Urine-based human papillomavirus DNA testing as a screening tool for cervical cancer in high-risk women

Objective

To test the hypothesis that self-collected urine could be used to detect high-risk human papillomavirus (HPV) DNA with sensitivity and specificity comparable to those of standard cervical testing.

Methods

Women attending a gynecology clinic for evaluation of abnormal cytology were recruited. Fifty-two participants (21–60 years of age) collected urine samples, and clinicians collected cervical brush samples. When appropriate, cervical biopsies were obtained during colposcopy. HPV detection and typing were performed on DNA extracts from each sample, using commercial reagents for L1 consensus polymerase chain reaction (PCR) and type-specific hybridization. HPV 16 viral load was determined by quantitative PCR in HPV 16-positive samples. A diagnostic test analysis was conducted for urine samples.

Results

Fifty paired samples were analyzed, with 76% agreement between samples. The 12 discrepant pairs were all urine negative/cervix positive. The most common HPV types detected were 16, 51, 53, and 62. The urine test correctly identified 100% of the uninfected and 65% of the infected patients.

Conclusion

The results indicate that HPV DNA detection using urine is less sensitive than cervical sampling in a population with abnormal cytology. Further exploration is warranted to determine clinical utility when other options are unavailable.     

Comparison of urine and self-collected vaginal samples for detecting human papillomavirus DNA in pregnant women

Objective

To investigate the utility of urine sampling for detecting human papillomavirus (HPV) DNA among pregnant women and to compare HPV DNA detection in urine with detection in vaginal samples.

Methods

In a cross-sectional study, urine and vaginal samples were self-collected from pregnant women attending prenatal care at Hospital Divina Providencia, Frederico Westphalen, Brazil, between October 2006 and August 2007. Part of the L1 region of the HPV genome was amplified via GP5⁺/bioGP6⁺ primers. Positive urine was genotyped for high-risk HPV genotypes (HPV16, HPV18, HPV31, HPV33, HPV39, HPV45, and HPV59).

Results

During the study period, urine samples were obtained from 133 pregnant women, 63 of whom also self-collected vaginal samples. HPV DNA was detected in 54.0% (34/63) and 61.9% (39/63) of urine and vaginal samples, respectively. HPV infection was significantly associated with first intercourse at younger than 20 years of age (P = 0.008). There was substantial agreement in HPV DNA test results between the urine and vaginal samples (κ value, 77.3%; P < 0.0001). HPV31 and HPV16 accounted for 80.7% of the oncogenic types identified.

Conclusion

Detection of HPV DNA in urine showed good agreement with detection in self-collected vaginal samples, indicating that urine might be a reliable sample for HPV testing among pregnant women.     

A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix

Background

There remains uncertainty about the role of human papillomavirus (HPV) infection in causing small-cell neuroendocrine carcinoma (SCNC) and large-cell neuroendocrine carcinoma (LCNC) of the cervix. To clarify the role of HPV in the development of SCNC and LCNC, we conducted a systematic review and meta-analyses.

Telomere length in leukocytes and cervical smears of women with high-risk human papillomavirus (HR HPV) infection

ObjectivePersistent high-risk HPV (HR HPV) infection leads to the development of squamous intraepithelial lesions, which in turn may progress to cervical cancer. Telomere elongation or shortening may indicate a carcinogenesis process. In the present study, we analyzed telomere length from blood and cervical smears of women without and with high-risk HPV infection.Materials and methodsTelomere length was quantified by real-time PCR in blood and cervical smears from 48 women with high-risk HPV infection and HGSIL or LGSIL, 29 women HR-HPV positive without SIL, and 11 HPV-negative women.ResultsNo correlation was found between age and telomere length in blood and cervical smears. Women with high-risk HPV infection had shorter telomeres in cervical smears, but not in blood compared to the control group.ConclusionThese findings suggest that telomere shortening occurs in cervical cells of women with HR HPV infection both with LGSIL and HGSIL and may indicate the onset of carcinogenesis. In turn, there is no correlation between leukocyte telomere length and cervical cancer risk in women with HR HPV infection.     

高危型人乳头瘤病毒检测在宫颈癌筛查中的应用价值

目的探讨将HR-HPV检测作为宫颈癌筛查手段的意义和价值。方法2004-12-2005-04对301医院妇产科门诊就诊的1231例患者,进行HPVDNA的杂交捕获法二代(HPV-HCⅡ)和液基细胞学(Thinprepcytol-ogytest,TCT)的检测,作为宫颈癌及其癌前病变的初筛。131例因细胞学异常,或细胞学正常而HPV检测阳性,或细胞学正常HPV阴性、而临床高度怀疑病变的患者行阴道镜下多点活检,结合病理结果进行分析。结果(1)1231例样本中,经TCT检测正常者1077例(87·43%),ASCUS32例(2·60%),ASCUS-H34例(2·76),LSIL73例(5·93%),HSIL15例(1·22%)。131例阴道镜下多点组织活检,病理证实炎症68例(51·91%),CINⅠ20例(15·27%),CINⅡ18例(13·74%),CINⅢ16例(12·21%),浸润癌4例(4·35%),湿疣5例(3·82%)。(2)HPV总感染率34%,HPV阳性者418例,年龄平均(36·93±10·8)岁,HPV阴性者813例,年龄平均(39·68±11·8)岁,HPV阳性组的年龄明显小于HPV阴性组,P<0·01。各病理组HPV感染率分别为:炎症58·82%,CINⅠ80%,CINⅡ72·22%,CINⅢ100%,浸润癌100%,湿疣60%。(3)阴道镜下多点活检结果:TCT和HPV均(-)者,无高度病变的发生;TCT(-)和HPV( )者中,≥CINⅡ的检出率11·1%(1/9),TCT异常和HPV阳性同时存在的病例中,≥CINⅡ的检出率最高40·5%(32/79);仅TCT异常而HPV(-)者13·2%(5/38),且5例均为CINⅡ,无原位癌和浸润癌的发生。结论持续的HR-HPV感染与宫颈病变的演进有关;HR-HPV检测是有价值的辅助诊断技术,与细胞学联合检测,为最佳宫颈癌筛查方案。     

Human papillomavirus (HPV) genotyping by HPV DNA chip in cervical cancer and precancerous lesions

OBJECTIVES: The human papillomavirus (HPV) is a well-known cause of cervical cancer. HPV tests are used as an adjunct test to decrease the false-negative rate of cytological screening. However, attempts are being made to replace the cytological screening with HPV tests. Therefore, this study was performed to examine the possibility of using HPV tests as screening test. MATERIALS AND METHODS: The results of the tests that were performed at the same time including the ThinPrep cytology, the high-risk group hybrid capture II (HC-II) test, the HPV DNA chip (HD-C) test, and a punch biopsy were compared in 400 women who were referred to us due to abnormal cytology or cervicogram. The accuracy of each test was then evaluated, and the type of virus was investigated using a HD-C test. RESULTS: The positive predictive values detected by the high-risk group HC-II test and HD-C test according to the histological diagnosis outcomes were 56.8 and 53.8%, respectively, for cervicitis; 91.5 and 91.5%, respectively, for cervical intraepithelial neoplasia I (CIN I); 88.1% and 81.0%, respectively, for CIN II; 88.6 and 84.2%, respectively, for CIN III, and 92.5 and 88.7%, respectively, for cancer (in 53 patients). The most prevalent types of HPV according to the HPV tests were types 16, 58, 18, and 52 in which type 16 was detected in the more advanced lesions. The sensitivity was 88.4% for the ThinPrep cytology, 89.9% for the HC-II for the high-risk group, and 86.2% for the HD-C test. CONCLUSION: These results suggest the possibility of using the HC-II and HD-C tests as screening tests, which have a similar sensitivity as the ThinPrep cytology. Nonetheless, randomized controlled trials will be needed before the actual application of the HPV tests as screening tests. Despite the fact that the importance of HPV type 16 in cancer development was confirmed, the prevalence of types 58 and 52 were relatively high compared with those found in other studies, showing a need for further studies on this subject. These HPV types need to be considered in vaccine development.     

Human Papillomavirus Awareness in Haiti: Preparing for a National HPV Vaccination Program

Study Objective

Cervical cancer morbidity and mortality are pressing public health issues that affect women in Haiti. To inform efforts to develop a human papillomavirus (HPV) vaccination program in Haiti, we sought to understand HPV awareness and willingness to get HPV vaccination in Haiti.

Acceptability of self-collected human papillomavirus specimens in cervical cancer screening: A review

Cervical cancer morbidity and mortality is an important public health problem around the world. Some of the barriers to cervical cancer screening include the embarrassment, discomfort, lack of privacy and time and cost associated with clinician-collected, clinic-based screening with cytology or human papillomavirus tests. Self-collection of a human papillomavirus (HPV) test has been found to be generally more acceptable, less embarrassing, more comfortable, more private and easy to do and preferred to pelvic examination for cervical cytology by many women worldwide. The most commonly reported limitation to self-collection is a woman’s lack of confidence in her ability to perform it correctly. Self-collected human papillomavirus tests have been shown to be as or more sensitive than cytology or clinician-collected HPV tests. With confidence-building education about self-collection, it is likely a viable method to extend the reach of screening in high and low-resource areas around the world.     

Age-specific detection of high risk HPV DNA in cytologically normal, computer-imaged ThinPrep Pap samples

OBJECTIVE: Recent cervical cancer screening guidelines for women over age 30 seek to improve the sensitivity of cytology by incorporating high-risk (HR) human papillomavirus (HPV) DNA testing into the screening algorithm, a recommendation based largely on data that utilized the conventional Pap smear and were not stratified by patient age. Data on the rate of HR HPV among women over age 30 undergoing liquid-based Pap test screening are limited. The objective of this study was to determine the rate of HR HPV DNA positivity in women ages 30 and over with a cytologically negative liquid-based Pap test result. METHODS: Consecutive residual ThinPrep Pap samples from women with a cytologically negative result following computer-assisted screening were tested for HR HPV using the Hybrid Capture 2 (HC2) method. All HC2-positive samples were additionally tested with the Linear Array (LA) HPV Genotyping Test. RESULTS: 1000 cytologically negative specimens from women aged 30 to 45 years (38.9+/-4.7 years) were evaluated. The overall HC2 HR HPV positivity rate in this age group was 3.9% (confidence interval 2.8-5.3%). When stratified by age group, the rate was inversely proportional to age (ages 30-35: 6.7%; 36-40: 3.0%; 41-45: 2.6%) and lower than most previous reports (1-17%). Some of the cases that were positive for HR HPV by HC2 were negative by LA, or showed only low-risk virus. CONCLUSIONS: The HR HPV rates in women ages 30-45 with a cytologically negative, computer-imaged ThinPrep test result are low. If these findings are confirmed in future studies, the added benefit of HPV testing to liquid-based cytology for women ages 30 and over should be critically evaluated.     

Human papillomavirus (HPV) in an Icelandic population: correlation of HPV DNA to cyto- and histopathologic lesions and evaluation of treatment strategies

This study is based on 100 cases with cervical intra-epithelial neoplasia (CIN) smears referred for colposcopy and 200 controls with normal smears. The study analyses (a) the frequency of different grades of CIN and koilocytotic lesions among the cases based on cyto- and histopathologic findings; (b) the frequency of human papillomavirus (HPV) among the cases with Virapap/Viratype (V/V) in biopsies vs swabs and among the controls with V/V and polymerase chain reaction (PCR) in swabs; (c) the frequency of the HPV types according to the grade of CIN. Among the cases koilocytotic lesions were found in 98% of the biopsies and 27% of the smears. High-graded smears and high-risk viruses had at entry a positive predictive value (PPV) of 80% and 88% respectively and a sensitivity of 72% for histologically verified high-graded CIN lesions. Both tests combined increased the sensitivity to 88%. The false-negative rate of colposcopy was 3% and the undergraded rate of CIN I and unclassified CIN smears for histologically verified CIN II–III was 62%. Among the cases the rate of HPV positive tests increased with a higher CIN grade. Cytology and colposcopy are complementary for the diagnosis of CIN and the swabs and biopsies for the diagnosis of HPV. Among the cases the rate of HPV-positive tests with V/V was 62% (97% high-risk viruses) and among the controls 5.5% (78% high-risk viruses). Among the controls the frequency of HPV occurrence with PCR was 11.2% and decreased with older age. The therapeutic conclusions are that the high-graded CIN lesions should receive ablative treatment irrespective of HPV typing, whereas low-graded lesions with high-risk viruses should be treated or observed closely.     

Human papillomavirus testing for primary screening in women at low risk of developing cervical cancer. The Greek experience

OBJECTIVE: To compare the performance of human papillomavirus (HPV) DNA detection against routine Papanicolaou smear for the detection of low- and high-grade cervical intraepithelial neoplasia in a low-risk population. MATERIALS AND METHODS: A cross-sectional study was performed involving 1296 women attending six outpatient clinics in Northern Greece (Thessaloniki, Thermi, Mihaniona, Corfu, Veria, and Serres). Women underwent a gynecological examination, including collection of exfoliated cervical cells for Papanicolaou cytology and HPV DNA detection. Cytology was processed according the conventional routine manner, and HPV DNA was determined using the polymerase chain reaction technique. In positive cases of either method, a complete colposcopic evaluation was performed with directed biopsies. Tests (HPV DNA, cytology, and colposcopy) performance characteristics were determined using the histopathologic diagnosis as the reference standard. RESULTS: HPV DNA testing showed a significantly better sensitivity than the Papanicolaou smear in detecting cervical intraepithelial neoplasia (75% versus 50% for high-grade lesions and 81.2% versus 50% for lesions of any grade, respectively). Specificity, and positive and negative predictive values did not significantly differ. Even after dividing women in younger or older than 30 years, the sensitivity of the HPV DNA test was greater than cytology (100% and 70% versus 50% for cytology in both groups, respectively), with a 6.3% loss in specificity when performed in women younger than 30 years. CONCLUSION: HPV testing could be useful in screening women at low risk for cervical cancer, either as an adjunct tool to augment existing cytology programs or as a unique test of its own.     

The borderline or weakly positive Hybrid Capture II HPV test: a statistical and comparative (PCR) analysis

OBJECTIVES: Recent studies have hypothesized that laboratory contamination may influence interpretation of Hybrid Capture II (HCII) human papillomavirus (HPV) detection assay values. STUDY DESIGN: To test this hypothesis, 572 consecutive HCII samples were statistically evaluated to test the null hypothesis that cross-well contamination was not present. In addition, 874 consecutive paired samples from patients followed by both HCII and polymerase chain reaction (PCR) analysis were compared. RESULTS: A Kendall's tau measure of association among adjacent wells yielded a P value of .016, rejecting the null hypothesis of no contamination. Analysis of relative light unit values between 0.8 and 1.5 rejected the null hypothesis at P=.077. Moreover, PCR positivity was significantly higher for samples with HCII values above 1.5 vs 0.8 to 1.5 (P=.001). CONCLUSION: Cross-well contamination of samples occurs during processing, and may influence interpretation of some borderline positives. The proportion of cases at risk is low (<3%). Nevertheless, this information may be germane to the interpretation and reporting of marginally positive HCII test values.     

The diagnostics and prevalence of genital human papillomavirus (HPV) infection in Hungary

Objective: To show the prevalence and determine the type of human papillomavirus (HPV) in healthy women of reproductive age in Hungary. Study Design: We determined HPV nucleic acid using the Digene Hybrid Capture HPV-DNA assay from endocervical swabs of 1121 volunteer women of reproductive age. With the help of the hybridization antibody capture test we determined 14 HPV types (low risk, intermediate and high risk). Results: HPV prevalence was 17.5% considering the whole material. At the Szeged center 27.6% of the women screened were HPV positive, whereas at the three centers in Budapest, HPV prevalence did not exceed 15% in either of them. With a cytological examination out of 1100 cases, 117 (10.6%) were found to be HPV infected. The virus infection could be shown out of 1018 non-malignant cytologies in 60 (5.9%) cases and from 82 epithelial lesions 57 (69.5%) were infected. The cytological and molecular HPV diagnoses showed a significant relation to each other (P<0.001). The cytological method showed HPV infections with a low degree of efficiency (sensitivity: 23.8%). On the other hand, the specificity (92.2%) is an acceptable method for the real negativity of the light microscopic HPV infection. Conclusions: These facts mean regarding the detection of HPV-DNA genoms that HPV positive cytological reports are false negative and in dysplasias are false positive. Since in HPV infected women the development of CIN is a great risk, it is advisable to carry out the HPV determination and typing in the so-called “endangered” groups.     

人乳头状瘤病毒不同亚型感染与宫颈病变的相关性

目的 了解门诊高危人群和宫颈病变患者的人乳头状瘤病毒（HPV）感染的型别分布，探讨不同HPV亚型感染的致癌性。方法 采用导流杂交技术，对门诊就诊的1715名有性生活史妇女，进行下生殖道HPV感染分型筛查。其中463例经阴道镜下定点官颈活检，病理确诊分为官颈炎症234例、CINⅠ96例、CINⅡ80例和CINⅢ53例。分析人群HPV感染的型别分布、与宫颈病变相关性。结果 21种HPV亚型均被检出，1715名门诊妇女中HPV阳性率57．1％（978／1715），宫颈病变中为76．9％（356／463），而在CINⅢ中达98．1％（52／53）。常见的5种亚型分布：高危人群为HPV16、58、52、33和6型；宫颈病变为HPV16、58、52、33和31型；CINⅢ中为HPV16、33、58、31和52型。HPV16、33和31型与宫颈病变程度相关（P〈0．05），Logistic回归分析，高级别鳞状上皮内瘤变（HSIL，CINⅡ＋CINⅢ）的主要风险也是感染HPV16、33和3l型（OR9．59、2．99和2．52，95％CI4．805～11．989、1．231～7．296和1．174～5．429）。结论 本地区官颈病变的常见型别是HPV16、58、52、33和31型，HPV16、33和31型是HSIL的主要致病型。     

两种HPV检测方法在宫颈癌筛查中准确性比较的Meta分析

目的:评价HPV E6/E7 mRNA(Aptima)和HPV DNA二代杂交捕获(HC2)检测对宫颈上皮内瘤变2级(CIN2)及以上病变(≥CIN2)的诊断价值。方法:检索Cochrane图书馆、Pubmed、Embase、中国知网和万方数据库,收集Aptima和HC2用于宫颈癌筛查的研究数据。通过meta分析合并诊断效应量,比较Aptima和HC2对≥CIN2的诊断效能。结果:共纳入13篇文献,初筛人群累计31523例(其中Aptima 15767例,HC2 15756例)。转诊人群累计13982例(其中Aptima 7004例,HC2 6978例)。初筛人群中,Aptima和HC2诊断≥CIN2的汇总敏感度分别为0.95(95%CI为0.91~0.98)和0.95(95%CI为0.90~0.97),汇总特异度分别为0.90(95%CI为0.90~0.98)和0.85(95%CI为0.84~0.86)。转诊人群中,Aptima和HC2诊断≥CIN2的汇总敏感度分别为0.93(95%CI为0.92~0.94)和0.95(95%CI为0.93~0.96),汇总特异度分别为0.47(95%CI为0.45~0.48)和0.38(95%CI为0.36~0.39)。初筛人群中,Aptima和HC2诊断≥CIN2的AUC分别是0.9672和0.8888,Q*统计量分别为0.9154和0.8194;转诊人群中,Aptima和HC2诊断≥CIN2的AUC分别是0.8389和0.8766,Q*统计量分别为0.7708和0.8070,差异均无统计学意义。结论:Aptima与HC2对≥CIN2病变的诊断敏感度和诊断效能相当,但Aptima的特异度相对更高。     

Type-specific human papillomavirus DNA testing with the genotyping array: a comparison of cervical and vaginal sampling

Objective

To compare the detection and typing of human papillomavirus (HPV) between vaginal and cervical specimens by using polymerase chain reaction (PCR)-based reverse-blot genotyping arrays.

Study design

Two hundred and fifty-two women were referred to colposcopy clinics because of suspicious or positive results in a community-based cervical cancer-screening program. Genital tract cells were sampled from the cervix and self-collected from the vagina and tested with the HPV Blot kit.

Results

The HPV Blot kit identified HPV infection in 24.7% of vaginal specimens and in 30.2% of cervical collections. Cervical sampling detected significantly more infections compared to vaginal sampling only for HPV type 52; cervical sampling also detected significantly more high-risk HPV infection overall. The sensitivities of detecting histology ≥cervical intraepithelial neoplasia (CIN) grade 3 using the HPV Blot in vaginal and cervical specimens were 75.0% (95% CI, 47.6-92.7%) and 87.5% (95% CI, 61.6-98.4%), respectively (P = 0.48). Both sampling methods were thus statistically effective at detecting high-grade lesions and cervical cancer (P < 0.0001).

Conclusions

The HPV Blot yielded similar results for both vaginal sampling and cervical sampling in the detection of CIN grade 3 or worse. These findings indicate that self-sampling for HPV testing is a viable cervical cancer screening option.