Detection Of CIN2 Research Articles

Self-collected versus clinician-collected cervical samples for the detection of HPV infections by 14-type DNA and 7-type mRNA tests

BackgroundHPV self-sampling has been widely supported by the scientific community following a strong body of literature on the subject. Self-sampling is important in cervical cancer screening as it has been shown to improve participation. It is well documented that HPV-testing has proven superior to cytology with regards to sensitivity in detection of CIN and cancer. The value of self-collected samples is reliant on the quality of the molecular testing performed, as well as the patients’ preference in sampling procedure and compliance to follow up on positive test results. Due to the incompatibility of self-samples and cytology, triage of HPV-DNA positives by testing for molecular biomarkers is highly warranted.MethodsOur objective was to compare the detection rate of genital Human Papillomavirus (HPV) infection in self- and clinician-collected samples by a 14-type HPV-DNA test and a 7-type mRNA E6/E7 test.ResultsFive hundred five women were recruited. Each study participant had two sample collection procedures performed upon the same visit, alternating order in execution of the self-collection or the clinician-taken procedure first or second, 1010 samples in total. HPV-DNA prevalence was 22.8% in self-collected versus 19.2% in clinician-collected samples (P = 0.19). Overexpression of mRNA E6/E7 from 7 HPV types was 7.1 and 6.3%, respectively (P = 0.71). The difference between HPV-DNA and HPV-mRNA positivity rates were statistically significant in both self-collected (22.8% versus 7.1%, P < 0.001) and clinician-collected samples (19.2% versus 6.3%, P < 0.001). Overall agreement between the two collection methods was fair, with a concordance rate of 78.2% (390/505), k = 0.34 (95% CI: 0.25–0.44), P < 0.001, for the HPV-DNA test and 92.5% (467/505), k = 0.40 (95% CI, 0.25–0.56), P < 0.001, for the mRNA test, respectively. 96.8% of the participants reported they felt confident carrying out the self-collection themselves, and 88.8% reported no discomfort at all performing the procedure.ConclusionsThis comparative study of two sampling methods reports fair agreement of HPV positivity rates between the self-collected and clinician-collected specimens using Abbott hrHPV and PreTect HPV-Proofer’7 tests. Only one third of HPV-DNA positive women had overexpression of mRNA E6/E7.Trial registrationISRCTN77337300.

Respective prevalence of high-risk HPVgenotypes in cervical neoplasia in Senegal.

Withthe perspective of prophylactic vaccination against high-risk human papillomavirus (HPV), we analyzed the viral epidemiology of cervical neoplasia in Senegal. All patients were treated at the Institut Joliot Curie du Cancer in Dakar. HPV genotypes were characterized using a real-time polymerase chain reaction-based approach and sequencing. Histologically, there were 224 invasive carcinomas, 17 high-grade intraepithelial neoplasia (CIN), and five undetermined histologies. Molecular analysis was conclusive in 241 cases. HPV DNA was found in 207/241 (85.9%) cases while 34/241 (14.1%) remained HPV negative. There was one single genotype in 127/207 (61.4%) cases and several in 80/207 (38.6%) corresponding to 308 genotypes identified. Viral genotyping found HPV16 in 175 (56.8%) cases, HPV18 in 45 (14.6%), HPV45 in 40 (13.0%), HPV58 in 35 (11.4%), HPV33 in 6 (2.0%), HPV35 in 3 (1.0%), HPV31 in 2 (0.6%), HPV39 and HPV56 in one (0.3% each). Our analysis showed that 98.4% of the HPV-positive cases were associated with viral genotypes covered by the 9-valent HPV vaccine. However, 14.1% of cases remained HPV negative. Therefore, prophylactic vaccination using a 9-valent vaccine should dramatically reduce the incidence of HPV-associated neoplasia but the detection and treatment of CIN remain necessary for the optimal prevention of cervical cancer.

Clinical evaluation of p16INK4a immunocytology in cervical cancer screening: A population-based cross-sectional study from rural China.

Cervical cancer screening with cytology suffers from low sensitivity, whereas the efficiency of human papillomavirus (HPV)-based screening is limited by low specificity. The authors evaluated a novel p16INK4a immunocytology approach in cervical cancer screening compared with HPV-based and cytology-based screening. In total, 2112 women aged 49 to 69 years from Shanxi, China were screened from March to July 2019. HPV testing, liquid-based cytology (LBC), and p16INK4a immunocytology were performed on samples from all women. Any positive result triggered a referral to colposcopy with biopsy, if indicated. Screening performance for detecting cervical intraepithelial neoplasia grade 2 and 3 or worse (CIN2+/CIN3+) was evaluated using multiple algorithms. p16INK4a had a lower positive rate (10.0%) than LBC abnormality (vs 12.1%; P = .004) and a high-risk HPV positivity (21.4%; P < .001). For the detection of CIN3+, the relative sensitivity of p16INK4a compared with HPV and LBC was 0.93 (95% CI, 0.82-1.07) and 1.12 (95% CI, 0.95-1.32), respectively. The specificity of p16INK4a was significantly higher than that for HPV and LBC, with a relative specificity of 1.13 (95% CI, 1.11-1.16) and 1.02 (95% CI, 1.01-1.04), respectively. In addition, p16INK4a alone yielded a clinical performance very similar to that of the current mainstream strategy of using HPV16/18 with reflex cytology (ASC-US+, atypical squamous cells of undetermined significance or worse). The immediate risk of CIN3+ was 14.6% if p16INK4a results were positive and 0.2% if p16INK4a results were negative. With minimal colposcopy referrals, p16INK4a screening demonstrated promising utility for risk stratification and yielded a better balance between sensitivity and specificity compared with HPV and LBC primary screening. Moreover, with accuracy and efficiency similar to what is achieved using mainstream cotest algorithms, p16 may simplify the screening practice. More evidence will be required before clinical recommendation.

Optimizing biopsy procedures during colposcopy and detection of high-grade cervical lesions

Objective: To investigate the value of biopsies on diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN Ⅱ+), and optimize biopsy procedures of risk-based colposcopy practice. Methods: A prospective study was performed on 346 women referred to colposcopy following abnormal cervical cancer screening results at the First Affiliated Hospital of Nanjing Medical University, from April 2017 to December 2019. Up to 4 cervical biopsies were taken during colposcopy and each biopsy specimen was evaluated separately in histology. CIN Ⅱ+ identified by any biopsy was the reference standard of disease used to evaluate the diagnostic value of targeted biopsy and random biopsy, and to quantify the improved detection of CIN Ⅱ+ by taking multiple biopsies. Cervical cytology, HPV genotyping, and colposcopic impression were used to establish different risk strata to select various multiple biopsies procedures during colposcopy to improve accuracy and efficiency of CIN Ⅱ+ detection. Results: In total 346 women, 190 (54.9%, 190/346) cases of them were diagnosed as CIN Ⅱ+. (1) In total 346 women, 96.8% (184/190) CIN Ⅱ+ were detected by targeted biopsies, 27.9% (53/190) CIN Ⅱ+ were detected in biopsies targeted grade 1 abnormal colposcopic findings (G1) on the cervix, and 68.9% (131/190) CIN Ⅱ+ were detected in biopsies targetrd grade 2 abnormal colposcopic findings (G2) on the cervix. Colposcopy had a sensitivity of 68.9% when the biopsy threshold was G2, sensitivity increased to 96.8% when the biopsy threshold was defined to be G1. Among women with G1, adding 2 targeted biopsies to the first biopsy were sufficient to detect all CIN Ⅱ+, among women with G2, adding 1 targeted biopsy was sufficient. (2) Among 270 women, random biopsies targeted normal colposcopic findings on the cervix were performed in addition to targeted biopsies and in total 3.2% (6/190) additional CIN Ⅱ+ were detected. As the number of cervical quadrants involved by abnormal colposcopic images increased, random biopsy detected fewer CIN Ⅱ+ that would have otherwise been missed by targeted biopsies (P=0.010). (3) Women with atypical squamous cells,cannot exclude high grade squamous intraepithelial lesion (ASC-H), high grade squamous intraepithelial lesion (HSIL) or atypical glandular cell (AGC) referral cytology, HPV 16-positive, G2 were more likely to have CIN Ⅱ+(P<0.01); for those meeting only one category, the yield of CIN Ⅱ+ increased from 34.0% for one biopsy to 51.0% for two biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy was 17.0%, two biopsies were sufficient to detect all CIN Ⅱ+; for those meeting at least two categories, the yield of CIN Ⅱ+ increased from 90.7% for one biopsy to 92.6% for two biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy was 1.9%, two biopsies were sufficient to detect all CIN Ⅱ+; for those not meeting any category, the yield of CIN Ⅱ+ increased from 8.8% for one biopsy to 17.6% for two biopsies, to 23.5% for three biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy, from the second to the third biopsy was 8.8%, 5.9%, three biopsies were sufficient to detect all CIN Ⅱ+. Conclusions: Performing multiple targeted biopsies could improve efficiency of CIN Ⅱ+ detection. Adding random biopsies to multiple targeted biopsies showed very limited additional benefit for detection of CIN Ⅱ+. The biopsy procedures undertaken during the colposcopy visit could be modified based on various colposcopic impressions and reasons for referral.

Risk stratification of HPV-positive women in routine cervical screening.

High risk HPV primary screening is replacing organised cytology-based screening based on increased sensitivity to detect high grade intra-epithelial neoplasia and the very high negative predictive value which will allow extended screening intervals. The benefit of increased CIN detection and cancer prevention needs to balance against the disbenefits to screen positive women in over investigation not least the psychological impact.

DNA methylation marker for the triage of hrHPV positive women in cervical cancer screening: Real-world evidence in Taiwan

ObjectiveHuman papillomavirus (HPV) testing as the primary cervical cancer screening followed by reflex cytology if high-risk HPV is present (hrHPV+) is recently adopted in some countries. However, reflex cytology's sensitivity is variable, and a suitable triage approach for hrHPV+ remains controversial. Here, we compared the performance of three triage tools in hrHPV+ women. MethodsThree triage tools—cytology, HPV16/18 genotyping, and DNA methylation biomarker PAX1m—were analyzed for their clinical performance in hrHPV+ women. In addition, women without cervical cancer at enrollment were followed for histologically confirmed high-grade cervical intraepithelial neoplasia or worse (CIN3+) annually using Papanicolaou smear. ResultsOf 4762 women aged ≥20 years enrolled, 502 (10.5%) were hrHPV+. PAX1m and cytology demonstrated similar accuracy (>90%), sensitivity (>78%), and specificity (>92%) as triage tools in 429 hrHPV+ women aged 30–64 years. PAX1m had better accuracy and specificity (91.6% and 92.5%, respectively) than HPV16/18 (76.9% and 76.8%, respectively). The incidence of CIN3+ among hrHPV+ women was 10.7 cases/1000 person-years. The incidence was significantly greater in PAX1m-positive women than in PAX1m-negative women. ConclusionsPAX1m has comparable clinical performance to cytology and better accuracy and specificity than HPV16/18 as the triage tool for detecting CIN3+ in hrHPV+ women. The PAX1m assay is thus a promising molecular-based triage tool for early detection of CIN and predicting disease progression in hrHPV+ women. It can be especially useful in countries where adequate cytology-based infrastructure is lacking, such as some Southeast Asian countries, for cervical cancer screening and prevention.

Cervical Cancer Screening in HIV-Positive Women in India: Why, When and How?

Cervical cancer is an AIDS-defining illness, and HIV-positive women are at high risk. The present study aimed to determine the magnitude of the problem, compare the performance of screening tests and assess factors affecting participation. HIV-positive women aged 30-59years attend the anti-retroviral therapy (ART) clinicswere screened by conventional Pap, HPV testing (Hybrid Capture 2) and visual inspection with acetic acid (VIA). A cohort of HIV-negative women from the community matched for age and parity were screened similarly. Screen-positive women underwent colposcopy and biopsy. Factors affecting participation were assessed. Pap, VIA and HPV were positive in 48 (23.8%), 65 (32.2%) and 76 (37.6%) subjects, respectively, among HIV-positive women, and in 12 (5.9%), 10 (4.9%) and 12 (5.9%) subjects, respectively, among HIV-negative women. CIN2 + was present in 12 (6.4%) HIV-positive women and in 1(0.5%) HIV-negative woman (p = < 0.004). Sensitivity of HPV, Pap and VIA for detection of CIN2 + lesions was 91.7%, 75.0% and 75.0%, respectively; specificity was 68.4%, 83.9% and 72.5%, respectively. Lack of availability of screening facilities in the ART clinic and long waiting times were a strong deterrent to participation among HIV-positive women. There was higher prevalence of HPV infection and CIN2 + lesions in HIV-positive women. VIA showed equivalent sensitivity to Pap and could be a good substitute in low resource settings. Setting up cervical screening services in ART clinics and sensitising physicians can improve outcomes among these women.

Use of extended HR-HPV Genotyping in improving the Triage Strategy of 2019 ASCCP recommendations in Women with positive HR-HPV diagnosis and Simultaneous LSIL Cytology Results.

Objective: According to the 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) recommendations, women with a positive high-risk human papillomavirus (HR-HPV) diagnosis and low-grade cervical intraepithelial lesion (LSIL) cytology result should be referred for further colposcopy examination. However, this strategy results in over-treatment in several cases. In this study, we assessed the performance of extended HR-HPV genotyping in women with a simultaneous positive HR-HPV and LSIL diagnosis with the aim of improving the current triage strategy.Methods: This study was an observational analysis of women from the Fujian Province Cervical Lesion Screening Cohorts (FCLSCs). Women who were HR-HPV-positive and had a cytological examination of LSIL, which were followed up with colposcopy and biopsy, from 2015 to 2018 were included. The study endpoint was defined as the detection of histological cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We combined HR-HPV genotypes according to the prevalence rate in histological CIN2+ and ranked them from high to low to establish HR-HPV genotyping models. Outcomes were assessed with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and colposcopy referral rate.Results: Overall, 56,788 women undergoing preliminary screening for HR-HPV genotyping were included in this study. Among them, 10,499 women positive for HR-HPV underwent a cytology examination, and 902 women with LSIL cytology diagnosed and subsequent biopsy results were included in the final evaluation. Among these patients, 25.1% (226/902) were found to have CIN2+ in histology. HPV-16, -58, -52, -18, -33, and -31 infections were the most common genotypes, and HPV-16, -18, -58, -33, and -31 (odds ratio [OR] = 5.41, 2.98, 1.38, 1.24, and 1.21, respectively) were associated with the potential for histological CIN2+, from the highest to lowest. In the detection of CIN2+ lesions in HR-HPV-positive LSIL women of different HR-HPV genotyping models, the extended HPV 16/18/31/33/52/58 genotyping model was found to have better efficacy with higher sensitivity (92.9%) and NPV (93.0%), but a significantly lower colposcopy referral rate (74.7%) than the ASCCP-recommended HR-HPV non-genotyping model.Conclusion: For HR-HPV-positive women with LSIL, the HPV 16/18/31/33/52/58 genotyping model can serve as an alternative approach to the ASCCP recommendations, potentially reducing the unnecessary colposcopy referral burden in China.

DNA ploidy measurement and human papillomavirus in abnormal cervical cytology.

To compare the efficacy of high-risk human papillomavirus (HR-HPV) and DNA image cytometry (DNA-ICM) status for identifying high-grade cervical intraepithelial neoplasia or worse (≥CIN2). This cross-sectional study was performed in women undergoing follow-up procedure after a previous abnormal cervical cytology. Cervical cells were collected for HPV detection and DNA ploidy measurement. Biopsy samples were taken for histological confirmation. Sensitivity and specificity values for ≥CIN2 detection with HR-HPV and DNA-ICM were determined. HR-HPV was present in 74.5% of the women. The most frequent HPV infection was HPV 16, followed by HPV 31, 33 and 58. Aneuploidy was observed in 60.6% of all cases. Referral cytology revealed 78.0% sensitivity and 68.6% specificity for detecting a≥CIN2 lesion. The HR-HPV test alone showed 92.7% sensitivity, albeit it was not statistically different from DNA-ICM (88.1%, P>.05). Positivity for HPV or DNA-ICM resulted in 100% sensitivity. Higher specificity was observed for the combination of HR-HPV and DNA-ICM (88.6%), with no difference from DNA-ICM alone (85.7%, P>.05). DNA-ICM or HR-HPV positivity identified all cases of≥CIN2 in women undergoing follow-up procedure after a previous abnormal cervical cytology. Routine cervical cancer screening could be improved by the incorporation of DNA-ICM as a complementary method to primary screening to identify which women need closer follow-up.

Performance and Diagnostic Accuracy of Human Papillomavirus Testing on Self-Collected Urine and Vaginal Samples in a Referral Population.

PurposeThe study aimed to evaluate the diagnostic accuracy of polymerase chain reaction–based high-risk human papillomavirus (HPV) assays on self-collected vaginal and urine samples for detection of precancerous cervical lesions in referral population.Materials and MethodsWomen referred for colposcopy following abnormal cytology, were included this study. A total of 314 matched urine, vaginal, and cervical samples were collected. All samples were tested for HPV DNA using the RealTime HR-S HPV and Anyplex II HPV 28 assays. Primary endpoints were sensitivity for cervical intraepithelial neoplasia (CIN) 2+/CIN3+ and specificity for <CIN2. Secondary endpoints were the relative accuracy of high-risk HPV (hrHPV) test results in vaginal and urine samples versus cervical samples.ResultsThe sensitivity of Realtime HR-S and Anyplex HPV assay was 93.13% (95% confidence interval [CI], 87.36 to 96.81) and 90.08% (95% CI, 83.63 to 94.61) for CIN2+ (n=130); specificity for <CIN2 was 32.69% (95% CI, 25.03 to 38.97) and 33.33% (95% CI, 26.26 to 41.00), respectively. Relative sensitivity of Realtime HR-S and Anyplex HPV tests for the detection of CIN2+ in vaginal versus cervical samples were 0.91 (95% CI, 0.90 to 1.03) and 0.87 (95% CI, 0.75 to 1.02), respectively; urine versus cervical comparisons were 0.79 (95% CI, 0.70 to 0.92) and 0.74 (95% CI, 0.61 to 0.89).ConclusionThe detection performance for hrHPV and CIN2+ on self-collected vaginal samples was comparable to that of clinician-collected cervical samples. On the other hand, HPV tests using urine were inferior to those using clinician-collected cervical samples in terms of detecting hrHPV and CIN2+.

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

Objective strategies are required in cervical cancer screening. We have identified several DNA methylation markers with high sensitivity and specificity to detect cervical intraepithelial neoplasia 2 or worse (CIN2+) in Dutch women. Our study aims to analyze the diagnostic characteristics of these markers in a Chinese cohort. A total of 246 liquid‐based cytology samples were included, of which 205 women underwent colposcopy due to an abnormal cytology result (atypical squamous cells of undetermined significance [ASCUS] or worse), while 227 were tested high‐risk human papillomavirus (hrHPV) positive. All six individual markers (ANKRD18CP, C13ORF18, EPB41L3, JAM3, SOX1 and ZSCAN1) showed enhanced methylation levels and frequency with increasing severity of the underlying lesion (P ≤ .001). In cytological abnormal women, sensitivity to detect CIN2+ was 79%, 76% and 72% for the three panels (C13ORF18/EBP41L3/JAM3, C13ORF18/ANKRD18CP/JAM3 and ZSCAN1/SOX1, respectively), with a specificity of 57%, 65% and 68%. For the first two panels, these diagnostic characteristics were similar to the Dutch cohort, while for ZSCAN1/SOX1 the sensitivity was higher in the Chinese cohort, but with a lower specificity (both P < .05). In hrHPV‐positive samples, similar sensitivity and specificity for the detection of CIN2+ were found as for the abnormal cytology cohort, which were now all similar between both cohorts and non‐inferior to HPV16/18 genotyping. Our analysis reveals that the diagnostic performances are highly comparable for C13ORF18/EBP41L3/JAM3 and C13ORF18/ANKRD18CP/JAM3 methylation marker panels in both Chinese and Dutch cohorts. In conclusion, methylation panels identified in a Dutch population are also applicable for triage testing in cervical cancer screening in China.

A study of papanicolaou stain and cervical acid phosphatase papanicolaou stain in the detection of cervical intra epithelial neoplasm a comparative study

Introduction: In order to increase the sensitivity of the routine PAP test, a new test was introduced called the CAP-PAP test. In this test, lysosomal enzyme and cervical acid phosphatase (CAP) enzyme are labeled with conventional PAP test which will help in detecting abnormal squamous cells of cervix. This enzyme can be used as a biomarker for cervical dysplasia when CAP positivity is detected inside abnormal squamous cells of cervix and can also be used as a surrogate in detection of CIN. Aims: To perform CAP-PAP and PAP staining on cervical smears. To compare CAP-PAP results with PAP results and correlate with cervical histopathology reports. Methods and Materials: 150 females undergoing cervical cancer screening at OBG Department, of our institute were studied. Two cervical smears each were collected from all patients for PAP and CAP-PAP staining. The results were compared and correlated with respective histopathology reports.| Statistical Analysis Used: Chi-square test, Kappa statistics, P value of Results: 75 PAP positive cases out of which 34 were LSIL, 17 were HSIL, 13 were ASCUS, 9 were ASC-H, and 2 were SCC cases. In the remaining 75 PAP negative smears, 38 cases were inflammatory smears and 37 cases were of NLIM smears. Among the PAP positive cases, CAP-PAP results were similar to PAP results in all the LSIL, HSIL, ASCUS, ASC-H and SCC cases. Among the PAP negative cases, CAP-PAP was negative in all the 37 NILM cases, but of the 38 inflammatory cases, CAP-PAP was negative in 30 cases but was positive in 8 cases. CAP-PAP results had good agreement with PAP results and correlated well with histopathology results. Conclusion: CAP positivity is identified by presence of res granules in abnormal squamous cells which helps in its early detection. In screening of cervical cancer on a large scale. CAP PAP acts as a quick and efficient method. The test promises a great future in health centers as the technicians can be easily trained for identification of abnorma

Differential diagnosis of high-grade squamous intraepithelial lesions and benign atrophy in older women using p16 immunocytochemistry

BackgroundFor cervical cancer screening, routine cytology has a high specificity but a lower sensitivity. In older women, atrophy, which may mimic HSIL, presents a diagnostic challenge. p16 is a widely used biomarker for histological diagnosis of HSIL. Our objective was to evaluate PathCIN® p16INK4a immunocytology in identification of high grade dysplasia vs. benign atrophy. MethodsAs part of a multi-center screening program, 3351 women were co-tested by p16 immunocytology. Among women referred for colposcopy on basis of cytology and high-risk HPV status, those with atrophy were older than the population screened (52 vs. 43 years). Cases from older women with atrophy (n ​= ​116) and controls without atrophy (n ​= ​47) were identified by re-examination of Pap smears. The detection of CIN2+ was compared for p16, cytology and HR-HPV results. ResultsThe sensitivity of routine cytology (≥LSIL) was much lower for cases with atrophy (17%) than non-atrophic cases (75%). The sensitivity of p16 immunocytology and of HR-HPV testing was high (88%–100%) both with and without atrophy. The specificity of routine cytology (≥LSIL) was higher for cases with atrophy (79%) than non-atrophic cases (38%). The specificity of p16 immunocytology was high (88–95%) and the specificity of HR-HPV testing was low (31%–33%) both with and without atrophy. Combining p16 with HPV testing and/or routine cytology had no benefit, as compared to p16 staining alone. Conclusionsp16 immunocytology compares favorably with routine cytology and HPV testing in the differential diagnosis of HSIL and benign atrophy. It is more sensitive than cytology for atrophic specimens, and is more specific than HPV testing. p16 immunocytology may decrease the need for colposcopy referrals and could be a useful tool for early detection of cervical cancer in peri- and post-menopausal women, who are more likely to have HSIL coexisting with atrophy.

Screening test accuracy of portable devices that can be used to perform colposcopy for detecting CIN2+ in low- and middle-income countries: a systematic review and meta-analysis

BackgroundPortable devices that can be used to perform colposcopy may improve cervical cancer screening in low- and middle-income countries (LMIC) where access to colposcopy is limited. The objective of this study was to systematically review the diagnostic test accuracy (DTA) of these devices for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+).MethodsIn accordance with our protocol (Prospero CRD42018104286), we searched Embase, Medline and the Cochrane Controlled Register of Trials up to 9/2019. We included DTA studies, which investigated portable devices with moderate-to-high optical magnification (≥ 6×) for colposcopy, as described in the manual for Colposcopy and Treatment by the International Agency for Research on Cancer, with a histopathological reference standard. We used the QUADAS-2 tool to assess study quality. We examined results for sensitivity and specificity in paired forest plots, stratified by stages in the clinical pathway. We pooled estimates of test accuracy for the index test, used as an add-on to other tests, using a bivariate random-effect model.ResultsWe screened 1737 references and assessed 239 full-text articles for eligibility. Five single-gate DTA studies, including 2693 women, met the inclusion criteria. Studies evaluated two devices (Gynocular™ and Pocket) at different stages of the screening pathway. In three studies, which used the index test in an add-on capacity in 1273 women, we found a pooled sensitivity of 0.79 (95% CI 0.55–0.92) and specificity of 0.83 (95% CI 0.59–0.94). The main sources of bias were partial verification, incorporation and classification bias.ConclusionFew studies have evaluated portable devices able to perform colposcopy, so their accuracy for the detection of CIN2+ remains uncertain. Future studies should include patient-relevant and long-term outcomes, including missed cases, overtreatment, residual and recurrent disease. To meet the challenge of eliminating cervical cancer in LMIC, methods for visual assessment of the cervix need urgent redress.

Management of low-grade cervical cytology in young women. Cohort study from Denmark

Objective Cytology findings of atypical squamous cells of unknown significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) are common among women under 30, but evidence on best management strategy is insufficient. We therefore investigated how different management strategies used in Denmark influenced biopsy rates and detection of cervical intraepithelial neoplasia (CIN). Methods Register-based cohort study including Danish women aged less than 30 years and born 1980–95, with ASCUS/LSIL as their first abnormal cervical cytology in 2008–16. Rates and relative risks (RR) of biopsy and detection of CIN3+, CIN2 and < CIN2 during two years follow-up were compared between women referred directly to colposcopy after ASCUS/LSIL or undergoing additional testing, including mRNA or DNA test for high risk HPV or repeat cytology. Results 19,946 women with ASCUS and 19,825 with LSIL were included in the study of whom 92% had adequate information about follow-up. Among women referred directly to biopsy, CIN3+ was detected among 21%, CIN2 in 17%, while 62% had < CIN2. Repeating cytology after 6 months reduced the biopsy rate to 44% of which 53% had < CIN2. Biopsy rates with HPV test were 67% for DNA test, 77% with 14-type mRNA test and 58% with 5-type mRNA test. The detection of CIN3+ was somewhat higher, between 13% and 14% for the three HPV tests vs. 11% with repeat cytology. However, the detection of < CIN2 (not indicating treatment) also increased with RR 2.11 (95% CI 2.01–2.21) for 14-type mRNA test, 1.35 (95% CI 1.29–1.41) for 5-type mRNA test, and 1.86 (95% CI 1.76–1.97) with HPV DNA test. Conclusions The choice of management strategy influences both the detection rate for severe lesions (CIN3+) and the proportion of women followed up for potentially insignificant findings.

HPV-16 E2/E6 and POU5F1B as Biomarkers to Determine Cervical High-Grade Squamous Lesions and More.

PurposeHuman papillomavirus-16 (HPV-16) is the most carcinogenic HPV genotype. This study aimed to evaluate the clinical value of POU5F1B and HPV-16-E2/E6 by cervical cytology specimens to predict the cervical intraepithelial neoplasia two grade and more (CIN2+).MethodsFinally, 248 patients with HPV-16 single infection were enrolled. Using cytology specimen by real-time quantitative PCR (qPCR), POU5F1B mRNA and HPV-16-E2/E6 were detected. The relationship of POU5F1B, HPV-16-E2/E6 and CIN2+ were analyzed, and the optimal cut-off values of POU5F1B and HPV-16-E2/E6 to predict CIN2+ were calculated.ResultsThe mean HPV-16-E2/E6 decreased significantly with cervical lesions development, especially compared with CIN2+ (p<0.05). And the POU5F1B demonstrated higher expression in CIN2+ than that of normal cervical tissue and CIN1 (p<0.05). What is more, POU5F1B was negatively correlated with HPV-16-E2/E6. It demonstrated that the area under the receiver operating characteristic curve (AUC) for POU5F1B (0.9058) was higher than that for HPV-16-E2/E6 (0.8983), and the sensitivity and specificity of POU5F1B in the diagnosis of CIN2+ were higher than HPV-E2/E6. Furthermore, it demonstrated that the POU5F1B had the highest odds ratio (OR= 16.84; 95% CI (8.00–35.46)) for the detection of CIN 2+.ConclusionHPV-16-E2/E6≤0.6471 or POU5F1B≥1.0310 in cervical exfoliated cells can be used as a reliable predictor of CIN2+. POU5F1B can be used as a new auxiliary biomarker to determine the HPV infection status and a reliable predictor of CIN2+. The expression of POU5F1B≥1.0310 had the highest OR for the detection of CIN2+.

The value of p16(INK4a) cytology for early diagnosis of cervical cancer

Objective: To investigate the use of p16(INK4a) immuno-stained cytology as the primary screening for cervical cancer prevention. Methods: From March to August 2018, 902 women from Shenzhen and surrounding area were recruited for cervical cancer screening with ThinPrep Cytologic Test (TCT), cobas4800 HPV test, and p16(INK4a) co-test. Colpo/biopsies were performed using the point of interest biopsy protocol of directed and random cervical biopsies plus endocervical curettage for all women, any of whose tests was positive. Two senior cytopathologists interpreted TCT and p16(INK4a) test. The performance of p16(INK4a) for early detection of CIN2+ and inter-observer reproducibility of the interpretation of p16(INK4a) were evaluated. Results: The positive rates of HPV test, p16(INK4a) co-test and TCT diagnosed as LSIL/AGC or higher grade were 8.1% (73/902), 6.8% (61/902) and 4.7% (42/902), respectively. Colposcopy referring rate was 79.6% (109/137), among which 10 cases were diagnosed as CIN2+ (5 cases of CIN2 and 5 cases of CIN3). The sensitivity and specificity for CIN2+ of p16(INK4a) test, TCT (LSIL/AGC or higher grade) and HPV test were 90.0%, 80.0%, 100.0% and 90.9%, 91.9%, 82.5%, respectively. Compared to TCT and HPV test, there was no significant difference in sensitivity and specificity between p16(INK4a) and TCT/HPV test (P>0.05). The Kappa value of the 2 cytopathologists in interpreting p16(INK4a) and TCT was 0.944 and 0.425, respectively (P<0.05). Conclusions: p16(INK4a) for cervical cancer screening is equally sensitive to HPV test and specific to TCT while subjective difference of cytopathologists' interpretation of p16(INK4a) is small. Therefore, p16(INK4a) can be used as a new cervical cancer screen method for its better diagnostic performance.

Role of molecular biomarker human papilloma virus (HPV) E6 oncoprotein in cervical cancer screening

ObjectiveThe Onco E6™ Cervical Test, based on detection of the E6 oncoprotein of HPV 16 and 18 genotypes is evaluated as a screen for the early detection cervical neoplasia in resource-limited countries. MethodsThis prospective study from June 2018 to June 2019 evaluated 235 women aged 21–65 years, who came to Gynaecological Oncology Outpatient Department by VIA, cytology, E6 oncoprotein test and by colposcopy. Screen-positive women by any of the tests or women with suspicious findings were further evaluated by biopsy at colposcopy. The McNemar test was used to compare the performance of E6 oncoprotein test with other screening tests. ResultsThe E6 oncoprotein positivity rate was 6.8% (n = 16) with 81.25% HPV 16 positive and 18.75% HPV 18 positive. Among VIA positive cases (n = 100), E6 oncoprotein was positive in 9% (p < .001). In histopathology confirmed chronic cervicitis, CIN I, CIN II, CIN III and invasive cervical cancer, E6 test was positive for 2.8%, 4.7%, 25%, 50% and 100% respectively. E6 oncoprotein test had the highest specificity and Positive Predictive Value (PPV; 97% and 75%) compared to VIA (42% and 18%), cytology (95% and 46%) and colposcopy (94% and 59%). Sensitivity of the E6 oncoprotein test for detection of CIN3+ was significantly higher than that of cytology (52% VS 25%) but lower than that of VIA (52% VS 74%). ConclusionsThe HPV E6 oncoprotein test is highly specific and is an effective triage test to reduce colposcopy referrals for the large number of false positive test outcomes seen with VIA.

Cost-effectiveness analysis of repeated self-sampling for HPV testing in primary cervical screening: a randomized study

BackgroundHuman papillomavirus (HPV) testing is recommended in primary cervical screening to improve cancer prevention. An advantage of HPV testing is that it can be performed on self-samples, which could increase population coverage and result in a more efficient strategy to identify women at risk of developing cervical cancer. Our objective was to assess whether repeated self-sampling for HPV testing is cost-effective in comparison with Pap smear cytology for detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) in increasing participation rate in primary cervical screening.MethodsA cost-effectiveness analysis (CEA) was performed on data from a previously published randomized clinical study including 36,390 women aged 30–49 years. Participants were randomized either to perform repeated self-sampling of vaginal fluid for HPV testing (n = 17,997, HPV self-sampling arm) or to midwife-collected Pap smears for cytological analysis (n = 18,393, Pap smear arm).ResultsSelf-sampling for HPV testing led to 1633 more screened women and 107 more histologically diagnosed CIN2+ at a lower cost vs. midwife-collected Pap smears (€ 229,446 vs. € 782,772).ConclusionsThis study resulted in that repeated self-sampling for HPV testing increased participation and detection of CIN2+ at a lower cost than midwife-collected Pap smears in primary cervical screening. Offering women a home-based self-sampling may therefore be a more cost-effective alternative than clinic-based screening.Trial registrationNot registered since this trial is a secondary analysis of an earlier published study (Gustavsson et al., British journal of cancer. 118:896-904, 2018).

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

Background/ObjectiveHuman papillomavirus (HPV) genotyping and cytology have been recommended for colposcopy triage, but it is unclear which combinations of high-risk HPV (hrHPV) types and cytology with various thresholds provide clinically useful information for the triage after primary HPV screening on self-collected samples.MethodChinese Multi-site Screening Trial (CHIMUST) database focused on self-collected samples was reviewed using the results of Cobas4800 HPV assay. Absolute risks of each genotype for cervical intraepithelial neoplasia 2 or worse/ 3 or worse (CIN2+/CIN3+) were calculated. Triage of atypical squamous cells of undetermined significance (ASCUS) or worse cytology was used as the comparator, and diagnostic accuracy for paired comparisons between algorithms was obtained using McNemar’s test.ResultsA total of 10, 498 women were included, the overall prevalence of hrHPV, HPV16, HPV18, and Other hrHPV genotypes were 13.7%, 2.4%, 0.8%, and 10.5%, respectively. HPV16-positive women had the highest absolute risk among various genotypes for CIN2+/CIN3+ whether in normal or abnormal cytology (ASCUS or worse) and among all age groups. When compared with the comparator, combining HPV16 positivity and/or high-grade squamous intraepithelial lesion (HSIL) or worse yielded higher specificity (97.7% vs. 97.0%, p<0.0001), similar sensitivity (90.7% vs. 96.3%, p = 0.256) for detection of CIN3+, and a decrease in colposcopy referral rate from 3.5% to 2.7%, similar results were found for CIN2+. Positivity for HPV16 and/or (ASCUS or worse), and positivity for (HPV16 and/or HPV18) and/or (ASCUS or worse) achieved favorable sensitivity compared with the comparator (80.6% and 81.3% vs. 70.1% respectively for CIN2+, p<0.0001; both 96.3% vs. 96.3% for CIN3+, p = 1.000), these algorithms would reduce the colposcopy referral rate to 5.0% and 5.6% respectively, compared with 13.7% of that for HPV alone.ConclusionsTriage of HPV-positive women on self-collected samples by combining HPV16 or HPV16/18 genotyping with different thresholds of cytology could provide tradeoffs in sensitivity for detecting cervical lesions and colposcopy referral rates, and tailor management in various circumstances of clinical practice.