Worldwide use of HPV self-sampling for cervical cancer screening.

An increasing body of evidence supports the validity of self-sampling as an alternative to clinician collection for primary Human Papillomavirus (HPV) screening. Self-sampling effectively reaches underscreened women and can be a powerful strategy in low- and high-resource settings for all target ages. This work aims to summarize the current use of HPV self-sampling worldwide. It is part of a larger project that describes cervical cancer screening programmes and produces standardized coverage estimates worldwide. A systematic review of the literature and official documents supplemented with a formal World Health Organisation country consultation was conducted. Findings show that the global use of HPV self-sampling is still limited. Only 17 (12%) of countries with identified screening programs recommend its use, nine as the primary collection method, and eight to reach underscreened populations. We identified 10 pilots evaluating the switch to self-sampling in well-established screening programs. The global use of self-sampling is likely to increase in the coming years. COVID-19's pandemic has prompted efforts to accelerate HPV self-sampling introduction globally, and it is now considered a key element in scaling up screening coverage. The information generated by the early experiences can be beneficial for decision-making in both new and existing programs.

Does the number of doses matter? A qualitative study of HPV vaccination acceptability nested in a dose reduction trial in Tanzania.

BACKGROUND: The multi-dose regimen is a known barrier to successful human papillomavirus (HPV) vaccination. Emerging evidence suggests that one vaccine dose could protect against HPV. While there are clear advantages to a single dose schedule, beliefs about vaccine dosage in low and middle income countries (LMICs) are poorly understood. We investigated acceptability of dose-reduction among girls, and parents/guardians of girls, randomised to receive one, two or three doses in an HPV vaccine dose-reduction and immunobridging study (DoRIS trial) in Tanzania. METHODS: Semi-structured interviews with girls (n = 19), and parents/guardians of girls (n = 18), enrolled in the study and completing their vaccine course. RESULTS: Most participants said they entrusted decisions about the number of HPV vaccine doses to experts. Random allocation to the different dose groups did not feature highly in the decision to participate in the trial. Given a hypothetical choice, girls generally said they would prefer fewer doses in order to avoid the pain of injections. Parental views were mixed, with most wanting whichever dose was most efficacious. Nonetheless, a few parents equated a higher number of doses with greater protection. CONCLUSION: Vaccine trials and programmes will need to employ careful messaging to explain that one dose offers sufficient protection against HPV should emerging evidence from ongoing dose-reduction clinical trials support this.

Long-term predictors of residual or recurrent cervical intraepithelial neoplasia 2-3 after treatment with a large loop excision of the transformation zone: a retrospective study.

OBJECTIVE: To assess the long-term risk factors predicting residual/recurrent cervical intraepithelial neoplasia (CIN 2-3) and time to recurrence after large loop excision of the transformation zone (LLETZ). DESIGN: Retrospective study. SETTING: Colposcopy clinic. POPULATION: 242 women with CIN 2-3 treated between 1996 and 2006 and followed up until June 2016. METHODS: Age, margins, and high-risk human papillomavirus (HR-HPV) were estimated using Cox proportional hazard and unconditional logistic regression models. The cumulative probability of treatment failure was estimated by Kaplan-Meier analysis. MAIN OUTCOME MEASURE: Histologically confirmed CIN 2-3, HR-HPV, margins, age. RESULTS: CIN 2-3 was associated with HR-HPV (HR = 30.5, 95% confidence interval [CI] = 3.80-246.20), age >35 years (HR = 5.53, 95% CI = 1.22-25.13), and margins (HR = 7.31, 95% CI = 1.60-33.44). HR-HPV showed a sensitivity of 88.8% and a specificity of 80%. Ecto+ /endocervical+ (16.7%), uncertain (19.4%) and ecto- /endocervical+ margins (9.1%) showed a higher risk of recurrence (odds ratio [OR] = 13.20, 95% CI = 1.02-170.96; OR = 15.84, 95% CI = 3.02-83.01; and OR = 6.60, 95% CI = 0.88-49.53, respectively). Women with involved margins and/or who were HR-HPV positive had more treatment failure than those who were HR-HPV negative or had clear margins (P-log-rank <0.001). CONCLUSIONS: HR-HPV and margins seem essential for stratifying post-LLETZ risk, and enable personalised management. Given that clear margins present a lower risk, a large excision may be indicated in older women to reduce the risk. TWEETABLE ABSTRACT: After LLETZ for CIN 2-3, recurrences appear more often in women with positive HR-HPV and involved margins and aged over 35.

HPV vaccination of immunocompromised hosts.

It is well-established that immunocompromised people are at increased risk of HPV-related disease compared with those who are immunocompetent. Prophylactic HPV sub-unit vaccines are safe and immunogenic in immunocompromised people and it is strongly recommended that vaccination occur according to national guidelines. When delivered to immunocompromised populations, HPV vaccines should be given as a 3-dose regimen.

Differential HPV16 variant distribution in squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma.

Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16-monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1-3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non-random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.

Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study.

BACKGROUND: Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma. METHODS: We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study. RESULTS: Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women. CONCLUSIONS: Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes.

Disagreement in high-grade/low-grade intraepithelial neoplasia and high-risk/low-risk HPV infection: clinical implications for anal cancer precursor lesions in HIV-positive and HIV-negative MSM.

Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% confidence interval 2.1-10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our findings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

AIM: This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. METHODS: We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. RESULTS: HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. CONCLUSIONS: HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

Interlaboratory reproducibility and proficiency testing within the human papillomavirus cervical cancer screening program in Catalonia, Spain.

In Catalonia, a screening protocol for cervical cancer, including human papillomavirus (HPV) DNA testing using the Digene Hybrid Capture 2 (HC2) assay, was implemented in 2006. In order to monitor interlaboratory reproducibility, a proficiency testing (PT) survey of the HPV samples was launched in 2008. The aim of this study was to explore the repeatability of the HC2 assay's performance. Participating laboratories provided 20 samples annually, 5 randomly chosen samples from each of the following relative light unit (RLU) intervals: <0.5, 0.5 to 0.99, 1 to 9.99, and ≥10. Kappa statistics were used to determine the agreement levels between the original and the PT readings. The nature and origin of the discrepant results were calculated by bootstrapping. A total of 946 specimens were retested. The kappa values were 0.91 for positive/negative categorical classification and 0.79 for the four RLU intervals studied. Sample retesting yielded systematically lower RLU values than the original test (P<0.005), independently of the time elapsed between the two determinations (median, 53 days), possibly due to freeze-thaw cycles. The probability for a sample to show clinically discrepant results upon retesting was a function of the RLU value; samples with RLU values in the 0.5 to 5 interval showed 10.80% probability to yield discrepant results (95% confidence interval [CI], 7.86 to 14.33) compared to 0.85% probability for samples outside this interval (95% CI, 0.17 to 1.69). Globally, the HC2 assay shows high interlaboratory concordance. We have identified differential confidence thresholds and suggested the guidelines for interlaboratory PT in the future, as analytical quality assessment of HPV DNA detection remains a central component of the screening program for cervical cancer prevention.

Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled InterLymph [correction of IinterLlymph] analysis.

OBJECTIVES: We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. METHODS: Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. RESULTS: Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2-3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. CONCLUSIONS: Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE.

Differential presence of Papillomavirus variants in cervical cancer: an analysis for HPV33, HPV45 and HPV58.

BACKGROUND: Certain human papillomaviruses (HPVs) are the causative agents of cervical carcinomas in humans. The identification of the link between infection and cancer has resulted in the successful establishment of clinical strategies such as screening or vaccination programs, aiming to prevent this pathology. More than 150 different HPVs have been described and classified and the large majority of them are not related to cancer. The genus Alphapapillomavirus encompasses many PVs, some of which are identified in humans as oncogenic, according to the epidemiological connection between infection and cervical cancer. Variants of some of these "high-risk" HPVs may have an increased involvement in cervical cancer, although definitive data are still wanting. The aim of the present work was to analyze the presence of HPV33, HPV45 and HPV58 variants in cases of cervical cancer. METHODS: Samples from cervical lesions in the context of different cervical cancer surveys were analyzed for presence of HPV DNA. Samples positive for HPV33, HPV45 or HPV58 DNA were selected and the E6/E7 genes were amplified and sequenced. The phylogenetic relationships of these sequences were inferred using an evolutionary placement algorithm and accordingly classified at the variant level. RESULTS: All viral E6/E7 sequences were successfully placed in the classification schemes of the corresponding viruses. For HPV33 (n=23), 45 (n=61) or 58 (n=29), the distribution of variants found in cases of cervical cancer is not a random sample of the corresponding diversity. In all three HPVs, the respective A variants were more prevalent in the viral DNA-positive cases of cervical cancer analyzed. This is the first study trying to discern the phylogenetic connection between variants of the oncogenic HPV33, 45 and 58, and squamous cell carcinoma of the cervix.

Antibodies against lytic and latent Kaposi's sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study.

BACKGROUND: Kaposi's sarcoma-associated herpes virus is associated with primary effusion lymphoma and multicentric Castleman's disease. METHODS: Seropositivity to lytic and latent Kaposi's sarcoma herpes virus (KSHV) antigens were examined in 2083 lymphomas and 2013 controls from six European countries. RESULTS: Antibodies against KSHV latent and lytic antigens were detectable in 4.5% and 3.4% of controls, respectively, and 3.6% of cases (P>0.05). The KSHV seropositivity was associated with splenic marginal zone lymphoma (SMZL) (odds ratio (OR)=4.11, 95% confidence interval (CI)=1.57-10.83) and multiple myeloma (OR=0.31, 95% CI=0.11-0.85). CONCLUSION: The KSHV is unlikely to contribute importantly to lymphomagenesis among immunocompetent subjects. However, the observed association with SMZL may underline a chronic antigen mechanism in its aetiology.

Appraisal of the burden of genital warts from a healthcare and individual patient perspective.

OBJECTIVE: Worldwide, genital warts, caused by human papillomavirus (HPV) is a common, sexually transmitted disease. The overall disease management strategy for genital warts should be determined not only by the prevalence, but also by the impact of the disease on individuals and society. The purpose of this study was therefore to investigate the epidemiological, economic and quality of life (QoL) burden of genital warts. METHODS: A systematic literature review was conducted on the epidemiology, QoL and management cost of genital warts in the USA, UK and France, based on studies published between 1998 and 2008. Due to scarcity of data, all studies reporting standardized QoL assessments among patients with genital warts were utilized, regardless of country of origin. Original studies were preferred over information cited in review articles. RESULTS: Data from three countries suggest that genital warts occur in 0.06-0.23% of the population each year. Despite the fact that spontaneous remissions occur frequently (up to 40%), patients often prefer immediate treatment. While treatment can be costly in absolute terms (€163-510 per treatment episode), these costs are lower compared with other sexually transmitted infections (STIs). Modest reductions in QoL have been noted, which may be mitigated through adequate patient education and support. CONCLUSIONS: While genital warts are an inconvenience for many patients, the occurrence may be lower than often quoted in the literature, and the economic burden on society is less than for other prominent STIs. However, concerted efforts to establish improved data collection and surveillance systems are needed in order to accurately define the burden of genital warts on individuals and society.

Worldwide burden of cervical cancer in 2008.

BACKGROUND: The knowledge that persistent human papillomavirus infection is the main cause of cervical cancer has resulted in the development of assays that detect nucleic acids of the virus and prophylactic vaccines. Up-to-date and reliable data are needed to assess impact of existing preventive measures and to define priorities for the future. MATERIALS AND METHODS: Best estimates on cervical cancer incidence and mortality are presented using recently compiled data from cancer and mortality registries for the year 2008. RESULTS: There were an estimated 530,000 cases of cervical cancer and 275,000 deaths from the disease in 2008. It is the third most common female cancer ranking after breast (1.38 million cases) and colorectal cancer (0.57 million cases). The incidence of cervical cancer varies widely among countries with world age-standardised rates ranging from <1 to >50 per 100,000. Cervical cancer is the leading cause of cancer-related death among women in Eastern, Western and Middle Africa; Central America; South-Central Asia and Melanesia. The highest incidence rate is observed in Guinea, with ∼6.5% of women developing cervical cancer before the age of 75 years. India is the country with the highest disease frequency with 134,000 cases and 73 000 deaths. Cervical cancer, more than the other major cancers, affects women <45 years. CONCLUSIONS: In spite of effective screening methods, cervical cancer continues to be a major public health problem. New methodologies of cervical cancer prevention should be made available and accessible for women of all countries through well-organised programmes.

Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study.

BACKGROUND: Several studies have suggested an association between occupational exposure to solvents and lymphoma risk. However, findings are inconsistent and the role of specific chemicals is not known. Objective To investigate the role of occupational exposure to organic solvents in the aetiology of B-cell non-Hodgkin's lymphoma (B-NHL) and its major subtypes, as well as Hodgkin's lymphoma and T-cell lymphoma. METHODS: 2348 lymphoma cases and 2462 controls participated in a case-control study in six European countries. A subset of cases were reviewed by a panel of pathologists to ensure diagnostic consistency. Exposure to solvents was assessed by industrial hygienists and occupational experts based on a detailed occupational questionnaire. RESULTS: Risk of follicular lymphoma significantly increased with three independent metrics of exposure to benzene, toluene and xylene (BTX) (combined p=4 x 10(-7)) and to styrene (p=1 x 10(-5)), and chronic lymphocytic leukaemia (CLL) risk increased with exposure to solvents overall (p=4 x 10(-6)), BTX (p=5 x 10(-5)), gasoline (p=8 x 10(-5)) and other solvents (p=2 x 10(-6)). Risk of B-NHL for ever exposure to solvents was not elevated (OR=1.1, 95% CI 1.0 to 1.3), and that for CLL and follicular lymphoma was 1.3 (95% CI 1.1 to 1.6) and 1.3 (95% CI 1.0 to 1.7), respectively. Exposure to benzene accounted, at least partially, for the association observed with CLL risk. Hodgkin's lymphoma and T-cell lymphoma did not show an association with solvent exposure. CONCLUSION: This analysis of a large European dataset confirms a role of occupational exposure to solvents in the aetiology of B-NHL, and particularly, CLL. It is suggested that benzene is most likely to be implicated, but we cannot exclude the possibility of a role for other solvents in relation to other lymphoma subtypes, such as follicular lymphoma. No association with risk of T-cell lymphoma and Hodgkin's lymphoma was shown.

Differences in the risk of cervical cancer and human papillomavirus infection by education level.

BACKGROUND: Cervical cancer risk is associated with low education even in an unscreened population, but it is not clear whether human papillomavirus (HPV) infection follows the same pattern. METHODS: Two large multicentric studies (case-control studies of cervical cancer and HPV prevalence survey) including nearly 20 000 women. GP5+/GP6+ PCR was used to detect HPV. RESULTS: Education level was consistently associated with cervical cancer risk (odds ratio (OR) for 0 and >5 years vs 1-5 years=1.50, 95% confidence interval (CI): 1.25-1.80 and 0.69, 95% CI: 0.57-0.82, respectively, P for trend <0.0001). In contrast, no association emerged between education level and HPV infection in either of the two IARC studies. A majority of the women studied had never had a Pap smear. The association between low education level and cervical cancer was most strongly attenuated by adjustment for age at first sexual intercourse and first pregnancy. Parity and screening history (but not lifetime number of sexual partners, husband's extramarital sexual relationships, and smoking) also seemed to be important confounding factors. CONCLUSION: The excess of cervical cancer found in women with a low socio-economic status seems, therefore, not to be explained by a concomitant excess of HPV prevalence, but rather by early events in a woman's sexually active life that may modify the cancer-causing potential of HPV infection.