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To compare all available accuracy data on screening strategies for identifying cervical intraepithelial neoplasia grade ≥ 2 in healthy asymptomatic women, we performed a systematic review and network meta-analysis. MEDLINE and EMBASE were searched up to October 2020 for paired-design studies of cytology and testing for high-risk genotypes of human papillomavirus (hrHPV). The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, random-effects network meta-analysis of test accuracy, and GRADE rating. Twenty-seven prospective studies (185,269 subjects) were included. The combination of cytology (atypical squamous cells of undetermined significance or higher grades) and hrHPV testing (excepting genotyping for HPV 16 or 18 [HPV16/18]) with the either-positive criterion (OR rule) was the most sensitive/least specific, whereas the same combination with the both-positive criterion (AND rule) was the most specific/least sensitive. Compared with standalone cytology, non-HPV16/18 hrHPV assays were more sensitive/less specific. Two algorithms proposed for primary cytological testing or primary hrHPV testing were ranked in the middle as more sensitive/less specific than standalone cytology and the AND rule combinations but more specific/less sensitive than standalone hrHPV testing and the OR rule combination. Further research is needed to assess these results in population-relevant outcomes at the program level., (© 2022. The Author(s).)

Rationale: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC)., Patient Concerns: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its "endometrioid" morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive)., Diagnoses: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA., Interventions: The patient underwent total hysterectomy with lymph node dissection., Outcomes: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination., Lessons Subsections: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Visual inspection of the cervix with acetic acid is used to control the burden of cervical cancer in low- and middle-income countries. This method has some limitations and HPV DNA testing may be an alternative, but it is expensive and requires a laboratory setup. Cheaper and faster HPV tests have been developed. This study describe the agreement between a fast HPV test (careHPV) and hybrid capture 2 (HC2) in detection of high-risk HPV among Tanzanian women., Material and Methods: The study involved women attending routine cervical cancer screening at the Ocean Road Cancer Institute and Kilimanjaro Christian Medical Centre in Tanzania. The women were offered HIV testing. Two cervical samples were subsequently obtained; the first sample was processed at the clinics using careHPV and the second sample was transported to Denmark and Germany for cytology and HC2 analysis. Kappa statistic was calculated to assess the agreement between careHPV and HC2. The sensitivity, specificity and predictive values of careHPV were calculated using HC2 as reference. The analyses were done for the overall study population and stratified by testing site and HIV status., Results: A total of 4080 women were enrolled, with 437 being excluded due to invalid information, lack of careHPV or HC2 results. Overall agreement between the tests was substantial with a kappa value of 0.69 (95% confidence interval [CI] 0.66-0.72). The sensitivity and specificity of careHPV was 90.7% (95% CI 89.6-91.8) and 84.2% (95% CI 81.2-86.8), respectively. The agreement was similar in the stratified analyses where the kappa values were 0.75 (95% CI 0.70-0.79) in women aged 25-34, 0.66 (95% CI 0.62-0.70) in women aged 35-60, 0.73 (95% CI 0.70-0.77) at the Ocean Road Cancer Institute, 0.64 (95% CI 0.60-0.69) at the Kilimanjaro Christian Medical Center, 0.73 (95% CI 0.68-0.79) in HIV-positive and 0.66 (95% CI 0.63-0.70) in HIV-negative women. The kappa value of 0.64 (95% CI 0.39-0.88) for cervical high-grade lesions indicates a substantial agreement between careHPV and HC2 in detecting HPV among women with cervical high-grade lesions., Conclusions: A substantial agreement was found between careHPV and HC2 in detecting HPV overall as well as detecting HPV among women with cervical high-grade lesions. However, given the limited resources available in low and middle-income countries, the HPV testing assay should be weighed against the cost-effectiveness of the test., (© 2021 Nordic Federation of Societies of Obstetrics and Gynecology.)

The aim of this study was to investigate the prevalence of peritoneal human papillomavirus (HPV) infection in different clinical cervical cancer (CC) settings, and its association with potential clinical and/or histological factors. This is a single-center, prospective, observational study. Consecutive patients with newly diagnosed or recurrent/persistent CC, between March 2019 and April 2020, were included. A group of patients undergoing surgery for benign gynecological conditions was included as control group. All patients underwent HPV-DNA test in the cervix and in the peritoneal cavity simultaneously at time of surgery. Two-hundred seventy-two patients had cervical and peritoneal HPV test analyzed. Cervical and peritoneal HPV positivity (PHP) was found in 235 (88.0%) and 78 (28.7%) patients, respectively; the prevalence of PHP was 17.7% in early stage, 28.8% in locally advanced cervical cancer (LACC) and 46.6% in the metastatic/persistent/recurrent setting (P = .001). No control patient was found to have peritoneal HPV infection. Higher frequency of PHP was documented in patients with larger tumor size (P = .003), presence of cervical HPV 16/18 genotypes (P < .001), higher number of cervical high-risk (HR)-HPV per patient (P = .018) and peritoneal carcinomatosis (P < .001). Multivariate analysis demonstrated that lack of preoperative cervical conization in early stages (P = .030), while higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = .021) and presence of cervical HPV 16/18 (P = .001) in LACC, was associated with PHP. This is a proof-of-concept study. A number of potential clinical implications, including prognosis, could be obtained by further studies., (© 2020 Union for International Cancer Control.)

High-throughput HPV typing assays with increased automation, faster turnaround and type-specific digital readout would facilitate studies monitoring the impact of HPV vaccination. We evaluated the NanoString nCounter ® platform for detection and digital readout of 48 HPV types in a single reaction. NanoString (NS) used proprietary software to design CodeSets: type-specific probe pairs targeting 48 HPV types and the globin gene. We tested residual DNA extracts from epidemiologic specimens and defined samples (HPV plasmids at 10 to 10 4 copies/reaction) directly (No-PCR) as well as after L1 consensus PCR of 45 (PCR-45) or 15 cycles (PCR-15). Assay and interpretation followed NS recommendations. We evaluated analytic performance by comparing NanoString results for types included in prior assays: Roche Linear Array (LA) or HPV TypeSeq assay. No-PCR results on 40 samples showed good type-specific agreement with LA (k = 0.621) but sensitivity was 65% with lower limit of detection (LOD) at 10 4 plasmid copies. PCR-45 results showed almost perfect type-specific agreement with LA (k = 0.862), 82% sensitivity and LOD at 10 copies. PCR-15 results on 75 samples showed substantial type-specific agreement with LA (k = 0.796, 92% sensitivity) and TypeSeq (k = 0.777, 87% sensitivity), and LOD at 10 copies of plasmids. This proof-of-principle study demonstrates the efficacy of the NS platform with HPV CodeSet for type-specific detection using a low number of PCR cycles (PCR-15). Studies are in progress to evaluate assay reproducibility and analytic validation with a larger number of samples.

Introduction: Alternative methods of dry storage and transportation may be a viable alternative to the use of liquid storage medium for cervical samples, especially for screening programs in places with few resources., Objective: The objective of this study is to verify the viability and efficacy of human papillomavirus DNA (HPV-DNA) detection in cervical cell samples collected and stored on a Flinders Technology Associates (FTA) card (Whatman Indicating FTA® Elute Micro Card) and subsequently recovered in ethanol-based liquid medium and to compare the results to those obtained using samples stored directly in ethanol-based liquid medium., Study Design: Thirty-four women submitted to ETZ (excision of the transformation zone of the cervix) were included in this study. Before ETZ, 2 samples of exfoliated cervical cells were collected from each woman by a doctor and stored in ethanol-based liquid medium and on an FTA card. DNA recovery from FTA samples was performed using ethanol-based liquid medium. Detection of HPV-DNA in the samples was performed using the Cobas® 4800 HPV Test Platform., Results and Conclusions: The HPV-DNA detection positivity rates were 70.6% for the samples collected directly in liquid medium and 64.7% for the samples stored on the FTA card, with high detection accuracy in the DNA samples recovered from the FTA card (area under the curve = 0.958; 95% confidence interval = 0.890-1.000). The concordance between the results obtained using the 2 storage media was 94.1% (Kappa = 0.866). These preliminary results suggest that collection of cervical material on an FTA card may be an alternative to storage in liquid medium since the liquid medium has some limitations. In addition, DNA recovery from the card using ethanol-based liquid medium streamlines the workflow in the laboratory and reduces the cost associated with reagents, thereby facilitating access to the HPV test in places with few resources and potentially improving cervical cancer screening., (© 2021 S. Karger AG, Basel.)

Objectives: This work is aimed to summarize the first year of the high-risk human papillomavirus (hrHPV) screening test and compare it to the cytology screening test, regarding positivity rates and premalignant lesions diagnosed in the Israeli population. A specific consideration is for the age group 25-30 that is not considered mandatory for the HPV primary screening testing., Methods: A retrospective study was performed in women who were screened for prevention of cervical cancer in Maccabi HealthCare HMO from March 2017 to March 2019. Screening methods included hrHPV typing for types 16, 18, and the other 12 hrHPV types and the PAP LBC test., Results: A total of 115,807 cervical samples were tested for HPV presence and 91% (105,225) were found negative for hrHPV. The other 9% (10,582) were positive for one or more of the 14 hrHPV types tested, and 37% (3,916) of them showed abnormal PAP LBC results. In the age group of 25-30, 3,104 (17.5%) women were found positive for hr-HPV (825 had hrHPV types 16 and/or 18), of which 42% (1,293) of them showed abnormal PAP LBC results. During the hrHPV versus PAP LBC screening era, 258 more women were diagnosed with precancerous cervical lesions (CIN2/3), 70% increased detection versus cytology screening., Conclusions: The hrHPV screening test is currently the best method for the detection of precancerous cervical lesions and cervical cancer, and it is better started at age 25., (© 2021 S. Karger AG, Basel.)

Option recommended by World Health Organization (WHO) includes human papillomavirus (HPV) primary screening followed by visual inspection with acetic acid (VIA) triage. We implemented a program based on a 3T-approach (Test-Triage and Treat). Our objective was to verify the effectiveness of the program by defining a set of performance indices. A sensitization campaign was performed in Dschang (Cameroon) and women aged 30-49 years were invited to participate for screening based on the 3T-approach. Participants performed HPV self-sampling (Self-HPV), analyzed with the point-of-care Xpert HPV assay followed by VIA/VILI triage and treatment if required. Key performance indicators (KPIs) for screening, diagnosis, treatment and follow-up were defined, and achievable targets were described for which the approach is likely to be running optimally. A total of 840 women with a mean age of 39.4±5.9 years participated. The KPIs included (i) the screening rate (8.4% at 7 months, target =20% at 12 months), (ii) HPV positivity rate (19.8%, expected range 18-25%), (iii) compliance to referral to VIA/VILI and complete test (100%, target >90%), (iv) compliance to referral to thermal ablation (100%, target >90%), (v) VIA/VILI positivity rate (50.6%, expected range 45-55%), (vi) a single visit from diagnostic to treatment (79.8%, target >80%), (vii) compliance to follow-up at 1 month (96.4%, target >80%) and (viii) at 6 months (70.6%, target >80%). Program performance based on the single-visit 3T-approach corresponded to defined targets and preliminary results support adequateness of KPIs for periodic monitoring., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Human papillomavirus (HPV) testing is highly sensitive compared to cytology, with the trade-off of being less specific. We investigated whether select combinations of HPV genotypes, ascertained by Linear Array (LA) and Xpert HPV (GX), can optimize sensitivity/specificity trade-offs to detect high-grade cervical intraepithelial neoplasia (CIN2+). In a study in Cape Town, South Africa, 586 women living without and 535 living with HIV, aged 30-65 years, were recruited. Each woman underwent a pelvic exam to collect cervical samples (tested by LA and GX for 14 high-risk HPV genotypes) and underwent colposcopy with histological sampling to determine CIN2+. In multivariable logistic regression of LA results, only HPV genotypes 16, 18, 31, 33, 35, 52, 58 were significantly associated with CIN2+ (P < .05). Xpert includes these seven types along with HPV 45 within three of the test's five channels and we defined these eight types as restricted genotyping (ie 16, 18, 31, 33, 35, 45, 52, 58). Full genotyping was defined as all 14 high-risk types. Sensitivity estimates for full genotyping using LA were similar to that of restricted genotyping: 83.9% (full) vs 79.0% (restricted) in women without HIV and 93.0% (full) vs 88.9% (restricted) in women living with HIV. Specificity estimates improved for restricted vs full genotyping: 87.4% (full) vs 90.8% (restricted) in women without HIV and 63.7% (full) vs 71.4% (restricted) in women living with HIV. To optimize the performance of HPV testing for cervical cancer screening in high-burden, under-resourced settings like South Africa, only HPV 16, 18, 31, 33, 35, 45, 52, 58 could be included to define screen-positive. We recommend the inclusion of HPV45 for its known link to adenocarcinoma., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Nearly all cervical cancers are initiated by a persistent infection with one of the high-risk human papillomaviruses (high-risk HPV). High-risk HPV DNA testing is highly sensitive but cannot distinguish between active, productive infections and dormant infections or merely deposited virus. A solution for this shortcoming may be the detection of transcriptional activity of viral oncogenes instead of mere presence of high-risk HPVs. In this study, fresh-frozen cervical tissues (n = 22) were subjected to high-risk HPV DNA detection using the line probe assay and to targeted RNA next-generation sequencing using single-molecule molecular inversion probes. Targeted RNA sequencing was applied for (1) RNA-based genotyping of high-risk HPV, giving information on specific HPV-subtype (2) discrimination of E2, E6, and E7 transcripts and (3) discovery of possible non-HPV cancer biomarkers. Data were analyzed using computational biology. Targeted RNA sequencing enabled reliable genotyping of high-risk HPV subtypes and allowed quantitative detection of E2, E6, and E7 viral gene expression, thereby discriminating cervical lesions from normal cervical tissues. Moreover, targeted RNA sequencing identified possible cervical cancer biomarkers other than high-risk HPV. Interestingly, targeted RNA sequencing also provided high-quality transcription profiles from cervical scrape samples, even after 1 week of dry storage or storage in Preservcyt fixative. This proof of concept study shows that targeted RNA sequencing can be used for high-risk HPV genotyping and simultaneous detection of high-risk HPV gene activity. Future studies are warranted to investigate the potential of targeted RNA sequencing for risk assessment for the development of cervical lesions, based on molecular analysis of cervical scrapes.

Objective: The causal association of human papillomavirus (HPV) in uterine cervical cancer was well established and this oncogenic virus was reported to be a biomarker for overall recurrence and central pelvic recurrence. The objective of the present systematic review and meta-analysis was to assess the role of HPV DNA testing in early detection of recurrence among cervical cancer survivors after radiotherapy., Methods: We performed a systematic review and meta-analysis by means of searching electronic databases for published articles between January 1984 and June 2018, on the basis of standard systematic review guidelines prescribed by major agencies namely Cochrane Collaboration (https://www.cochrane.org) and Campbell Collaboration (https://www.campbellcollaboration.org). The meta-analysis component was further modified appropriately for the synthesis of sensitivity and specificity results., Results: A total of 1,055 cervical cancer cases who had received pelvic radiation with or without chemotherapy from ten cohort studies were evaluated. The overall pooled sensitivity and specificity of HPV DNA testing was 0.84 (95% confidence interval [CI]= 0.66-0.94) and 0.35 (95% CI=0.20-0.54) respectively. The positive likelihood ratio was 1.3 (95% CI=1.0-1.7) and the negative likelihood ratio was 0.45 (95% CI=0.18-1.10) with an estimated diagnostic odds ratio of 3 (95% CI=1-9)., Conclusion: The screening for HPV DNA testing during follow-up facilitates early detection of recurrence after radiotherapy., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Cervical cancer screening with human papillomavirus (HPV) DNA testing has been incorporated into El Salvador's national guidelines. The feasibility of home-based HPV self-collection among women who do not attend screening at the clinic (i.e., non-attenders) has been demonstrated, but cost-effectiveness has not been evaluated. Using cost and compliance data from El Salvador, we informed a mathematical microsimulation model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis from the societal perspective. We estimated the reduction in cervical cancer risk, lifetime cost per woman (2017 US$), life expectancy, and incremental cost-effectiveness ratio (ICER, 2017 US$ per year of life saved [YLS]) of a program with home-based self-collection of HPV (facilitated by health promoters) for the 18% of women reluctant to screen at the clinic. The model was calibrated to epidemiologic data from El Salvador. We evaluated health and economic outcomes of the self-collection intervention for women aged 30 to 59 years, alone and in concert with clinic-based HPV provider-collection. Home-based self-collection of HPV was projected to reduce population cervical cancer risk by 14% and cost $1210 per YLS compared to no screening. An integrated program reaching 99% coverage with both provider- and home-based self-collection of HPV reduced cancer risk by 74% (compared to no screening), and cost $1210 per YLS compared to provider-collection alone. Self-collection facilitated by health promoters is a cost-effective strategy for increasing screening uptake in El Salvador., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: 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., Patients and Methods: 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., Results: 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., Conclusions: 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.

Background: Until recently, no HPV test had been US FDA-approved for SurePath preservative. Clinical performance remains incompletely understood. The clinical performances of the Cobas HPV Test (Cobas) and Hybrid Capture 2 High-Risk HPV DNA Test (HC2) with PreservCyt and SurePath preservatives were compared., Methods: Cervical cytology samples were collected in both preservatives in random order from women age 21+ (n = 244) referred for colposcopy. Before cytology processing and pelleting, SurePath samples were tested by the Cobas test with and without buffered SDS heat pretreatment. SurePath pellets were tested by the HC2 test and by the Cobas test (with pretreatment). Performance characteristics were calculated in relation to cases of cervical in-traepithelial neoplasia grade 2 or higher (CIN2+) as the clinical target outcome. All HPV-positive samples were also genotyped with the Linear Array test., Results: CIN2+ was detected in 42 patients (17.2%). For both HPV tests, there was a trend towards higher positivity and sensitivity for SurePath compared to PreservCyt preservative. The Cobas test had higher sensitivity than HC2 and the HC2 test had higher specificity than Cobas. Pretreated SurePath samples produced results similar to untreated ones, despite a two-fold dilution during pretreatment [sensitivity %: 95.1 (82.2 - 99.2) vs. 94.3 (79.5 - 99.0); specificity %: 33.0 (26.6 - 40.1) vs. 33.0 (26.4 - 40.3)]., Conclusions: There was good agreement between the preservatives and HPV tests in detecting HPV and between the Cobas and Linear Array tests for genotyping HR-HPV. These trends were not statistically significant due to the limited number of CIN2+ cases. However, these data may help in evaluations of preservative selection for colposcopy samples. Pre-treatment for Cobas testing eliminated invalid results due to clots. The Cobas test has been FDA-approved for use with heat pretreated SurePath samples.

Objective: In order to increase overall participation in cervical cancer screening, several investigators propose a concept of introducing self-tests. The study presented here compared test results of the Pap test and 4 different HPV test systems of self-collected and physician-collected vaginal specimens., Study Design: 208 patients of a colposcopy clinic had physician-taken and self-taken vaginal samples. All cell samples enabled a liquid-based Pap test and testing for carcinogenic HPV genotypes. In addition, all patients had a colposcopy with or without cervical biopsy and/or conisation., Results: 99 patients had the histological diagnosis of CIN2+. The HPV test sensitivity of self-collected samples differed significantly in this patient group depending on the test system performed. The sensitivity of the self-collected Pap test was significantly lower than HPV testing, but the positive predictive value of the Pap self-test was very high., Conclusion: The results of this study indicate that under the circumstances of self-testing HPV test systems differ in test sensitivity and specificity. Self-collected Pap tests can provide a test result with a very high positive predictive value and introduce therapeutic strategies. In order to improve screening strategies, it could be an opportunity to combine HPV and Pap tests in self-taken vaginal samples, especially in countries with a low income level. In countries with a good medical infrastructure, self-testing has to be introduced with caution., (The Author(s). Published by S. Karger AG, Basel.)

Background: Uterine cervical cancer is the fourth most common female cancer in the world. In Japan, we have an apparently low rate of joining cervical cancer screening programs compared with Western countries. Furthermore, the incidence and mortality rate of cervical cancer among the younger generation has been increasing., Object: The aim of this study was to assess the effectiveness of cervical cancer screening with human papillomavirus (HPV) testing and cytology in Japan., Methods: Collaborating with Saga City government, we initiated a cervical cancer screening system consisting of HPV testing and baseline cervical cytology from April 2011 as a social experiment. A total of 17,284 participants have been screened with this new combination system., Results: After HPV testing with cytology-based cervical cancer screening, the number of screenings done in women aged under 40 years has significantly increased. In addition, the number of women diagnosed with cervical intraepithelial neoplasia grade 3 has increased (25 of 14,025 vs. 146 of 23,049 under 50 years: p < 0.001)., Conclusion: These data suggested that the introduction of HPV testing with cytology-based cervical cancer screening as an adjunct to conventional cytology resulted in better efficiency and more accurate screening among the Japanese population., (© 2019 S. Karger AG, Basel.)

Objectives: Pap smear and high-risk human papillomavirus (HR-HPV) DNA testing are the most widely applied methods for cervical cancer screening, but both methods are limited by their low specificity and lack of association with patient prognoses. The aim of this study was to compare the clinical and prognostic significance of HPV E6/E7 mRNA as an early biomarker with cytology and HPV DNA detection in cervical cancer screening., Methods: This study evaluated the performance of the Optimygene HR-HPV RT-qDx assay, which is an HPV E6/E7 mRNA-based assay, to detect 16 HR-HPV subtypes: HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, and 69. The clinical evaluation was conducted using 563 ThinPrep liquid-based cytology samples and the results were compared to those of cytological and histological diagnoses and HPV DNA testing., Results: The clinical sensitivity and specificity of the Optimygene HR-HPV RT-qDx assay for the detection of high-grade lesions, according to cervical cytology, were 92.4% (95% confidence interval (CI) 0.9167-0.9972, p<0.0001) and 96.9% (95% CI 0.8632-0.9524, p<0.0001), respectively; they were 85.9% (95% CI 0.7631-0.9211, p<0.0001) and 82.5% (95% CI 0.7491-0.8825, p<0.0001), respectively, for CIN2+. This assay showed a higher specificity and positive predictive value for cytological and histological diagnosis than HPV DNA testing. Overall, the agreement between the Optimygene HR-HPV RT-qDx assay and HPV DNA testing in cytological and histological diagnosis was 87.9% (κ=0.76, 95% CI 0.7054-0.8128, p<0.0001) and 90.5% (k=0.81, 95% CI 0.7338-0.8878, p<0.0001), respectively. In this study, the most frequently detected HPV genotypes among HR-HPV-positive women were HPV 16 (37.9%), HPV 33-58 (21.5%), and HPV 18 (11.4%)., Conclusions: These findings suggest that the higher specificity and positive predictive value of the Optimygene HR-HPV RT-qDx assay are valuable for predicting insignificant HPV DNA infections among patients with a borderline cytological diagnosis. This assay could be used to prevent unnecessary biopsy procedures and the over-referral of patients with transient HPV infections, as well as reduce patient anxiety during the follow-up period., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess the impact of HPV testing on longstanding problems faced by screening programs in Latin America, using the case of the Jujuy Demonstration Project (JDP) in Argentina., Materials and Methods: . The study measured the level of impact produced by the introduction of HPV-testing on problems faced by cytology programs by analyzing modifications on specific problems produced during the JDP. Impact was classified as direct/indirect, and positive/negative., Results: Direct/positive impact was found in issues concerning age and screening frequency,cytology laboratories and screening sensitivity, and low coverage. Direct/negative impact was mainly related to the adherence to triage cytology by HPV+ women with self-collected-tests, and the delivery and labelling of samples. Indirect impact of HPV-Test was mostly positive, and related to the programmatic reorganization which was facilitated by the introduction of HPV testing., Conclusions: HPV testing provides an opportunity window for improving primary screening, but does not solve programmatic problems., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Primary screening for cervical cancer is transitioning from the longstanding Pap smear towards implementation of an HPV-DNA test, which is more sensitive than Pap cytology in detecting high-risk lesions and offers greater protection against invasive cervical carcinomas. Based on these results, many countries are recommending and implementing HPV testing-based screening programs. Understanding what factors (e.g., knowledge, attitudes) will impact on HPV test acceptability by women is crucial for ensuring adequate public health practices to optimize cervical screening uptake. We used mixed methods research synthesis to provide a categorization of the relevant factors related to HPV primary screening for cervical cancer and describe their influence on women's acceptability of HPV testing. We searched Medline, Embase, PsycINFO, CINAHL, Global Health and Web of Science for journal articles between January 1, 1980 and October 31, 2017 and retained 22 empirical articles. Our results show that while most factors associated with HPV test acceptability are included in the Health Belief Model and/or Theory of Planned Behavior (e.g., attitudes, knowledge), other important factors are not encompassed by these theoretical frameworks (e.g., health behaviors, negative emotional reactions related to HPV testing). The direction of influence of psychosocial factors on HPV test acceptability was synthesized based on 14 quantitative studies as: facilitators (e.g., high perceived HPV test benefits), barriers (e.g., negative attitudes towards increased screening intervals), contradictory evidence (e.g., sexual history) and no impact (e.g., high perceived severity of HPV infection). Further population-based studies are needed to confirm the impact of these factors on HPV-based screening acceptability., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate adoption and implementation of scaling up of HPV self-collection (SC) strategy offered doorto-door by Community Health Workers CHWs) in Jujuy, Argentina., Materials and Methods: A self-administered questionnaire was applied to 478 CHWs.RE-AIM model was used to evaluate adoption and implementation dimensions., Results: Adoption:81.8% offered SC and 86.4% were satis- fied with the strategy. Implementation: main problems were delays in the delivery of tubes (61.3%) and results (70.0%), lack of human resources (28.3%) and difficulties in obtaining an appointment for triage (26.1%). The main obstacle was the excessive workload of CHWs (50.2%).Training (38.0%) and the list of women to be offered the test (28.7%) were identified as facilitators., Conclusions: The adoption of SC strategy was high among CHWs.Program strategiesshould be strengthened to motivate and reduce the excessive workload of CHWs when implementing SC strategy., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Background: Cervical cancer screening with assays detecting DNA of high-risk human papillomavirus (hrHPV) types is more effective than cytology-based screening. This study completes the diagnostic accuracy assessment conducted previously within the framework of VALGENT-2 (Validation of HPV genotyping Tests) and aims to determine whether the reproducibility of Xpert HPV is in line with international validation criteria., Methods: Validation of new hrHPV DNA assays requires demonstration of good reproducibility and non-inferior clinical accuracy for cervical precancer compared to a standard comparator assay. The international reproducibility criteria are: lower bound of 95% confidence interval of the intra- and inter-laboratory agreement regarding detection of high-risk HPV DNA exceeding 87% with kappa ≥0.5., Results: The Xpert HPV assay showed high intra-laboratory reproducibility with an overall positivity/negativity agreement of 96.9% and a kappa of 0.925. Inter-laboratory testing showed an agreement of 97.8% with a kappa of 0.948., Conclusions: The Xpert HPV assay fulfills the HPV test reproducibility criterion requirement for use in cervical cancer screening.

Objective: To evaluate the performance of high risk human papillomavirus (HR-HPV) DNA test for triage ASC-US in Chinese population. Methods: The study population was from Jiyuan city in Henan Province where a cervical cancer screening cohort (4 026 women) was set up from April to July in 2017. Women with ASC-US and complete recall information of colposcope were selected as the study objects. Self-designed questionnaire was used to survey the general information and medical history of cervical cancer, thencervical cytological speciments were collected for cytodiagnosis and HPV DNA test, followed by colposcopy, lesion biopsy and histology diagnose. The diagnosis of histology was used as the gold standard. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) as well as corresponding 95% confidential interval ( CI ) were calculated. Results: The average age of the included 393 women with ASC-US were (50.81±9.22) years old. The positivity of high risk human papillomavirus (HR-HPV), HPV16 and HPV18 were 35.6%, 10.69% and 2.80%, respectively. The sensitivity, specificity, PPV and NPV for HR-HPV to detect CIN2+ were 84.38% (68.25%-93.14%), 68.70% (63.74%-73.26%), 19.29% (13.61%-26.61%) and 98.02% (95.46%-99.15%). When compared with HR-HPV, HPV16/18 had a lower sensitivity (59.38% (42.26%-74.48%)) and a higher specificity(91.14% (87.75%-93.65%)), the PPV and NPV were 59.38% (25.32%-50.98%) and 91.14% (93.61%-97.77%). Conclusion: It was more effective for HR-HPV to triage ASC-US than HPV16/18. In order to improve the effect of HPV16/18, it should include more HR-HPV types which were more prevalent in Chinese population.

Background: The detection of human papillomavirus (HPV) E6/E7 mRNA indicates a risk of further deterioration in cervical lesions. We explored the clinical value of HPV E6/E7 mRNA detection in cervical cancer screening in women positive for HPV or with abnormal thin-prep cytology test (TCT) results in the Xinjiang region of China., Methods: A total of 6,800 women were screened in our hospital for cervical cancer by both TCT and HPV DNA testing from August 2013 to June 2015. Of these, 197 had abnormal cytological or HPV test results and subsequently underwent HPV E6/E7 mRNA detection and histopathological examination, while 101 underwent an HPV DNA typing test. Using pathological results as the gold standard, we compared the accuracies of HPV E6/E7 mRNA detection or HPV DNA type testing alone, in parallel, and in series for diagnosing high-grade cervical lesions., Results: Pathological examination revealed 80 cases of chronic cervicitis, 16 cases of cervical intraepithelial neoplasia (CIN)-I, 50 cases of CIN-II-III, and 51 cases of cervical cancer. The area under the receiver operating characteristic (ROC) curve (AUC) for diagnosing high-grade cervical lesions by HPV E6/E7 mRNA detection was 74.95% (sensitivity, 85.15%; specificity, 66.67%; Youden index, 0.139; positive predictive value, 72.9%; negative predictive value, 81.0%; positive likelihood ratio, 2.555; negative likelihood ratio, 0.222; and post-test probability, 72.9%)., Conclusions: HPV E6/E7 mRNA detection is superior to HPV DNA type testing for diagnosing high-grade cervical lesions.

Background: Testing for high-risk human papillomavirus (HPV) infection using mailed, self-collected samples is a promising approach to increase screening in women who do not attend clinic screening at recommended intervals., Methods: To assess this intervention among high-risk women in the United States, 429 women without a Papanicolaou (Pap) test in 4 or more years (overdue by US guidelines) were recruited from the general population. Participants aged 30 to 65 years were mailed a kit to self-collect a cervicovaginal sample at home, return the sample by mail, and receive HPV results by telephone, with referral to follow-up cytological Pap testing at a local clinic. Cervicovaginal self-samples were collected with a Viba brush, stored in Scope mouthwash, and tested by Hybrid Capture 2. Data were collected in 2010 to 2011 and analyzed in 2017., Results: Two-thirds (64%) of participants returned a self-collected sample, of whom 15% tested HPV DNA positive. Human papillomavirus self-test-positive women reported higher rates of follow-up Pap tests (82%) than did those with self-test negative results (51%). No demographic differences were found in self-test return rate or HPV positivity. High acceptability was reported in participant surveys: most women (81%) had "mostly positive" overall thoughts about the self-test, and most reported being comfortable receiving the kit in the mail (99%), returning their self-collected sample by mail (82%), and receiving their test results by telephone (97%)., Conclusions: Conducting HPV self-testing through population-based recruitment, mailed kit delivery and return by mail, and results delivery by telephone has the potential to reach a broad segment of US underscreened women.

Objective: Our objective was to verify the sensitivity and specificity of dual immunocytochemistry staining for p16 and Ki-67 in liquid-based samples (the "dual" assay) for cervical lesion screening, compared to biopsy findings and human papillomavirus (HPV) DNA molecular detection., Study Design: Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for the "dual immunocytochemistry assay" were calculated and compared to histopathological results and to high-risk HPV DNA detection in adult women or teenagers submitted to cervical cancer screening., Results: A total of 151 women were included. The majority (96.2%) of those with negative dual assay results had lower biopsy grades (p < 0.001). Women with cytology results suggestive of cervical cancer had positive dual immunocytochemistry assay results more frequently (p < 0.001), and these positive results were also significantly associated with biopsy findings (p < 0.001) and with high-risk genotype HPV infection (p = 0.007). Specificity and PPV for the dual assay were 0.972 (0.855-0.999) and 0.800 (0.284-0.995), respectively, and 1.000 (0.590-1.000) and 1.000 (0.631-1.000) for HPV detection., Conclusions: The dual immunocytochemistry assay had high specificity and PPV. It reveals a persistent HPV infection, avoiding the need for new tissue collections for biopsies or hybrid capture., (© 2018 S. Karger AG, Basel.)

Background: The causal relation between human papillomavirus (HPV) and cervical cancer has enabled HPV self-sampling to be envisaged as a possible screening method., Objectives: The aim of this study is to explore the acceptability and reliability of HPV DNA self-sampling as an alternative option for cervical screening among female sex workers., Methods: Sixty-eight participants carried out self-sampling for HPV testing, gave a clinician-obtained sample for HPV testing, and a Papanicolaou test. After the samplings, the participants were questioned on the acceptability of the tests., Results: Most participants (65.6%) preferred to adopt HPV DNA self-sampling in the future; in particular, those without previous experience of Papanicolaou tests marginally significantly preferred self-sampling (86.7%, P = .055). The overall crude agreement in HPV detection rates between clinician and HPV DNA self-sampling was 85.3% (58/68), with a κ of 0.69 (95% confidence interval, 0.51-0.87). The sensitivity and specificity of self-collected samples were 66.7% and 66.1%, respectively, and the positive and negative predicted values were 24.0% and 92.5%, respectively. The prevalence of HPV was slightly higher in self-collected samples (39.7%, 27/68) than in clinician-collected samples (36.8%, 25/68). The participants expressed positive attitudes toward self-sampling but were less confident in their skills of self-sampling compared with clinicians (70.6% versus 91.2%)., Conclusions: The findings showed that self-sampling could be incorporated into current cervical cancer screening approaches., Implications for Practice: Self-sampling could potentially increase compliance to cervical cancer screening and thus reduce the morbidity and mortality from cervical cancer. Further research and education on self-sampling will be required for women of diverse backgrounds.

Objective: To determine whether high-risk types of human papilloma virus (hrHPV) DNA testing is reliable for selection patients in need of further investigation with colposcopy in women with increased risk of high-grade cervical lesions as a result of false negative cytology. The secondary objective was to compare the sensitivity of hrHPV testing on self-collected versus physician-collected samples for the detection of histological high-grade cervical intraepithelial neoplasia (CIN2+)., Methods: Sixty-three patients identified with a missed abnormality following the re-evaluation of benign cervical cytology were included. A patient-collected and a physician-collected sample for HPV, colposcopy and cervical specimen collection for histology and cytology were performed., Results: The sensitivity of hrHPV testing of physician-collected samples for CIN2+ was 100% (95% CI 82.7-100), and the negative predictive value (NPV) was 100% (95% CI 93.3-100). The sensitivity of the self-sampling device to identify CIN2+ was 84.6% (95% CI 59.1-96.7), and the NPV was 94.4% (95% CI 83.4-98.8). The differences in the sensitivity and NPV between the 2 methods were non-significant. The agreement between the 2 methods regarding the HPV results was good, with a kappa value of 0.74 (95% CI 0.57-0.91)., Conclusion: The current findings indicate that physician-collected samples for hrHPV DNA testing may be used as triage for the colposcopy of women with false negative cytology., (© 2018 S. Karger AG, Basel.)

Objective: The aim of this study was to assess the correlation between atypical squamous cells (ASC) and inflammatory infiltrate and vaginal microbiota using cervical liquid-based cytological (SurePath®) and high-risk human papillomavirus (HR-HPV) tests., Study Design: A cross-sectional study was conducted using a 6-year database from a laboratory in Fortaleza (Brazil). Files from 1,346 ASC cases were divided into subgroups and results concerning inflammation and vaginal microorganisms diagnosed by cytology were compared with HR-HPV test results., Results: An absence of specific microorganisms (ASM) was the most frequent finding (ASC of undetermined significance, ASC-US = 74%; ASC - cannot exclude high-grade squamous intraepithelial lesion, ASC-H = 68%), followed by bacterial vaginosis (ASC-US = 20%; ASC- H = 25%) and Candida spp. (ASC-US = 6%; ASC-H = 5%). Leukocyte infiltrate was present in 71% of ASC-US and 85% of ASC-H (p = 0.0040), and in these specific cases HR-HPV tests were positive for 65 and 64%, respectively. A positive HR-HPV test was relatively more frequent when a specific microorganism was present, and Candida spp. was associated with HR-HPV-positive results (p = 0.0156), while an ASM was associated with negative HR-HPV results (p = 0.0370)., Conclusion: ASC-US is associated with an absence of inflammation or vaginosis, while ASC-H smears are associated with Trichomonas vaginalis and inflammatory infiltrate. A positive HR-HPV is associated with Candida spp. in ASC cytology., (© 2017 S. Karger AG, Basel.)

Objectives: The aim of this study was to evaluate the diagnostic significance of high-risk human papillomavirus (hrHPV) testing for managing women with atypical glandular cells (AGC) and to explore the distribution of hrHPV genotypes., Methods: We analyzed cytologic and histopathologic diagnoses in patients referred to our institution due to AGC or atypical squamous cells of undetermined significance (ASC-US). All patients underwent hrHPV testing and genotyping, and positive (PPV) and negative predictive values (NPV) for cervical intraepithelial neoplasia (CIN) 2 or worse [CIN2+/adenocarcinoma in situ (AIS)+] were calculated., Results: Among 41 cases previously diagnosed with AGC, 22 (53%) were classified as CIN2+ (2 squamous cell carcinomas), whereas only 2 were AIS or adenocarcinoma. Twenty-seven (65.8%) cases in the AGC group were hrHPV positive. The most frequent genotypes in both the ASC-US and AGC groups were HPV16 and HPV52. The PPV of hrHPV testing for CIN2+/AIS+ was significantly higher in the AGC than in the ASC-US group (74.1 vs. 35.0%; p = 0.0005). The NPV for CIN2+/AIS+ was significantly lower in the AGC than in the ASC-US group (74.4 vs. 100%; p = 0.0441)., Conclusion: In patients with AGC, both glandular and squamous lesions must be monitored. hrHPV testing is useful for detecting CIN2+/AIS+ in AGC., (© 2018 S. Karger AG, Basel.)

Background: Oral leukoplakia is considered a potentially malignant lesion for the development of squamous cell carcinoma, and various risk factors may be related to its development and malignant transformation, including the human papillomavirus (HPV). The aim of this case-control study was to detect the presence of HPV in fresh tissue, plasma and saliva samples obtained from patients with and without oral leukoplakia, and verify the correlation of the presence of DNA of HPV between different sources of materials., Methods: In this study, 32 patients with oral leukoplakia and 24 patients selected in a case-control manner were included. DNA extraction from the samples was performed, and afterwards it was amplified by nested polymerase chain reaction (nPCR) for the detection of HPV (nPCR: MY09-MY11/GP05+-GP06+)., Results: The DNA of HPV was found in 68.75% of the fresh tissue samples; in 50% of plasma, and in 62.5% of saliva samples in the group of patients with leukoplakia; in comparison with 45.8%, 54%, and 45.8%, in the fresh tissue, plasma and saliva samples, respectively, in the control group., Conclusion: Based on the present study, there was no difference in the rate of HPV detection in patients with or without oral leukoplakia. However all sources tested in this study were considered suitable for HPV detection, especially plasma samples, which showed be an important non-invasive source of HPV detection in leukoplakia patients., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Conclusion: The detection of human papillomavirus (HPV)-DNA in oral rinse with auto-nested GP5+/GP6 + PCR is useful as a biomarker of oropharyngeal cancer., Background: This study aimed to determine the usefulness of oral rinse to detect HPV-DNA as a biomarker of HPV-positive oropharyngeal cancer (OPC)., Patients and Methods: One hundred and ten patients with various head and neck diseases, including 19 patients with OPC, were enrolled. Oral rinse and tonsillar swab were collected, and auto-nested GP5+/GP6 + PCR for HPV-DNA was performed. For oropharyngeal cancer, p16 immunostaining was also conducted., Results: The rate of HPV-DNA detection in both oral rinse and tonsillar swab was significantly higher in OPC compared with non-OPC upper respiratory tract cancer and non-cancer diseases. HPV-DNA was detected in oral rinse in nine out of 12 p16-positive OPC cases, while none of the p16-negative OPC cases demonstrated detectable HPV-DNA. All p16-positive cases were also positive for HPV-DNA in tumor tissue. Based on p16 immunostaining, the sensitivity and specificity of HPV-DNA detection in oral rinse were 75% and 100%, respectively. Among eight of nine evaluable OPC cases positive for HPV-DNA in oral rinse at diagnosis, HPV-DNA was undetectable in oral rinse in seven cases after treatment.

The fourth edition of the World Health Organization classification set up new entities of endocervical adenocarcinoma (ECA), namely the "usual type" and "gastric type." These 2 types are considered to be distinct histogenetically because of their differing immunophenotypes, human papillomavirus (HPV) status, and prognoses. Usual-type ECAs (U-ECAs) are virtually always associated with high-risk human papillomavirus (HR-HPV) infection. Gastric-type ECAs (G-ECAs) are believed not to be associated with HR-HPV infection. Morphologically, U-ECA cells are characterized by mucin-poor and eosinophilic cytoplasm, resembling endometrioid carcinoma (a pseudoendometrioid feature). G-ECA cells are characterized by abundant clear or pale, mucinous cytoplasm and distinct cell borders. However, in routine practice we noticed that some ECAs contain morphologically usual type-like components and gastric type-like components in a single tumor; we have named these "G+U" ECAs. The histogenesis of such tumors has not been investigated. We conducted the present study to clarify the clinicopathologic and immunohistochemical features and HPV status of G+U ECAs, and to determine whether G+U ECAs are genuine G-ECAs mimicking U-ECAs or genuine U-ECAs with gastric type-like morphology. We retrospectively analyzed a series of 70 consecutive cases of ECA diagnosed as mucinous ECA, endocervical type, and we reclassified them on the basis of the latest World Health Organization classification. We identified 48 (69%) pure U-ECAs, 9 pure G-ECAs, and 13 G+U ECAs. Ten of the 13 G+U ECAs (77%) showed no HR-HPV infection by in situ hybridization (HPV-unrelated G+U ECAs) and showed frequent HIK1083 expression and aberrant p53 expression in both usual type-like and gastric type-like components. The other 3 G+U ECAs showed HR-HPV infection (HPV-related G+U EACs) and frequent p16+/p53-/HIK1083- immunophenotype in both usual type-like and gastric type-like components. The U-ECAs were characterized by HR-HPV infection detected by in situ hybridization and frequent p16+/p53-/HIK1083- immunophenotype, similar to that of the HPV-related G+U ECAs. In contrast, the pure G-ECAs were characterized by the absence of HPV infection and frequent HIK1083 expression and aberrant p53 expression, similar to that of HPV-unrelated G+U ECAs. G+U ECAs thus represent a heterogenous group composed of genuine G-ECAs and genuine U-ECAs. Most of the G+U ECAs we examined were genuine HPV-unrelated G-ECAs with usual type-like components showing mucin-poor, eosinophilic cytoplasm (pseudoendometrioid morphology). A small population of G+U ECAs was genuine HPV-related U-ECAs with gastric type-like components showing mucin-rich, voluminous cytoplasm. Thus, both types of ECAs can occasionally display patterns of differentiation suggesting a component of the other type but true mixed tumors do not appear to exist. Ancillary techniques (immunohistochemical analysis of p16, p53, and HPV DNA detection assays) should be used to assure proper classification of tumors with mixed morphologic features.

Dysregulated expression of oncogenic types of E6 and E7 is necessary for human papillomavirus (HPV)-driven carcinogenesis. An HPV E6/E7 mRNA in situ hybridization (ISH) assay covering 18 common high-risk types ("HR-RISH," aka HR-HPV RNA18 ISH) has not been extensively studied in the anogenital tract or validated on automated technology. We herein compare HR-RISH to DNA polymerase chain reaction (PCR), p16 immunohistochemistry, and a previously available HPV DNA ISH assay in HPV-related anogenital and head and neck (H&N) neoplasia. A total of 102 squamous intraepithelial lesions (16 CIN1, 25 CIN3, 3 AIN1, 12 AIN3, 9 VIN3)/invasive squamous cell carcinomas (17 cervical, 2 anal, 18 H&N) as well as 10 normal and 15 reactive cervix samples were collected. HR-RISH, DNA ISH, and p16 immunohistochemistry were performed on whole formalin-fixed, paraffin-embedded sections. RNA ISH for 6 low-risk HPV types (LR-RISH) was also performed. RNA and DNA ISH assays used automated systems. HR-HPV PCR was performed on morphology-directed formalin-fixed, paraffin-embedded punches. HR-RISH was ≥97% sensitive for PCR+ and p16+ neoplasia, as well as morphologically defined anogenital high grade squamous intraepithelial lesion/invasive squamous cell carcinoma. HR-RISH was also positive in 78% of anogenital low grade squamous intraepithelial lesion, including 81% of CIN1. Furthermore, a subset of PCR-negative/invalid and p16-negative lesions was positive for HR-RISH. Only 1 problematic reactive cervix sample and no normal cervix samples stained. These results demonstrate that HR-RISH is a robust method for the detection of HR-HPV-related neoplasia and provides insight into HPV pathobiology. Performance meets or exceeds that of existing assays in anogenital and H&N lesions and may play a role in resolving diagnostically challenging CIN1 versus reactive cases.

Human papillomavirus (HPV) infection is closely associated with cervical cancer. This study analyzed HPV genotype prevalence in 75 cases of formalin-fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with cervical cancer. Genotype prevalence was assessed using Reverse Blot Assay (REBA) and quantitative polymerase chain reaction (qPCR), which target the HPV L1 and HPV E6/E7 genes, respectively. HPV DNA chip tests were also performed using liquid based preparation (LBP) cytological samples from the same patients who provided the FFPE histological samples. We observed a slight difference in HPV genotype distribution as assessed by DNA chip versus REBA. One possible explanation for this difference is that normal regions could be mixed with lesion regions when cytological samples are extracted from each patient with cancer. For the detection of moderate dysplasia, the main target of diagnosis, this difference is anticipated to be greater. We also made several unexpected observations. For example, HPV multi-infection was not detected. Moreover, the rate of HPV positivity varied radically depending on the cancer origin, e.g. squamous cell carcinoma versus adenocarcinoma. Our results imply that it is important to determine whether cytological specimens are suitable for HPV genotyping analysis and cervical cancer diagnosis. Future research on the mechanisms underlying cervical cancer pathogenesis is also necessary., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The reported range of involvement of human papillomavirus (HPV) in laryngeal squamous cell carcinoma (SCC) is wide because of the methods used to detect HPV., Data Sources: A computerized Medline study was carried out using the following as key words: "Papillomavirus Infections"[Mesh] and "Laryngeal Neoplasms"[Mesh]., Materials and Methods: Studies that were included were written in English and reported results of HPV DNA with RNA in laryngeal SCC., Results: There were six reported HPV mRNA extraction. Among these studies, Lewis et al reported that out of the 31 cases analyzed, only 2 were HPV DNA+ and of these only 1 was mRNA HPV+ (3%). Halec et al reported 102 cases of which 32 were HPV DNA+ cases and of which only 6 were mRNA+ (5%). Chernock et al reported 76 cases of which 13 were HPV DNA+ cases and of which 4 were mRNA+ (5%). Masand et al reported 8 cases of which 1 was HPV DNA+ case and none was mRNA+. Gheit et al reported 43 cases of which 4 were HPV DNA+ cases and of which 2 were mRNA+ (4%). Castellsagné et al reported 1042 cases of which 59 were HPV DNA+ case and of which 51 were mRNA+ (4.8%) CONCLUSIONS: When determining the role of HPV in laryngeal SCC, evidence of HPV DNA warrants further examination for E6/E7 mRNA as simple assays such as p16 are nonspecific in laryngeal SCC. Further studies of HPV and its role in laryngeal SCC are warranted., (Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim was to assess the performance of two commercial assays for the detection of high-risk human papillomavirus (hrHPV): Aptima HPV Assay (Hologic, Inc., Marlborough, MA, USA) which detects mRNA of 14 different hrHPV types, and Hybrid Capture 2 HPV DNA test (HC2; Qiagen, Gaithersburg, MD, USA), which detects the DNA of 13 different hrHPV types. Test performance was compared in the settings of a standard colposcopy clinic, among the regular patient flow., Material and Methods: Two separate cervical cell samples for Aptima and HC2 testing were collected from women referred to colposcopy or a cervical follow-up visit. Altogether, 481 paired samples were analyzed and all positive samples were also tested using the Aptima HPV 16 18/45 Genotype Assay. Results from the two assays were compared directly and with stratification by histology and cytology from the same sampling visit., Results: The overall agreement between HC2 and Aptima assays was 92.9% (Kappa coefficient of 0.855). The sensitivity and specificity of the assays in detecting CIN2 + were 92.5 and 58.2% for HC2, and 94.0 and 59.3% for Aptima, respectively. No significant differences between the assays were found (p-values >0.5). Both assays detected all CIN3 (n = 30) and carcinoma (n = 2) cases., Conclusions: The mRNA-based Aptima assay and the extensively studied DNA-based HC2 test performed equally well in detecting high-grade cervical lesions. Our data contribute to the growing evidence base indicating that the mRNA-based Aptima assay could be used for the triage of patients with HPV-associated cervical disease., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background/aim: In patients with premalignant cervical lesions, human papillomavirus (HPV) infection, at any moment, may be spontaneously eliminated, or may persist or transform cervical epithelium from a lower to a higher degree. Due to that, it is necessary to wisely select the patients who are at high risk of cancer development. The aim of the study was to establish the interdependence between a suspicious Papanicolaou (Pap) test and colposcopy with the infection caused by high-risk genotypes of human papillomavirus and the presence of premalignant cervical lesions., Methods: This prospective study used cytological, colposcopy, real-time polymerase chain reaction (PCR) of high-risk genotypes of human papillomavirus and histopathological analysis of cervical biopsy specimen. Out of 2,578 female patients sent to cytological analyses in Clinical Center of Montenegro, during 2012, 2013 and 2014, the study included 80 women who had to submit their biopsy specimens due to a suspicious Pap test and atypical colposcopy results., Results: In the group of 80 (3.1%; n = 80/2,578) of the selected female patients with suspicious Pap test and colposcopy, 2/3 or 56 (70%) of them had cervicitis, and 1/3 or 24 (30%) had cervical intraepithelial neoplasia. The most common type in cervical intraepithelial neoplasia was HPV16 in 8 female patients, ie 61.53% out of the number of infected, or 33.33% out of the total number of premalignant lesions, Conclusion: Patients with suspicious Papanicolaou test, colposcopy results and infection which is caused by high-risk HPV infection (HPV 16 in particular) often have premalignant cervical lesions. In these cases, histopathological confirmation of lesions is mandatory, since it serves as a definitive diagnostic procedure.

Currently, clinical data for primary HPV screening alone are lacking in China. Here, we evaluate cervical cancer screening with primary HPV genotyping, as well as possible future screening strategy. Overall, high-risk HPV (hrHPV) prevalence was 18.2% among hospital-based population in Taizhou area. For cervical intraepithelial neoplasia 2 or worse (CIN2+), the sensitivity of primary hrHPV genotyping strategy and current cervical cancer screening strategy were 93.5%, and 71.1%, respectively; whereas the specificity was 17.5%, and 62.4%, respectively. Current cervical screening strategy had slightly higher positive predictive values (28.4%) for CIN2+ than hrHPV genotyping strategy (21.9%), whereas primary hrHPV genotyping strategy demonstrated higher negative predictive values (94.7%) than current cervical screening strategy (91.1%). Compared to HPV35/39/45/51/56/59/66/68 genotypes, the odds ratios (OR) for CIN2+ in HPV16/18/31/33/52/58 infection women were 3.2 (95% confidence interval [CI] 2.3-4.1). Primary hrHPV genotyping strategy provides a better predictive value than HPV16/18 genotyping alone in guiding the clinical management of the current cervical cancer screening. HPV testing without adjunctive cytology may be sufficiently sensitive for primary cervical cancer screening.

Background: High-risk Human papillomavirus (HR-HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a distinct epidemiologic and pathologic disease. The data of HR-HPV testing on fine-needle aspiration (FNA) materials of cervical lymph nodes in patients with metastatic HNSCC are limited., Methods: We retrospectively reviewed metastatic HNSCC cases with cervical lymph node FNAs which were tested for p16 immunohistochemistry (IHC) and HR-HPV DNA in situ hybridization (ISH)., Results: Of the 87 cases studied, the overall adequacy rate of cell block material was 86% for HR-HPV ISH, 93% for p16 IHC, 84% for both and 95% for either one. Pathologist-performed FNAs showed significantly higher percentage of satisfactory specimens for p16 and HR-HPV tests than clinician-performed FNAs. Of the 73 cases adequate for both p16 IHC and HR-HPV ISH, the concordant rate between p16 and HR-HPV results was 78%. P16 positivity had sensitivity of 90% and specificity of 75% to predict primary oropharyngeal HNSCC, while HR-HPV test showed a similar high sensitivity (91%) but a better specificity (94%)., Conclusion: FNAs of cervical lymph nodes yield adequate materials for reliable HR-HPV testing in metastatic HNSCCs and should be incorporated into routine pathologic evaluation for these patients. The high concordance between p16 IHC and HR-HPV ISH suggests p16 IHC may serve as a surrogate for HR-HPV ISH in metastatic HNSCC cases with oropharyngeal origin and is helpful to pinpoint primary tumor site. Diagn. Cytopathol. 2016;44:792-798. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Human papillomavirus (HPV)-related head and neck squamous cell carcinomas (HNSCC) are radiosensitive tumors and have a better prognosis than the conventional keratinizing HNSCC. Despite extensive radiographic and clinical evaluation in approximately 3% to 5% of patients who present with cervical lymph node metastases, the primary tumor remains occult. The lack of a clinically identifiable primary tumor usually leads to more aggressive therapy, which can result in higher morbidity. Herein, we report a case of a patient with an occult HPV-related HNSCC, diagnosed detecting HPV in a fine needle aspiration cytology (FNAC) of metastatic laterocervical lymph nodes., (© Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Objectives: Papillomavirus Dumfries and Galloway (PaVDaG) assessed the performance of a high-risk human papillomavirus (hrHPV) PCR-based assay to detect high-grade cervical intraepithelial neoplasia (CIN2+) in self-collected vaginal and urine samples., Setting: Women attending routine cervical screening in primary care., Participants: 5318 women aged 20-60 years provided self-collected random urine and vaginal samples for hrHPV testing and a clinician-collected liquid-based cytology (LBC) sample for cytology and hrHPV testing., Interventions: HrHPV testing. All samples were tested for hrHPV using the PCR-based cobas 4800 assay. Colposcopy was offered to women with high-grade or repeated borderline/low-grade cytological abnormalities; also to those who were LBC negative but hrHPV 16/18 positive., Primary and Secondary Outcome Measures: The self-tests' absolute sensitivity and specificity for CIN2+ were assessed on all biospecimens; also, their relative sensitivity and specificity compared with clinician-taken samples. Interlaboratory and intralaboratory performance of the hrHPV assay in self-collected samples was also established., Results: HrHPV prevalence was 14.7%, 16.6% and 11.6% in cervical, vaginal and urine samples, respectively. Sensitivity for detecting CIN2+ was 97.7% (95% to 100%), 94.6% (90.7% to 98.5%) and 63.1% (54.6% to 71.7%) for cervical, vaginal and urine hrHPV detection, respectively. The corresponding specificities were 87.3% (86.4% to 88.2%), 85.4% (84.4% to 86.3%) and 89.8% (89.0% to 90.7%). There was a 38% (24% to 57%) higher HPV detection rate in vaginal self-samples from women over 50 years compared with those ≤29 years. Relative sensitivity and specificity of hrHPV positivity for the detection of CIN2+ in vaginal versus cervical samples were 0.97 (0.94 to 1.00) and 0.98 (0.97 to 0.99); urine versus cervical comparisons were 0.53 (0.42 to 0.67) and 1.03 (1.02 to 1.04). The intralaboratory and interlaboratory agreement for hrHPV positivity in self-samples was high (κ values 0.98 (0.96 to 0.99) and 0.94 (0.92 to 0.97) for vaginal samples and 0.95 (0.93 to 0.98) and 0.90 (0.87 to 0.94) for urine samples)., Conclusions: The sensitivity of self-collected vaginal samples for the detection of CIN2+ was similar to that of cervical samples and justifies consideration of this sample for primary screening., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: Despite the widespread screening programs, cervical cancer remains the third most common cancer in developing countries. Based on the implementation of cervical screening programs with the referred adoption of improved screening methods in cervical cytology with the knowledge of the important role of the human papilloma virus (HPV) it's incidence is decreased in the developed world. Even if cervical HPV infection is incredibly common, cervical cancer is relatively rare. Depending on the rarity of invasive disease and the improvement of detection of pre-cancerous lesions due to the participation in screening programs, the goal of screening is to detect the cervical lesions early in order to be treated before cancer is developed. In populations with many preventive screening programs, a decrease in cervical cancer mortality of 50-75% is mentioned over the past 50 years. The preventive examination of vagina and cervix smear, Pap test, and the HPV DNA test are remarkable diagnostic tools according to the American Cancer Association guidelines, in the investigation of asymptomatic women and in the follow up of women after the treatment of pre-invasive cervical cancer. The treatment of cervical cancer is based on the FIGO 2009 cervical cancer staging.

Esophageal cancer is a poor-prognosis malignancy that ranks eighth among all cancer types, and its prevalence shows differences among geographical regions. Although the most important risk factors for esophageal carcinoma are alcohol and smoking, viral infections, particularly HPV infection, are also considered among etiological agents. Our study aims to detect the presence of HPV in esophageal cancers in our patient population and to investigate its correlation with clinico-pathological parameters. We investigated the presence of HPV-DNA by real-time polymerase chain reaction in a total of 52 patients with esophageal cancer. Subtype analysis was performed in positive cases and was correlated with selected clinico-pathological parameters. Five (9.6%) of 52 tumor samples, 3 squamous cell carcinomas (3/33 cases) and 2 adenocarcinomas (2/19 cases), were HPV-DNA-positive. Subtype analysis could be performed in four HPV-DNA-positive cases, of which three were HPV type-39 and 1 was type-16. The Marmara region, where the present study was carried out, is a region with low-moderate risk for esophageal cancer, and the prevalence of HPV-DNA in these tumors is similar to the prevalence of HPV-DNA reported in the literature for regions with similar risk. In conclusion, we detected HPV DNA in a subset of esophageal and gastroesophageal junction tumors. HPV infection may have a role in esophageal carcinogenesis and high-risk HPV subtypes can particularly be considered among risk factors since the prevalence of high risk HPV infection has also been found to be increased in regions with a high risk for esophageal cancer compared to low-moderate risk regions., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background: The rate of uptake of the Papanicolaou (Pap) smear is generally low. Its causal relationship with human papillomavirus (HPV) DNA allows HPV DNA self-sampling to be used as an alternative screening tool for cervical cancer., Objectives: This study explored the acceptability of HPV DNA self-sampling and its impact on the rate of compliance with cervical cancer screening., Methods: A crossover randomized clinical trial was conducted in community-based clinics. Participants were allocated to 1 of the following 2 arms: arm 1: self-sampling before a Pap smear; and arm 2: a Pap smear before self-sampling. After completing the 2 screening methods, participants in each arm took part in face-to-face interviews using standardized, structured questionnaire., Results: The participants accepted both self-sampling (7.7/10) and a Pap smear (7.8/10) for cervical cancer screening. However, participants without previous experience of Pap smears or who had more than 2 sexual partners preferred self-sampling (P < .05). The participants expressed overall positive feelings toward self-sampling, and there was good agreement in HPV detection between the 2 screening methods (κ = 0.65). We estimate that the introduction of HPV DNA self-sampling could increase the future rate of uptake of cervical cancer screening by 6.5% and would entail lower costs., Conclusion: Human papillomavirus DNA self-sampling could be an alternative screening method to increase the coverage of cervical cancer screening., Implications for Practice: Human papillomavirus DNA self-sampling could overcome the barriers raised by Pap smears and enhance the coverage of cervical cancer screening. Promotional publicity and education are essential.

With cervical cancer screening the choice of 1-year as a period of follow-up in positive high-risk HPV women without cytological lesions is still under discussion. We evaluated the management of these women and the role of HPV genotyping test. We did a cervical cancer screening study of women aged 35-64 with primary high-risk HPV test. Women positive for high-risk HPV with negative cytology were followed-up after 1 year. In this study we selected women with high-risk HPV+/PapTest- resulted high-risk HPV+ at recall and performed the PapTest and HPV genotyping test. The detection rate of squamous high grade (CIN2+) relative to the total screened cohort was 2.1‰, and it was 0.2‰ at the 1-year recall. The colposcopy performed in women referred at the 1-year recall accounted for 48.8% of the total (baseline + 1-year recall), and 84.3% of these women had no cytological lesions. The most frequent hr-HPV genotype detected was HPV16 and 66.7% of co-infections were due to HPV16 and HPV18. 54.5% of women presented a persistent infection at 1-year recall with the same HPV subtype, 50% of persistent infections was due to HPV16 and 16.7% of these were determined to be CIN2+ histological lesions. Our data show that it may be useful to extend the period of follow-up for women hr-HPV+/PapTest- so as to reduce the number of unnecessary colposcopies due to the transitory infections and that the genotyping test could help to identify the persistent infections in which HPV16 is involved.