High-risk Human Papillomavirus DNA Testing Research Articles

Aptima HPV messenger RNA testing and histopathologic follow‐up in women with HSIL cytology: A study emphasizing additional review of HPV‐negative cases

High-risk human papillomavirus (hrHPV) messenger RNA (mRNA) testing, the Food and Drug Administration-approved testing platform since 2013, has been increasing as a cervical screening alternative to hrHPV DNA testing methods. This study reports the largest routine clinical follow-up study reported to date of hrHPV mRNA cotesting and histopathologic follow-up results for women with high-grade squamous intraepithelial lesion (HSIL) cytology results. HSIL Papanicolaou test results for women cotested with Aptima hrHPV mRNA testing between June 2015 and November 2020 were analyzed along with recorded histopathologic follow-up results within 6 months of screening. Aptima hrHPV mRNA-positive results were reported for 95.2% of the cotested HSIL cytology cases (905 of 951). Histopathologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was diagnosed on follow-up in 538 of 701 hrHPV mRNA-positive cases (76.8%) and in 15 of 36 hrHPV mRNA-negative cases (41.7%). Additional reviews of the hrHPV mRNA-negative HSIL cases showed variable interpretations, and confirmatory blinded-review interpretations of HSIL or atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion were more likely in cases with histopathologic CIN2+ (77.5% [93 of 120]) than those with cervical intraepithelial neoplasia grade 1 or negative findings (63.1% [101 of 160]; P < .01). This large routine-clinical-practice study confirms the previously reported high sensitivity of hrHPV mRNA testing for the detection of high-grade cervical dysplasia and cervical cancers. The blinded-review findings indicate that additional cytology review may be helpful for confirming an interpretation of HSIL in daily practice, especially for hrHPV-negative HSIL cases.

Diagnostic accuracy of cervical cancer screening and screening-triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study.

Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen-triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. WLHIV aged 25-50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol's iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%-52.7%) and CIN3+ (56.1%, 95% CI 43.3%-68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%-81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%-93.2%) for CIN2+ and 86.4% (95% CI 75.7%-93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%-58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%-76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%-86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28-2.32; CIN3+: 1.18, 95% CI 0.94-1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%-77.9%; CIN3+: 80.8%, 95% CI 67.5%-90.4%) and specificity (81.6%, 95% CI 77.6%-85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%-91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%-47.1%; relative specificity = 0.57, 95% CI 0.52-0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%-3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%-3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%-1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.

Comparing Anal Cancer Screening Algorithms Using Cytology and Human Papillomavirus DNA Testing in 3 High-Risk Populations.

Screening strategies for high-risk human papillomavirus (hrHPV)-associated anal cancer are evolving. Herein, we compare anal cytology to hrHPV DNA testing and 2 novel cytology/hrHPV cotesting algorithms among 3 high-risk populations. Anal cytology, hrHPV DNA testing, and high-resolution anoscopy (HRA)-guided biopsy results were analyzed from 1837 participants (1504 HIV-infected men who have sex with men (MSM), 155 HIV-uninfected MSM, and 178 HIV-infected women). Performance to detect histological high-grade squamous intraepithelial lesions (HSIL)/cancer was compared between 4 strategies with distinct HRA referral thresholds: cytology (atypical squamous cells of undetermined significance, ASCUS); hrHPV testing (any hrHPV positive); algorithm A (benign cytology/HPV16/18 positive or ASCUS/hrHPV positive); and algorithm B (benign or ASCUS/hrHPV positive). Histological HSIL/cancer was detected in 756 (41%) participants. Cytology had the lowest sensitivity (0.76-0.89) but highest specificity (0.33-0.36) overall and for each subgroup. Algorithm B was the most sensitive strategy overall (0.97) and for MSM (HIV-infected 0.97; HIV-uninfected 1.00). For women, hrHPV testing and both algorithms yielded higher sensitivity than cytology (0.96, 0.98, and 0.96). Specificity was low for all strategies/subgroups (range, 0.16-0.36). Screening algorithms that incorporate cytology and hrHPV testing significantly increased sensitivity but decreased specificity to detect anal precancer/cancer among high-risk populations.

P16INK4a/ki67 Immunocytochemistry in Improving the Predictive Value for High Grade Cervical Intraepithelial (≥CIN2) Neoplasia in Pap Smear.

Introduction:Cervical cytology has limited sensitivity to detect cervical pre-cancerous lesions. High-risk human papillomavirus (hr-HPV) DNA testing has high sensitivity but its specificity is limited. This study was done to assess the utility of p16INK4a/ki-67 dual stained cytology in improving the predictive value for high-grade cervical (CIN2+) lesions.Aim/Objective:To assess the significance of P16/Ki-67 immunocytochemistry in improving the predictive value for high-grade cervical intraepithelial (≥CIN 2+) lesions on Pap smear.Material and Methods:This was a prospective diagnostic study that included 93 patients with ASC-US/LSIL/ASC-H and HSIL on thin prep cervical smears and who also underwent hr-HPV DNA test and colposcopy-guided biopsy. Biopsy was the gold standard against which the performance of P16INK4a/Ki-67 and hr-HPV results were compared.Results:In women of all ages, sensitivity of (96.8%) hr-HPV test and p16/Ki-67 dual immunocytochemistry (≥1 positive cell) were similar and negative predictive value (NPV) was (97.1% vs. 97.9%) but the latter test showed better specificity (69.4% vs. 53.2%) and positive predictive value (PPV, 61.2% vs. 50.8%) for ≥CIN 2 lesions. A higher cut off of at least 10 positive cells gives a higher specificity and PPV, with slightly decreased sensitivity and NPV.Conclusion:Because high-risk HPV test has a high sensitivity and NPV, whereas P16/Ki-67 dual immunocytochemistry (≥10 positive cells) has a high specificity and PPV, the latter can be recommended as an ancillary test in hr-HPV-positive women to reduce the number of women going for colposcopy and biopsies.

Therapeutic Efficacy of a Coriolus versicolor-Based Vaginal Gel in Women with Cervical Uterine High-Risk HPV Infection: A Retrospective Observational Study.

A Coriolus versicolor-based vaginal gel is available for treating women with cervical uterine high-risk human papillomavirus (HPV) infection through re-epithelizing and re-balancing microbiota actions. A longitudinal retrospective observational study was performed to evaluate efficacy and safety of the gel. Women treated with Coriolus versicolor-based vaginal gel were compared with women not treated with the gel. Both groups were monitored for HPV infection by an HPV DNA test, Pap smear (cytology) and colposcopy at baseline and after 6months. Overall, 183 high-risk HPV positive women were enrolled (97 treated and 86 controls). After 6months, the HPV DNA test became negative in 67.0% versus 37.2% of treated and controls, respectively (p < 0.0001). Furthermore, 76.1% versus 40.8% registered a colposcopy improvement (p = 0.0005) and 60.4% versus 40.8% showed a remission (p = 0.05), for treated versus controls, respectively. Regarding to cytology, 78.5% of treated versus 37.7% of controls registered an improvement, while 70.8% of treated versus 34.8% of controls had a remission (p < 0.0001 for both variables). At multivariate analyses adjusted for age, smoking habit, and use of estroprogestinic pill, compared to controls, women treated with the gel showed a significantly higher likelihood to experience the clearence of HPV DNA (OR 4.81; 95% 2.43-9.53), and remission at colposcopy (OR 2.30; 95% 1.00-5.31), and cytology (OR 5.13; 95% 2.40-10.96) at 6months. No adverse event was reported during the follow-up. The use of a Coriolus versicolor-based vaginal gel in high-risk HPV patients is safe and effective based on all examined tests.

HrHPV testing vs liquid-based cytology in cervical cancer screening among women aged 50 and older: a prospective study

IntroductionEvidence supports high-risk human papilloma virus (HPV) testing as the primary cervical cancer screening tool. However, benefits and harms should be carefully considered before replacing liquid-based cytology. In women age...

Novel concepts in cervical cancer screening: a comparison of VIA, HPV DNA test and p16INK4a/Ki-67 dual stain cytology in Western Kenya

BackgroundScreening of unvaccinated women remains essential to mitigate the high morbidity/mortality of cervical cancer. Here, we compared visual inspection with acetic acid (VIA), recommended by WHO as the most cost-effective screening approach in LMICs, with HPV-based screening, and usage of p16INK4a/Ki-67 dual stain cytology.MethodsWe prospectively enrolled women participating in a VIA-based cervical cancer screening program in two peri-urban health centers of Kenya. Consenting women had a VIA examination preceded by collection of a liquid-based cytology sample from the cervix stored in PreservCyt medium (Hologic®). Analysis of all samples included a hrHPV DNA test and evaluation of a p16INK4a /Ki-67 (CINtecPLUS®) dual stained slide that was prepared using the ThinPrep® 2000 Processor and evaluated by a pathologist trained in the methodology.ResultsIn 701 of a total of 800 women aged 18–64 years, all three investigations were performed and data could be analyzed. The HPV, VIA and dual stain cytology positivity were 33%, 7%, and 2% respectively. The HPV positivity rate of VIA positive cases was 32%. The five most common HPV types were HPV16, 52, 68, 58 and 35. The OR among HIV infected women of an HPV infection, VIA positivity and positive dual stain cytology were 2.6 (95%CI 1.5–4.3), 1.9 (95%CI 0.89–4.4) and 3.4 (95%CI 1.07–10.9) respectively. The sensitivity of VIA to detect a p16INK4a/Ki-67 positive transforming infection was 13% (95%CI 2–38).ConclusionsPrimary HPV testing appears feasible and should be considered as a primary screening test also in LMICs. The poor sensitivity of VIA renders it unsuitable as a triage test for HPV positive women. The utility of p16INK4a/Ki-67 dual stain cytology as a triage test for HPV positive women in LMICs should be further studied.

CyclinA1 Promoter Methylation in Self-Sampling Test.

Background:Self sampled HPV testing is a cervical cancer screening method . However, cytology in self-sampled specimen cannot be used as a triage test. Therefore, other methods for triage should be considered. CyclinA1 (CCNA1) promoter methylation has strong association with cervical precancerous and cancerous lesion. The objective of this study was to compare the diagnostic value of CCNA1 and self-sampled specimen for detecting high-grade cervical intraepithelial lesions or worse (CIN2+). Materials and Methods:A cross sectional study was conducted. Women with abnormal cytology or positive for high risk HPV (hrHPV) indicated for colposcopic examination were enrolled. Self-collected sampling for hrHPV DNA (SS-HPV) and CCNA1 were performed. hrHPV DNA testing was done by Cobas 4800 method. CCNA1 promoter methylation was detected by CCNA1 duplex methylation specific PCR. Histopathologic result as CIN2+ obtaining from colposcopic directed biopsy or excisional procedure was considered as positive a gold standard. The results of hrHPV and CCNA1 were reported as positive or negative. Sensitivity specificity, positive predictive value, and negative predictive value of SS-HPV and CCNA1 were calculated by comparing the results with the gold standard. Results:Two hundreds and eighty women were recruited. High-grade cervical lesions and cervical cancer (CIN2+) were diagnosed in 21.8% (61 cases) of the patients. The most common type of hrHPV was non 16, 18 subtype, followed by HPV16 and 18. CCNA1 was positive in 13 patients out of whom, twelve were CIN2+. Sensitivity of CCNA1 was 19.7 % and its specificity and accuracy were 99.5% and 82.14%, respectively. The sensitivity of SS-HPV was 70.5%, and its specificity and accuracy were 39.2% and 43.3%, respectively. Conclusion: Due to high specificity and positive predictive value of CCNA1, it can be used as alarming sign of having high-grade cervical intraepithelial lesions, especially in patient who has positive hrHPV DNA test based on self-collected sampling.

Cost effectiveness of strategies for cervical cancer prevention in India.

The establishment of link between high-risk human papillomavirus (HPV) infection and occurrence of cervical cancer has resulted in development of various HPV related control strategies for the prevention of cervical cancer. The objective of the present study was to assess the cost effectiveness of various screening strategies for cervical cancer and human papilloma virus (HPV) vaccination in India. A Markov model based on societal perspective was designed to estimate the lifetime costs and consequences of screening (with either visual inspect with acetic acid (VIA), Papanicolaou test or HPV DNA test at various time intervals) in a hypothetical cohort of 30–65 years age women or vaccination among adolescent girls. Diagnostic accuracy of the screening strategies, efficacy of HPV vaccination and data on transition probabilities was based on the results of the existing meta-analyses. Primary data was collected for assessing per person cost of screening, cost of treating cervical cancer and quality of life. We found that introduction of different screening strategies leads to reduction in lifetime occurrence of cervical cancer cases caused by HPV 16/18 from 20% to 61%, and cervical cancer deaths from 28% to 70%, as compared to no screening. Among various screening strategies, screening with both VIA 5 yearly and VIA 10 yearly came out to be cost effective at 1-time per capita GDP, with VIA every 5 years providing greater health benefits as compared to VIA 10 years. Hence, screening with VIA 5 years at an incremental cost of US$ 829 (INR 54,881) per QALY gained is the recommended strategy for India. Further, with regards to HPV vaccination, it leads to 60% reduction in cancer cases and mortality caused by HPV 16/18 as compared to no vaccination. Moreover, when this vaccinated cohort of adolescent girls is also screened later in their life (with VIA every 10 years and VIA 5 years), it leads to 69%-76% reduction in cancer cases and 71%-81% reduction in cancer deaths. As compared to no vaccination and no screening, both HPV vaccination alone and vaccination plus screening (with VIA every 5 yearly and VIA 10 yearly) appears to be cost effective with ICERs in the range of US$ 86 (INR 5,693) to US$ 476 (INR 31,511) per QALY gained. In the long run, when the cohort of adolescent girls, who were immunized for HPV, reach the age of 30 years, the screening frequency using VIA should be determined based on the coverage of HPV vaccination in that cohort.

Evaluation of a Chip-Based, Point-of-Care, Portable, Real-Time Micro PCR Analyzer for the Detection of High-Risk Human Papillomavirus in Uterine Cervix in India.

PURPOSECurrently available human papillomavirus (HPV) detection devices are expensive, requiring a continuous power supply, high-priced reagents, skilled laboratory personnel, and infrastructure. These make it difficult to implement primary HPV screening in high-risk (HR) populations, particularly in low-income settings such as in India. The objective of our study was to evaluate the diagnostic performance of a point-of-care, portable, battery-operated device called Truenat, which detects 4 HR HPV genotypes (16, 18, 31, and 45), as a potentially cost-effective alternative to conventional HPV diagnostic tests.PATIENTS AND METHODSThis was a single-site, blinded, cross-sectional study that evaluated the performance of the Trunat HPV-HR using cervical samples collected from nonpregnant women > 30 years old via consecutive sampling. The comparison was conducted against the Hybrid Capture 2 (HC2) method. All the positive samples were validated by 14 Real-TM Quant Kit.RESULTSOf 615 cervical samples, the HR-HPV DNA test was positive in 78 women (12.7%) by HC2 and in 49 (8%) by Truenat. With the consideration of limited genotype inclusivity, the sensitivity and specificity of Truenat HPV-HR were 97.7% and 98.9%, respectively.CONCLUSIONThe performance of Truenat HPV-HR test was comparable to that of HC2 in the 4 HPV genotypes and would be appropriate to consider for use in primary HR cervical cancer screening and particularly in low-income settings.

The role of body mass index in incidence and persistence of cervical human papillomavirus infection

PurposeThis study aimed to assess the association between body mass index and incident or persistent cervical high-risk human papillomavirus (hrHPV) infection. MethodsThis cohort study included 6809 women from the general Danish population who participated in two clinical visits (in 1991–1993 and in 1993–1995). Height and weight were measured by nurses, lifestyle data were obtained by structured interviews, and cervical cytology samples were obtained for hrHPV DNA testing. We conducted log-binomial regression to estimate risk ratios (RRs) with 95% confidence intervals (CIs) of incident and type-specific persistent hrHPV infection according to body mass index, adjusting for age, education, smoking, and the number of sexual partners in the past year. ResultsWe found no increased risk of incident hrHPV infection in women who were underweight (RRadjusted, 0.97; 95% CI, 0.64–1.48), overweight (RRadjusted, 0.98, 95% CI, 0.82–1.17), or obese (RRadjusted, 0.93; 95% CI, 0.63–1.36) compared with women of normal weight. The risk of hrHPV persistence was similar in overweight (RRadjusted, 0.98; 95% CI, 0.71–1.34) and obese (RRadjusted, 1.00; 95% CI, 0.56–1.79) women compared with women of normal weight, whereas underweight women had a lower risk (RRadjusted, 0.32; 95% CI, 0.11–0.95). ConclusionsOverweight and obesity were not associated with HPV incidence or persistence when adjusting for sexual behavior.

Improved Rates of Cervical Cancer Screening Among Transmasculine Patients Through Self-Collected Swabs for High-Risk Human Papillomavirus DNA Testing.

Introduction: Nearly all cervical cancer cases are caused by one of several high-risk strains of the human papillomavirus (hr-HPV). Transmasculine (TM) individuals (persons who have a masculine spectrum gender identity, but were recorded female at birth) have low adherence to standard cervical cancer screening modalities. Introduction of self-collected vaginal swabs for hr-HPV DNA testing may promote initiation and adherence to cervical cancer screening among TM individuals to narrow screening disparities. The purpose of this study was to assess the rate of cervical cancer screening among TM individuals following the introduction of self-collected swabbing for hr-HPV DNA testing in comparison to clinician-administered cervical specimen collection.Methods: Rates of uptake and adherence to cervical cancer screening among TM individuals were assessed before and after the clinical introduction of self-collected swab testing in October 2017. Rates were compared with the rates of cervical cancer screening among cisgender women at a colocated Comprehensive Health Program during the time period of review.Results: Of the 121 TM patients seen for primary care in the 6-month baseline period before the October 2017 introduction of self-collected swabbing for hr-HPV DNA testing, 30 (25%) had cervical cancer screening documented in the electronic medical record. Following the implementation of self-swabbing, of 193 patients, 98 (51%) had a documented cervical cancer screening, a two-fold increase in the rates of adherence to cervical cancer screening (p<0.001).Conclusion: Self-collected swab testing for hr-HPV can increase rates of adherence to screening recommendations among an otherwise under-screened population.

Negative Predictive Value of Human Papillomavirus Testing: Implications for Anal Cancer Screening in People Living with HIV/AIDS.

Objectives People living with HIV/AIDS (PLWHA) have an increased incidence of anal squamous cell carcinoma. Since high-risk human papillomavirus (hrHPV) is the primary cause, hrHPV DNA testing may play an important role in anal cancer screening. This study aims to determine the negative predictive value (NPV) of hrHPV testing in PLWHA as well as factors that may lead to false-negative results. Methods Anal swabs were collected for cytology and Cobas® 4800 HPV test for 14 hrHPV types. Patients underwent concomitant high-resolution anoscopy (HRA) examination and biopsy. High-grade squamous intraepithelial lesions (HSIL, synonymous with anal intraepithelial neoplasia AIN2 and 3) detected in Cobas-negative patients were genotyped for 22 HPV types using BioPerfectus Multiplex Real-time PCR. Results 156 PLWHA tested negative for hrHPV on anal swab samples (i.e., Cobas-negative). HRA-guided biopsy detected HSIL/AIN3 in 13 patients (8%, NPV 92%), HSIL/AIN2 in 5 patients (3%), low-grade squamous intraepithelial lesions in 82 (LSIL, 53%), or benign findings in 56 (36%). No cancer was found. The HSIL group was similar to the LSIL/benign group regarding age, gender, race/ethnicity, clinical HIV parameters, cytological diagnoses, history of receptive anal sex, and smoking (p ≥ 0.02). Genotyping HSIL tissue derived from Cobas-negative patients revealed hrHPV (n=7), possibly carcinogenic HPV53, 67, 73, 82 (n=12), or absence of hrHPV (n=4). Conclusions In this series, anal hrHPV DNA testing offered 92% NPV for PLWHA; in other words, a 8% risk of occult precancer remains for those who test hrHPV negative on anal swab samples.

Outcomes in women with biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal cervix and related cofactors: A 15-year population-based cohort study from China

ObjectiveTo estimate long-term outcomes of biopsy-confirmed cervical intraepithelial neoplasia grade 1 (CIN1) or normal cervix and identify the cofactors during disease progression. MethodsIn 1999, a cervical cancer screening cohort in Shanxi, China, enrolled 1997 women aged 35–45. They were followed up at year 6, 11, and 15 after enrollment with high-risk human papillomavirus (hrHPV) DNA testing, liquid-based cytology, and visual inspection with acetic acid. Progression, persistence, and regression rates were calculated, stratified by baseline hrHPV and cytological status. Risk factors associated with hrHPV acquisition, persistence, and progression were examined. ResultsThe cumulative rates of progression to CIN2+ among CIN1 over 6, 11, and 15 years were 7.5%, 21.4%, and 24.0%, respectively; the regression rates to normal cervix were 85.0%, 76.7%, and 72.9%, respectively. Over 6, 11, and 15 years, 0.7%, 2.9%, and 5.2% of normal cervix developed CIN2+, respectively, but over 90% remained normal after 15 years. CIN1 or normal cervix positive for hrHPV had significantly higher progression rates to CIN2+ than those without hrHPV. Similarly, the severity of cytological status was found to be associated with an increased risk of developing CIN2+. Women who had an earlier sexual debut were at a higher risk of acquiring new HPV infection and repeated HPV infections. ConclusionsClinical follow-up strategies for women with CIN1 or normal cervix could be adjusted accordingly based on hrHPV/cytology status.

Sensitivity and specificity values of high-risk HPV DNA, p16/ki-67 and HPV mRNA in young women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL).

The aim of the study was to evaluate the sensitivity and specificity values of high-risk HPV DNA test, p16/ki-67, and HPV mRNA in histologically high-grade cervical intraepithelial lesions (CIN2-CIN3) in women aged 21-24 years with diagnosis of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) at pap smear. 342 patients between 21-24 years old, attending spontaneously our clinics, 118 with ASCUS and 224 with LSIL, were enrolled in the study. All patients underwent colposcopy and biopsies were performed in the areas with major changes. All patients were tested at the same time for p16/ki-67, high-risk HPV DNA and HPV mRNA. Nineteen out of 118 women with ASCUS showed a high-grade cervical intraepithelial lesion, 11 out of 118 (9.32%) CIN2, and 8 out of 118 (6.78%) CIN3. The sensitivity of high-risk HPV DNA was 99.9%, and the specificity 23.2%; p16/ki-67 pointed out a sensitivity of 90.9%, and a specificity of 81.8%; HPV mRNA showed a sensitivity of 81.8%, and specificity of 87.9% in CIN2 lesions. In CIN3 lesions, the sensitivity of high-risk HPV DNA was 99.9%, while the specificity was 19.1%; p16/ki-67 showed a sensitivity of 99.9%, and a specificity of 73.7%; HPV mRNA relived a sensitivity of 87.5%, and a specificity of 80.8%. In women with LSIL, a total of 42/224 (18.75%) of CIN2 were found at the histopathological examination, while 17/224 (7.59%) women presented a CIN3. No case of invasive cancer was identified. High-risk HPV DNA was positive in 190/224 (84.8%), p16/ki-67 in 119/224 (53.1%), and HPV mRNA in 104/224 (46.4%). In women with CIN2, the sensitivity of high-risk HPV DNA was of 92.8%, and the specificity 17.5%, the sensitivity of p16/ki-67 was 95.2%, and specificity 61.8%. HPV mRNA showed a sensitivity of 88.8% and a specificity of 87.8%. In women with CIN3, the sensitivity of high-risk HPV DNA was 88.2%, and the specificity 29.7%; p16/ki-67 pointed out a sensitivity of 94.1%, and a specificity of 49%; HPV mRNA showed a sensitivity of 88.2% and a specificity of 80.6. Taking into account the high rate of spontaneous regression of high-grade lesions in young women, these tests, in particular, the HPV mRNA test, used as a triage test for ASCUS or LSIL, can modify follow-up triage strategy. In fact, this biomarker, due to its high specificity, could lead to a cytology repetition instead of an immediate colposcopy, avoiding over diagnosis and potential overtreatment in this category of women.

Clinical and Economic Value of p16INK4a for the Differential Diagnosis of Morphologic Cervical Intraepithelial Neoplasia 2.

The detection of high-grade intraepithelial lesions requires highly sensitive and specific methods that allow more accurate diagnoses. This contributes to a proper management of preneoplastic lesions, thus avoiding overtreatment. The purpose of this study was to analyze the value of immunostaining for p16 in the morphologic assessment of cervical intraepithelial neoplasia 2 lesions, to help differentiate between low-grade (p16-negative) and high-grade (p16-positive) squamous intraepithelial lesions. The direct medical cost of the treatment of cervical intraepithelial neoplasia 2 morphologic lesions was estimated. A retrospective observational cross-sectional study was carried out. This study analyzed 46 patients treated with excisional procedures because of cervical intraepithelial neoplasia 2 lesions, using loop electrosurgical excision procedures. Immunostaining for the biomarker was performed. For the estimation of overtreatment, percentages (%) and their 95% confidence interval were calculated. Of the 41 patients analyzed, 32 (78%) showed overexpression of p16 and 9 (22%) were negative (95% confidence interval, 11%-38%). Mean follow-up was 2.9 years, using cervical cytology testing (Pap) and colposcopy. High-risk human papillomavirus DNA tests were performed in 83% of patients. These retrospective results reveal the need for larger biopsy samples, which would allow a more accurate prediction of lesion risk. Considering the cost of p16 staining, and assuming the proper management of the low-grade lesion, an average of US$919 could be saved for each patient with a p16-negative result, which represents a global direct cost reduction of 10%.

High-Risk HPV Testing in Primary Screening for Cervical Cancer in the Public Health System, São Paulo, Brazil

Every year there are approximately 16,000 new cases of cervical cancer in Brazil. Novel screening technologies may reduce this number by expanding the population coverage but also by improving the detection rate of precursor lesions. We aimed to evaluate human papillomaviruses (HPV)-DNA testing in the context of routine cervical cancer screening in the public health system of the city of São Paulo, Brazil. Women participating in the primary screening program were invited to enroll. Liquid-based cytology samples were collected and cytology and Hr-HPV DNA testing were performed in parallel. Cytologists were blind to HPV results. Women older than 24 years with a positive high-risk HPV test and/or cytology class ≥ ASC-US were referred to colposcopy. From December 2014 to December 2016, 16,102 women joined the study. High-risk human papillomavirus (HR HPV) DNA prevalence was 14.9%, whereas cytologic abnormalities were found in 7.2% of the women. Per protocol, 1,592 Hr-HPV+ women, in addition to 72 patients with cytologic classification > low-grade squamous intraepithelial lesion (LSIL) were referred. A total of 80 cervical intraepithelial neoplasia (CIN2+) cases were diagnosed, 79 were Hr-HPV DNA+ and 18 had normal cytology. Hr-HPV DNA detected a significant number of patients with premalignant lesions missed by cytology and all 16 CIN3+ cases were Hr-HPV DNA+ HPV genotyping may be useful in the management of Hr-HPV+ women, reducing the burden of colposcopic referral for those harboring genotypes with a weaker association to CIN3+ Use of HPV-DNA testing was shown to be feasible and advantageous over current cytologic screening in the public health system.

Long-term observational approach in women with histological diagnosis of cervical low-grade squamous intraepithelial lesion: an Italian multicentric retrospective cohort study

ObjectiveTo evaluate the risk of progression to high-grade squamous intraepithelial lesion (HSIL) (CIN2-3) or invasive cancer in women with histopathological diagnosis of low-grade squamous intraepithelial lesion (LSIL) (CIN1), managed in...

Comparison of detection rate of high risk HPV infection between self-collected HPV testing and clinician-collected HPV testing in cervical cancer screening

to correlate the detection rate of high risk HPV (HR-HPV) DNA between self-collected and clinician-collected testing. A cross-sectional analytic study was conducted in 400 women undergoing cervical cancer screening program during February and May 2015. The procedure began with self-collected method and then clinician-collected method. Then, the specimens were processed and interpreted with the same technique. If the results from either methods were positive for HPV genotype 16 or 18, colposcopy was performed. We also conducted cytology testing for the participants. If the results were abnormal (ASC-US+), colposcopy was also performed. The detection rate of HR-HPV DNA was 10.0% and 7.5% by self-collected and clinician-collected specimen, respectively (kappa=0.73). HR-HPV positive rate in cytology ASC-US+ was no significantly different between groups. HR-HPV DNAs were positive in every HSIL (100% detection rate). HPV DNA test positive for detection CIN+ was not significantly different between self-collected and clinician-collected testing. self-collected HPV testing can be used as an alternative option for primary cervical screening program. Detection rate of high grade lesion is similar to clinician-collected test.

HPV-ISH-Negative Invasive Cervical Squamous Cell Carcinoma: Histologic and Pap Test Results

Introduction: A causal link between infection with a high-risk strain of human papilloma virus (hrHPV) and the development of cervical squamous cell carcinoma (SCC) is well established. However, a small number of SCCs are hrHPV-negative by either HPV co-DNA testing and/or HPV-in situ hybridization (HPV-ISH) at the time of diagnosis. These apparently hrHPV-negative lesions are poorly understood, specifically whether hrHPV-positive precursor lesions exist, which would be detected through hrHPV-based screening. Methods: A search of the pathology archives at the Johns Hopkins Hospital identified women with a diagnosis of hrHPV-negative cervical SCC on surgical specimen. All prior pathologies, including cervical cytology and surgical pathology specimens, and associated hrHPV DNA test results, p16 immunohistochemistry, and HPV-ISH were reviewed. Results: A total of 25 women were identified having a surgical specimen diagnosed as SCC with either negative or equivocal HPV-ISH. Fifteen had a Pap test in the 6 months preceding a diagnosis of SCC, with cytology diagnoses as follows: high-grade squamous intraepithelial lesion n = 14/15; atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion n = 1/15. hrHPV co-testing was performed for 5 of these 15 women and was negative in 2/5 cases. Cervical biopsy was performed for 24 women. HPV-ISH testing, performed on 14 of the biopsy specimens, was negative for 11/14 patients. Of 15 specimens stained for p16, 14 were positive. Conclusion: A subset of patients exist in whom hrHPV is not detectable at or near the time of progression to SCC. Additional research is necessary to further describe this population and determine whether maintaining cytological screening would provide benefit.