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.     

Population-based prevalence, type- and age-specific distribution of HPV in women before introduction of an HPV-vaccination program in Denmark

Knowledge about the prevalence of human papillomavirus (HPV) on a population level is important. We conducted a large population-based study in Denmark to determine the overall and age-specific HPV prevalence, and HPV type distribution in women. Liquid-based cytology samples (SurePath) were collected consecutively. HPV testing was performed with Hybrid Capture 2 (HC2; Digene) (high-risk and low-risk probes), and LiPA (Innogenetics) was used for genotyping. We analyzed samples from 11,617 women; 94.0% had normal cytology, 4.3% atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion and 1.6% had high-grade squamous intraepithelial lesion (HSIL). The HPV prevalence was 26.4% with a peak in women 20-24 years (50.2%) and then decreased without a second peak in older women. Among the youngest women (15-19 years), 14% had HPV 16/18 and 16% had HPV 6/11. Prevalence of high-risk HPV types increased from 19.2% in women with normal cytology to 100% in women with cervical intraepithelial neoplasia grade 3 (CIN3)/cervical cancer. HPV 16 was the most prevalent type (6.0% of all women), and was also the most prevalent in women with HSIL (35.1%) and CIN3 (53.2%). Other common HPV types in women with CIN3 included HPV 52, 51, 31, 33 and 18. HPV 16/18 alone was present in 23% of CIN3 lesions and 67% of cervical cancers, and HPV 16/18 together with other high-risk HPV types was present in 41% of CIN3 lesions. This suggests that an efficacious HPV 16/18 vaccine will have a substantial preventive potential in the general female population.     

Lower cost strategies for triage of human papillomavirus DNA‐positive women

Using human papillomavirus (HPV) testing for cervical cancer screening in lower‐resource settings (LRS) will result in a significant number of screen‐positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV‐positive women in LRS. This was a population‐based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self‐collected and two clinician‐collected specimens. The self‐collected and one clinician‐collected specimen were tested by two HPV DNA tests—careHPV? and Hybrid Capture 2; the other clinician‐collected specimen was tested for HPV16/18/45 E6 protein. CareHPV?‐positive specimens were tested for HPV16/18/45 DNA. HPV DNA‐positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA‐positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA‐positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.     

Prevalence of human papillomavirus in women with invasive cervical carcinoma by HIV status in Kenya and South Africa

Data on the prevalence of human papillomavirus (HPV) types in cervical carcinoma in women with HIV are scarce but are essential to elucidate the influence of immunity on the carcinogenicity of different HPV types, and the potential impact of prophylactic HPV vaccines in populations with high HIV prevalence. We conducted a multicentre case-case study in Kenya and South Africa. During 2007-2009, frozen tissue biopsies from women with cervical carcinoma were tested for HPV DNA using GP5+/6+-PCR assay. One hundred and six HIV-positive (mean age 40.8 years) and 129 HIV-negative women (mean age 45.7) with squamous cell carcinoma were included. Among HIV-positive women, the mean CD4 count was 334 cells/μL and 48.1% were on combined antiretroviral therapy. HIV-positive women had many more multiple HPV infections (21.6% of HPV-positive carcinomas) compared with HIV-negative women (3.3%) (p < 0.001) and the proportion of multiple infections was inversely related to CD4 level. An excess of HPV18 of borderline statistical significance was found in HIV-positive compared with HIV-negative cases (Prevalence ratio (PR) = 1.9, 95% confidence interval (CI): 1.0-3.7, adjusted for study centre, age and multiplicity of infection). HPV16 and/or 18 prevalence combined, however, was similar in HIV-positive (66.7%) and HIV-negative cases (69.1%) (PR = 1.0, 95% CI: 0.9-1.2). No significant difference was found for other HPV types. Our data suggest that current prophylactic HPV vaccines against HPV16 and 18 may prevent similar proportions of cervical SCC in HIV-positive as in HIV-negative women provided that vaccine-related protection is sustained after HIV infection.     

Comparison of human papillomavirus genotyping and cytology triage,COMPACT Study: Design,methods and baseline results in 14 642 women

Although cytology‐based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high‐grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV‐positive women to avoid over‐referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3‐year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high‐risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high‐grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV‐based screening program. Results should help policy‐makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.     

Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical papanicolaou smears with atypical squamous cells of undetermined significance

BACKGROUND:

High‐risk (HR) human papillomavirus (HPV) testing is standard practice for triaging women who have Papanicolaou (Pap) smears with atypical squamous cells of undetermined significance (ASC‐US), however, only 5% to 17% of these women have underlying cervical intraepithelial neoplasia 2 (CIN‐2)/CIN‐3. Recent reports have demonstrated that the presence of either HPV type 16 (HPV‐16) or HPV‐18 confers an elevated risk for CIN‐2/CIN‐3. The current study was designed to determine the prevalence of HPV‐16 and HPV‐18 in ASC‐US Pap smears and to determine whether further typing would enhance the risk stratification of patients for CIN‐2/CIN‐3.

METHODS:

One hundred seventy‐eight Pap smears with ASC‐US were screened retrospectively for HR HPV by using the proprietary Invader screening assay followed by typing for HPV‐16 and HPV‐18 by using Invader type‐specific probes on 100 of the samples. Clinical follow‐up results were correlated with HPV types.

RESULTS:

Fifty‐one percent of the ASC‐US samples were positive for HR HPV, the majority of which (70%) harbored non‐HPV‐16/HPV‐18 HR HPV types; 27% were associated with HPV‐16, whereas only 3% contained HPV‐18. The screening assay indicated that 46% of women who had Pap smears with ASC‐US were in need of further HPV‐16/HPV‐18 typing. Testing for HPV‐16 stratified women with ASC‐US into 3 groups: 1) 14% of women were positive for HPV‐16 and had a high risk (54%) of CIN‐2/CIN‐3 on follow‐up biopsy, 2) 35% of women were positive for non‐HPV‐16 HPV types and had an intermediate risk (9%), and 3) 51% of women were negative for HPV and had a negligible risk for CIN‐2/CIN‐3.

CONCLUSIONS:

The combined application of a proprietary screening assay and a type‐specific HPV‐16 assay demonstrated global potential for the development of tailored management protocols for women who have Pap smears with ASC‐US. Cancer 2009. © 2009 American Cancer Society.     

Human papillomavirus genotype in cervical intraepithelial neoplasia grades 2 and 3 of Taiwanese women

We aimed to assess the distribution of human papillomavirus (HPV) genotypes in high‐grade cervical lesions in Taiwan. The study included 1,086 paraffin‐embedded, formaldehyde‐fixed cervical intraepithelial neoplasia (CIN) 2/3 specimens. HPV genotyping was performed using polymerase chain reaction (PCR)‐based methods. Multiple HPV types were validated by E6 type‐specific PCR, direct sequencing and/or real‐time PCR. HPV DNA was detected in 995 (91.6%) specimens, and multiple HPV types were identified in 192 (19.3%) samples. The leading HPV types were HPV16 (24%), HPV52 (20%), HPV58 (20%), HPV33 (13%), HPV31 (8%) and HPV18 (4.6%). Although the leading six types consisted of 87.6%, HPV16 or 18 comprised only 30.9%. The prevalence of different HPV types showed a significant association with age. In women older than 50 yr, HPV16 and 18 comprised 21.3% (83/389), while HPV52, 58 and 33 represented 55.5% (216/389). In women aged less than 50 yr, HPV16 and 18 comprised 32.1% (224/697, p < 0.0001), while HPV 52, 58 and 33 represented 47.9% (334/697, p = 0.02). The distribution of HPV genotypes was compared with previously reported findings for Taiwanese women with cervical cancer (CC). The overall HPV16 positivity rate was significantly higher in CC than in CIN 2/3 (odds ratio: 2.14, 95% CI: 1.91–2.40). In addition, HPV18, 39 and 45 were significantly overrepresented in CC, whereas HPV52, 58, 33, 31, 35, 51 and 53 were underrepresented. We concluded that an effective vaccine against the most common HPV types could prevent a significant proportion of cervical cancer cases that occur in Taiwan.     

High‐risk human papillomavirus DNA load in a population‐based cervical screening cohort in relation to the detection of high‐grade cervical intraepithelial neoplasia and cervical cancer

In a population‐based cervical screening cohort, we determined the value of type‐specific viral load assessment for the detection of high‐grade cervical intraepithelial neoplasia and cervical cancer (≥CIN2). Viral load was determined by type‐specific real‐time PCR in women with single HPV16,‐18,‐31 and ‐33 infections, as determined by GP5+/6+‐PCR. Study endpoints were the detection of cumulative ≥CIN2 or ≥CIN3 within 18 months of follow‐up. High viral loads of HPV16,‐31, and ‐33 were predictive for ≥CIN2 (relative risk of 1.6 (95% CI: 1.3–1.9), 1.7 (95% CI: 1.1–2.7) and 1.9 (95% CI: 1.1–3.1) per 10‐fold change in viral load, respectively). For HPV18, the relative risk was of similar magnitude (1.5, 95% CI: 0.7–3.1), though not significant (p = 0.3). Subsequently, we determined the sensitivities of viral load for ≥CIN2 and ≥CIN3 in HPV DNA‐positive women using viral load thresholds previously defined in a cross‐sectional study. These thresholds were based on the 25th, 33rd and 50th percentiles of type‐specific HPV16,‐18,‐31 or ‐33 viral load values found in women with normal cytology. For all types, combined sensitivities for ≥CIN2 were 93.5%, 88.8% and 77.7% for the 25th, 33rd and 50th percentile thresholds, respectively. Response‐operator‐characteristics (ROC) curve analysis showed that viral load testing on HPV DNA‐positive women in addition to or instead of cytology may result in an increased sensitivity for ≥CIN2, but at the cost of a marked decrease in specificity in relation to cytology. Similar results were obtained when using ≥CIN3 as endpoint. In conclusion, in a cervical screening setting viral load assessment of HPV16, 18, 31 and 33 has no additive value to stratify high‐risk HPV GP5+/6+‐PCR‐positive women for risk of ≥CIN2 or ≥CIN3. © 2008 Wiley‐Liss, Inc.     

Age-dependent prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic vaccination and screening

We determined the prevalence of type-specific hrHPV infections in the Netherlands on cervical scrapes of 45 362 women aged 18-65 years. The overall hrHPV prevalence peaked at the age of 22 with peak prevalence of 24%. Each of the 14 hrHPV types decreased significantly with age (P-values between 0.0009 and 0.03). The proportion of HPV16 in hrHPV-positive infections also decreased with age (OR=0.76 (10-year scale), 95% CI=0.67-0.85), and a similar trend was observed for HPV16 when selecting hrHPV-positive women with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (OR=0.76, 95% CI=0.56-1.01). In women eligible for routine screening (age 29-61 years) with confirmed CIN2+, 65% was infected with HPV16 and/or HPV18. When HPV16/18-positive infections in women eligible for routine screening were discarded, the positive predictive value of cytology for the detection of CIN2+ decreased from 27 to 15%, the positive predictive value of hrHPV testing decreased from 26 to 15%, and the predictive value of a double-positive test (positive HPV test and a positive cytology) decreased from 54 to 41%. In women vaccinated against HPV16/18, screening remains important to detect cervical lesions caused by non-HPV16/18 types. To maintain a high-positive predictive value, screening algorithms must be carefully re-evaluated with regard to the screening modalities and length of the screening interval.     

Comparing the performance of FAM19A4 methylation analysis,cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high‐risk HPV‐positive women of a gynecologic outpatient population (COMETH study)

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high‐grade cervical intraepithelial neoplasia and cervical cancer (≥CIN3) in high‐risk HPV (hrHPV)‐positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥CIN3 detection in hrHPV‐positive women participating in a prospective observational multi‐center cohort study. The study population comprised hrHPV‐positive women aged 18–66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy‐directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation‐specific PCR (qMSP). Sensitivities and specificities for ≥CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV‐positive women, the sensitivities for ≥CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥30 years (n = 287), ≥CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2–96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0–94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8–68.4) compared to 47.6% (95%CI: 41.1–54.1)]. In conclusion, among hrHPV‐positive women from an outpatient population aged ≥30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥CIN3.     

The role of human papillomavirus type 16/18 genotyping in predicting high‐grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results

BACKGROUND:

The authors compared the predictive value of type 16 and/or 18 human papillomavirus (HPV) versus non‐16/18 HPV types for high‐grade (grade ≥2) cervical neoplasm/vaginal intraepithelial neoplasm and carcinoma (CIN/VAIN2+) in women with mildly abnormal Papanicolaou (Pap) results (ie, atypical squamous cells of undetermined significance [ASCUS] or low‐grade squamous epithelial lesion [LSIL]).

METHODS:

The authors retrospectively selected Pap specimens with HPV testing results obtained from 243 women (155 with ASCUS and 88 with LSIL Pap results) in their Department of Pathology. HPV genotyping was performed using the EasyChip HPV blot assay. The Pap specimens with HPV16/18 and non‐16/18 HPV types were compared with follow‐up biopsy results. Follow‐up duration ranged from 1 month to 58 months (mean, 26 months).

RESULTS:

In total, 58 of 155 specimens (37%) that had ASCUS and 29 of 88 specimens (33%) that had LSIL were positive for HPV16/18. CIN/VAIN2+ biopsies were identified in 43 of 155 women (28%) with ASCUS and in 28 of 88 women (32%) with LSIL. Women with ASCUS and HPV16/18 had a significantly higher rate (43%) of CIN/VAIN2+ than women with ASCUS and non‐16/18 HPV types (19%; P = .003; odds ratio, 3.10; 95% confidence interval, 1.48‐6.53). There was no statistically significant difference in the rate of CIN/VAIN2+ between women who had LSIL and HPV16/18 (45%) and those who had LSIL and non‐16/18 HPV types (29%; P = .16; odds ratio, 1.96; 95% confidence interval, 0.77‐4.97).

CONCLUSIONS:

HPV genotyping for HPV16/18 improved risk assessment for women with ASCUS Pap results and may be used to predict the risk of CIN/VAIN2+ to better guide follow‐up management. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Reduction in HPV16/18 prevalence among young women with high‐grade cervical lesions following the Japanese HPV vaccination program

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12‐16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population‐level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1‐3 (CIN1‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012‐2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6‐year period were observed in CIN1 (50.0% to 0.0%, P_trend < .0001) and CIN2‐3/AIS (83.3% to 45.0%, P_trend = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18‐attributable CIN2‐3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch‐up vaccination (P = .04). The HPV16/18 prevalence in CIN2‐3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18‐positive CIN/AIS in Japan; however, our data did not support catch‐up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government’s suspension of its vaccine recommendation could benefit from receiving catch‐up vaccination before age 20 years.     

Detection of human papillomavirus types 6/11, 16 and 18 in exfoliated cells from the uterine cervices of Japanese women with and without lesions

Human papillomavirus (HPV) infection of the uterine cervices of Japanese women with and without lesions was identified by the filter in situ hybridization method. Exfoliated cervical cells from 23 cervical papillary condylomas, 70 cervical intraepithelial neoplasia (CIN) grade I/II, 26 CIN III, 31 invasive cervical cancers and 666 cervices without evidence of disease (including 53 pregnant women) were tested for the presence of HPV types 6/11, 16 and 18. The positive rates for the detection of HPV types 6/11, 16 and 18 DNA were 47.8%, 26.1% and 8.7% in cervical condylomas, 5.7%, 15.7% and 8.6% in CIN I/II, 0, 34.6% and 0 in CIN III, 3.2%, 38.7% and 9.7% in invasive cervical cancers and 0.9%, 1.8% and 0.6% in the control cervices. These data suggest that, in Japan, HPV6/11, HPV16 and HPV18 infections are also prevalent in cervical cells with normal phenotype, and the type of HPV infection of the uterine cervix is related to the histological diagnosis.     

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.     

Detection of Human Papillomavirus Types 6/11, 16 and 18 in Exfoliated Cells from the Uterine Cervices of Japanese Women with and without Lesions

Human papillomavirus (HPV) infection of the uterine cervices of Japanese women with and without lesions was identified by the filter in situ hybridization method. Exfoliated cervical cells from 23 cervical papillary condylomas, 70 cervical intraepithelial neoplasia (CIN) grade I/II, 26 CIN III, 31 invasive cervical cancers and 666 cervices without evidence of disease (including 53 pregnant women) were tested for the presence of HPV types 6/11, 16 and 18. The positive rates for the detection of HPV types 6/11, 16 and 18 DNA were 47.8%, 26.1% and 8.7% in cervical condylomas, 5.7%, 15.7% and 8.6% in CIN I/II, 0, 34.6% and 0 in CIN III, 3.2%, 38.7% and 9.7% in invasive cervical cancers and 0.9%, 1.8% and 0.6% in the control cervices. These data suggest that, in Japan, HPV6/11, HPV16 and HPV18 infections are also prevalent in cervical cells with normal phenotype, and the type of HPV infection of the uterine cervix is related to the histological diagnosis.     

Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub‐Saharan Africa

In sub‐Saharan Africa, invasive cervical cancer (ICC) incidence and mortality are among the highest in the world. This cross‐sectional epidemiological study assessed human papillomavirus (HPV) prevalence and type distribution in women with ICC in Ghana, Nigeria, and South Africa. Cervical biopsy specimens were obtained from women aged ≥21 years with lesions clinically suggestive of ICC. Histopathological diagnosis of ICC was determined by light microscopy examination of hematoxylin and eosin stained sections of paraffin‐embedded cervical specimens; samples with a confirmed histopathological diagnosis underwent HPV DNA testing by polymerase chain reaction. HPV‐positive specimens were typed by reverse hybridization line probe assay. Between October 2007 and March 2010, cervical specimens from 659 women were collected (167 in Ghana, 192 in Nigeria and 300 in South Africa); 570 cases were histologically confirmed as ICC. The tumor type was identified in 551/570 women with ICC; squamous cell carcinoma was observed in 476/570 (83.5%) cases. The HPV‐positivity rate in ICC cases was 90.4% (515/570). In ICC cases with single HPV infection (447/515 [86.8%]), the most commonly detected HPV types were HPV16 (51.2%), HPV18 (17.2%), HPV35 (8.7%), HPV45 (7.4%), HPV33 (4.0%) and HPV52 (2.2%). The prevalence of single and multiple HPV infections seemed higher among HIV‐positive women and HPV type distribution appeared to differ according to tumor type and HIV status. In conclusion, HPV16, 18, 45 and 35 were the most common HPV types in sub‐Saharan African women with ICC and HPV infections were more common in HIV‐positive women.     

Eight-type human papillomavirus E6/E7 oncoprotein detection as a novel and promising triage strategy for managing HPV-positive women

The management of HPV-positive women becomes particularly crucial in cervical cancer screening. Here we assessed whether detection of E6 or E7 oncoproteins targeting eight most prevalent HPV types could serve as a promising triage option. Women (N = 1,416) aged 50–60 from Shanxi, China underwent screening with HPV testing and liquid-based cytology (LBC), with any positive results referring to colposcopy and biopsy if necessary. Women with HPV-positive results received further tests using DNA-based genotyping, E6 or E7 oncoprotein detection targeting HPV16/18 (for short: E6 (16/18) Test) or HPV16/18/31/33/35/45/52/58 (for short: E6/E7 (8 types) Test), respectively. Among HPV-positive women, E6/E7 (8 types) oncoproteins had lower positivity (17.37%) compared to DNA-based genotyping for same eight types (58.30%) and LBC with ASC-US threshold (50.97%); HPV16 was the genotype showing the highest frequency (8.49%) for oncoprotein detection followed by HPV52 (3.47%), 58 (2.32%), 33 (1.54%), 18 (1.16%), 45 (0.77%), 35 (0.39%) and 31 (0%). For detection of cervical intraepithelial neoplasia Grade 3 or higher (CIN3+), E6/E7 (8 types) Test had similar sensitivity (100.00%) and superior specificity (85.94%) as well as positive predictive value (PPV, 22.22%) compared to both LBC and DNA-based genotyping (8 types); For detection of CIN2+, E6/E7 (8 types) Test was less sensitive (67.74%) but still more specific (89.47%) and risk predictive with PPV of 46.67%. Notably, E6/E7 (8 types) Test remarkably decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ (2.14 and 4.50). E6/E7 oncoprotein detection showed a good “trade-off” between sensitivity and specificity with more efficient colposcopy referrals, which is of great importance to maximize the benefits of HPV-based screening program, especially applicable for the areas with high HPV prevalence and low-resources.     

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+.     

Incidence risk of cervical intraepithelial neoplasia 3 or more severe lesions is a function of human papillomavirus genotypes and severity of cytological and histological abnormalities in adult Japanese women

We examined incidence probabilities of cervical intraepithelial neoplasia 3 (CIN3) or more severe lesions (CIN3+) in 1,467 adult Japanese women with abnormal cytology in relation to seven common human papillomavirus (HPV) infections (16/18/31/33/35/52/58) between April 2000 and March 2008. Sixty‐seven patients with multiple HPV infection were excluded from the risk factor analysis. Incidence of CIN3+ in 1,400 patients including 68 with ASCUS, 969 with low grade squamous intraepithelial lesion (LSIL), 132 with HSIL without histology‐proven CIN2 (HSIL/CIN2(?)) and 231 with HSIL with histology‐proven CIN2 (HSIL/CIN2(+)) was investigated. In both high grade squamous intraepithelial lesion (HSIL)/CIN2(?) and HSIL/CIN2(+), HPV16/18/33 was associated with a significantly earlier and higher incidence of CIN3+ than HPV31/35/52/58 (p = 0.049 and p = 0.0060, respectively). This association was also observed in LSIL (p = 0.0002). The 1‐year cumulative incidence rate (CIR) of CIN3+ in HSIL/CIN2(?) and HSIL/CIN2(+) according to HPV genotypes (16/18/33 vs. 31/35/52/58) were 27.1% vs. 7.5% and 46.6% vs. 19.2%, respectively. In contrast, progression of HSIL/CIN2(+) to CIN3+ was infrequent when HPV DNA was undetected: 0% of 1‐year CIR and 8.1% of 5‐year CIR. All cervical cancer occurred in HSIL cases of seven high‐risk HPVs (11/198) but not in cases of other HPV or undetectable/negative‐HPV (0/165) (p = 0.0013). In conclusion, incidence of CIN3+ depends on HPV genotypes, severity of cytological abnormalities and histology of CIN2. HSIL/CIN2(+) associated with HPV16/18/33 may justify early therapeutic intervention, while HSIL/CIN2(?) harboring these HPV genotypes needs close observation to detect incidence of CIN3+. A therapeutic intervention is not indicated for CIN2 without HPV DNA.     

HPV prevalence and cervical intraepithelial neoplasia among HIV-infected women in Yunnan Province, China: a pilot study

Objectives: To determine the prevalence of HPV and cervical neoplasia among HIV-infected women insouthwestern China. Methods: Cervical cytology, HPV detection by Hybrid Capture-2™ assay, and diagnosticcolposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyzeassociations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinicaland laboratory parameters. Results: Colposcopic-histopathologically proven CIN2+ lesions were present in7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes.HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than womenwith 相似文献