Type‐dependent association between risk of cervical intraepithelial neoplasia and viral load of oncogenic human papillomavirus types other than types 16 and 18

Studies of the clinical relevance of human papillomavirus (HPV) DNA load have focused mainly on HPV16 and HPV18. Data on other oncogenic types are rare. Study subjects were women enrolled in the atypical squamous cells of undetermined significance (ASC‐US) and low‐grade squamous intraepithelial lesion (LSIL) triage study who had ≥1 of 11 non‐HPV16/18 oncogenic types detected during a 2‐year follow‐up at 6‐month intervals. Viral load measurements were performed on the first type‐specific HPV‐positive specimens. The association of cervical intraepithelial neoplasia grades 2–3 (CIN2/3) with type‐specific HPV DNA load was assessed with discrete‐time Cox regression. Overall, the increase in the cumulative risk of CIN2/3 per 1 unit increase in log₁₀‐transformed viral load was statistically significant for four types within species 9 including HPV31 (adjusted hazard ratio [HR _adjusted] = 1.32: 95% confidence interval [CI], 1.14–1.52), HPV35 (HR _adjusted = 1.47; 95% CI, 1.23–1.76), HPV52 (HR _adjusted = 1.14; 95% CI, 1.01–1.30) and HPV58 (HR _adjusted = 1.49; 95% CI, 1.23–1.82). The association was marginally significant for HPV33 (species 9) and HPV45 (species 7) and was not appreciable for other types. The per 1 log₁₀‐unit increase in viral load of a group of species 9 non‐HPV16 oncogenic types was statistically significantly associated with risk of CIN2/3 for women with a cytologic diagnosis of within normal limits, ASC‐US, or LSIL at the first HPV‐positive visit but not for those with high‐grade SIL. Findings suggest that the viral load‐associated risk of CIN2/3 is type‐dependent, and mainly restricted to the species of HPV types related to HPV16, which shares this association.     

Hierarchical clustering of human papilloma virus genotype patterns in the ASCUS-LSIL triage study

Anogenital cancers are associated with ～13 carcinogenic human papilloma virus (HPV) types in a broader group that cause cervical intraepithelial neoplasia (CIN). Multiple concurrent cervical HPV infections are common, which complicates the attribution of HPV types to different grades of CIN. Here we report the analysis of HPV genotype patterns in the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study with the use of unsupervised hierarchical clustering. Women who underwent colposcopy at baseline (n = 2,780) were grouped into 20 disease categories based on histology and cytology. Disease groups and HPV genotypes were clustered with the use of complete linkage. Risk of 2-year cumulative CIN3+, viral load, colposcopic impression, and age were compared between disease groups and major clusters. Hierarchical clustering yielded four major disease clusters: cluster 1 included all CIN3 histology with abnormal cytology; cluster 2 included CIN3 histology with normal cytology and combinations with either CIN2 or high-grade squamous intraepithelial lesion cytology; cluster 3 included older women with normal or low-grade histology/cytology and low viral load; and cluster 4 included younger women with low-grade histology/cytology, multiple infections, and the highest viral load. Three major groups of HPV genotypes were identified: group 1 included only HPV16; group 2 included nine carcinogenic types, plus noncarcinogenic HPV53 and HPV66; and group 3 included noncarcinogenic types, plus carcinogenic HPV33 and HPV45. Clustering results suggested that colposcopy missed a prevalent precancer in many women with no biopsy/normal histology and high-grade squamous intraepithelial lesion. This result was confirmed by an elevated 2-year risk of CIN3+ in these groups. Our novel approach to study multiple genotype infections in cervical disease with the use of unsupervised hierarchical clustering can address complex genotype distributions on a population level.     

Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types

Human papillomavirus (HPV) is essential in cervical carcinogenesis, however, less is known about the carcinogenic potential of individual HPV types. Our aim was to examine the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after persistence of 13 individual oncogenic HPV types. Liquid-based cervical samples (n = 40,399) collected in 2002–2005 were tested for HPV by hybrid capture 2 and genotyped with INNO-LiPAv2. Persistence was defined as having the same genotype twice 1–4.5 years apart. The absolute risk of CIN3+ was estimated by the Aalen-Johansen estimator and Cox proportional hazard regression was used to compare the rates of CIN3+ according to HPV type adjusting for age and time between HPV tests. Of 2,875 oncogenic HPV-positive women, 874 had persistence of one or more types and 761 persisted for one oncogenic HPV type only. Persistent HPV16 infection was associated with the highest risk of CIN3+, with an 8-year absolute risk of 55% (95% CI: 45%–66%), followed by HPV33 (33% (95% CI: 20%–50%)), HPV18 (32% (95% CI: 20%–48%)) and HPV31 (31% (95% CI: 21%–46%)). Other HPV types, including HPV52 and HPV45, were also associated with high risks. Persistent HPV56 had the lowest 8-year absolute risk of CIN3+ (3% (95% CI: 0.4%–20%)). In Cox analyses, a similar pattern remained after adjustment for age and time between tests. Our results add knowledge about the varying carcinogenic potential of individual persistent oncogenic HPV types, which may have implications for the clinical use of HPV testing.     

Human papillomavirus types in cervical dysplasia among young HPV-vaccinated women: Population-based nested case–control study

Human papillomavirus (HPV) vaccines protect against infections with the most oncogenic HPV types, cervical intraepithelial neoplasia (CIN) and cervical cancer. We investigated whether development of cervical intraepithelial neoplasia (CIN) lesions in HPV-vaccinated women is associated with vaccine-targeted HPV types or not. Linkage of the Swedish vaccination and cervical screening registries identified all females born 1980–2000 who had been HPV vaccinated before December 31, 2014 (n = 305,320) and had attended cervical screening in 2006–2018 (n = 79,491). We further selected women HPV vaccinated below 17 years of age and screened in the capital region (n = 5,874). Among those, 125 developed CIN and had a cervical cryopreserved sample available (42.5% of all eligible CIN cases). After 1:2 matching to disease-free HPV vaccinated controls (n = 242), samples were analyzed for HPV DNA and associations between HPV type and CIN diagnosis were estimated with conditional logistic regression. Vaccine-targeted HPV types were rare among both CIN cases (2.4% HPV16, 0.8% HPV18) and their matched controls (0.4% HPV16 and 18). No woman had HPV6 or 11. The CIN lesions were associated with the nonvaccine HPV types 31, 33, 42, 45, 51, 52, 56, 59 and 66. CIN lesions among young HPV vaccinated women are mostly attributable to infection with nonvaccine HPV types. The phenomenon may be important for surveillance and design of cervical cancer control strategies.     

Risk stratification and long‐term risk prediction of E6 oncoprotein in a prospective screening cohort in China

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five‐year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA) and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five‐ and ten‐year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and 10‐year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year 10, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted = 40.0 and 21.2, respectively). E6 oncoprotein could serve as a low‐cost, highly specific, strongly indicative point‐of‐care method in the triage and treatment of HPV positive women.     

The relative distribution of oncogenic types of human papillomavirus in benign, pre-malignant and malignant cervical biopsies. A study with human papillomavirus deoxyribonucleic acid sequence analysis

The aim of the present investigation was to define the spectrum of oncogenic types of human papillomavirus (HPV) present in benign, pre-malignant (low-grade and high-grade squamous intraepithelial lesions, LSIL and HSIL) and malignant cervical lesions. The study comprises 215 HPV-positive biopsies, analysed with PCR, followed by sequence analyses of the HPV DNA. Fifeteen oncogenic types of HPV were identified. In 170 benign or pre-maligant alterations, the most common being HPV 16 (51%), HPV 31 (8%), HPV 18 (7%) and HPV 45 (6%). HPV 33, 35, 51, 56, 58, 66, and 70 occurred in about 1-4%. The prevalence of HPV 39, 52, 56, 59 and 73 was <1%. All the observed types of HPV, except 39 and 52, occurred in SIL lesions. The most common oncogenic HPV types (16 and 18), occurring in 45 invasive squamous carcinomas, comprised 76 per cent of the tumours, whereas less frequent HPV types (31, 33, 52, 56, 67, 70 and 73) were each found in about 2-4%. Double HPV infections were not observed. In conclusion, a total of 15 different oncogenic HPV types were identified, of which 13 types were present in pre-malignant cervical lesions and 9 in malignant lesions. This information may have some relevance when HPV analyses are considered as an adjunct to the organised screening of cervical cancer and for those working with the development of HPV vaccines for the prevention of cervical cancer.     

Human papillomavirus infections among Japanese women: age-related prevalence and type-specific risk for cervical cancer

To obtain baseline data for human papillomavirus (HPV) screening and vaccination in Japan, we analyzed HPV DNA data from 2282 Japanese women (1517 normal cytology, 318 cervical intraepithelial neoplasia [CIN] grade 1, 307 CIN2–3, and 140 invasive cervical cancer [ICC]) that visited the University of Tsukuba Hospital or Ibaraki Seinan Medical Center Hospital for screening or treatment of cervical diseases between 1999 and 2007. An L1-based PCR method was used for individual HPV genotyping. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16 (40.5%), HPV18 (24.4%), HPV52 (8.4%), HPV58 (3.1%), and HPV33 (3.1%). Based on the comparison of HPV type distributions between normal cytology and CIN2–3 and ICC, estimated risk of disease progression varied considerably by genotype: HPV16, HPV18, HPV31, HPV33, HPV35, HPV52, and HPV58 (prevalence ratio, 1.92; 95% confidence interval 1.58–2.34); other oncogenic types (0.31, 95% confidence interval 0.19–0.50); and non-oncogenic types (0.09, 95% confidence interval 0.03–0.43). HPV16 and/or HPV18, including coinfections with other types, contributed to 67.1% of ICC and 36.2% of CIN2–3 among Japanese women. More importantly, the overall prevalence of HPV16 and/or HPV18 varied greatly according to the women's age: highest in women aged 20–29 years (ICC, 90.0%; CIN2–3, 53.9%), decreasing with age thereafter, and lowest in women aged 60 years or older (ICC, 56.3%; CIN2–3, 25.0%). In conclusion, type-specific HPV testing may help identify Japanese women at high risk of progression to CIN2–3 and cancer. In Japan, current HPV vaccines are estimated to provide approximately 70% protection against ICC and may be more useful in reducing the incidence of cervical cancer and precancer in young women of reproductive age. ( Cancer Sci 2009; 100: 1312–1316)     

Mucosal immunoglobulin-A and -G responses to oncogenic human papilloma virus capsids

Oncogenic human papilloma virus (HPV) infection is the most important risk factor for developing cervical cancer. It is known that serum antibody responses against these viruses are associated with persistent infection. We conducted an epidemiological study of 627 women to detect cervical mucosal immunoglobulin (Ig)A and IgG responses to oncogenic HPV capsids. Antibody reactivity and cervical HPV infection genotypes were examined by enzyme-linked immunosorbent assay (ELISA) using HPV types 16, 18, 31, and 45 virus-like particles, and a polymerase chain reaction-based method, respectively. HPV infection was defined as being positive for HPV DNA. Multivariate analysis revealed that a mucosal IgA response was associated with the HPV infection, whereas the IgG response was associated with high-grade cervical squamous intraepithelial lesions (SIL)/squamous cell cancer (SCC) and subject age (40-49 years). IgA was positive in 72% of women with oncogenic HPV infections, whereas IgG was positive in 64% of women with high-grade SIL/SCC. The longitudinal study demonstrated that the IgA response was elicited earlier than the IgG response, and the IgG response was barely induced in the preclinical HPV infection. However, once an IgG response was induced, it persisted longer after HPV clearance. The mucosal IgA response reflects current HPV infection, whereas an IgG response may be induced with the development of cervical lesions.     

Evaluation of cytology and visual triage of human papillomavirus‐positive women in cervical cancer prevention in India

Although virtually all cervical cancers and most cervical intraepithelial neoplasia (CIN) are caused by persistent human papillomavirus (HPV) infection, only a small proportion of HPV‐positive women have or will develop CIN. Triaging HPV‐positive women has been suggested to reduce the false‐positive rate and proportion of women referred for CIN confirmation and/or treatment. In two cross‐sectional studies and one randomized trial in India, we evaluated the impact of using cytology or visual inspection with acetic acid (VIA) to triage HPV‐positive women on the proportion of women who would be referred for CIN confirmation and on the detection rates of high‐grade CIN. We present the numbers of HPV test‐positive women found and the CIN detected among them. We further assess the proportions that would be referred for CIN confirmation with colposcopy/biopsy and CIN that would be detected if cytology triage or VIA triage were used. Using cytology triage at atypical squamous cells of undetermined significance threshold or VIA triage reduced referrals for colposcopy by about 62% and 59%, respectively (p‐value = 0.012), but missed around 16% and 18%, respectively, of the high‐grade CIN (p‐value = 0.539) indicating similar performance of both triaging approaches. The choice of a triage test in different low‐ and middle‐income countries (LMIC) would depend on the availability and affordability in the particular setting. Cytology triage may be considered in settings where adequate infrastructure exists, whereas VIA triage may be suitable in settings with limited or no cytology infrastructure.     

Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study

The control arm of the phase III VIVIANE (Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; NCT00294047) study in women >25 years was studied to assess risk of progression from cervical HPV infection to detectable cervical intraepithelial neoplasia (CIN). The risk of detecting CIN associated with the same HPV type as the reference infection was analysed using Kaplan–Meier and multivariable Cox models. Infections were categorised depending upon persistence as 6‐month persistent infection (6MPI) or infection of any duration. The 4‐year interim analysis included 2,838 women, of whom 1,073 (37.8%) experienced 2,615 infections of any duration and 708 (24.9%) experienced 1,130 6MPIs. Infection with oncogenic HPV types significantly increased the risk of detecting CIN grade 2 or greater (CIN2+) versus non‐oncogenic types. For 6MPI, the highest risk was associated with HPV‐33 (hazard ratio [HR]: 31.9 [8.3–122.2, p < 0.0001]). The next highest risk was with HPV‐16 (21.1 [6.3–70.0], p < 0.0001). Similar findings were seen for infections of any duration. Significant risk was also observed for HPV‐18, HPV‐31, and HPV‐45. Concomitant HPV infection or CIN grade 1 or greater associated with a different oncogenic HPV type increased risk. Most women (79.3%) with an HPV infection at baseline cleared detectable infections of any duration, and 69.9% cleared a 6MPI. The risk of progression of HPV infection to CIN2+ in women >25 years in this study was similar to that in women 15–25 years in PATRICIA.     

Screening with a primary human papillomavirus test does not increase detection of cervical cancer and intraepithelial neoplasia 3

Aim:To determine cross-sectional validity of primary human papillomavirus (HPV) screening in comparison to cytological screening.Methods:During 2003–2004, 61,149 women were individually randomised to screening with a test for oncogenic HPV DNA or to conventional cytological screening within the Finnish cervical screening programme.Results:For HPV screening, cross-sectional relative sensitivity for cervical intraepithelial neoplasia (CIN) or cancer was 1.58 (95 % confidence interval 1.19–2.09) in comparison to cytology. At the level of CIN 3 or cancer no increase in relative sensitivity was observed. Cross-sectional specificity estimates for the screening arms were comparable, but the specificity of screening with sole HPV DNA test was clearly inferior.Conclusions:Primary HPV screening with cytology triage finds more CIN lesions compared to conventional screening but mild lesions are overrepresented. This is likely to result in overdiagnosis since most mild lesions are regressive.     

Human Papillomavirus Infection and Risk Determinants for Squamous Intraepithelial Lesion and Cervical Cancer in Japan

A case control design was used to investigate human papillomavirus (HPV) prevalence and risk factors associated with development of cervical squamous intraepithelial lesion (SIL) and cervical cancer (CC) in Japan, One hundred and twenty-three women with histologically confirmed SIL or CC were compared to a control group of 778 cytologically normal women. With the use of a polymerase chain reaction (FCR)-hased method for detection of low-risk (types 6 and 11) and high-risk (types 16, 18, 31, 33, 35, 52 and 58) HPVs, a high prevalence of HPV infection was observed in smokers among the controls. Logistic regression analysis demonstrated that high-risk HPV infection was the most significant risk determinant for LSIL (OR=9.4, 95% CI=4.5–19), HSIL (OR=77, 95% CI=28–217) and CC (OR=97, 95% CI=35–269). It also showed that unmarried women, women married for 5 to 19 years and smokers represented high risk groups for SIL, while smokers and women with a history of many pregnancies/parities had increased risk for CC. Smoking was the only HPV infection-independent factor for CC, suggesting that smoking may have a carcinogenic effect on the cervix. Since neither history of other cancer nor family cancer history was associated with SIL or CC, genetic factors appear to play little role in cervical carcinogenesis. The risk for cervical neoplasia due to HPV infection increased after marriage in Japan, suggesting a role for husbands as carriers of HPV transmission. Protection from high-risk HPV infection may be of greatest importance for prevention of cervical cancer.     

The Impact of Triage for Atypical Squamous Cells of Undetermined Significance with Human Papillomavirus Testing in Cervical Cancer Screening in Japan

Background: One of the features of cervical cancer screening using the combination of cytology and humanpapillomavirus (HPV) testing is the triage for atypical squamous cells of undetermined significance (ASC-US). Theeffectiveness of the triage has been recognized widely. However, there are few reports evaluating this triage process inJapan. Material and Methods: We retrospectively examined the results of cytology and HPV co-testing for cervicalcancer screening in the Oyama area of Tochigi Prefecture between 2012 and 2014. Women who were ASC-US/HPVpositive and had cytologic abnormalities [low-grade squamous intraepithelial lesions (LSIL) or worse] were examinedby colposcopy. The results of the colposcopy testing were evaluated. In addition, we also examined the results of thosewho underwent co-testing a year after a ASC-US/HPV-negative result. Results: A total of 21,342 women receivedtheir first screening test during the study period, with 542 (2.5%) found to have ASC-US. Of the ASC-US-positivewomen, 289 (53.3%) were also HPV positive. The prevalence of CIN+ (cervical intraepithelial neoplasia or higher)in the ASC-US/HPV-positive group was 63.2%, with 81.8%, 16.4% and 4.8%. showing CIN 1, CIN 2 and CIN 3+,respectively. The prevalence of CIN+ in the LSIL group was 66.8%, with the majority having a low risk CIN 1 (76.6%)compared to CIN 2 (18.6%), and CIN 3+ (4.8%). No significant difference was observed between the LSIL and ASC-US/HPV-positive groups. The prevalence of women diagnosed with CIN in the ASC-US/HPV-negative group, followingco-testing a year after colposcopy was low (3%). Conclusions: The ASC-US/HPV-positive group was comparable tothe LSIL group in terms of prevalence of CIN+ lesions. Furthermore, low CIN prevalence after one year in the ASCUS/HPV-negative group provides confirmation that the screening interval could be extended. The application of HPVtriage (which is routine in other countries) to identify these groups would be of benefit in Japan.     

Detection of High-Risk Human Papillomaviruses in the Prevention of Cervical Cancer in India

Human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses that infect epithelial tissues. Specific genotypes of human papillomavirus are the single most common etiological agents of cervical intraepithelial lesions and cervical cancer. Cervical cancer usually arises at squamous metaplastic epithelium of transformation zone (TZ) of the cervix featuring infection with one or more oncogenic or high-risk HPV (HRHPV) types. A hospital- based study in a rural set up was carried out to understand the association of HR-HPV with squamous intraepithelial lesions (SILs) and cervical cancer. In the present study, HR-HPV was detected in 65.7% of low-grade squamous intraepithelial lesions (LSILs), 84.6% of high grade squamous intraepithelial lesions (HSILs) and 94% of cervical cancer as compared to 10.7% of controls. The association of HPV infection with SIL and cervical cancer was analyzed with Chi square test (p<0.001). The significant association found confirmed that detection of HR-HPV is a suitable candidate for early identification of cervical precancerous lesions and in the prevention of cervical cancer in India.     

Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort

Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.     

The APTIMA HPV assay versus the hybrid capture 2 test in triage of women with ASC‐US or LSIL cervical cytology: A meta‐analysis of the diagnostic accuracy

Testing for DNA of 13 high‐risk HPV types with the Hybrid Capture 2 (HC2) test has consistently been shown to perform better in triage of women with cervical cytology results showing atypical squamous cells of undetermined significance (ASC‐US) but often not in triage of low‐grade squamous intraepithelial lesions (LSIL) detected in cervical cancer screening. In a meta‐analysis, we compared the accuracy of the APTIMA HPV test, which identifies RNA of 14 high‐risk HPV types, to HC2 for the triage of women with ASC‐US or LSIL. Literature search‐targeted studies where the accuracy of APTIMA HPV and HC2 for detection of underlying CIN2/3+ was assessed concomitantly including verification of all cases of ASC‐US and LSIL. HSROC (Hierarchical Summary ROC) curve regression was used to compute the pooled absolute and relative sensitivity and specificity. Eight studies, comprising 1,839 ASC‐US and 1,887 LSIL cases, were retrieved. The pooled sensitivity and specificity of APTIMA to triage ASC‐US to detect underlying CIN3 or worse was 96.2% (95% CI = 91.7–98.3%) and 54.9% (95% CI = 43.5–65.9%), respectively. APTIMA and HC2 showed similar pooled sensitivity; however, the specificity of the former was significantly higher (ratio: 1.19; 95% CI = 1.08–1.31 for CIN2+). The pooled sensitivity and specificity of APTIMA to triage LSIL were 96.7% (95% CI = 91.4–98.9%) and 38.7% (95% CI = 30.5–47.6%) for CIN3+. APTIMA was as sensitive as HC2 but more specific (ratio: 1.35; 95% CI = 1.11–1.66). Results were similar for detection of CIN2 or worse. In both triage of ASC‐US and LSIL, APTIMA is as sensitive but more specific than HC2 for detecting cervical precancer.     

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case–control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25–65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50 <CIN2); Group 2: 103 HPV+, normal cytology with HPV persistence at 12 mo. (53 CIN2/3; 50 <CIN2); Group 3: 50 HPV+, normal cytology with HPV clearance at 12 mo. (assumed <CIN2), total n=257. For the combined groups, S5 risk score CIN2/3 relative sensitivity, specificity and positive predictive value (PPV) were compared with other triage approaches. Methylation showed a highly significant increasing trend with disease severity. For CIN3, S5 relative sensitivity and specificity were: 93.2% (95%CI: 81.4–98.0) and 41.8% (35.2–48.8), compared to 86.4% (75.0–95.7) and 49.8% (43.1–56.6) respectively for combined abnormal cytology/HPV16/18 positivity (differences not statistically significant at 5% level); adjusted PPVs were 18.2% (16.2–20.4) and 19.3% (16.6–22.2) respectively. S5 was also positive in baseline specimens from eight cancers detected during or after trial participation. The S5 methylation score had high sensitivity and PPV for CIN3, compatible with US and European thresholds for colposcopy referral. Methylation signatures can identify most HPV positive women at increased risk of cervical cancer from their baseline screening specimens.     

Human papillomavirus types in 115,789 HPV-positive women: A meta-analysis from cervical infection to cancer

Genotyping may improve risk stratification of high-risk (HR) human papillomavirus (HPV)-positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta-analysis of cross-sectional HR HPV-type distribution in 115,789 HPV-positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low-grade squamous intraepithelial lesions (LSIL) and 6,616 high-grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR-based studies worldwide. No strong differences in HPV-type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20-28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios = 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios = 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV-positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV-based screening programs.     

Cervical human papillomavirus infection and squamous intraepithelial lesions in rural Gambia, West Africa: viral sequence analysis and epidemiology

The development of effective strategies against cervical cancer in Africa requires accurate type specific data on human papillomavirus (HPV) prevalence, including determination of DNA sequences in order to maximise local vaccine efficacy. We have investigated cervical HPV infection and squamous intraepithelial lesions (SIL) in an unselected cohort of 1061 women in a rural Gambian community. Squamous intraepithelial lesions was diagnosed using cytology and histology, HPV was typed by PCR-ELISA of DNA extracts, which were also DNA sequenced. The prevalence of cervical HPV infection was 13% and SIL were observed in 7% of subjects. Human papillomavirus-16 was most prevalent and most strongly associated with SIL. Also common were HPV-18, -33, -58 and, notably, -35. Human papillomavirus DNA sequencing revealed HPV-16 samples to be exclusively African type 1 (Af1). Subjects of the Wolof ethnic group had a lower prevalence of HPV infection while subjects aged 25-44 years had a higher prevalence of cervical precancer than older or younger subjects. This first report of HPV prevalence in an unselected, unscreened rural population confirms high rates of SIL and HPV infection in West Africa. This study has implications for the vaccination of Gambian and other African populations in the prevention of cervical cancer.     

Prognostic factors associated with the clinical outcome of cervical intraepithelial neoplasia: a cohort study in Japan

One hundred and eighty-five Japanese women with cervical intraepithelial neoplasia (CIN) were enrolled in this follow-up study. On the basis of the prevalence of human papillomavirus (HPV) DNA in Japanese cervical cancer patients, HPV types were categorized into three groups as follows: (1) high risk (types 16, 18, 33, 52, and 58), (2) intermediate risk (types 31, 35, 39, 51, 56, 59, 68, and 70), (3) low risk (type 6, 30, 42, 53, 54, 55, 66 and unclassified types). High-risk HPV infection was a risk factor for progression of the disease. The regression rate in the HPV negative group was higher (83.3%) than those in the HPV positive groups, but the differences in regression were no longer significant after adjustment for age and CIN grade. It is also noted that a lower cytomegalovirus IgG level and a smaller number of past pregnancies might be associated with the regression of CIN lesions.