CIN Lesions Research Articles

Course of cervical intraepithelial neoplasia diagnosed during pregnancy.

Management of high-grade cervical intraepithelial neoplasia [CIN grade 2 or 3 (CIN2-3)] diagnosed during pregnancy is controversial. Monitoring with colposcopy and cytology every 8-12weeks is advised by the most current guidelines. This study analyzes the course of disease in pregnant women with abnormal cytologies or clinically suspicious cervixes. In total, 139 pregnant women, at a median age of 31years (range 19-49), treated at the Colposcopy Unit of the University Medical Center Hamburg-Eppendorf between 2011 and 2017 were identified. During pregnancy, at least one biopsy was performed on 70.5% of patients. In 84.7% of cases, CIN2-3 (CIN2 n = 14 (14.3%), CIN3 n = 69 (70.4%)) was detected, 7.1% (n = 7) of women were diagnosed with CIN1, while no dysplasia was found in 8.2% (n = 8) of cases. No interventions were necessary during pregnancy. Despite explicit invitation, only 72.3% of women with CIN2-3 attended postpartal consultations. While 61.7% showed persistent lesions, 5% were diagnosed with CIN1 and 33.3% with complete remission. During pregnancy, 68.7% of women with prepartal CIN2-3 were tested for HPV infection. Later, 49.1% were followed up postpartally by means of HPV testing and histology. HPV clearance was observed in 36.4% of women with complete histological remission. Postpartum conization was performed on 44.6% of patients with prepartal CIN2-3 diagnosis. CIN2-3 was histologically confirmed in 97.3% cases. Progression from persistent CIN3 to microinvasive carcinoma was observed in a single case. High-grade CIN lesions, diagnosed during pregnancy, show a high rate of regression postpartum; whereas, progression to carcinoma is rare. Close and continuous monitoring rarely has any therapeutic consequences. Compliance for postpartal follow-up needs to be improved.

Abstract A35: Methanobrevibacter is associated with cervical dysplasia in Hispanics with HPV infections

Abstract Bacteria have been extensively associated with several disease phenotypes. Archaea, a major neglected component of the microbiome, accounts for a relatively small percentage of the microbiota and has mostly been studied in the gastrointestinal tract. We hypothesized that dysbiosis in the genital tract included changes in both bacterial and archaeal organisms according to human papillomavirus infections and levels of dysplasia. We analyzed 62 patient samples from recruited patients coming for colposcopy clinics at the UPR and San Juan City clinics (Puerto Rico). From these, 52 were HPV positive and 10 were HPV negative and were stratified according to cytology results. From genomic DNA extracted from cervical swabs, we sequenced 16S rRNA genes and selected 10 patient samples for additional shotgun metagenomics. The patients were grouped in those without epithelial lesions, CIN 1 and CIN3. DNA data analyses were done with shotgun and QIIME. Analyses of the 16S rRNA reads revealed 16 archaeal OTUs, revealing an abundance of Methanobrevibacter associated with CIN3 lesions. Shotgun data revealed Methanosarcina to be dominant across all samples with higher dominance in patients without lesions and an increased dominance in Methanobrevibacter and Methanococcus in CIN3 lesions. No archaeal significant differences were found according to HPV risk (HPV infection); however, a significant decrease in Lactobacilli was associated with dysplasia. We found that archaea are commensals of the cervical mucosa and may contribute to dysbioses. Acetoclastic Methanosarcina are dominant across samples, and CIN3 lesions revealed a higher dominance of hydrogenotrophic methanogens such as Methanobrevibacter. The significance of these preliminary results may indicate that archaea cannot be taken out of the ecological context for future cervical cancer prevention strategies. Grant support: Research reported in this abstract was partially supported by NIH National Institute on Minority Health and Health Disparities: RCMI Grant No. 2U54MD007600, an Institutional Development Award (IDeA) from the NIH National Institute of General Medical Sciences (Grant No. P20GM103475) and by the NIH/NIMHD Endowment program HiREC S21MD001830. Citation Format: Filipa Godoy-Vitorino, Josefina Romaguera. Methanobrevibacter is associated with cervical dysplasia in Hispanics with HPV infections [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A35.

Assessing the feasibility of a rapid, high-volume cervical cancer screening programme using HPV self-sampling and digital colposcopy in rural regions of Yunnan, China

ObjectiveImplementation of a novel, rapid, high-volume, see-and-treat cervical cancer screening programme using self-swab human papillomavirus (HPV) testing and digital colposcopy in underserved regions of Yunnan China.Design480–980 women per day self-swabbed...

Efecto de la Vacuna del Papiloma Humano en la prevención del cáncer cervicouterino: Metaanálisis

El objetivo de esta investigación es analizar y evaluar la eficacia de la vacuna profiláctica contra el Virus del Papiloma Humano para prevenir el cáncer cervical. Esto se logró mediante la búsqueda, a través de la plataforma MEDLINE, de ensayos clínicos controlados y aleatorizados que evaluaran la eficacia de la vacuna bivalente y cuadrivalente contra el desarrollo de lesiones tipo CIN. La vacuna bivalente Cervarix disminuyó el riesgo un 19.35% (0.24 [0.13-0.44], la vacuna activa bivalente 2% (0.02 [0.00-0.28).Además , la vacuna cuadrivalente Gardasil disminuyó el riesgo un 16% (0.19.08-0.48]) y la vacuna activa cuadrivalente un 3% (0.03 [0.01-0.08).Estos resultados demuestran que en el grupo tratamiento siempre se obtuvo un resultado positivo comparado con el grupo control y ambas vacunas son efectivas para reducir el desarrollo de lesiones CIN+.

Treatment of Residual or Recurrent CIN with Topical Imiquimod: a Retrospective Study

Abstract Objective In this retrospective case study, we determine the results, side effects and long-term outcome features of treatment with imiquimod 5% in women with recurrent or residual cervical intraepithelial neoplasia (rrCIN). Methods The study was set in three outpatient clinics of hospitals in the Netherlands. Women diagnosed with rrCIN and treated with imiquimod 5% intravaginally between 2010 and up to and including 2017 were included. Data were extracted from medical records. The main outcome measures were complete regression or partial regression of SIL (squamous intraepithelial lesions) (cytology) or CIN (histology), side effects and long-term outcome in terms of the need for further excisional treatment during the follow-up period. Outcomes were assessed using descriptive statistics. Results The 18 studied women tolerated imiquimod well: all completed the treatment, with a temporary stop or dose reduction in two. The treatment was successful in 11 women overall (61%) of whom 8 women (80%) with high grade CIN (grades II-III). Of these 11 women, 4 women developed a recurrence of which 3 women were treated successfully with imiquimod or a LLETZ procedure. One woman died in the follow up without treatment of the CIN lesion. Of the remaining seven women with unsuccessful treatment, four patients underwent additional therapy. Two women underwent a hysterectomy, one woman underwent multiple procedures and the last woman underwent laser therapy and imiquimod, but died in the follow up. Of the remaining three out of those 7 women with unsuccessful treatment, two women refused further therapy and one woman required no further therapy since she cleared HPV and showed no dysplasia in the follow-up period. Conclusions In studied population, imiquimod treatment was well tolerated and associated with resolution or regression of SIL/CIN in 61% of women. We have started a randomized controlled trial to compare the efficacy of imiquimod with that of LLETZ in recurrent or residual CIN.

Comparison of HPV Testing and Colposcopy in Detecting Cervical Dysplasia in Patients With Cytological Abnormalities

The aim of the study was to compare the diagnostic value of HPV testing and colposcopy in patients with abnormal cytology results. A total of 186 women with cytological abnormalities were included in the study. The patients underwent colposcopy examinations and DNA HPV testing of cervical smear with genotyping. The HPV test was demonstrated to be more sensitive (79.4%) than specific (60.2%) and was more sensitive than colposcopy for detecting CIN changes (79.4% vs. 73.7%). Combined tests achieved a high sensitivity (90.9%) and negative predictive value (96.1%) in detecting patients with CIN2+ and demonstrated the highest positive predictive value (77.3%) for detecting CIN1+. Colposcopy had a very good specificity (83.5%) and positive predictive value (71.2%) in finding CIN1+ cases. HPV tests showed a higher sensitivity than colposcopy, but colposcopy results presented higher specificity. Combining HPV testing and colposcopy proved to be the most efficient method for detecting CIN lesions.

Diagnostic Yield and Performance of a Large Population-Based Cervical Cancer Screening Program in High-Risk Rural China.

Primary cervical cancer screening by liquid-based cytology alone or with adjunctive HPV testing are available worldwide. However, little if any information is available about cervical cancer diagnostic yield of population-based cervical cancer screening in China. In response to it, we conducted a large prospective study on 40,000 women cervical cancer screening within six-month period in rural Shanxi Province, where has been reported as the highest cervical cancer rates in China. A standard cross-sectional survey by self-completed questionnaire was collected and followed by the liquid-based cytology screening. Follow-up biopsy with the diagnosis of cervical intraepithelial neoplasia 2 or higher lesion (CIN2+) were analyzed. Of initial 40,000 women participating in this study, 6.76% (2702/40,000) women had ASC-US or higher cytology screening results with ASC/SIL ratio at 6.14 (2381:388). Among them, 1.96% (782/40,000) women were found CIN lesions (95% CI, 1.68-2.23%) on confirmatory biopsies, including 0.55% (218/40,000) CIN2+ and 19 SCCa (47.5/100,000, 95% CI, 29-74/100,000). Women in Yangqu County had lower ASC/SIL ratio, but higher CIN2+ detection rate in comparison with that of Jiexiu County (6.69 vs. 8.84 and 56.7% vs. 43.9%), which reflects the cervical cancer distribution in different populations and regions. Analysis in age-stratified cytology results indicated women aged 60-65 years had the highest incidence of cytologic abnormality among all the age group; likewise, women aged >50 years were at higher risk in developing cervical high grade dysplasia or cancer than women aged <50 years (0.82% vs. 0.49%). This large-scale cervical cancer screening study provided important references as the instructive for establishing the nation-wide cervical cancer screening strategy.

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.

Combining HPV DNA load with p16/Ki-67 staining to detect cervical precancerous lesions and predict the progression of CIN1\u20132 lesions

BackgroundHuman Papilloma Virus (HPV) DNA tests are highly sensitive and can triage women with mild lesions, improving the prognosis and diagnosis of cervical lesions. However, additional efficient strategies should be developed to improve the specificity of these tests.MethodsThis study aimed to evaluate the clinical value of HPV DNA load in improving the diagnosis and prognosis of cervical lesions by p16/Ki-67 testing. Histological samples were collected from 350 women with HR-HPV genotyping and analyzed by qRT-PCR. Immunohistochemical staining was used to assess p16 and Ki-67 expression and clinical performance characteristics were calculated.ResultsOf the cases, 271 had detectable HR-HPV infection, in which HPV-16 was most prevalent (52.0%), followed by HPV-58 (22.5%). P16/Ki-67-positivity increased with histological severity but not for HR-HPV infection. Amongst the 13 HR-HPV genotypes, only HPV-16 (P = 0.016) and HPV-58 (P = 0.004) viral loads significantly correlated with lesion severity. The P16/Ki-67/HPV DNA load co-test indicated an increased sensitivity for the detection of cervical intraepithelial neoplasia (CIN) lesions compared to p16/Ki-67 staining in HPV-16 and/or 58 positive cases. Viral load did not improve the sensitivity of p16/Ki-67 co-test in non-HPV-16 or 58 positive cases. The clinical performance of the p16/Ki-67/HPV DNA load co-test was limited for the prediction of the outcome of CIN1 lesions. However, amongst the 12 HPV-16 and/or 58 positive CIN2 cases in which return visit results were obtained, the behavior of the lesions could be predicted, with a sensitivity, specificity, positive prediction rate (PPV), and negative prediction rate (NPV) of 0.667, 1, 1 and 0.5, respectively.ConclusionCombination of the assessment of HPV DNA load with the intensity of p16 and Ki-67 staining could increase the sensitivity of CIN lesion diagnosis and predict the outcome of CIN2 in patients with a HPV-16 and/or 58 infection.

Clinical Utility of Biomarkers in Diagnosis and Management of High Grade Cervical Intraepithelial Neoplasia (HSIL)

Objective of the study: The increasing inter- and intra-observer variability in the diagnosis of CIN by histopathology has led to the advent of different biomarkers. The aim of this study is to evaluate Ki-67 and p16 INK4a marker in differentiating CIN lesions and the clinical utility of it in the management of high grade squamous intraepithelial lesions (HSIL).&#x0D; Materials and methods: This cross-sectional study has been carried out among the biopsy proved cases of CIN2 and CIN3 in which P16 and Ki-67 immunostain was performed in the Colposcopy clinic, Bangabandhu Sheikh Mujib Medical University (BSMMU) and Department of Pathology, BSMMU respectively from 14-3-17 to 30-05-18. Thirty-two cases were incorporated in the study by purposive sampling. Data was analyzed using SPSS version 17.&#x0D; Results: Among 32 cases of HSIL, 25 were diagnosed as CIN 2 (78.13 %) and 7 cases as CIN 3 (21.87 %) by histopathology. All the cases were subjected to immunohistochemistry with P16 and Ki 67. Regarding the status of P16, it was found positive only in 32% cases of CIN 2 but in 100% cases of CIN 3. Similarly, Ki67 was found positive in 36 % of CIN2 cases but in all cases of CIN 3 lesions. Thus immunostain confirmed one third histopathologically diagnosed CIN 2 cases. On the other hand, all cases of CIN 3 were confirmed as HSIL with the immunostain. All the cases of CIN 2 were reviewed for consensus opinion. Only 8 (32%) cases of CIN 2 were both immunostain positive , the review diagnosis by consensus opinion was also CIN 2 in those cases. One case (4%) of CIN 2 was P16 negative but Ki 67 positive, which ultimately revealed as immature squamous metaplasia. Sixteen cases of CIN 2 were negative for both P16 and Ki 67. Among these, majority cases (52%) , consensus opinion revealed as CIN 1 and 12% cases as immature squamous metaplasia. Therefore, an HSIL diagnosed by histopathology could be false positive in a significant number of cases and overtreatment of a false positive CIN 2 lesion can affect future reproductive status, also have some psychological consequences and economic burden in the health sector.&#x0D; Conclusion: By using the biomarkers, overtreatment and undertreatment of CIN can be avoided. All cases of CIN 2 should be carefully dealt with either review of the slides by consensus opinion or by doing immunohistochemistry if facility is available.&#x0D; Bangladesh J Obstet Gynaecol, 2019; Vol. 34(2): 79-86

Cervical precancerous lesions classification using pre-trained densely connected convolutional networks with colposcopy images

Colposcopy is currently a common medical technique for preventing cervical cancer. However, with the increase of the workload, screening by artificial vision has the problems of misdiagnosis and low diagnostic efficiency. Based on transfer learning, pre-trained densely connected convolutional networks are used to propose a computer-aided-diagnosis (CAD) method for automatic classification of cervical precancerous. The proposed method is applied to determine CIN2 or higher-level lesions in cervical images. In the present work, image data are initially prepossessing with ROI extraction and data augmentation. Then, parameters of all layers are fine-tuning with pre-trained DenseNet convolutional neural networks from two datasets (ImageNet and Kaggle). The impact of different training strategies on the model performance with limited training data is analyzed, including random initialization (RI) training from scratch, fine-tuning (FT) pre-trained model, different size of training data and K-fold cross-validation. Experimental results show that our method (FT) achieves an accuracy of 73.08% (AUC ≈ 0.75) in 600 test images. Compared with previous related work and clinicians, the performance of our approach can effective diagnosis CIN2+ and comparable with a senior physician, which proves the feasibility and promising of the proposed computer-aided diagnostic method.

Performance of Different Combination Models of High-Risk HPV Genotyping in Triaging Chinese Women With Atypical Squamous Cells of Undetermined Significance.

Objective: The purpose of this study was to evaluate the effect of different combination models of high-risk human papilloma viruses (HPV) genotyping in triaging Chinese women with atypical squamous cells of undetermined significance (ASCUS).Methods: We established a screening cohort of 3,997 Chinese women who underwent cervical cytology and HPV genotyping test. Women with ASCUS cytology underwent punch biopsy under colposcopy/endocervical curettage. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of different combination models of HR-HPV genotyping calculated that cervical intraepithelial neoplasia 2 or higher (CIN2+) on histology were endpoints.Results: Of the full sample, 393 women had ASCUS. Among ASCUS women with a CIN2 lesion, the prevalence for HPV were 40.0% (type 16), 10.0% (type 18), 0.0% (type 33), 30.0% (type 52), 40.0% (type 58), and 30.0% (other nine types). For ASCUS women with a CIN3 lesion, the prevalence for HPV were 68.4% (type 16), 15.8% (type 18), 10.5% (type 33), 31.6% (type 52), 15.8% (type 58), and 36.8% (other nine types). Combination model including HPV16/18/33/52/58 for predicting CIN2+ lesion in women with ASCUS had relatively higher sensitivity [93.1% (78.0, 98.1)], specificity [75.8% (71.2, 79.9)], PPV [23.5% (16.7, 32.0)], and NPV [99.3% (97.4, 99.8)] than other combination models. Moreover, the referral rate of HPV16/18/33/52/58 (29.3%) was lower than HR-HPV (36.1%).Conclusions: The study demonstrates that specific HR-HPV types HPV16/18/33/52/58 may be an effective strategy in ASCUS triage. This improves the subsequent selection of ASCUS patients.

Follow-up with histopathology and HPV testing on LSIL cytology in China's largest academic woman's hospital.

Cervical cancer remains a major health problem in China. To provide baseline data for establishing the appropriate screening strategy, the authors investigated the histopathologic follow-up and human papillomavirus (HPV) testing results of low-grade squamous intraepithelial lesion (LSIL) cytology in the Chinese Largest Women Hospital. Women with LSIL cytology, human papillomavirus (HPV) testing, and immediate histopathologic follow-up between 2011 and 2016 were analyzed. The frequency of LSIL among 1,095,022 Papanicolaou (Pap) tests was 1.4%, and was significantly higher in cases using liquid-based cytology (LBC; 1.5%-1.6%) compared with conventional Pap smears (CPS; 0.5%). The CPS method had performance for predicting cervical intraepithelial neoplasia (CIN) that was comparable to that of LBC (75% vs 69.1% and 71.9%). Among 8079 LSIL cases with an immediate histopathologic diagnosis, CIN-2/3 or higher (CIN-2/3+) was found in 11.9% of cases and carcinoma in 0.3% of cases. A total of 158 patients (15.7%) with HPV-positive LSIL had a diagnosis of CIN-2/3 compared with 18 patients (5.5%) with HPV-negative LSIL. In postmenopausal women with LSIL cytology, the detection rate for CIN-2/3 in HPV-negative patients was significant lower than that in HPV-positive patients. Furthermore, HPV type 16 (HPV-16) was the most common genotype noted in patients with CIN-2+ lesions, whereas HPV-18 was the most common in patients with CIN-1. Although its reporting rate is lower than that of LBC, CPS is useful due to its low cost and comparable predictive value. HPV testing is helpful for stratifying postmenopausal women with LSIL into lower and higher risk groups. HPV-16 is the most commonly identified genotype in CIN-2+ lesions diagnosed in Chinese women with LSIL cytology, whereas HPV-18 is the most commonly identified genotype in patients with CIN-1 lesions.

Colposcopic Evaluation of Visual Inspection with Acetic Acid Positive Cases of Unhealthy Cervix

Cervical cancer is the commonest form of cancer in women in virtually all developing countries1. It is the third most common cancer among women worldwide2. Almost 80% of cervical cancer occurs in developing countries. In developed nations, the figure for invasive cervical cancer are much lower due to adaptation of different screening tests1. All sexually active women are at risk of acquiring a Human Papilloma Virus (HPV) infection which may lead to cervical cancer in the future3. Cervical cancer is a preventable disease as the different screening, diagnostic and therapeutic procedures are effective. The screening procedures are VIA (Visual inspection of cervix with acetic acid), Pap’s smear and HPV DNA test. Colposcopy is the triage in screening, taking colpospoy directed biopsy as well as treatment of CIN such as cold coagulation, cryotherapy, and LEEP (Loop electro-surgical excision procedure)4. Objective: To study the role of Colposcopy in the evaluation VIA positive cases of unhealthy cervix, to localize the leisons to obtain the biopsies from the selected areas and detection of precancerous lesion of cervix for early management. Meterials and Methods: This was a prospective observational study done among 306 married women aged 18-65 years who had clinically unhealthy cervix attending the VIA and colposcopy clinic in Department of Obstetrics and Gynaecology of Sir Salimullah Medical College and Mitford Hospital from January 2015 to December 2016. All the patients were subjected to VIA test. Colposcopic evaluation done in VIA positive cases and the findings were noted. Colposcopy directed biopsy was taken from colposcopically suspected areas. Results: Out of 306 cases, 63 women had positive VIA tests and 233 women had negative VIA tests. Colposcopic evaluation were undertaken among 63 VIA positive cases. Colposcopy directed punch biopsy revealed that 28 (60.32%) cases had positive lesions like CIN or invasive carcinoma and 25 (39.68%) had neither CIN or invasive lesions . Among positive leisons about 30.16% had CINI, 1.59 % had CIN II, 0% had CIN III and 28.57% had invasive carcinoma. In this study sensitivity and specificity of colposcopy examination of VIA positive cases were found 94.74% and 56% respectively. Conclusion: It is evident that colposcopy plays a very important role in the evaluation of VIA positive cases of unhealthy cervix. So that early diagnosis and treatment of preinvasive and early invasive carcinoma of cervixis is possible. So wide use of colposcopy in screening program of Bangladesh speciallly in the VIA positive cases can reduce the many young women’s morbidity and mortality.&#x0D; J Bangladesh Coll Phys Surg 2019; 37(2): 60-65

Post-hoc analysis from phase III trials of human papillomavirus vaccines: considerations on impact on non-vaccine types

ABSTRACTBackground: Substantial heterogeneity has been reported in efficacy against high-grade cervical intraepithelial neoplasia (CIN) irrespective of HPV type in phase III results for bivalent and quadrivalent human papillomavirus virus (HPV) vaccines (AS04-HPV and qHPV). Real-world data recently confirmed a very high overall impact of AS04-HPV, supporting the validity of the observed heterogeneity. To explore the reasons for heterogeneous efficacy, we assessed vaccine impact on high-grade lesions not caused by vaccine types.Research methods: We extracted case counts of CIN lesions containing (1) at least one vaccine HPV type, (2) at least one vaccine HPV type and a high-risk non-vaccine type (co-infections) and (3) no vaccine types (non-vaccine or no high-risk HPV types). Based on these, Phase III cross-protective efficacies were estimated with exclusion (3) and with inclusion (2 and 3) of co-infections.Results: Cross-protective efficacy of AS04-HPV against CIN3 lesions ranges from 81.3% (95%CI: 34.7;96.5) (excluding co-infections) to 88.5% (95%CI:62.4;97.8) (including co-infections). For qHPV the efficacy ranges from −58.7% (95%CI: −180.5;8.5) (excluding co-infections) to 13.1% (95%CI: −39.0;45.9) (including co-infections).Conclusions: Heterogenous overall efficacy against CIN3 between AS04-HPV and qHPV is driven by differential efficacy against lesions that do not contain vaccine types, which may be related to the impact of different adjuvants on the immune response.

Squamous cell precancerous lesions of the cervix uteri

The histological and immunohistochemical evaluation of tissue samples obtained in the course of the investigation and treatment of precancerous squamous lesions of the cervix uteri is an essential task of the pathologist. Given the surprising variety of morphological findings, including the many possible differential diagnoses of dysplastic changes, this is not an easy task. Biologically, only two prognostically different groups can be distinguished, which according to the WHO classification are referred to as low-grade or high-grade squamous intraepithelial lesions (LSILs or HSILs). An additional distinction as CIN1, CIN2 or CIN3 should also be made, in particular because CIN2 lesions represent a heterogeneous group of dysplastic changes. The p16 biomarker, which has been widely studied, is extremely helpful in the diagnosis and differential diagnosis of these lesions, as regenerative and reparative changes as well as non-HPV-associated squamous cell metaplasia, are p16 negative or show patchy staining only. The indications for its use were clearly defined in the LAST project. In contrast to the diagnostic advantage, the prognostic significance of p16 in the low-grade intraepithelial lesions is controversial. Other markers such as CK7 and HPVE4 may help here. The immunohistochemistry for p16 may also be useful in examining the resection margins of aconization specimen, especially if thermoeffects make it difficult to make an unambiguous assessment. However, for the prognostic assessment of the clinical course after conization, the HPV test is more important because it better captures the risk of persistence or the risk of recurrence.

Distribution of high-risk human papillomavirus genotype prevalence and attribution to cervical precancerous lesions in rural North China.

ObjectivePrecise prevention is more desired for cervical cancer due to the huge population, high prevalence of human papillomavirus (HPV) infection in China and the vision of screen-and-treat strategies in low- and middle-income countries (LMICs). Considerations of combining type-specific prevalence and attribution proportion to high-grade cervical intraepithelial neoplasia are informative to more precise and effective region-specific cervical cancer prevention and control programs. The aim of the current study was to determine the genotype distribution of HPV and attribution to cervical precancerous lesions among women from rural areas in North China.MethodsA total of 9,526 women participated in the cervical cancer screening project in rural China. The samples of women who tested positive for HPV were retested with a polymerase chain reaction (PCR)-based HPV genotyping test. The attribution proportion of specific high-risk human papillomavirus (HR-HPV) types for different grades of cervical lesions was calculated by using the type contribution weighting method.ResultsA total of 22.2% (2,112/9,526) of women were HR-HPV positive and HPV52 (21.7%) was the most common HR-HPV genotype, followed by HPV58 (18.2%), HPV53 (18.2%) and HPV16 (16.2%). The top three genotypes detected in HR-HPV-positive cervical intraepithelial neoplasia (CIN)1 were HPV16 (36.7%), HPV58 (20.4%), HPV56 (15.3%). Among CIN2+, the most frequent genotypes were HPV16 (75.6%), HPV52 (17.8%), HPV58 (16.7%). HPV16, 56, 58, 53, 52, 59, 68, and 18 combined were attributed to 84.17% of all CIN1 lesions, and HPV16, 58, and 52 combined were attributed to 86.98% of all CIN2+ lesions.ConclusionsThe prevalence of HR-HPV infection among women from rural areas in North China was high and HPV16, HPV58, HPV52 had paramount attributable fraction in CIN2+. Type-specific HPV prevalence and attribution proportion to cervical precancerous lesions should be taken into consideration in the development of vaccines and strategy for screening in this population.

Menstrual pad, a cervical cancer screening tool, a population-based study in rural India.

In the rural areas of India, women generally use a piece of old cloth as a menstrual device. The aim of this study was to detect human papilloma virus (HPV) from menstrual blood on the menstrual pad and assess whether this could be a useful screening tool for cervical cancer. In Jamkhed area of rural Maharashtra, (population A), we collected menstrual pads from women who provided consent in the 30-50 year age group. The women who had provided menstrual pads underwent HC2 testing. We standardized the method for extracting DNA by PCR from the menstrual pad. The women who tested HPV positive, on the basis of HC2/PCR testing, underwent colposcopy. In the rural population of Pune area of Maharashtra state (population B), menstrual pads were collected. HPV was tested using the PCR method. HPV-positive women and a few HPV-negative women, selected randomly, underwent colposcopy and HC2 testing. In population A, 164 women provided their used menstrual pads and also underwent an HC2 screening test. Of these, six (3.2%) cases were reported as HPV positive. In population B, 365 women provided their used menstrual pads for HPV testing, of which 18 (4.9%) cases were diagnosed as HPV positive. The women who tested HPV positive, on the basis of PCR testing, and 10% randomly selected HPV-negative cases (37) and 18 women who voluntary requested testing underwent colposcopy and HC2 testing. The sensitivity of menstrual pad HPV testing compared with gold standard HC2 testing was 83% [95% confidence interval (CI): 0.47-0.97], 67% (95% CI: 0.30-0.91) and specificity was 99% (95% CI: 0.96-0.99), 88% (95% CI: 0.77-0.94) in population A and population B, respectively. The sensitivity of diagnosing CIN lesion was 83% (95% CI: 0.44-0.97) and specificity was 95% (95% CI: 0.91-0.97). On the basis of the sensitivity and specificity results, and the completely noninvasive, simple and convenient method of detecting HPV, menstrual pad might be considered a cervical cancer screening tool in rural Indian women.

Cervicovaginal Fungi and Bacteria Associated With Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Infections in a Hispanic Population.

The human cervicovaginal microbiota resides at an interface between the host and the environment and may affect susceptibility to disease. Puerto Rican women have high human papillomavirus (HPV) infection and cervical cancer rates. We hypothesized that the population structure of the cervicovaginal bacterial and fungal biota changed with cervical squamous intraepithelial lesions and HPV infections. DNA was extracted from cervix, introitus, and anal sites of 62 patients attending high-risk San Juan clinics. The 16S rRNA V4 region and ITS-2 fungal regions were amplified and sequenced using Illumina technology. HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. HPV prevalence was 84% of which ∼44% subjects were infected with high-risk HPV, ∼35% were co-infected with as many as 9 HPV types and ∼5% were infected with exclusively low-risk HPV types. HPV diversity did not change with cervical dysplasia. Cervical bacteria were more diverse in patients with CIN3 pre-cancerous lesions. We found enrichment of Atopobium vaginae and Gardnerella vaginalis in patients with CIN3 lesions. We found no significant bacterial biomarkers associated with HPV infections. Fungal diversity was significantly higher in cervical samples with high-risk HPV and introitus samples of patients with Atypical Squamous Cells of Undetermined Significance (ASCUS). Fungal biomarker signatures for vagina and cervix include Sporidiobolaceae and Sacharomyces for ASCUS, and Malassezia for high-risk HPV infections. Our combined data suggests that specific cervicovaginal bacterial and fungal populations are related to the host epithelial microenvironment, and could play roles in cervical dysplasia.

Toll-like receptors: Important immune checkpoints in the regression of cervical intra-epithelial neoplasia 2.

Toll-like receptors (TLRs) are innate immune defenders thought to be critical for the clearance of human papillomavirus (HPV) infections hence preventing the development of HPV-associated high-grade cervical intra-epithelial neoplasia (CIN2 or 3), a potential cervical cancer precursor. However, the role of TLRs in the regression of established cervical lesions, such as CIN2, is hindered by a lack of prospective design studies. Using SYBR green real-time PCR assays, we have examined the gene expression of TLR2, TLR3, TLR7, TLR8 and TLR9, in cytobrush collected endocervical cells of 63 women diagnosed with CIN2 at study entry (baseline) and followed over a 3-year period. Wilcoxon rank-sum test was used to examine the association between TLR expression levels, measured at baseline, and CIN2 outcome (regression vs. persistence/progression) over time. HPV genotyping was performed using Roche Linear Array Assay detecting 37 HPV types. Women with CIN2 regression showed significantly higher baseline levels of TLR2 (p = 0.006) and TLR7 (p = 0.007), as well as a non-significant trend for a higher TLR8 expression (p = 0.053) compared to women with CIN2 persistence/progression. Six women with CIN2 regression, who presented with an HR-HPV DNA-negative CIN2 lesion at study entry, had significantly higher baseline levels of TLR2 (p = 0.005), TLR7 (p = 0.013) and TLR8 (p = 0.012), compared to women with CIN2 persistence/progression, suggesting their role in clearance of HPV prior to clearance of the lesion. Our results confirm a key role of TLRs in regression of CIN2 and support the potential use of TLR-agonists for treatment of these lesions.