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.     

Viral load of high-risk human papillomavirus in cervical squamous intraepithelial lesions.

OBJECTIVES: This case-control study was conducted to investigate the role of viral load of high-risk human papillomaviruses (HPVs) in the development of cervical squamous intraepithelial lesions (SILs) and invasive cancers. METHODS: A total of 30 female cases who had histological evidence of low-grade SIL (n=10) or high-grade SIL and above (n=20) were identified as the case group at the Tri-Service General Hospital, Taipei between September 1998 and March 1999. In addition, 80 female controls who had normal cervical cytology were enrolled and individually matched on age (+/-5 years) and date of recruitment to each case. Cervical swabs collected from study subjects were tested for the positivity and viral load of high-risk HPVs by Hybrid Capture II assay. Additionally, subjects completed a risk factor questionnaire. RESULTS: Among sex behavioral factors studied, younger age at first intercourse was associated with a significantly elevated risk of cervical SIL and invasive cancers. With respect to HPV infection, high-risk HPV DNA was present in 70% (21/30) of case and 21% (17/80) of control subjects, resulting in an odds ratio (OR) of 6.6 [95% confidence interval (C.I.)=2.6-17.0]. Moreover, women who had a high viral load were at significantly greater risk for cervical SIL and invasive cancers than those who were infected with a low viral load (OR=18.0, 95% C.I.=3.0-108.5). CONCLUSIONS: Among the variables tested, infection with a high viral load of high-risk HPVs is the strongest determinant for cervical SIL and cervical cancers in Taiwan.     

高危型人乳头瘤病毒载量与宫颈上皮内瘤变病变程度相关性

目的:探讨高危型人乳头瘤病毒(HR-HPV)载量与宫颈上皮内瘤变(cervi-cal intraepithelial neoplasia,CIN)病变程度相关性。方法:对2008年1月~2010年6月于上海市第一人民医院行阴道镜检查的1035例患者,用HCⅡ方法检测其HR-HPV病毒载量,分为阴性组(0.00~1.00)、低度载量组(1.0~10.00)、中度载量组(10.00~100.00)、高度载量组(100.00~1000.00)和极高度载量组(≥1000.00);将病理结果按照宫颈病变程度分为阴性组(慢性黏膜炎和挖空细胞)、低级别病变组(CINⅠ)和高级别病变组(CINⅡ、CINⅢ)。多分类Logistic回归分析HPV病毒载量和CIN病变程度相关性。结果:病理诊断为慢性黏膜炎、挖空细胞、CINⅠ、Ⅱ、Ⅲ的HR-HPV病毒载量的中位数(感染率)分别是2.70(58.22%)、56.00(79.07%)、88.05(79.66%)、323.90(93.27%)和364.07(92.47%),基本呈递增趋势。CIN的各级别病毒载量的分布差异显著(P均<0.05),低级别病变组和高级别病变组的各级别病毒载量组(低度载量组、中度载量组、高度载量组和极高度载量组)对于病理阴性组的危险度(OR值)依次递增:低级别病变组0.677、2.406、2.893和2.943;高级别病变组2.177、4.262、6.354和20.177。结论:CIN的发生与高危型人乳头瘤病毒载量有关,病毒载量越高,CIN发生危险度越高。     

Mechanisms and predictors of high-risk human papillomavirus (HPV) clearance in the uterine cervix

Cervical cancer (CC) and its precursor lesions (CIN) are unique in that we can study the natural history of one disease at two different levels; i) by assessing the clinical lesions, and ii) by analysing the viral events of human papillomavirus (HPV) infections, their prime etiological agent. In this review, we are interested in mechanisms and predictors of clearance of oncogenic HPV infections in the uterine cervix. The outcome (natural history) of CIN has been well established by a large number of prospective cohort studies covering over 25,000 patients, and the figures for regression, persistence and progression are well established. The outcome of HPV infections is far more complex with at least six distinct patterns being demonstrated in long-term cohort studies. There is little doubt that the mechanistic explanation for HPV clearance is by specific immunological reactions, where competent humoral and cell-mediated immune mediators are needed. To understand this process in detail still necessitates a substantial amount of clinical and laboratory research, however. In general, HPV outcomes follow the pattern where a dynamic balance exists between incident infections and virus clearance. Following a rapid accumulation of incident infections after onset of sexual activity (women < 20 years of age), there is a transition of this balance in favour of virus clearance soon after age 25. This explains the constantly declining age-specific prevalence of HPV infections until menopause. Failure to eradicate the virus at postmenopause is not uncommon, however, explaining the deep second peak in HPV prevalence now reported in many different populations. The importance of HPV clearance/non clearance (= persistence) has been recognised recently, and the number of studies addressing these issues has increased substantially during the past few years. The data are now rather unanimous concerning the times and rates (usually expressed per 1,000 women/months at risk, WMR) of HPV clearance. On the other hand, data are still incomplete and in part inconsistent as to the cofactors that regulate these events. A wide variety of variables have been explored as potential co-determinants and/or predictors of HPV clearance, as reviewed in this communication. Until now, all efforts attempting to identify suitable biomarkers as such predictors, have been disappointing, but fortunately, this is a largely unexplored area as yet. Similarly, data on the two extremes of life, i.e., early infancy and postmenopause, are still far too fragmentary to enable creating a comprehensive view, how these viral infections behave in early life, and what makes many women incapable of clearing their virus at postmenopause. Both issues are of utmost importance and have widespread clinical implications; we need to know how and why some infants and children contract HR-HPV infections well before the onset of their sexual activity, to be able to select the proper targets for prophylactic HPV vaccination. Similarly, we need to know why some women over 55 years of age are likely to remain HR-HPV carriers, while the vast majority successfully clears their infection well before the menopausal age. Early detection of cervical cancer precursors among these elderly HR-HPV positive women past the usual age of organised screening remains a major challenge also in the future.     

宫颈病变患者配偶人乳头瘤病毒检测结果分析

目的了解宫颈病变患者配偶人乳头瘤病毒(HPV)感染情况,为宫颈病变的预防提供依据。方法对2009年12月至2011年4月在深圳市人民医院妇科门诊就诊,有宫颈病变且高危型HPV检测阳性的患者共86例及健康妇女35例(其配偶分别为研究组86例和对照组35例),采用PCR体外扩增和DNA反向点杂交相结合的DNA芯片技术,检测其配偶阴部HPV感染情况。结果研究组HPV检出阳性率为45.35%(39/86),明显高于正常对照组的17.14%(6/35)(P﹤0.01)。研究组HPV阳性者中有53.8%(21/39)的夫妻双方感染相同的HPV亚型,其中52型占首位。结论宫颈病变患者配偶HPV感染明显高于正常人群,且部分夫妻感染相同的HPV亚型,故对配偶进行HPV检测和健康宣教有利于宫颈病变的预防。     

高危型HPV负荷量与宫颈癌及其前期病变关系的研究

目的:探讨高危型HPV负荷量与宫颈癌及其前期病变的关系。方法:对2005年1月至2006年12月于本院行宫颈癌筛查的1221例患者临床资料进行统计分析,观察高危型HPV负荷量和宫颈癌及其前期病变的关系,并用ROC曲线分析,确定HC-Ⅱ法检测高危型HPV-DNA判断宫颈病变≥CINⅡ理想的RLU/CO界值。结果:1221例患者组织学诊断为慢性宫颈粘膜炎667例,CIN407例(其中CINⅠ109例、CINⅡ～Ⅲ298例),宫颈癌147例。慢性宫颈炎、CINⅠ、CINⅡ～Ⅲ和宫颈癌患者高危HPV-DNA负荷量的中位数分别为32.58,58.16,103.83和173.68。根据ROC曲线,统计结果中各可能切点的灵敏度和特异度,发现确定预测≥CINⅡ宫颈病变最佳RLU/CO值为3.155,该点灵敏度88%,特异度57%,Youden指数0.446。结论:高危型HPV负荷量与宫颈癌及其前期病变存在明显相关性,预测≥CINⅡ宫颈病变高危HPV负荷量最佳值为3.155。     

No confirmed case of human papillomavirus DNA-negative cervical intraepithelial neoplasia grade 3 or invasive primary cancer of the uterine cervix among 511 patients

OBJECTIVE: This study was undertaken to analyze the prevalence and peculiarities of high-grade cervical neoplasias that are not associated with human papillomavirus (HPV) DNA. STUDY DESIGN: Four hundred nineteen women with a first-time diagnosis of cervical intraepithelial neoplasia grade 3 and 92 women with cervical cancer were examined prospectively with a commercially available HPV DNA test. Negative samples were re-tested by polymerase chain reaction (PCR) with general and type-specific primers while the corresponding histology specimens were evaluated by immunohistochemistry. RESULTS: Of the 511 cases examined, 14 were HPV DNA negative on initial analysis. Of these, 7 were found not to be high-grade cervical neoplasia on histologic review, 3 cases were found to contain high-risk HPV types by PCR, and 2 samples were found to be inadequate for analysis. The 2 remaining HPV-negative cases were FIGO stage III and IV tumors. Immunohistochemistry was consistent with a primary adenocarcinoma of the ovary in 1 case and a primary bladder tumor in the other, although a primary cancer of the cervix could not be ruled out completely. CONCLUSION: After exclusion of inadequate samples and erroneous diagnoses, HPV DNA was associated with all confirmed cervical intraepithelial neoplasia grade 3 and primary cervical cancers.     

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.     

Association between high-risk human papillomavirus DNA load and precursor lesions of cervical cancer in Mexican women

OBJECTIVE: Our objective was to determine the association between viral load of high risk human papilloma virus (HPV) using the Hybrid Capture II (HC II) system and cervical intraepithelial neoplasia (CIN) lesion stage. METHODS: A total of 182 consecutive women with confirmed diagnoses of CIN 1-3 and 182 healthy women with negative Pap were included. All subjects underwent structured interviews focused on socioeconomic and reproductive factors. HC II testing was used to detect human papilloma virus (HPV) DNA. Viral load was measured by light measurements expressed as relative lights unit (RLU) ratio (specimens/control). Log(10)RLU ratios were categorized for analysis into four groups: negative (相似文献   

Efficiency of three surgical procedures in eliminating high-risk human papillomavirus infection in women with precancerous cervical lesions

PURPOSE OF INVESTIGATION: To establish the efficiency of laser vaporization (LV), large loop excision of the transformation zone (LLETZ) and cold knife conization, done for precancerous cervical lesions, in eliminating high-risk human papillomavirus (HPV) infection. Additionally, we determined whether the same HPV genotype persisted after surgery. METHODS: A total of 214 women were tested for HPV infection by the Hybrid Capture II (HCII) test prior to surgery. HPV-positive women were followed by HCII test ten months after surgery. In persistently HPV-positive women, HPV genotypes were determined by PCR - PGMY09/PGMY11. RESULTS: The HCII test showed elimination of HPV infection after LV, LLETZ and cold knife conization in 67.6%, 86.3%, and 100% (p < 0.05) of women, respectively. In seven (38.9%) women a different HPV genotype was found to be present after surgery, the corrected efficiency thus being 79.4%, 92.7% and 100% (p = NS), respectively. CONCLUSIONS: The three analyzed surgical procedures are effective in eliminating high-risk HPV infection. HPV testing is useful at follow-up, since it can identify a small proportion of women requiring close surveillance and potential treatment.     

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。     

Prevalence of human papillomavirus DNA in cervical tissue. Retrospective analysis of 855 cervical biopsies

The histopathologic features of 855 cervical biopsies were correlated with the presence of human papillomavirus DNA using in situ hybridization (ISH) with biotin labeled type specific probes for Human Papilloma Virus (HPV) types 6, 11, 16, 18, 31, 33 and 51. HPV-DNA was found in 18% (13/72) of cervical intraeptihelial neoplasia I (CIN I), 30% (35/115) of CIN II, 28% (57(206) of CIN III, in 84% (21/25) of flat condyloma and in 13% (15/112) of normal cervical tissue. HPV DNA was detectable in 11% (5/46) of cervical adenocarcinoma and in 21% (59/279) of squamous cell carcinoma (SCC) of the cervix. High risk HPV types were identified more often than low risk HPV types in CIN I, CIN II, CIN III and SCC. HPV type 16/18 predominates over HPV type 31/33/51 in CIN I, flat condyloma and in SCC. The prevalence of HPV was strongly associated with the grade of differentiation of SCC. It was identified in 59% (23/39) of well differentiated SCC, in 18% (25/142) of moderately differentiated and in 11% (11/98) of poorly differentiated SCC. Received: 29 March 1996 / Accepted: 15. August 1996     

Recombinant human interferon gamma in the treatment of cervical intraepithelial neoplasia (CIN) associated with human papillomavirus (HPV) infection

Human papillomavirus (HPV) proteins E6 & E7 are considered to be the constitutively expressed neoantigens in a vast majority of cervical squamous intraepithelial lesions and cancers. Data available from in-vitro, animal, and small clinical trials suggest that the immunological properties of interferon gamma might enhance early viral protein presentation, thus stimulating a cytotoxic response. In order to study this effect in vivo we undertook a trial in which 20 women with a definite diagnosis of cervical intraepithelial neoplasia (CIN) grade I or II with coexistent high-risk HPV infection (detected by the Hybrid Capture System) underwent four months observation followed by intracervical administration of INFgamma in cases without spontaneous regression (17 cases). Human recombinant interferon gamma 1-b (Imukin) was administered intracervically four times in equal doses in two-day intervals to a total dose of 6,000,000 IU. The results of therapy were verified by punch biopsy evaluation and HPV-DNA testing two months after completion, and revealed a complete response in nine women (complete regression of CIN and remission of HPV infection in 53% of treated cases) and partial response in four cases (lower grade of CIN or/and remission of HPV infection--23.5%). The differences between spontaneous (before treatment) and treatment-related regressions were significant at p < 0.05. We conclude that in selected cases (mainly young women who have not completed their procreation and are compliant with the therapy) a conservative approach to CIN management with intracervical IFNgamma injections seems to be a valuable method.