Specificity For Cervical Intraepithelial Neoplasia Research Articles

Evaluation of Host Gene Methylation as a Triage Test for HPV-Positive Women-A Cohort Study.

This study was designed to evaluate the performance of a host gene methylation marker panel (ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671) in the triage of human papillomavirus (HPV)-positive women, its possible impact in a cervical cancer screening program, and the possible influence of the variation of the rate of HPV16/18 in its performance. Cohort study in which consecutive women referred for colposcopy in an organized cervical cancer screening program had repeated HPV testing, colposcopy, and biopsies. The women that remained HPV positive at the time of colposcopy were tested with the panel of DNA methylation markers. The performance of the test was evaluated and compared to standard practice. The study test had a sensitivity and specificity for cervical intraepithelial neoplasia (CIN) 2+ of 60.8% (49.1-71.6%) and 88.4% (83.2-92.5%), respectively. For CIN3+, it was of 78.0% (64.0-88.5%) and 86.0% (80.8-90.2%), respectively.The rate and level of methylation positively correlated with the severity of disease. The use of methylation reduces the referral for colposcopy to 25.5%, while detecting 78.0% of the CIN3+ cases. Referral of all HPV16/18-positive cases and triage of the other high-risk HPV-positive cases with methylation, detects 90.0% of the cases of CIN3+, while reducing the number of referrals to 43.2%.The variation in the rate of HPV16/18 does not relevantly affect the performance of the methylation panel. The studied methylation panel has a high sensitivity and specificity for CIN3+ and reduces the rate of referrals for colposcopy, without relevant variation according to the rate of HPV16/18.

Utility of Extended HPV Genotyping as Primary Cervical Screen in an Unscreened Population With High HIV Co-Infection Rate.

Screening with primary human papillomavirus (HPV) testing has been evaluated in highly prescreened populations with lower HPV and HIV prevalence than what is the case in South Africa. High prevalence of HPV and underlying precancer in women living with HIV (WLWH) affect the clinical performance of screening tests significantly. This study investigates the utility and performance of an extended genotyping HPV test in detection of precancer in a population with a high coinfection rate with HIV. A total of 1,001 women aged 25 to 65 years with no cervical cancer screening in the preceding 5 years were tested with cytology and primary extended genotyping HPV testing. The cohort of 1,001 women included 430 WLWH (43.0%) and 564 HIV-negative (56.3%) women. Abnormal cytology (atypical squamous cells of undetermined significance or higher) was significantly higher in WLWH (37.2% vs 15.9%) and high-grade squamous intraepithelial lesion or above (23.5% vs 5.2%). The WLWH also tested positive more often for any HPV type (44.3% vs 19.6%; p < .0001) The specificity for cervical intraepithelial neoplasia 2+ at 91.2% of a combination of HPV types, 16/18/45 (very high risk) and 31/33/58/52 (moderate risk), performed better than cytology or any HPV-positive result to predict cervical intraepithelial neoplasia 3+ on histology. The additional genotype information supports direct referral to treatment or colposcopy in a larger proportion of the screen-positive population. The potential contribution of extended genotyping is demonstrated. The ideal choice of sensitivity and specificity ultimately depends on the health budget. More information will allow a screening algorithm, guiding management according to risk.

Evaluation of the effectiveness of BMRT-HPV for cervical cancer screening

Objective: Evaluation of the clinical value of the BioPerfectus multiplex real time (BMRT)-HPV for cervical cancer screening. Methods: Physician-collected specimens of 1 495 women who were positive of Cobas 4800 HPV (Cobas-HPV), HPV genotyping based on SEQ uencing (SEQ-HPV), and (or) cytology ≥low grade squamous intraepithelial lesion (LSIL) in the primary screening of Chinese Multiple-center Screening Trial (CHIMUST), and 2 990 women selected from those who were negative of primary screening in the same project through nested control randomization with age-matching were tested for BMRT-HPV, which reported type-specific viral loads/10 000 cells in each specimen. With comparing to Cobas-HPV results and taking cervical histopathological diagnosis as the endpoint, the concordance of high-risk (HR)-HPV subtypes among the three assays was explored ,and the sensitivity and specificity of BMRT-HPV for cervical cancer screening were evaluated. Results: (1) The overall agreenment of HR-HPV subtypes between BMRT-HPV and Cobas-HPV, or SEQ-HPV test sample was 94.8%, 94.4%, with Kappa values 0.827, 0.814. (2) The sensitivity and specificity for cervical intraepithelial neoplasia (CIN) Ⅱ+ of BMRT-HPV, Cobas-HPV and SEQ-HPV were 92.62%, 94.26%, 93.44% and 84.67%, 83.25%, 82.76%, respectively. There were no significant difference in sensitivity among the three HPV assays (all P>0.05), but the specificity of BMRT-HPV for CIN Ⅱ+ was higher than those of Cobas-HPV and SEQ-HPV (P<0.01). The sensitivity for CIN Ⅲ+ of three HPV assays were all 100.00%, and the specificity for CIN Ⅲ+ of BMRT-HPV was higher than those of Cobas-HPV and SEQ-HPV (83.40% vs 81.95%, 83.40% vs 81.50%; P<0.01). The number of pathological examinations of colposcopy for cervical biopsy detected in 1 case of CIN Ⅱ+ or CIN Ⅲ+ in BMRT-HPV was less than those in Cobas-HPV and SEQ-HPV (P<0.01). When using HPV 16/18 + cytology ≥atypical squamous cell of undetermined signification (ASCUS) to triage HPV positive women among three assays, there was no different in the sensitivities of detecting CIN Ⅱ+ and CIN Ⅲ+ (P>0.05). The specificity BMRT-HPV was slightly higher than those in Cobas-HPV or SEQ-HPV (all P<0.05), and the colposcopy referral rate was lower than those in Cobas-HPV and SEQ-HPV (all P<0.05). Conclusions: BMRT-HPV is as sensitive as Cobas-HPV or SEQ-HPV for primary cervical cancer screening, and has higher specificity. Therefore it could be used as a primary screening method for cervical cancer, which is worthy of clinical application.

Performance of the Swede score to predict cervical intraepithelial neoplasia in women with HIV-1 in Johannesburg, South Africa.

To evaluate the performance of the Swede score to detect cervical intraepithelial neoplasia (CIN) in women with HIV-1 in Johannesburg, South Africa. A cross-sectional study using secondary data analysis from the HPV in Africa Research Partnership (HARP) study that compared the performance of three different screening tests to detect CIN. Colposcopy was performed on any woman who screened positive and findings were recorded using the Swede score. A biopsy of any lesion and a four-quadrant biopsy was taken. The score was evaluated against a histological diagnosis of >CIN1. The sensistivity, specificity, PPV and NPV for each score was calculated. Median age and CD4+ count of the 576 women eligible from the Johannesburg cohort was 34years (IQR, 30-39) and 427cells/mm3 (IQR, 323-579), respectively. Almost two-thirds (64%) were on ART and about 21% had CIN2+ on histology. A Swede score of 5 or greater had the best combination of sensitivity and specificity for CIN2+ with an AUC of 0.72 (95% CI, 0.68-0.76) corresponding to a sensitivity of 72.1 (95% CI, 63.5-79.6) and specificity of 71.8 (95% CI, 67.4-75.9). The Swede score can assist in determining whether women with HIV/AIDS should have treatment at the first colposcopy visit versus those who may be followed up, thereby individualizing treatment.

A Clinical Trial to Verify the Efficiency of the LC-1000 Exfoliative Cell Analyzer as a New Method of Cervical Cancer Screening

Objective: The exfoliative cell analyzer, LC-1000 (Sysmex Corporation, Japan), is a medical device that presents the cell proliferation index and 23 research parameters as indicators of cellular proliferative potential. The objective was to evaluate the clinical usability of qualitative assessment by LC-1000 compared with cytology, the human papillomavirus (HPV) test, and histology as gold standard. Study Design: Women that visited 3 sites between July 2015 and March 2017 were registered. The primary endpoint in this study was the comparison between LC-1000 measurement and HPV test for sensitivity and specificity for cervical intraepithelial neoplasia 2+ (CIN2+). A tree model algorithm was newly constructed by a statistical method and its relationship with histological results was evaluated. Results: The sensitivity and specificity of LC-1000 were 78.3 and 74.1%, while those of the HPV test were 94.7 and 85.4%, respectively. A tree model comprising five categories was constructed. The proportion of advanced lesions was higher with the change in the rank classification results from 1 to 5. The positive predictive values of CIN2+ in the categories 4 and 5 were high. Despite the small number of subjects, cancer was undetected in categories 1 and 2. In addition, the comparison with follow-up results in 19 women assessed as CIN1 showed that the rate of progression in the categories 3–5 was 50% (7/14); progression in the categories 1 and 2 was 0% (0/5). Conclusions: LC-1000 may be useful for cervical cancer screening as an index to qualitatively evaluate CIN and cancer based on the changes in characteristics of cells.

The potential of biobanked liquid based cytology samples for cervical cancer screening using Raman spectroscopy.

Patient samples are unique and often irreplaceable. This allows biobanks to be a valuable source of material. The aim of this study was to assess the ability of Raman spectroscopy to screen for histologically confirmed cases of Cervical Intraepithelial neoplasia (CIN) using biobanked liquid based cytology (LBC) samples. Two temperatures for long term storage were assessed; 80°C and -25°C. The utility of Raman spectroscopy for the detection of CIN was compared for fresh LBC samples and biobanked LBC samples. Two groups of samples were used for the study with one group associated with disease (CIN 3) and the other associated with no disease (cytology negative). The data indicates that samples stored at -80°C are not suitable for assessment by Raman spectroscopy due to a lack of cellular material and the presence of cellular debris. However, the technology can be applied to fresh LBC samples and those stored at -25°C and is, moreover, effective in the discrimination of negative samples from those where CIN 3 has been confirmed. Pooled fresh and biobanked samples are also amenable to the technology and achieve a similar sensitivity and specificity for CIN 3. This study demonstrates that cervical cytology samples stored within biobanks at temperatures that preclude cell lysis can act as a useful resource for Raman spectroscopy and will facilitate research and translational studies in this area.

Evaluation of a multiplex real time PCR assay for the detection of human papillomavirus infections on self-collected cervicovaginal lavage samples

Self-collection of cervical samples for human papillomavirus (HPV) testing can help to raise the participation rate in cervical cancer screening among non-responders. This study was conducted to compare the analytical and clinical performance of the Abbott RealTime High-Risk HPV Test (RealTime) with the Hybrid Capture 2 assay (HC2) on self-collected cervicovaginal lavage samples. One hundred samples from women referred for colposcopy (reference smears and biopsies in case of abnormalities) were included. Fifty-seven women had a normal cytology, 27 had low grade and 16 had high grade squamous intraepithelial lesions. Fourteen of 49 biopsies (28.6%) were benign, 14 (28.6%) cervical intraepithelial neoplasia 1, 11 (22.4%) cervical intraepithelial neoplasia 2, 8 (16.3%) cervical intraepithelial neoplasia 3 and 2 (4.1%) invasive cancer. The agreement between RealTime and HC2 in the self-collected and in the reference samples was 85% (κ=0.665) and 83% (κ=0.620), respectively. The agreement between self-sampling and the reference smears was higher with RealTime (93%; κ=0.849) than with HC2 (89%; κ=0.741). In the self-collected samples, the sensitivity and specificity for cervical intraepithelial neoplasia 2 or worse of RealTime/HC2 were 81.0%/66.7% (p=0.25) and 53.6%/57.1%, respectively. The sensitivity for cervical intraepithelial neoplasia 3 or worse of RealTime and HC2 were 80.0% and 70.0% (p=1.0). The specificity for cervical intraepithelial neoplasia 3 or worse was 43.6% (RealTime) and 51.3% (HC2). This study shows that RealTime can be used for HR-HPV testing of self-collected lavage samples in a referral population with at least equal quality and performance as HC2.

Primary Cervical Cancer Screening and Triage Using an mRNA Human Papillomavirus Assay and Visual Inspection

Mexican Cervical Cancer Screening Study II (MECCS II) seeks to develop a highly sensitive and highly specific screening program able to be adapted to all socioeconomic levels in Mexico. The objectives of MECCS II are (1) to compare the sensitivity and specificity for cervical intraepithelial neoplasia (CIN) 3 or cancer of self-collected vaginal specimens tested for high-risk types of the human papillomavirus (HR-HPV) by APTIMA with those tested for HR-HPV by Hybrid Capture 2 (HC2); and (2) determine the efficacy of cryotherapy in the treatment of HR-HPV-positive and acetic acid-aided visual inspection (VIA)-positive and -negative women after VIA triage. The study was conducted in rural Mexico. Women aged 30 to 50 years, nonpregnant, with no history of hysterectomy or pelvic irradiation and varied histories of screening, participated. A direct endocervical sample was tested for cytology, HC2, and APTIMA assay (AHPV). Subjects positive on any test were recalled for triage VIA, biopsies, and immediate cryotherapy. Tests were compared using McNemar test. Two thousand forty-nine patients have complete results. Mean age of the patients was 39.2 years; 7.7% presented with ≥atypical squamous cells of uncertain significance (ASCUS), 1.8% ≥low-grade squamous intraepithelial neoplasia, and 0.5% ≥high-grade squamous intraepithelial neoplasia. Two percent of patients had ≥CIN2, and 0.78% had ≥CIN3 (including 2 with invasive disease). The sensitivity of ThinPrep (>ASCUS), HC2, and AHPV for >CIN3 for direct endocervical collection was 87.5%, 100%, and 100%, respectively. The specificity of ThinPrep (>ASCUS), HC2, and AHPV for >CIN3 was 94.1%, 92.2%, and 93.5%, respectively. Specificities of HC2 and AHPV differed significantly. The overall percentage of agreement among HPV assays (HC2 vs APTIMA) is 97%. Four hundred sixty-nine women returned for VIA. Two hundred ninety-one women were treated with cryotherapy. The specificity of the APTIMA assay along with high sensitivity is an advantage for primary screening. Follow-up evaluation will be important to determine the true impact of potential undertreatment in the screening algorithm. Self-sampling applications are explored.

Patient Safety and the Next Generation of HPV DNA TestsThe Authors’ ReplyPostscript

The article by Kinney et al1 in the August 2010 issue of the Journal expressed concern about the approval by the US Food and Drug Administration (FDA) of the Cervista HPV HR (high-risk human papillomavirus) test (Third Wave Technologies, Madison, WI; now owned by Hologic, Bedford, MA) and questioned the safety of the device owing to the positivity rate seen in the study population for women 30 years and older with negative cytologic findings (NILM ≥30). The clinical cutoff for the Cervista HPV HR test was set in the same manner as for the only other FDA-approved HR-HPV test, Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD), by evaluating clinical sensitivity and specificity in the population with atypical squamous cells of undetermined significance (ASC-US). The rationale for this approach is that the ASC-US population, as a population with equivocal cytologic findings, provides an informative profile of how an HPV test performs in an intended-use population in which disease prevalence is sufficient for characterizing a clinical cutoff and disease end points can be readily assessed. A head-to-head comparison against the HC2 test was performed during review of the Cervista HPV HR device. This evaluation revealed equivalent clinical specificity for cervical intraepithelial neoplasia (CIN) 2 or worse for the 2 tests in the Cervista ASC-US data set, and the Cervista HPV HR test detected 100% of cases of CIN 3 or worse. In determining whether an in vitro diagnostic device is safe and effective, the FDA must consider whether the probable benefits of using the device outweigh the probable risks when the device is used in accordance with its approved labeling. Per current screening guidelines,2 the predominant use of HPV testing in the NILM ≥30 population is to extend cervical cancer screening intervals in HPV– women. In a worst-case scenario in …