人乳头瘤病毒与人类宫颈癌

鉴于人乳头瘤病毒（HPV）与人类宫颈上皮内瘤样病变以至宫颈癌的发病有密切的关系，为此作者复习相关文献，就HPV的结构、女性生殖道HPV感染的流行病学、HPV感染与宫颈癌的关系等方面加以扼要的综述。     

Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors

Human papillomavirus (HPV) is the central etiologic factor for cervical cancer, and prior studies suggested C. trachomatis may act as an HPV cofactor. We examined the C. trachomatis-cervical cancer association by serotype, histology, HPV type in the tumor, and other HPV cofactors. We conducted a population-based study in the Seattle-Puget Sound area of 302 women with invasive squamous cell carcinomas (SCC), 185 women with adenocarcinomas of the cervix (AC), and 318 HPV seropositive control women. The risk of SCC associated with antibodies to C. trachomatis was increased (OR 1.6, 95% CI 1.1-2.2) but not for AC (OR 1.0, 95% CI 0.6-1.5). This association was independent of HPV type in the SCC tumor tissue. There was an association between specific serotypes of C. trachomatis and SCC for 6 of the 10 serotypes: B (OR 3.6, 95% CI 1.5-8.4), D (OR 2.1, 95% CI, 1.2-3.5), E (OR 2.4, 95% CI, 1.4-3.9), G (OR 3.0, 95% CI, 1.1-7.9), I (OR 4.2, 95% CI, 1.5-11.7), and J (OR 2.3, 95% CI, 1.0-5.1), but not for the 4 types (C, F, H, and K) that were present at very low prevalence in this population. There was an increased risk of SCC, but not AC, associated with antibodies to C. trachomatis that was not serotype specific.     

High risk HPV types in southern Iranian patients with cervical cancer

This study was undertaken to assess the rate of HPV infection in cervical carcinoma among southern Iranian patients. 101 archival cervical carcinoma tissue samples of a 10 year period were studied for the presence of HPV DNA in southern Iran by a polymerase chain reaction method. In addition, the presence of high risk HPV-16 and HPV-18 genotypes was investigated. In total, 88 (87.1%) of the samples were HPV DNA positive, of which 83 were squamous cell carcinomas and 5 were adenocarcinomas. HPV-16 genotype was detected in 26.7% of HPV positive cervical carcinomas; however, none of the samples were positive for the existence of HPV-18 genotype. Collectively, these results suggest that HPV-16 and HPV-18 are not the frequent high risk HPV types in our patients and circulating HPV types in southern Iranian population are different from many other populations.     

人乳头瘤病毒变异株与宫颈疾病

人乳头瘤病毒(HPV)感染是发生宫颈癌的必要条件。根据病毒基因组核苷酸序列,在亚型的基础上可以进一步将HPV分为不同的变异株。HPV变异株的分布与地理位置关系密切。某些特定的HPV变异株感染可能增加发生宫颈癌的风险,其可能的机制是免疫逃逸、改变病毒癌基因的表达等。     

Influence of HPV type on prognosis in patients diagnosed with invasive cervical cancer

While much is known about the influence of HPV type on the progression of pre‐invasive cervical lesions, the impact of HPV type on cervical cancer prognosis is less evidenced. Thus, we assessed the impact of HPV type on the survival of women diagnosed with cervical cancer. A total of 370 cases of cervical cancer were assessed. Univariate analysis is presented using Kaplan–Meier survival curves and log‐rank statistics and multivariable Cox proportional hazard models were generated using age group, socio‐economic deprivation, FIGO stage, differentiation and HPV type. HPV grouping was considered in a number of ways with particular reference to the presence or absence of HPV 16 and/or 18. In the univariate analysis, FIGO, age at diagnosis and treatment were associated with poorer survival (p < 0.0001) as was absence of HPV 16 and/or 18 (p = 0.0460). The 25% mortality time in the non‐HPV 16/18 vs. HPV16/18 positive group was 615 days and 1,307 days respectively. An unadjusted Cox PH model based HPV16/18 vs. no HPV 16/18 resulted in a hazard ratio of 0.669 (0.450, 0.995). Adjusting for deprivation, FIGO and age group resulted in a hazard ratio of 0.609 (0.395, 0.941) p = 0.025. These data indicate that cancers associated with HPV 16 and/or 18 do not confer worse survival compared to cancers associated with other types, and may indicate improved survival. Consequently, although HPV vaccine is likely to reduce the incidence of cervical cancer it may not indirectly improve cervical cancer survival by reducing the burden of those cancers caused by HPV16/18.     

HLA class II alleles associated with infection by HPV16 in cervical cancer in situ

HLA class II alleles have been associated with an increased risk of developing cervical cancer through infection with oncogenic forms of human papilloma virus (HPV). We have examined the association of variation at the DRB1 and DQB1 loci with HPV16 infection and risk of development of cervical cancer by analysis of 440 cases diagnosed with cervical cancer in situ and 476 age-matched controls in a retrospective case-control study. The infection history of a woman was studied by analysis of cervical smears taken at multiple times during a period of up to 27 years (1969-95). The frequency of a number of alleles are either increased (DRB1*0801, DRB1*1501, DQB1*0402 and DQB1*0602) or decreased (DRB1*0101, DRB1*1301, DQB1*0501 and DQB1*0603) in the cancer patients compared to the controls. After correction for multiple testing, only the DQB1*0602 and the DRB1*1501 alleles remain associated with cancer and only in HPV16-infected patients (DQB1*0602: 102/264 (39%) vs. 130/476 (28%), p = 0.028 and DRB1*1501: 104/259 (40%) vs. 132/469 (28%), p = 0.027). These alleles are associated primarily with infection by HPV and only indirectly affect the risk of developing cervical cancer in situ. To study the impact of these alleles on persistence of infection, women with short-term infections were compared to those with long-term infections. Carriers of DQB1*0602 and DRB1*1501 were more frequent in the group with long-term HPV infections, indicating that these class II alleles contribute to the inability to clear an HPV infection.     

女性下生殖道HPV感染与宫颈上皮内瘤变及宫颈癌关系的病理研究

目的：探讨女性下生殖道高危型人乳头状瘤病毒（high risk human papillomavirus,HR－HPV）感染与宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）及宫颈癌的关系。方法：选择2013年2月－2015年4月我院收治的236例CIN及宫颈癌患者为观察组,进行下生殖道HPV（人乳头状瘤病毒）检测,分析CIN及宫颈癌与HPV感染的关系,并与对照组有宫颈炎但无CIN及宫颈癌的126例患者进行对比研究。结果：HR－HPV感染率随着患者CIN 的严重程度而升高,宫颈癌的HR－HPV感染率最高为91．89％,明显高于对照组差异具有统计学意义（P＜0．05）。HR－HPV双重感染率以及HR－HPV多重感染率与单一HR－HPV患者的病毒感染率相比较高,差异具有统计学意义（P＜0．05）。且患者随着病情的加重,单型、双重、多重HR－HPV感染率从CINⅠ期、CINⅡ期、CINⅢ期呈递增趋势。结论：HR－HPV感染及HR－HPV多重感染是导致宫颈上皮内瘤变及宫颈癌发生的重要诱因,对高危型 HPV 病毒的持续感染,及时的诊断并予以有效的治疗,能够阻滞癌前病变的发展,对于预防宫颈上皮内瘤变及宫颈癌,降低宫颈癌的死亡率具有重要临床意义。     

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.     

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.     

Association between high-risk HPV types, HLA DRB1* and DQB1* alleles and cervical cancer in British women

Cervical scrapes from 116 British women referred with cervical cancer were tested for the presence of high oncogenic risk human papillomavirus (HPV) genotypes (HPV(hr)). Ninety-four per cent of the scrapes had one or more of these virus types and 66% were HPV16-positive. HPV18 was more frequent in adenocarcinoma. No evidence was found for an increased cancer risk associated with the HPV16 E6 350G variant. The HLA DRB1* and DQB1* alleles in these women and in 155 women with normal cytology and negative for HPV(hr) DNA were compared. DQB1*0301 alone (2P = 0.02) and in combination with DRB1*0401 (2P = 0.02) was found to be associated with cervical cancer. This was more marked in cancers positive for HPV types other than HPV16. In contrast, DRB1*1501 alone and in combination with DQB1*0602 was not significantly elevated in cancers overall, but did show some excess in HPV16-positive cancers (2P = 0.05), associated with HPV16-positive cervical cancers. Taking all cancers together, a marginally significant protective effect was found for DQB1*0501 (2P = 0.03) but no protective effect could be seen for DRB1*1301.     

Impact of multiple HPV infection on response to treatment and survival in patients receiving radical radiotherapy for cervical cancer

To obtain information on the incidence and the clinical significance of infection with various types of the human papillomavirus (HPV) in cancer of the uterine cervix, we retrospectively examined the HPV status of 106 patients who had received radical radiotherapy for cervical cancer stages IB to IIIB. DNA was extracted from formalin-fixed, paraffin-embedded biopsies and PCR was carried out to identify HPV types 16, 18, 31, 35, 33 and 45. To detect additional HPV types, consensus PCR products were cloned and sequenced. A catalyzed signal-amplified colorimetric in situ hybridization was carried out in 84 of 106 specimens as a positive control. Response to therapy, progression-free survival (PFS) and cervical cancer-specific survival (CCSS) were the statistical endpoints. Survival analysis was carried out using univariate and multivariate analysis (Cox regression). Ninety-six patients (90.6%) were HPV-positive and 42/96 (43.7%) were positive for multiple HPV types. Eight patients had persistent disease after radiotherapy. From these 8 patients, 7 were infected with multiple HPV types and only 1 patient had an infection with a single HPV type. After a median follow up period of 50 months, patients with multiple HPV infection had a significantly shorter PFS and CCSS compared to those with single HPV infection (24.8% and 34.9% vs. 64% and 60.8%, Log rank, p < 0.01 and 0.04). In multivariate analysis, the presence of multiple HPV types (RR 1.9), node status (RR 2.3), tumor size (RR 3.2) and histologic type (RR 4.8) were independent prognostic factors of CCSS. Our results demonstrate that the presence of multiple HPV types is associated with poor response and with reduced survival in cervical cancer patients who receive radiotherapy as the primary treatment.     

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.     

A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine

The object of our study is to project the impact of a prophylactic vaccine against persistent human papillomavirus (HPV)-16/18 infection on age-specific incidence of invasive cervical cancer. We developed a computer-based mathematical model of the natural history of cervical carcinogenesis to incorporate the underlying type-specific HPV distribution within precancerous lesions and invasive cancer. After defining plausible ranges for each parameter based on a comprehensive literature review, the model was calibrated to the best available population-based data. We projected the age-specific reduction in cervical cancer that would occur with a vaccine that reduced the probability of acquiring persistent infection with HPV 16/18, and explored the impact of alternative assumptions about vaccine efficacy and coverage, waning immunity and competing risks associated with non-16/18 HPV types in vaccinated women. The model predicted a peak age-specific cancer incidence of 90 per 100,000 in the 6th decade, a lifetime cancer risk of 3.7% and a reproducible representation of type-specific HPV within low and high-grade cervical precancerous lesions and cervical cancer. A vaccine that prevented 98% of persistent HPV 16/18 was associated with an approximate equivalent reduction in 16/18-associated cancer and a 51% reduction in total cervical cancer; the effect on total cancer was attenuated due to the competing risks associated with other oncogenic non-16/18 types. A vaccine that prevented 75% of persistent HPV 16/18 was associated with a 70% to 83% reduction in HPV-16/18 cancer cases. Similar effects were observed with high-grade squamous intraepithelial lesions (HSIL) although the impact of vaccination on the overall prevalence of HPV and low-grade squamous intraepithelial lesions (LSIL) was minimal. In conclusion, a prophylactic vaccine that prevents persistent HPV-16/18 infection can be expected to significantly reduce HPV-16/18-associated LSIL, HSIL and cervical cancer. The impact on overall prevalence of HPV or LSIL, however, may be minimal. Based on the relative importance of different parameters in the model, several priorities for future research were identified. These include a better understanding of the heterogeneity of vaccine response, the effect of type-specific vaccination on other HPV types and the degree to which vaccination effect persists over time.     

Vaccine-related HPV genotypes in women with and without cervical cancer in Mozambique: burden and potential for prevention

Knowledge about the burden of Human Papillomavirus (HPV) infections in Sub-Saharan Africa is very limited. We collected cervical samples from 262 women from the general population and 241 tumor samples from women with invasive cervical cancer in Mozambique and tested them for HPV genotyping by the SPF(10)-LiPA(25) PCR system. Among the 195 women without cervical abnormalities by cytology HPV prevalence was 75.9%. In this group of women, the most frequently identified HPV types among HPV-positive women were in descending order of frequency: HPV51 (23.6%), HPV35 (19.6%), HPV18 (14.2%), HPV31 (13.5%) and HPV52 (12.8%). In women with cervical cancer HPV DNA detection was 100%. The type-specific distribution of the most frequent types in descending order of frequency was: HPV16 (47.0%), HPV18 (31.3%), HPV51 (14.8%), HPV52 (14.3%), HPV45 (12.6%), HPV35 (10.4%), HPV33 (4.8%) and HPV31 (2.6%). HPVs 16/18 and HPVs 16/18/31/45 were detected in 71.7% and 80.9% of cervical cancer tissue, respectively. While HPVs 51 and 35 were the two most common types in cytologically normal women in Mozambique, HPVs 16 and 18 remained the two most frequently identified types in cervical cancer. The introduction of an efficacious HPV 16/18 vaccine could potentially prevent the occurrence of 72% of cervical cancer cases and up to 81% of the cases if full cross-protection against HPVs 31 and 45 is assumed.     

Knowledge of cervical cancer and HPV vaccine post- vaccination among mothers and daughters in Vietnam

Background: Limited human papillomavirus (HPV) related knowledge might be a barrier to future vaccineacceptance. From 2008-2010, PATH conducted an HPV vaccination demonstration project in partnership withthe government immunization program in Vietnam, which included awareness campaigns prior to vaccination.Objective: To assess and compare knowledge and attitudes about cervical cancer and HPV vaccines betweenmothers and daughters, and whether knowledge was associated with vaccination status. Methods: We analyzedHPV-related knowledge and attitude data from mother-daughter paired responses to a cross-sectional householdsurvey. After parents completed the survey, daughters were asked the same questions. We calculated the frequencyof responses for each question and devised a scaled composite measure for knowledge. Results: Participantsbelieved they had received enough information about cervical cancer and HPV vaccines and it was sufficient tomake a decision about vaccination. Fifty percent of the participants knew HPV causes cervical cancer and 80%knew the HPV vaccine prevented cervical cancer. Mothers had more knowledge about cervical cancer and HPVinfection (p<0.01), compared to daughters, who had more vaccine specific knowledge (p<0.01). However, thetotal mean knowledge score was similar for the groups. Girls not fully vaccinated had a lower mean knowledgescore than fully vaccinated girls (p<0.001). Conclusions: Our results suggest that the purpose of the HPVvaccine was clearly messaged; however, some misconceptions about cervical cancer and HPV still exist. Limitedknowledge about the magnitude of cervical cancer, HPV as a cause of cervical cancer, and HPV vaccines mayhave contributed to incomplete vaccination.     

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25–65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56–1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43–1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14–65) and intervention 43 (95% CI: 25–73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1–0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.