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Objective. The aim of this study was to design a cervical cancer screening algorithm for the developing world that is highly sensitive for cervical intraepithelial neoplasia (CIN) II, III, and cancer and highly specific for CIN II and III, making it possible to ablate the transformation zone without histologic confirmation. Methods. In rural Shanxi Province, China, we examined 1997 women ages 35–45. Each subject underwent a self-test for intermediate and high-risk HPV (by HC-II assay), fluorescence spectroscopy, a liquid-based Pap (read manually and by computer and used as a direct test for HPV), a visual inspection (VIA) diagnosis, and colposcopy with multiple cervical biopsies. Results. Mean age was 39.1 ± 3.16 years, mean number of births was 2.6 ± 0.93. Based on tests administered, 4.3% subjects had ≥CIN II. All subjects with ≥CIN II had either a ThinPrep Pap (≥ASCUS) or a positive HPV direct test. The sensitivity and specificity for the detection of ≥CIN II were, respectively, 83 and 86% for the HPV self-test, 95 and 85% for the HPV direct test, 94 and 78% for the ThinPrep Pap (≥ASCUS), 77 and 98% for the ThinPrep Pap (≥HGSIL), 94 and 9% for fluorescence spectroscopy, 71 and 74% for VIA, and 81 and 77% for colposcopy. Conclusion. Based on these data and the existing healthcare infrastructure in China, we believe that further refinement of primary HPV screening using centralized labs is indicated. Self-testing in the local villages may be effective with improvements in the devices and techniques.

Human papillomavirus (HPV) DNA detection in cervical specimens was correlated with cytologic and histologic diagnoses for 151 women who were referred to the Johns Hopkins Hospital colposcopy clinic for evaluation of an abnormal Pap smear. HPVs were identified as "high-risk" or "low-risk" by Hybrid Capture. The final disease status was categorized as high-grade squamous intraepithelial lesion (HSIL) by histology ( n = 26), low-grade squamous intraepithelial lesion (LSIL) by histology ( n = 43), equivocal [histology negative, cytology atypical squamous cells of undetermined significance (ASCUS) or higher, n = 42], and negative (both histology and cytology negative, n = 40). Thirty-five percent of disease-negative women and 84% of the women with biopsy-proven or equivocal disease were HPV-positive. Ninety-two percent of the HPV-positive women harbored high-risk HPVs, either high-risk HPVs alone (77%) or high-risk HPVs along with low-risk HPVs (15%). High-risk HPVs predominated in disease-negative as well as disease-positive women. Collection of specimens with a cytobrush was more efficient for HPV DNA detection than collection by cervicovaginal lavage. Large amounts of HPV DNA correlated with presence of HSIL or LSIL. For detection of HSIL, considering only brush samples, the sensitivities of abnormal cytology (ASCUS or higher), of high-risk HPVs, and of the two combined were, respectively, 87, 93, and 100%; the corresponding specificities were 30, 30, and 20%. HPV DNA detection may be most beneficial in populations with low HPV prevalence.

Objectives We compared the screening performance of conventional Pap cytology and two human papillomavirus (HPV) DNA assays, the original Hybrid Capture 2 (HC2) and an expanded version that tests for 4 additional HPV types (HC2+4; Qiagen Corporation), in the detection of cervical neoplasia among unscreened women in a primary care setting in a suburb of Kinshasa, Democratic Republic of the Congo. Methods All women 30years or older residing in the area were invited to participate, and 1528 were evaluated by Pap cytology and the two HPV assays, conducted at a European and US reference laboratory, respectively, followed by colposcopy. Cervical biopsies were obtained from all women with abnormal colposcopy and from 290 randomly chosen women with normal colposcopy (to correct for verification bias). Results Using a relative light unit of 1 as the cutoff for positivity, 169 and 168 (11%) women tested positive using HC2 and HC2+4, respectively. HC2 and HC2+4 were in agreement in 98.6% of cases (Kappa=0.94; 95% confidence interval: 0.91–0.96). Both assays were sensitive (~83%) and specific (~91%) for the detection of cervical intraepithelial neoplasia-2 or worse disease. Irrespective of the cutoff point used to define positivity, Pap cytology was both less sensitive and more specific than HC2 or HC2+4. For instance, cytology was 63% sensitive and 97% specific when a cutoff point of low-grade squamous intraepithelial lesions or worse was used. Conclusions Among unscreened women, HC2 and HC2+4 had similar screening accuracy for cervical neoplasia, and both were more sensitive but less specific than Pap cytology.

While several different human papillomaviruses (HPV) have been associated with cancer of the cervix, it is yet to be determined if specific HPV types have clinical or prognostic significance. To address this question, 30 cases of invasive carcinoma (squamous carcinoma, adenosquamous carcinoma, and adenocarcinoma) with HPV DNA sequences detectable in the tissue were analyzed. HPV type was determined by Southern blot DNA hybridization. Clinical information was obtained by chart review, and all biopsy and surgical specimens were reviewed microscopically without knowledge of HPV type. HPV 16 was detected in 14 cases, HPV 18 in 6, and HPV 31 in 2. In eight samples there were distinctly different, but as yet uncharacterized, HPV DNAs. Of the factors evaluated, tumor grade was found to have a statistically significant relationship to HPV type. Eighty-three percent of HPV 18-associated tumors were grade 3 tumors (5 of 6) as compared to only 7% of HPV 16-associated tumors (1 of 14) (P = 0.002). Age at diagnosis and nodal status in relation to HPV type exhibited a trend but were not statistically significant. The mean age of the HPV 18 group was 37 years, compared to 49 years for the HPV 16 group. Similarly, among Stage IB cancers, nodal involvement was associated with 60% of HPV 18 cases (3 of 5) as compared with 36% of HPV 16 cases (4 of 11). These observations suggest that HPV 18 may be associated with a more aggressive form of cervical cancer than other HPV types.

Objective Testing for high risk human papillomavirus (HR-HPV) is increasing; however due to limitations in specificity there remains a need for better triage tests. Research efforts have focused recently on methylation of human genes which show promise as diagnostic classifiers. Methods Methylation of 26 genes: APC, CADM1, CCND2, CDH13, CDKN2A, CTNNB1, DAPK1, DPYS, EDNRB, EPB41L3, ESR1, GSTP1, HIN1, JAM3, LMX1, MAL, MDR1, PAX1, PTGS2, RARB, RASSF1, SLIT2, SOX1, SPARC, TERT and TWIST1 was measured by pyrosequencing in cytology specimens from a pilot set of women with normal or cervical intraepithelial neoplasia grade 3 (CIN3) histology. Six genes were selected for testing in Predictors 1, a colposcopy referral study comprising 799 women. The three genes EPB41L3, DPYS and MAL were further tested in a second colposcopy referral study, Predictors 2, comprising 884 women. Results The six genes selected from the pilot: EPB41L3, EDNRB, LMX1, DPYS, MAL and CADM1 showed significantly elevated methylation in CIN2 and CIN3 (CIN2/3) versus ≤CIN1 in Predictors 1 (p, Highlights • Methylation of 26 human genes assessed by pyrosequencing in 40 cytology specimens • Several methylated genes show promise for detecting CIN2/3. • EBP41L3 shows reproducible biomarker potential in high risk HPV positive women.