Human papillomavirus

Human papillomaviruses are ancient small DNA viruses and represent the most common sexually transmitted infection in the world. In the majority, HPV infection is cleared by an incompletely understood immune response. HPV is a necessary but not sufficient cause of cervical cancer, and responsible for a proportion of other anogenital cancers including vulval, vaginal, anal and oropharyngeal. Oncogenesis is likely mediated through viral proteins which hijack host-cell machinery in epithelial keratinocytes and disrupt host tumour-suppressor proteins. Much work has been undertaken to further characterise the natural history of HPV infection and cervical disease. Such efforts have been translated to important public health interventions like the introduction of HPV tests in cervical screening. HPV vaccination programmes are expected to further reduce the incidence of high-risk HPV infections and resultantly HPV-related disease.     

Human papillomavirus update (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, around one every two minutes. In the not so distant future cervical cancer may cause more deaths globally per year, (275,000 in 2008), than maternal deaths, (358,000 in 2008). Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persistent infection may cause intraepithelial neoplasia and invasive disease.Prophylactic HPV vaccines prevent disease caused by the included HPV types and potentially prevent 70–75% cases of cervical cancer. The UK added HPV vaccination to the national immunization programme in 2008. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period.Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice.Research is ongoing regarding therapeutic HPV vaccination and second generation prophylactic vaccines to prevent more cases of cancer.     

Human papillomavirus genotype prevalence in cervical biopsies from women diagnosed with cervical intraepithelial neoplasia or cervical cancer in Melbourne, Australia

Multicenter international phase III clinical trials using multivalent human papillomavirus (HPV) vaccines for cervical cancer (CC) prevention are underway. As HPV immunity is type specific, defining HPV genotype prevalence in different regions to ascertain whether predominant types differ geographically is considerably important prior to vaccine implementation. This study aimed to define HPV genotypes present in CC and high-grade dysplasia among women in Melbourne, Australia. HPV genotype analysis of a cross section of women in Melbourne with cervical dysplasia/cancer was performed. A total of 493 cervical biopsies from patients being treated for moderate (n= 122) or severe (n= 180) cervical intraepithelial neoplasia (CIN II/III) or CC (n= 191) were tested for HPV genotypes using the PGMY09/11 primer system and line blot assay. HPV detection rates were 63.9%, 72.8%, and 86.9% in CIN II, CIN III, and CC biopsies, respectively. The most prevalent HPV genotypes among CC biopsies were HPV-16 (52.9%), HPV-18 (18.3%), HPV-45 (6.3%), HPV-39 (3.1%), and HPV-73 (2.6%). Multiple HPV infections, comprising two to five types, were identified in 14.4% of biopsies, being significantly fewer (5.2%) among CC biopsies (P < 0.0001). These results indicate that the two most prevalent CC-associated HPV genotypes in Australia parallel those described internationally, with type variations thereafter.     

Human papillomavirus (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, almost two per minute. Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persisting infections can cause intra-epithelial neoplasia and invasive disease. Prophylactic HPV vaccines have been developed and prevent disease caused by the included HPV types. Current vaccines could prevent 70–75% cases of cervical cancer. The UK, in 2008 added HPV vaccination to the national immunization programme. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period. Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice. Research is ongoing regarding therapeutic HPV vaccination and improving prophylactic vaccines to prevent more cases of cancer.     

不同子宫颈癌筛查方案应用价值评价

目的评价不同方案进行宫颈癌筛查的临床应用价值。方法 2008年7月至2010年2月在中日友好医院妇科门诊同时采用宫颈液基细胞学检查（liquid-based cytologic test,LCT）和高危型人乳头瘤病毒（HR-HPV）筛查宫颈癌妇女1052例,对LCT提示≥ASC-US或HR-HPV阳性者或醋酸试验阳性者进行阴道镜下宫颈活组织检查,以病理结果为金标准评价LCT、HPV、LCT＋HPV平行试验、LCT-HPV系列试验、HPV-LCT系列试验5种方案筛查宫颈高度病变的价值。结果 LCT、HPV、LCT＋HPV平行试验、LCT-HPV系列试验与HPV-LCT系列试验筛查宫颈癌的敏感性分别为73.86%、93.18%、98.86%、90.34%和86.93%;特异性分别为90.87%、77.74%、71.57%、83.79%和86.76%;阳性预测值分别为61.90%、45.68%、41.13%、52.82%和56.88%;阴性预测值分别为94.54%、98.27%、99.68%、97.74%和97.06%;各筛查方案诊断价值相近,差异均无统计学意义（P〉0.05）;LCT-HPV系列试验的各项价值与LCT＋HPV平行试验相近,费用效益比更为理想。结论 LCT-HPV系列试验在获得良好筛查价值的同时显著降低了宫颈癌初筛的费用。     

Prevalence of cervical cancer and feasibility of screening in rural China: a pilot study for the Shanxi Province Cervical Cancer Screening Study

Abstract. Belinson J, Qiao Y, Pretorius R, Zhang W, Keaton K, Elson P, Fischer C, Lorincz A, Zahniser D, Wilbur D, Pan Q, Li L, Biscotti C, Dawson A, Li A, Wu L, Ma CP, Yang XP. Prevalence of cervical cancer and feasibility of screening in rural China: a pilot study for the Shanxi Province Cervical Cancer Screening Study.
For cervical cancer screening to be feasible in developing countries, it must be accurate, inexpensive, and easy to administer. We conducted a pilot study in rural Shanxi Province, People's Republic of China, to determine disease prevalence and study feasibility in preparation for a large-scale comparative trial of 6 screening tests.
One-hundred and thirty-six nonpregnant women with no history of hysterectomy, pelvic radiation, or Papanicolaou tests were screened in a rural clinic. Ten percent of the women enrolled reported abnormal vaginal bleeding and 45% reported abnormal vaginal discharge. The tests were the Papanicolaou test (both conventional and ThinPrep), a self-administered swab test by Hybrid Capture II for high-risk human papillomavirus (HPV), a test for high-risk HPV from residual PreservCyt medium, fluorescence spectroscopy, and visual inspection of the cervix by a clinician. All women also underwent colposcopy and biopsies as the reference standard.
Biopsies showed 12 of 136 women had ≥ high-grade squamous intraepithelial lesions (HGSIL). Screening was completed in 5 half-day sessions, the procedures went smoothly, and local cooperation was enthusiastic.
Disease prevalence in Xiangyuan and Yangcheng Counties, Shanxi Province, can be estimated at 8.8% (95% CI, 4.5% to 15.0%). Screening 1000–2000 patients would be sufficient to detect a 10% difference in accuracy between diagnostic tests. The proposed large-scale trial is feasible.     

人乳头瘤病毒亚型与宫颈上皮内瘤变的相关性

目的探讨人乳头瘤病毒(HPV)各亚型感染或多亚型感染与宫颈上皮内瘤变(CIN)的相关性。方法 2007年11月至2008年4月在天津医科大学总医院采用PCR扩增、基因芯片探针杂交分型检测法检测98例CIN患者的HPV亚型。以35岁为界将98例CIN患者分为两组,年龄≤35岁者为A组(43例);年龄>35岁者为B组(55例)。结果 98例CIN中HPV阳性率,CINⅠ为72.41%(21/29),CINⅡ为75%(27/36),CINⅢ为96.97%(32/33)。HPV单重感染率在CINⅠ、CINⅡ和CINⅢ中分别为41.38%(12/29),44.44%(16/36)和57.58%(19/33);HPV双重感染率在CINⅠ、CINⅡ和CINⅢ中分别为27.59%(8/29),19.44%(7/36)和27.27%(9/33);HPV多重感染率在CINⅠ、CINⅡ和CINⅢ中分别为3.45%(1/29),11.11%(4/36)和12.12%(4/33)。CINⅠ中主要为低危型HPV感染,CINⅢ中以HPV16为主导感染亚型。AB两组HPV16感染率分别为20.93%(9/43),40%(22/55),差异具...     

HPV感染年龄与高度宫颈上皮内瘤变的关系

目的探讨高危型人乳头瘤病毒（HR-HPV）感染患者年龄分布与高度宫颈上皮内瘤变和宫颈癌的关系。方法 2008年7月至2009年4月在中日友好医院同时采用液基薄层细胞学（LCT）和HPV检测行宫颈癌筛查的妇女948例,对LCT≥ASC-US和/或HR-HPV阳性的367例患者进行阴道镜下宫颈活检。结果 〈50岁年龄组妇女的HR-HPV感染率（34.27%）与≥50岁年龄组妇女（18.98%）比较,差异具有统计学意义（P〈0.01）;〈30岁、30～49岁和≥50岁3个年龄组HR-HPV阳性者中,≥CIN2患者的例数分别为18例（39.13%）、81例（43.78%）和17例（32.69%）,差异无统计学意义（P〉0.05）。结论各个年龄段感染HR-HPV的妇女发生≥CIN2的机会无明显差异,均应加强随访。     

乌鲁木齐市维吾尔族和汉族高度子宫颈上皮内瘤变中人乳头瘤病毒亚型临床分析

目的探讨高度子宫颈上皮内瘤变（CIN）中人乳头瘤病毒（HPV）亚型的感染状况。方法选择2010年1月至2013年1月新疆医科大学第一附属医院经病理证实的乌鲁木齐市高度CIN患者387例,采用基因芯片技术检测其宫颈组织中的HPV亚型。结果387例高度CIN患者HPV感染率为84．50％（327／387）,其中维吾尔族（简称维族）为89．19％（132／148）,汉族为81．59％（195／239）,两者比较,差异无统计学意义（P〉0．05）。CIN2组与CIN3组HPV感染率分别为79．21％（160／202）和90．27％（167／185）,两组比较,差异有统计学意义（P〈0．05）。其中,CIN2组患者维族与汉族HPV感染率分别为82．05％（64／78）和77．42％（96／124）,CIN3组患者分别为97．14％（68／70）和86．09％（99／115）,两组比较,差异均无统计学意义（P〉0．05）。在387例高度CIN患者中,汉族前四位HPV感染亚型为HPV16,52,18,58型;维族前四位HPV感染亚型为HPV16,18,56,58型;其中HPV16型（53．75％,208／387）是维族和汉族共同的高危HPV亚型,其次为HPV18型（7．75％,30／387）和HPV58型（6．20％,24／387）。CIN2组和CIN3组患者HPV多重感染率分别为22．28％（45／202）和23．78％（44／185）,两组比较,差异无统计学意义（P〉0．05）。结论乌鲁木齐市维族女性HPV感染率与汉族相似,均随CIN的加重,HPV感染率升高;乌鲁木齐市维族和汉族妇女感染HPV亚型大同小异,HPV16型为感染率最高的共同高危型。     

Human papillomavirus testing improves the accuracy of colposcopy in detection of cervical intraepithelial neoplasia

To assess the performance of human papillomavirus (HPV) testing and colposcopy in detection of cervical pathology. A series of 389 women referred for colposcopy due to an abnormal Pap smear had cervical swabs analyzed for oncogenic (high-risk [HR]) HPV types using Hybrid Capture II (HC2) assay. Loop electrical excision procedure cone biopsy (88%) or colposcopic biopsy (11%) was used as the gold standard. Of the atypical squamous cells of undetermined significance (ASCUS) smears, 48% were positive for HR HPV, as compared to 76.3% of low-grade squamous intraepithelial lesions (LSIL) smears. HR HPV was detected in 66.7% and 90% of patients with cervical intraepithelial neoplasia (CIN) 1 and CIN2 (or higher), respectively. The sensitivity of the Pap smear using an ASCUS threshold in detecting high-grade CIN was 94.5% (95% confidence intervals (CI): 91-97%) and that of colposcopy 98.5% (95% CI: 95-99%). The respective specificities were 30% (95% CI: 17-28%) and 35.6% (CI: 29-42%). HC2 test had comparable sensitivity, 90% (95% CI: 85-93%), but higher specificity, 54.3% (95% CI: 47-61%). Combining HC2 test with Pap increased specificity, 66.7% and 41.3% for ASCUS and LSIL cutoff, respectively. The minor-abnormality threshold together with HC2 increased specificity of colposcopy with no changes in sensitivity. High viral load (>100 relative light unit/positive control) was associated with significant disease. HPV DNA testing improves the accuracy of colposcopy in the detection of high-grade CIN in women with ASCUS or LSIL smears.     

Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia

A retrospective study of 227 patients presenting with abnormal cervical cytology was conducted to investigate the relationship between human papillomavirus (HPV) and progression of untreated cervical intraepithelial neoplasia (CIN) lesions. All patients had colposcopically directed biopsies for histologic diagnosis. The patients were followed cytologically and colposcopically for a mean of 19 months (range 6–42 months). Progression of a cervical lesion was defined as progression to a higher CIN grade confirmed histologically by directed biopsy. HPV DNA detection was done on material remaining from the cervical swabs by the general primer polymerase chain reaction (PCR) and type-specific PCR method, which made the detection of HPV types 6, 11, 16, 18, 31, 33 and not yet sequenced DNA types (X) possible. The presence of HPV DNA increased with the severity of the lesion ( P < 0.001). In CIN III, a 100% HPV DNA prevalence was found, with HPV type 16 being the most prevalent type in 75%. Progression was significantly related to the presence of HPV DNA, in particular HPV type 16. The percentage of progressive disease was 21% in the case of HPV DNA positive lesions ( n = 130) and 29% in the presence of HPV type 16, whereas HPV DNA negative lesions ( n = 97) showed no progression. The detection of HPV DNA and HPV genotype can be used to identify patients with high-risk cervical lesions, since the presence of HPV DNA and genotype 16 in particular are closely related to CIN progression.     

半乳糖凝集素-1在宫颈癌组织中的表达及其与高危型HPV感染的关系

目的探讨半乳糖凝集素-1(Galectin-1,Gal-1)在宫颈癌的发生、发展中作用及与高危型HPV的关系。方法免疫组织化学法检测柳州市人民医院2007年2月至2009年2月54例宫颈癌、35例宫颈上皮内瘤样病变(CIN)和20例宫颈正常组织中Gal-1蛋白的表达;并用HC-Ⅱ法检测高危型人乳头状瘤病毒(HR-HPV)感染情况。结果 Gal-1在正常宫颈、CINⅠ～Ⅱ、CIN Ⅲ和宫颈癌组织中的阳性表达率分别为5.0%、15.0%、53.3%、48.1%;晚期宫颈癌组织中Gal-1的表达率(83.1%)明显高于早期宫颈癌中的表达率(34.2%)。宫颈癌中Gal-1阳性表达与淋巴结转移(P<0.05)、肿瘤低分化(P<0.05)、临床分期(P<0.01)和HR-HPV的感染(P<0.05)有关,但与宫颈癌组织学类型无关。结论 Gal-1可能在宫颈癌的发生、发展中起着重要作用,HR-HPV可能通过诱导宫颈上皮高表达Gal-1而促使宫颈癌发生发展。     

The relationship between human papillomavirus infection and cervical intraepithelial neoplasia in Turkish women

To compare the prevalence of cervical human papillomavirus (HPV) infection in Turkish women with normal Papanicolaou (Pap) smear and cervical intraepithelial neoplasia (CIN). In between March 2002 and November 2005, the study was designed as case-control study. Cytologic abnormalities in Pap smears were classified according to the Bethesda System (2001). Identification of the presence of HPV was carried out by the Hybrid Capture II test for all patients. To compare the groups, Chi-square test was used. A total of 1353 reproductive aged women were screened. Of them, 1344 (99.3%) had normal or class I Pap smear. Remaining nine cases (0.7%) had CIN at several degrees (five CIN I, three CIN II, and one carcinoma in situ). While all these nine cases with cervical pathologies had HPV, only 20 cases from the other group (1.5%) had HPV (chi(2) 466.1; P = 0.0001). This is the first study of the evaluation of the association between HPV and preinvasive cervical lesions in Turkish population. In spite of low general frequency (2.1%) of cervical HPV colonization in this population, a strong correlation was found between HPV and CIN.     

Prophylactic human papillomavirus vaccines: the beginning of the end of cervical cancer

Persistent infection with one of the oncogenic human papillomavirus (HPV) types is a necessity for the development of cervical cancer. By HPV vaccination, cervical cancer could become a very rare disease. Two types of HPV vaccines can be distinguished: (i) therapeutic vaccines which induce cellular immunity targeted against epithelial cells infected with HPV and (ii) prophylactic vaccines inducing virus-neutralizing antibodies protecting against new but not against established infections. At present, several vaccines have been developed and tested in clinical trials. The vaccines are generally well tolerated and highly immunogenic. The current clinical data indicate that prophylactic vaccines are very effective against new persistent infections and the development of cervical intraepithelial lesions. The protection is type specific. However, the follow-up of the vaccination trials is still short. The effect of HPV vaccines on future cancer incidence will only be known after decades of follow-up. This article will address the status of recently terminated phase II and currently running phase III trials with prophylactic HPV vaccines.     

Is human papillomavirus testing an effective triage method for detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia?

OBJECTIVE: Our purpose was to assess the usefulness of the polymerase chain reaction assay for detection of human papillomavirus infection for prognostic value in the triage strategies for high-grade (grade 2 or 3) cervical intraepithelial neoplasia in women referred for colposcopy after abnormal Papanicolaou smears. STUDY DESIGN: A total of 1007 women referred to a colposcopic clinic providing care for an indigent population were studied. Four hundred fifty-four women were referred after two Papanicolaou smears reported as atypical squamous cells of undetermined significance or low grade-squamous cervical intraepithelial lesion, and 553 were referred after a single smear reported as high-grade squamous intraepithelial lesion. All women had a cervical smear, colposcopy-directed biopsy, and endocervical curettage performed. A sample for human papillomavirus deoxyribonucleic acid detection by polymerase chain reaction was obtained. RESULTS: High-risk human papillomavirus types were detected in 463 (46%) of 1007 women studied. There was a significant increase of the frequency of high-risk human papillomavirus by the increasing severity of biopsy findings ranging from 32.7% in women without cervical intraepithelial neoplasia on biopsy to 60% in women having grade 2 or 3 on the biopsy specimen. Women having a negative Papanicolaou smear found to have high-risk human papillomavirus deoxyribonucleic acid at the time of colposcopy had a significantly higher rate of grade 2 or 3 cervical intraepithelial neoplasia on the biopsy specimen than did women without high-risk human papillomavirus. There was no such difference observed in women with a cytologic finding of low- or high-grade squamous intraepithelial lesions at the time of colposcopy. The polymerase chain reaction assay appears to be more sensitive than the commercial human papillomavirus profile test. The positive predictive value for grade 2 or 3 cervical intraepithelial neoplasia of both tests was similar (21.7% and 22.8%, respectively). CONCLUSION: The human papillomavirus is associated with high-grade cervical intraepithelial neoplasia, but the screening for human papillomavirus deoxyribonucleic acid does not have prognostic value in women reported as having atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions on two precolposcopy Papanicolaou smears. (Am J Obstet Gynecol 1998;178:1235-44.)