Is stress related to the presence and persistence of oncogenic human papillomavirus infection in young women?

BACKGROUND: Persistent infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for the development of cervical cancer, but factors contributing to HR-HPV persistence are incompletely understood. The objective of this study was to test for associations of chronic stress and two aspects of diurnal cortisol secretion (i.e., the cortisol awakening response [CAR] and total cortisol output over the day [AUCgday]) with HR-HPV status at baseline and 12 months later (follow-up). METHODS: We evaluated 188 women (25 ± 3 years) at baseline. Follow-up investigation was restricted to HR-HPV infected women at baseline. Of the initial 48 HR-HPV positive participants, 42 completed the follow-up (16 HR-HPV positive and 26 HR-HPV negative). At baseline and follow-up, we determined HR-HPV status in cervical smears, assessed chronic stress, and repeatedly measured salivary cortisol over the day. At baseline, we analyzed salivary cortisol only in a subgroup of 90 participants (45 HR-HPV negative and 45 HR-HPV positive). RESULTS: At baseline, higher chronic stress (excessive demands at work: p = .022, chronic worrying: p = .032), and a higher CAR (p = .014) were related to baseline HR-HPV positivity. At follow-up, there was a statistical trend for a positive association between the CAR and HR-HPV positivity (p = .062). Neither the CAR nor the AUCgday mediated the associations between chronic stress and HR-HPV status. CONCLUSIONS: Our findings suggest that both chronic stress and diurnal cortisol are related to the presence of HR-HPV infection and may thus play a role in HPV-associated cervical carcinogenesis.

Cervical dysplasia in a patient with inherited epidermodysplasia verruciformis-A mere coincidence?

Epidermodysplasia verruciformis (EV) is a rare inherited or acquired genodermatosis caused by increased susceptibility to infection by the beta subtypes of human papillomavirus (HPV). The co-occurrence of EV with high-risk (HR) HPV infection leading to cervical dysplasia is unreported in the literature to date. We report a patient with inherited EV who developed extensive anogenital and cervical dysplasia linked to concurrent HR-HPV infection. Literature review suggests that there is a negative correlation of cervical dysplasia and cervical cancer with EV, which suggests that this patient's presentation and course are exceptional.

Analysis of HPV Integrations in Mexican Pre-Tumoral Cervical Lesions Reveal Centromere-Enriched Breakpoints and Abundant Unspecific HPV Regions.

Human papillomavirus (HPV) DNA integration is a crucial event in cervical carcinogenesis. However, scarce studies have focused on studying HPV integration (HPVint) in early-stage cervical lesions. Using HPV capture followed by sequencing, we investigated HPVint in pre-tumor cervical lesions. Employing a novel pipeline, we analyzed reads containing direct evidence of the integration breakpoint. We observed multiple HPV infections in most of the samples (92%) with a median integration rate of 0.06% relative to HPV mapped reads corresponding to two or more sequence breakages. Unlike cancer studies, most integrations events were unique (supported by one read), consistent with the lack of clonal selection. Congruent to other studies, we found that breakpoints could occur, practically, in any part of the viral genome. We noted that L1 had a higher frequency of rupture integration (25%). Based on host genome integration frequencies, we found previously reported integration sites in cancer for genes like FHIT, CSMD1, and LRP1B and putatively many new ones such as those exemplified in CSMD3, ROBO2, and SETD3. Similar host integrations regions and genes were observed in diverse HPV types within many genes and even equivalent integration positions in different samples and HPV types. Interestingly, we noted an enrichment of integrations in most centromeres, suggesting a possible mechanism where HPV exploits this structural machinery to facilitate integration. Supported by previous findings, overall, our analysis provides novel information and insights about HPVint.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Effects of exposure to polycyclic aromatic hydrocarbons combined with high-risk human papillomavirus infection on cervical intraepithelial neoplasia: A population study in Shanxi Province, China.

High-risk human papillomavirus (HR-HPV) infection is a major etiological agent in the progression of cervical intraepithelial neoplasia (CIN) and cervical cancer. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic pollutants that exist widely in the environment. We hypothesized that PAHs exposure was related to the progression of cervical cancer, and could increase the effect of HR-HPV on CIN. We investigated the effects of PAHs exposure combined with HR-HPV infection on CIN in community population in Shanxi Province, China. A total of 2,285 women were enrolled into the study. HR-HPV genotypes were detected by flow-through hybridization technology. 1-hydroxypyrene (1-OHP) was detected by high-performance liquid chromatography. The top three HR-HPV genotypes were 16, 58 and 52 in turn. With unconditional logistic regression analysis, we found that HR-HPV infection (adjusted odds ratio [aOR] = 4.08, 95% confidence interval [CI]: 3.00-5.54), HPV16 infection (aOR = 4.71, 95% CI: 3.39-6.53), HPV58 infection (aOR = 2.29, 95% CI: 1.41-3.73) and PAHs high exposure (aOR = 2.57, 95% CI: 1.82-3.62) increased the risk of CIN2/3, showing an increasing trend (p < 0.001) with the severity of cervical lesions. Compared to Q1 (<0.06 µmol/molCr) levels of 1-OHP, women with Q4 (>0.11 µmol/molCr) had a higher risk for CIN2/3 (aOR = 7.68, 95% CI: 4.83-12.22). Additionally, we observed that there was a synergic effect between high exposure to PAHs and HR-HPV infection in CIN2/3. Furthermore, the results from the generalized multifactor dimensionality reduction model showed that there were joint interactions of PAHs, HPV16, HPV58 and HPV52 on the risk of CIN2/3. Our study revealed that high exposure to PAHs could increase the risk for CIN, and it posed stronger risk when combined with HR-HPV infection.

Temporal changes in the vaginal microbiota in self-samples and its association with persistent HPV16 infection and CIN2.

BACKGROUND: The vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables. METHODS: In total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software. RESULTS: K-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036). CONCLUSIONS: The vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population-based national cohort study.

OBJECTIVE: To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN). DESIGN: Population-based national cohort study. SETTING AND POPULATION: All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries. METHODS: The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised. MAIN OUTCOME MEASURE: Vaginal cancer. RESULTS: We identified 898 incident cases of vaginal cancer. Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100 000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15 years of follow up: 65.7 (95% CI 21.2-203.6). CONCLUSIONS: Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening. TWEETABLE ABSTRACT: High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery.

Incidence of cervical intraepithelial neoplasia in women infected with human immunodeficiency virus (HIV) with no evidence of disease at baseline: Results of a prospective cohort study with up to 6.4 years of follow-up from India.

We report the incidence of cervical intraepithelial neoplasia (CIN) among HIV-infected women who did not have any colposcopic or histopathological evidence of CIN at baseline. Of the 1,023 women without any CIN at baseline, 855 (83.6%) have been followed up to a maximum of 6.4 years contributing 2,875 person years of observation (PYO). Among these 855 women, 54 cases of any CIN were observed resulting in incidence rate of any CIN of 1.9 per 100 PYO. The median time for follow-up for women with any CIN was 3.0 (IQR 1.6-3.7) years. The cumulative incidence rate per 100 PYO of CIN 2 or worse lesion in women with HPV-18 infection at baseline was 13.3% (95% CI 5.1-26.8); in women with HPV-16 infection was 10.8% (95% CI 4.4-20.9); in women with HPV-31 infection was 4.2% (95% CI 0.9-11.7); and in women with other high-risk HPV infections was 5.4% (95% CI 2.6-9.7). HPV-18 infection at baseline contributed highest frequency of incident CIN 2 or worse lesions followed by HPV-16 infection; however, other high-risk HPV types were also responsible for substantial number of incident CIN. The elevated risk of CIN2+ disease in the study cohort was non-significant in women with CD4 count <200, possibly because of the small number of cases. Our results emphasize the need for regular cervical cancer screening of HIV-infected women and urgent implementation of cervical cancer screening services in HIV programs in India and other low and middle-income countries.

Alinity m HR HPV Assay Fulfills Criteria for Human Papillomavirus Test Requirements in Cervical Cancer Screening Settings.

The Alinity m HR HPV assay (Alinity) is a novel human papillomavirus (HPV) assay that individually identifies genotypes HPV16, HPV18, and HPV45 while reporting on 11 other high-risk HPV (hrHPV) genotypes in two aggregates: HPV31/33/52/58 and HPV35/39/51/56/59/66/68. The clinical performance of Alinity for screening for cervical cancer was evaluated in population-based settings. For women aged ≥30 years, the clinical sensitivity (n = 68) and specificity (n = 3,077) for the detection of cervical intraepithelial neoplasia grade 2+ (CIN2+) of Alinity were 100.0% and 92.4%, respectively, and were not inferior to those of the Qiagen Digene Hybrid Capture 2 high-risk HPV DNA assay (hc2) (P = 0.0006 and P < 0.0001, respectively). The intralaboratory reproducibility and interlaboratory agreement of Alinity were 96.7% (kappa, 0.92) and 98.7% (kappa, 0.97), respectively. In the group ≥30 years of age, women who were baseline hrHPV negative had a lower risk for CIN2+ at 3 years using Alinity (0.04%) than those with a normal baseline cytology (0.65%) and had a risk comparable to that determined by the Abbott RealTime High Risk HPV assay (0.04%), hc2 (0.08%), or the Roche Cobas 4800 HPV assay (0.04%). High-risk HPV16/18 infection was associated with a significantly higher baseline and 3-year CIN2+ and CIN3+ risk than the absence of HPV16/18 or the presence of hrHPVs at the baseline (all P values were <0.05). The baseline CIN2+ risk was 8.8% for those with HPV31/33/52/58 infection and 2.5% for those with HPV35/39/51/56/59/66/68 infection, while the 3-year CIN2+ risk was 17.0% and 4.9%, respectively (relative risk, 3.4 [P = 0.03] and 3.5 [P = 0.003], respectively), suggesting that extended genotyping by Alinity may be valuable in improving patient risk stratification. Alinity fulfills international consensus guideline criteria for primary cervical cancer screening and can be considered clinically validated, demonstrating safety comparable to that of other clinically validated HPV tests.

CCR5 genetic variants and epidemiological determinants for HPV infection and cervical premalignant lesions.

Human papillomavirus (HPV) infection can lead to the development of productive epithelial lesions and cervical cancer. Most cervical HPV infections are solved by cell-mediated immunity within 1-2 years, and it is known that chronic inflammation predisposes to lesions progression and tumour development. In this context, we highlight the CC chemokine receptor 5 (CCR5) which is involved in leucocytes chemotaxis to sites of inflammation, controlling the immune response. The CCR5 rs333 genotyping of 164 HPV infected women and 185 non-infected women was performed using polymerase chain reaction (PCR). HPV infection was more frequent among women under 34 years old (p < 0.001), single (p = 0.001), that received 1 minimum wage or less (p = 0.002), tobacco smokers (p = 0.007), who had the first sexual intercourse before 17 years old (p = 0.038) and that had 4 or more sexual partners during lifetime (p = 0.001). No significant difference regarding genotypes and alleles distribution according to HPV infection was observed. CCR5/CCR5 genotype was observed in 94.1% of HPV non-infected women and in 89% of infected ones, CCR5/Δ32 in 5.9% of HPV infected and in 10.4% of non-infected women, and Δ32/Δ32 was observed in only one (0.6%) infected patient. CCR5 genotypes were also not associated with cervical lesions development among HPV infected women (p = 0.167). Since CCR5 may control the antitumour immune response and cervical lesions and the studied rs333 polymorphism is not very frequent, other studies are necessary, in order to establish CCR5 role on HPV infection and squamous intraepithelial lesions development.

Experiences of women with cervical dysplasia and associated diagnoses using electronic cigarettes for smoking substitution.

INTRODUCTION: The aim of this qualitative study was to describe the motivation and experiences of women with cervical dysplasia and associated diagnoses who used electronic cigarettes (ECs) to reduce the number of cigarettes they smoked. METHODS: Qualitative interviews were conducted with 26 women aged 18-65 years with cervical dysplasia and associated diagnoses who smoked at least three cigarettes daily for the past year or more and who enrolled in an intervention designed to substitute regular cigarettes with ECs. At the 12-week follow-up, patients were contacted by telephone. Semi-structured interviews were recorded, then transcribed, coded and analysed for themes. RESULTS: When confronted with a new diagnosis associated with smoking, women in this study were eager to try ECs to help them reduce their intake of cigarettes. Women reported that physical cues similar to smoking, delivery of nicotine sufficient to assist with smoking reduction and the security of having the device available to use in instances where temptations to smoke may occur were all positive experiences in trying the device. Other women in the study reported negative experiences, such as a lack of sufficient nicotine to eliminate cravings, heaviness of the device and the need to keep it charged. Depression, nicotine addiction and habit were factors that made it difficult to decrease cigarette consumption. CONCLUSIONS: Findings suggest that ECs may help with smoking substitution in patients who must reduce smoking due to medical conditions or diagnoses.

The Role of the Cervicovaginal Microbiome on the Genesis and as a Biomarker of Premalignant Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

Correlation between cervical carcinogenesis and tobacco use by sexual partners.

PURPOSE: Investigating the effects of active smoking, passive smoking and semen of tobacco smoking sexual partners on the carcinogenesis of uterine cervix. INTRODUCTION: It is now well-established that persistence of Human Papillomavirus (HPV) infection is the strongest epidemiologic factor associated with intraepithelial neoplasia and cancer of cervix, as well as in other related locations such as in the vagina, vulva, anus, oral cavity, etc. A 1999 study indicates that the worldwide HPV prevalence in cervical carcinomas is 99,7 per cent. Multiple factors seem to intervene on cervical carcinogenesis, many of them related to tobacco, especially by direct local carcinogenic effect and local immunosuppression. Many studies have also shown that active or passive smoking in women (family-work environment, meeting places, etc.) greatly affects the occurrence, progression and degree of malignancy of carcinogenesis. Furthermore, particularly increased levels of nicotine and cotinine in the cervical mucus as well as prostate sperm fluids and urinary cotinine:creatinine ratios in smokers and passive smokers indicate that tobacco constituents do indeed reach the uterine cervix and lead to increased modification of DNA in cervical epithelium, suggesting biochemical evidence consistent with smoking as a cause of cervical cancer. The research presented today, though it took place over 30 decades ago (1975-1986 at the University Gynecological and Obstetric Clinic of Homburg ad Saar), we hope will serve as a reminder and contributing factor for further examination of the increased risk of cervical cancer in non-smoking women living with smoking partners. STUDY: The study analyzed a total of one thousand five-hundred and forty (1,540) medical history sheets (krankenblätter) of women aged from eighteen to seventy-four (18-74) years old that were admitted, treated, examined (PAP TEST) or referred for further tests by their family physicians to the Homburg ad Saar Clinic between 1975-1986. The study evaluated the general medical history of the 1,540 women with a special focus on gynecological and obstetric related data and gathered additional information from patients through written questionnaires completed via phone, mail or personal interviews. Among a range of factors and data studied during the research, our current presentation and discussion will focus on the development of cervical neoplasms in women, examining results from three different study groups: smokers, passive-smokers and women with smoking sexual partners. RESULTS: Five hundred and forty-four cases (544) out of the overall study sample of one thousand five-hundred and forty (1,540) women, were identified as cases with pathological cell abnormalities (35.32%). Following diagnosis and treatment of transient lesions due to various inflammations (vaginitis, cervicitis etc.) one hundred and twelve (112) cases (20.59%) showed varying degrees of mild/reversible up to CIN 1-3 intraepithelial lesions. From the above sample of one hundred and twelve 112 cases, nineteen cases (19) were smoke free women who never smoked themselves, were not exposed to passive smoking and had non-smoker partners (16.96%). Forty-four (44) cases (39.29%) were female smokers, twenty-two (22) cases (19.64%) were women exposed to regular passive smoking (family-work environment) with a smoke-free partner and twenty-seven (27) cases (24.11%) were women non-smokers with a smoker partner. From the above findings, intraepithelial lesions were found to be higher (and with a progressive malign ratio) on the study groups that were associated with tobacco use either active or passive and therefore, the synergistic harmful effect of smoking, progressively from passive smokers to active smokers, is clearly evident on the occurrence and progression of cervical malignancies. As already mentioned above, the presence of HPV has been widely proven to be almost exclusively the cause of different degrees of neoplasia in the cervix for more than 99.7% of cervical carcinogenesis. However, the harmful effects of a) active smoking, b) passive smoking and c) the exposure to tobacco constituents through an active smoker partner, in women, should be sought and possibly attributed to the catalytic reduction of cervical self-defense and overall cervical immunity disruption which results to the exposure of cervix to elevated levels of nicotine-cotinine and cancer-causing chemicals related to smoking, may work together with certain types of HPV limiting the natural ability of the cervix to defend against carcinogenesis and therefore increase the likelihood of developing cancer. CONCLUSION: Since the almost exclusively cause of cervical neoplasms is due to the presence and carcinogenic activity of HPV, the harmful/synergistic effect of smoking, passive smoking and partner smoking cannot be attributed to the direct carcinogenic effect of nicotine but to the overall damage of the immune system as we as the reduction of cervical self-defense making it more vulnerable to the carcinogenic nature of HPV, in particular the increased pathogenic types 16 and 18. Lastly, another potential correlation that could be further examined is the potential effects of tobacco constituents in cervical fluids on the self-defense system of the male reproductive system.

Cervical cancer risk in HPV-positive women after a negative FAM19A4/mir124-2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow-up.

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124-2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV-positive women. To date, longitudinal data on the cancer risk of methylation test-negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124-2 methylation analysis in an HPV-positive screening cohort with 14 years of follow-up. Archived HPV-positive cervical scrapes of 1,040 women (age 29-61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124-2 methylation. By linkage with the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow-up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124-2 methylation, including 24 women with cervical cancer in follow-up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow-up. Within screening round capability of FAM19A4/mir124-2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5-100). Kaplan-Meier estimate of 14-year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66-3.0) among baseline methylation-negative and 2.4% (95% CI: 1.4-3.6) among baseline cytology-negative women (risk difference: 0.71% [95% CI: 0.16-1.4]). In conclusion, a negative FAM19A4/mir124-2 methylation test provides a low cervical cancer risk in HPV-positive women of 30 years and older. FAM19A4/mir124-2 methylation testing merits consideration as an objective triage test in HPV-based cervical screening programs.

Distribution of human papilloma virus genotype prevalence in invasive cervical carcinomas and precancerous lesions in the Yangtze River Delta area, China.

BACKGROUND: This study aimed to provide more information for cancer prevention strategies by determining the distribution of human papilloma virus (HPV) genotype prevalence in invasive cervical carcinoma (ICC) and precancerous lesion patients in the Yangtze River Delta area in China. METHODS: This multi-centre descriptive cross-sectional study involves four university hospitals in the Jiangzhehu area. Women with histologically confirmed cervical intraepithelial neoplasia (CIN) 1, CIN2, CIN3 or ICC who were diagnosed and treated in the four selected hospitals between February 2012 and April 2014 were eligible for recruitment. The average age of the patients was 40.93 ± 11.87 years old, among whom the youngest was 17 years old and the oldest was 76 years old.Those with immunodeficiency diseases or a previous history of cancer or CIN were excluded. HPV genotyping was performed by a central laboratory. The distribution and age and disease specificity of the HPV genotype prevalence were analysed. RESULTS: Of the 2181 collected samples, 251 were ICC and 1930 were CIN. The mean age of cervical cancer and CIN patients was 40.93 ± 11.8 years (range, 17-76 years). The five most commonly identified HPV types in each lesion class were as follows: CIN1: 52, 58, 16, 33, and CP; CIN2: 16, 58, 52, 33, and 31; CIN3: 16, 58, 33, 52, and 31; and ICC: 16, 58, 18, 52, and 33. CIN1 had an earlier age of onset (30-40 years) than CIN2, CIN3, and cervical cancer. The age of onset of cervical cancer exhibited two peaks at 40-44 and 50-54 years of age. In all infected patients, the frequency of HPV infection with a single type was 62.9%, and with multiple types, it was 38.1%. There was no difference in the frequencies of multiple types amongst the different cervical lesions. CONCLUSIONS: The most prevalent genotypes in the investigated area (52, 58, 16 and 18) justify the necessity of anti-HPV vaccination in teenagers and young girls under 24 years old in the Yangtze River Delta area in China. Infection with multiple high-risk HPV types versus single infection does not increase the risk for ≥ CIN2 in ICC development.

A prospective study of women with ASCUS or LSIL pap smears at baseline and HPV E6/E7 mRNA positive: a 3-year follow-up.

Human papillomavirus (HPV) testing is used in the triage of women with a borderline smear result. The efficiency of testing women with a low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells of undetermined significance (ASCUS) is less clear. For this reason we used a new HPV test that detects E6/E7 messenger RNA (mRNA), which might have a higher specificity. The objective of this prospective study was to assess whether HPV E6/E7 mRNA positivity in women with ASCUS and LSIL at baseline, is able to predict those women who have a high risk of developing a histological cervical intraepithelial neoplasia (CIN2) or worse lesion. We took into consideration the women's age and HPV DNA genotype and followed them up for 3 years. Cervical samples from women with high-risk HPV (HR-HPV) DNA-positive ASCUS (n = 90) or LSIL (n = 222) were tested for the presence of HR-HPV E6/E7 mRNA and the women were monitored for the development of histopathologically verified CIN2+. Thirteen patients with ASCUS and 17 with LSIL did not complete follow-up. All patients with LSIL and ASCUS, enrolled in this study, had confirmed lesions at the colposcopic examination. Follow-up was available for 312 women, 193 were positive in the HR-HPV DNA test and 93 had a HPV E6/E7 mRNA positive test. Finally, 22 women positive in the HPV DNA test for high-risk genotypes and with positive E6/E7 mRNA had a histologically confirmed CIN2+. Only two cases with negative HPV E6/E7 mRNA had CIN2+. The study shows that women positive in the HPV E6/E7 mRNA test have a greater risk of malignant progression of cervical lesions and therefore deserve greater attention and earlier check-ups.

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling.

To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1- CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERα) to CxCa, ERα expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERα to FSP1+, CD34+, SMA- precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1-, CD34-, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERα mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERα-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERα+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERα in tumor-associated stromal fibroblasts.

Diagnostic performance of HPV E6/E7 mRNA assay for detection of cervical high-grade intraepithelial neoplasia and cancer among women with ASCUS Papanicolaou smears.

PURPOSE: The aim of this study was to investigate the clinical performance of high risk (HR) HPV E6/E7 mRNA assay in detecting cervical high-grade intraepithelial neoplasia and cancer among women with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou (Pap) smears. METHODS: A total of 160 patients with ASCUS who underwent HR-HPV DNA assay, HR-HPV E6/E7 mRNA assay and colposcopy biopsy at Third Affiliated Hospital of Zhengzhou University, China, from December 2015 to March 2017, were enrolled. Logistic regression analysis was used to evaluate the relationship between pathological results with clinical biologic factors. RESULTS: Univariate analysis showed that the qualitative results of HR-HPV DNA, qualitative results of HR-HPV E6/E7 mRNA and expression levels of HR-HPV E6/E7 mRNA were risk factors of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (all P < 0.05). Multivariable analysis found that only the expression levels of HR-HPV E6/E7 mRNA was associated with high-grade CIN and cervical cancer (OR = 8.971, 95% CI = 2.572-31.289, P = 0.001). An optimal cut-off value of ≥ 558.26 copies/ml was determined using receiver operating characteristic curve, and specificity of cut-off value were higher than E6/E7 mRNA qualitative assay and DNA qualitative assay. CONCLUSION: HPV E6/E7 mRNA quantitative assay may be a valuable tool in triage of ASCUS pap smears. A high specificity of E6/E7 mRNA quantitative assay as a triage test in women with ASCUS can be translated into a low referral for colposcopy.