negative, HR-HPV-negative and co-test-negative population, respectively. Using CIN2+ and CIN3+ as the observed endpoints, the sensitivity and negative predictive value (NPV) of HR-HPV genotyping as a primary screening tool were 90.99%/99.49% and 91.57%/99.80%. Moreover, using HR-HPV genotyping primary screening could detect the same more CIN2+/CIN3+ cases in baseline-detection as co-testing (990/700 vs. 991/701) and far more than cytology primary screening (903/656, p<0.05). It also achieved the lowest misdiagnosis rate (8.01%/5.02%). Although HPV genotyping primary screening required an increased number of colposcopies (2.75/3.89 per CIN2+/CIN3+ case), it yielded an acceptable rate.

Conclusions: The PCR-RDB HPV genotyping test is a cost-effective and beneficial cervical cancer primary screening for hospital-based opportunistic screening.

Keywords: Cancer Screening; Cervical Cancer; Cytology; Genotype; Papillomaviridae.

Fig. 1. Flowchart of inclusion and exclusion criteria of the study population.

ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LEEP, loop electrosurgical excision procedure; LSIL, low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy; PCR-RDB, polymerase chain reaction-reverse dot blot; TCT, thinprep cytologic test. ^*HR-HPV (+): including HPV-16/-18 (+) (n=1,336) and HR-HPV non-16/18 (+) (n=2,599).

Fig. 2. Three cervical screening strategies to detect CIN2+/CIN3+. Effectiveness analysis of cervical screening strategies: primary screening algorithms. (A) Strategy I was co-testing, cytology combined with HPV using as the primary detection. (B) Strategy II was primary cytological detection with triaged by HPV testing. (C) Strategy III was primary HR-HPV testing with HPV-16/-18 genotype. In different strategies, the cases with ≥CIN2+ detected in the baseline screening, first year recall and the subsequent follow-up were listed in Fig. 2.

ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR-HPV, high-risk human papillomavirus; NILM, negative for intraepithelial lesion or malignancy.

Fig. 3. The examinations consumed by the three cervical screening strategies to detect CIN2+/CIN3+. (A) The cases of CIN2+ detected by three current cervical screening strategies were determined in baseline screening, first year re-call, and subsequent follow-up. (B) The cases of CIN3+ detected by three current cervical screening strategies were calculated in baseline screening, first year re-call, and subsequent follow-up. (C) For baseline screening, according to the different cervical screening strategies, the number of cytologic assays, HPV assays, and colposcopies that should be performed as well as analysis of CIN2+ cases that could be detected. (D) The three cervical screening strategies used for CIN3+ detection, with application of cytology assay, HPV assay, and colposcopy shown.

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; TCT, thinprep cytologic test.