HPV genotypes in CIN 2-3 lesions and cervical cancer: a population-based study

The distribution of human papillomavirus (HPV) varies between countries and continents leading to different effectiveness of upcoming prophylactic HPV vaccines. This study analyses the HPV distribution in CIN 2-3, recurrent CIN 2-3 and cervical cancer in Iceland. About 80% of incident cases with CIN 2-3 lesions in 1990 and 1999, 99% of cancer cases in 1990-1994 and 1999-2003, and cases with recurrent CIN 2-3 after conization in 1990 were tested with PCR analysis for the presence of 12 oncogenic HPV types. About 95% of the CIN 2-3 and 92% of the cancer cases tested positive for the included HPV types. HPV 16 was the most frequent type followed by HPV 33, 31, 52, 35, 18, 58, 56, 39, 45, 59 in CIN 2-3 and by HPV 18, 33 45, 31, 39, 52, 35, 51, 56 in cancer. HPV 16 and 18 were associated with a significantly increased cancer risk and HPV 52 and 31 with decreased cancer risk compared to the risk of CIN 3. The HPV distribution differed between histological cancer types, stages and age groups. The number of HPV types was not a significant predictor of cancer. Oncogenic HPV types were found in all persistent or recurrent CIN 2-3 disease after conization. Vaccination against HPV 16/18 is estimated to achieve a minimum 40% reduced rate of CIN 2-3 and a minimum 60% reduced cancer rate. This rate could, however, be increased to 95% and 92% respectively by including all the 12 HPV types tested for in this study.     

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Human papillomavirus (HPV) DNA sequences are associated with the large majority of invasive cervical carcinoma but the role of specific genotype(s) in the outcome of the disease is still debated. To determine the viral epidemiology in the French population of patients and the prognostic value of HPV genotypes in cervical cancer, we performed a retrospective study in 515 patients treated in our Institution from 1985 to 2005. Ninety‐six percent of the cases were found associated with HPV DNA whereas 4% remained HPV negative. High‐risk HPV 16/18 genotypes were found in 70% of the cases. HPV 18 was more frequently associated with adenocarcinoma (40.6%) than HPV 16 (10.4%) and found in tumours developed in younger women (mean age, 45.8 years) than HPV 16 (48.3 years) or other HPV types (53.6 years). In multivariate analysis, node involvement (p < 0.0001), parametria invasion (p = 0.009), tumour size (p = 0.01) and HPV status (p = 0.02) were associated with disease‐free survival (median follow‐up 95 months). Disease outcome was better in tumours associated with intermediate risk HPV types (HPV 31, 33, 35, 39, 52, 53, 58, 59, 73) than in tumours with high oncogenic types (HPV 16, 18, 45) (p = 0.03). Node status and tumour size remained prognostic factor for overall survival. Our data show that HPV genotype is one of the biological factors associated with the outcome of cervical cancer. One third of invasive carcinoma were not associated with HPV 16/18, indicating that the screening for cervical neoplasia should be maintained after prophylactic vaccination against these HPV genotypes. © 2008 Wiley‐Liss, Inc.     

Correlation between hybrid capture II high‐risk human papillomavirus DNA test chemiluminescence intensity from cervical samples with follow‐up histologic results

BACKGROUND:

The Hybrid Capture II high‐risk human papillomavirus (hrHPV) DNA test is a US Food and Drug Administration‐approved nucleic acid hybridization assay using chemiluminescence for the semiquantitative detection of hrHPV in cervical samples. Patient samples and controls are used to calculate results as negative for hrHPV if <1.0, positive for hrHPV if >2.5, and “equivocal” if between 1.0 and 2.5.

METHODS:

The authors reported on the cervical histologic results of 209 patients demonstrating “equivocal” results for hrHPV from SurePath (204 patients) or ThinPrep (5 patients) vials, and compared patients in this cohort with atypical squamous cells of undetermined significance (ASC‐US) cytology on the index cervical Papanicolaou (Pap) test (Group 1; n = 148 patients) with a patient cohort demonstrating unequivocal positive hrHPV test results (Group 2; n = 148 patients). The chemiluminescence intensity of hrHPV tests from patients in Group 2 were correlated with the presence and severity of dysplasia on subsequent histologic results, and patients were thereby stratified for their subsequent risk of cervical intraepithelial neoplasia (CIN) types II/III.

RESULTS:

Approximately 97% of hrHPV tests demonstrating “equivocal” results were found to be positive at the time of retesting, and 15% of biopsied cases demonstrated CIN II or III. Results of follow‐up histology after an ASC‐US diagnosis, expressed as a percentage of the biopsied cohort, were: CIN II/III: 16.5% in Group 1 and 22.4% in Group 2; CIN I: 27% in Group 1 and 23.5% in Group 2; and negative: 56.5% in Group 1 and 54.1% in Group 2. Chemiluminescence intensity did not appear to be correlated with the severity of dysplasia.

CONCLUSIONS:

The percentage of high‐grade CIN in the “equivocal” hrHPV cohort is highly significant and therefore the management of these patients should be similar to the unequivocally positive population. After an unequivocal positive hrHPV test, the hrHPV chemiluminescence intensity does not appear to further predict the rate of high‐grade CIN. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

Differences in human papillomavirus type distribution in high‐grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe

Knowledge of differences in human papillomavirus (HPV)‐type prevalence between high‐grade cervical intraepithelial neoplasia (HG‐CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV‐infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG‐CIN or ICC from 17 European countries were enrolled in two parallel cross‐sectional studies (108288/108290). Centralised histopathology review and standardised HPV‐DNA typing were applied to formalin‐fixed paraffin‐embedded cervical specimens dated 2001–2008. The pooled prevalence of individual HPV types was estimated using meta‐analytic methods. A total of 3,103 women were diagnosed with HG‐CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV‐positive, respectively. The most common HPV types in women with HG‐CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG‐CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/‘other’ (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/‘other’ (15/23/20/17 years). In Europe, HPV16 predominates in both HG‐CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG‐CIN and associated with a high median age of HG‐CIN, with a narrow age interval between HG‐CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45‐related cervical lesions.     

Cervical cancer screening program integrating Pap smear and HPV DNA testing: a population-based study

We conducted a population-based cohort study to evaluate the complementary value of HPV testing to Papanicolaou (Pap) smear and the prevalence and genotype distribution of HPV in Taiwan. In this report, we described the design of the whole study and analyzed the cross-sectional results. Female residents (age >or= 30 years) of Taoyuan, Taiwan were invited. After signing informed consent, every participant had a Pap smear and a HPV testing. Patients with Pap >or= atypical squamous cell of undetermined significance (Group I) or those with HPV-positive but normal cytology (Group II) were referred for a colposcopic examination. A total of 10,014 women were eligible. The overall HPV prevalence was 10.8% (95% confidence interval 10.5%-11.4%) in the study population. A total of 37 types of HPV were identified and the leading three were HPV-52, -18 and -58. There was a significant positive correlation of HPV prevalence with older age, postmenopausal status, current-user of oral contraceptives and never-user of hormone replacement therapy. Past users of oral contraceptives and never users of Pap were associated with higher risk of abnormal Pap, while age 40-49 strata had lower risk. Fifty-nine cases of cervical intraepithelial neoplasia (CIN) 2 from Group I and additional 11 from Group II were identified. The improvement of sensitivity with additional HPV testing was 15.3%. Besides, no specific subgroup was found to most benefit from the combined strategy. The value of adding HPV test to conventional Pap smear has to be evaluated after longer-term follow-up of this population-based cohort.     

The influence of type‐specific human papillomavirus infections on the detection of cervical precancer and cancer: A population‐based study of opportunistic cervical screening in the United States

There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (US) populations specifically where the delivery of opportunistic cervical screening takes place outside managed care and in the absence of organized national programs. Such data will inform the management of women with positive screening results before and after widespread human papillomavirus (HPV) vaccination and establishes a baseline preceding recent changes in US cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the 3‐year HPV type‐specific cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) detected during real‐world health care delivery across a diversity of organizations, payers, clinical settings, providers and patients. A stratified sample of 47,541 cervical cytology specimens from a screening population of 379,000 women underwent HPV genotyping. Three‐year risks for different combinations of cytologic interpretation and HPV risk group ranged from <1% (for several combinations) to approximately 70% for CIN2+ and 55% for CIN3+ in women with high‐grade (HSIL) cytology and HPV16 infection. A substantial proportion of CIN2+ (35.7%) and CIN3+ (30.9%) were diagnosed following negative cytology, of which 62.3 and 78.2%, respectively, were high‐risk HPV positive. HPV16 had the greatest 3‐year risks (10.9% for CIN2+,8.0% for CIN3+) followed by HPV33, HPV31, and HPV18. Positive results for high‐risk HPV, especially HPV16, the severity of cytologic interpretation, and age contribute independently to the risks of CIN2+ and CIN3+.     

Antibodies against high‐risk human papillomavirus proteins as markers for invasive cervical cancer

Different human papillomavirus (HPV) genes are expressed during the various phases of the HPV life cycle and may elicit immune responses in the process towards malignancy. To evaluate their association with cervical cancer, antibodies against proteins from HPV16 (L1, E1, E2, E4, E6 and E7) and HPV18/31/33/35/45/52/58 (L1, E6 and E7) were measured in serum of 307 invasive cervical cancer cases and 327 controls from Algeria and India. Antibody response was evaluated using a glutathione S‐transferase‐based multiplex serology assay and HPV DNA detected from exfoliated cervical cells using a GP5+/6+‐mediated PCR assay. Among HPV16 DNA‐positive cases, seroprevalence of HPV16 antibodies ranged from 16% for HPV16 E1 to 50% for HPV16 E6 and all were significantly higher than controls. Seroprevalence of E6, E7 and L1 antibodies for HPV18 and for at least one of HPV31/33/35/45/52/58 were also higher in cases positive for DNA of the corresponding type (50% and 30% for E6 of HPV18 and HPV31/33/35/45/52/58 combined, respectively). E6 and E7 antibodies were rarely found in controls, but cross‐reactivity was evident among cancer cases positive for DNA of closely phylogenetically‐related HPV types. E6 or E7 antibodies against any of the eight HPV types were detected in 66.1% of all cervical cancer cases, as compared to 10.1% of controls. E6, and to a lesser extent E7, antibodies appear to be specific markers of HPV‐related malignancy. However, even among cases positive for the same type of HPV DNA, approximately one‐third of cervical cancer cases show no detectable immune response to either E6 or E7.