宫颈上皮内瘤变与人类乳头瘤病毒不同亚型感染的关系

目的:探讨宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)与人类乳头瘤病毒(human papillomavirus,HPV)不同亚型感染之间的关系。方法:采用PCR-反向斑点杂交(PCR-reverse dot blot,PCR-RDB)基因芯片技术分别检测100例宫颈组织活检标本以及其中70例配对细胞刷检标本的HPV感染情况。结果:100例宫颈组织活检标本的HPV总检出率为82%,检出HPV亚型15种。高危型HPV检出HPV-16(37%)、HPV-58(11%)、HPV-33(11%)和HPV-52(7%);高危型HPV检出率自鳞化增生(16.67%)、CINⅠ(57.14%)、CINⅡ(68.18%)、CINⅢ(75.68%)至ICC(85.71%)呈明显增加趋势(P<0.05)。HPV-16在CINⅠ与CINⅡ和CINⅢ组中的检出率均有明显差异(P<0.05)。70例宫颈细胞刷检标本的HPV检出率为64.28%,组织活检标本HPV检出率为80.00%;HPV亚型检测完全一致率不够理想(kappa<0.40)。结论:高危型HPV特别是HPV-16感染与宫颈病变程度明显相关,低危型HPV感染的宫颈病变中常伴有高危型HPV感染,宫颈组织活检标本的HPV检出率高于细胞刷检标本。     

HPV基因亚型分布及其与CIN的相关性研究

[目的]探讨健康体检妇女HPV基因亚型分布状况,及HPV感染后宫颈上皮内瘤变的发生情况。[方法]2012年5月至2013年10月于深圳市妇幼保健院行健康体检HPV分型检测阳性的妇女,所有研究对象均进行宫颈HPV分型检测、阴道镜检查及宫颈组织活检。[结果]本研究共纳入妇女2578例,年龄18~70岁,病理结果为正常或炎症者1983例,CINⅠ为278例,CINⅡ/Ⅲ为308例,宫颈浸润癌9例。HPV基因亚型构成前5位高危型HPV为HPV52、43、16、58、56;CINⅠ中HPV基因亚型构成前5位依次为HPV52、16、58、56、43,CINⅡ/Ⅲ中HPV基因亚型构成前5位依次为HPV16、58、52、33、18;随着感染HPV亚型增多,CIN构成比升高,差异具有统计学意义（P〈0.01）;高度宫颈上皮内病变（CINⅡ/Ⅲ）以25~44岁年龄段相对多见。[结论]深圳市妇幼保健院健康体检妇女HPV基因亚型分布与其他地域存在差异。不同程度宫颈癌前病变HPV亚型分布可能存在差异,而HPV16、52、58在宫颈病变中均占有重要地位;HPV多重感染者,CIN风险明显增加;25~44岁有性生活妇女应为宫颈癌筛查的侧重点人群。     

318例高级别宫颈上皮内瘤变及宫颈癌患者的TCT和hrHPV检测分析

  目的  探讨如何使用现有的筛查方法, 减少高级别宫颈上皮内瘤变(cervical intraepithelial neoplasia grade 2 or 3, CIN2/3)及宫颈癌的漏诊。  方法  回顾性分析2014年6月至2018年8月318例中国医科大学附属航空总医院治疗的CIN2/3及宫颈癌患者的临床资料, 其中CIN2/3为296例、宫颈癌为22例, 采用宫颈液基薄层细胞学检查(thinprep cytology test, TCT)及高危型人乳头瘤病毒(high risk human papilloma virus, hrHPV)检测方法, 分析患者的年龄、TCT和hrHPV。  结果  296例CIN2/3患者中30~39岁患者为130例(43.92%)、占第1位, 20~29岁年轻患者为69例(23.31%)、占第3位。318例患者中TCT阳性为199例(62.58%), hrHPV阳性为308例(96.86%), 两者联合筛查阳性为313例, 阳性率为98.43%(313/318)。hrHPV分型检测主要亚型依次为16、52、58、33、18、31型。  结论  CIN2/3及宫颈癌的发病年龄年轻化, 年轻患者筛查不容忽视。TCT单独筛查较hrHPV单独筛查易漏诊高级别病变, TCT联合hrHPV筛查可提高检出率。TCT阴性, hrHPV非16、18亚型的其他hrHPV阳性, 尤其是hrHPV52、58、33、31亚型阳性患者也建议行阴道镜检查。      

HPV16/18 DNA分型对宫颈细胞学ASC-US女性的风险分层管理作用研究

摘 要：［目的］ 评估HPV16/18 DNA分型检测对宫颈未明确意义的非典型鳞状细胞（atypical squamous cells of undetermined significance,ASC-US）女性癌前病变风险预测的分层作用。［方法］ 在山西省宫颈癌筛查方法研究Ⅰ队列基础上开展,该队列所有随访对象均接受了hrHPV DNA检测（hybird capture 2,HC2）、液基细胞学检查和醋酸染色肉眼观察,任一结果阳性者转诊阴道镜,必要时取活检;同时对HC2阳性者进行HPV型别检测（LiPA）。以2005年和2014年随访时检出416例ASC-US女性为研究对象计算hrHPV DNA阴性组、hrHPV DNA阳性组、HPV16/18阳性组和其他hrHPV型别阳性组的中度及以上宫颈上皮内瘤样病变（cervical intraepithelial neoplasia grade 2 or worse,CIN2+）检出率,以及HPV16/18筛查CIN2+的临床效果。以2005年随访发现的253例ASC-US为研究对象,计算以上各组的5年CIN2+累计发病风险和相对危险度。［结果］ ASC-US且hrHPV阳性者中HPV16/18阳性占27.4%,其CIN2+检出率（9.7%）高于其他hrHPV型别阳性者（3.8%）,但差异无统计学意义(OR= 2.7,95%CI：0.4~17.3）,hrHPV阴性者中无CIN2+检出。基线hrHPV阴性组CIN2+ 5年累积发病风险为1.9%,与之相比,其他hrHPV型别阳性组、hrHPV阳性组、HPV16/18阳性组的5年发病风险逐渐增加,分别为5.3%(RR=2.7,95%CI：0.3~23.0）、8.5%(RR=4.5,95%CI：1.1~17.8）和11.8%(RR=6.2,95%CI：1.1~33.9）。与hrHPV DNA检测相比,HPV 16/18检测筛查CIN2+的灵敏度下降,特异度升高［相对灵敏度0.6（95%CI：0.3~1.2）,相对特异度1.3（95%CI：1.2~1.4）］。［结论］ 在ASC-US人群中利用HPV16/18分型检测筛查CIN2+,在获得较高特异度的同时会损失灵敏度;HPV16/18能有效区分ASC-US且hrHPV阳性人群的即时和长期发病风险,可用于ASC-US人群的临床分流管理。     

九价HPV疫苗所针对的高危型HPV亚型在宫颈癌及其癌前病变中应用有效性的初步预测

背景与目的：宫颈癌是世界范围内女性第4常见的恶性肿瘤,在我国其发病率和死亡率都呈上升趋势,高危型人乳头状瘤病毒(high-risk human papillomavirus,hrHPV)持续感染与浸润宫颈癌(invasive cervical carcinoma,ICC)及其癌前病变的发生、发展关系密切,HPV预防性疫苗的研制应用成为宫颈癌一级预防的有效措施。该研究拟通过分析九价HPV疫苗所针对的7种HPV高危亚型(HPV16、18、31、33、45、52和58)在经组织学证实的宫颈癌及癌前病变中的分布,为九价疫苗在本地区人群的应用前景评估提供更多依据。方法：回顾性收集复旦大学附属肿瘤医院病理科行聚合酶链反应-反向点杂交法(polymerase chain reaction-reverse dot blot,PCR-RDB)进行HPV基因分型检测的患者,经计算HPV阳性患者中特定HPV亚型的阳性比例来评价HPV亚型对宫颈癌及其癌前病变的相对贡献。采用比例权重归因(proportional weighting attribution,PWA)方法将多重感染中亚型占比折算至相应的单型别感染。结果：符合入组条件者共计624例,分别为117例未见上皮内病变及恶性病变(negative for intraepithelial lesion or malignancy,NILM),45例低级别鳞状上皮内病变(low-grade squamous intraepithelial lesion,LSIL),268例高级别鳞状上皮内病变(high-grade squamous intraepithelial lesion,HSIL)和194例ICC。HPV总感染率为84.29%(526/624),在LSIL、HSIL及ICC组中的感染率分别为71.11%,95.90%及91.75%。HPV16/18 PWA合计占比在LSIL、HSIL和ICC组中依次上升,分别为50.00%、70.44%和91.71%。九价疫苗针对的7种hrHPV的PWA合计占比均较HPV16/18提高,在LSIL、HSIL和ICC中分别为86.34%,98.61%和94.89%。额外增加的5种hrHPV(HPV31、33、45、52和58)的相对贡献在LSIL、HSIL和ICC组中依次下降,分别为36.34%、28.17%和3.18%。结论：九价疫苗额外增加的5种hrHPV型别在本地区有望令更高比例的ICC及癌前病变得到预防,尤其对于LSIL和HSIL的预防有较大改善。     

高危型 HPV 载量与分型检测对宫颈高级别病变预测价值的前瞻性队列研究*

目的:评价高危型人乳头瘤病毒（highriskhumanpapillomavirus,hrHPV ）载量和分型检测在中国农村地区妇女人群中预测宫颈鳞状上皮高级别病变发生的价值。方法:2012年5 月至2015年5 月以农村妇女人群为基础选取江西省兴国县、靖安县和玉山县2 257 例,年龄35～64岁纳入本前瞻性队列研究。同时采用HC- 2（hybridcapture-2）和导流杂交技术（HybriMax ）两种方法分别检测hrHPV 载量和亚型,两种方法中任一亚型阳性者行阴道镜及活检检查,并将HC- 2 检测阳性结果中病毒载量< 10.0 RLU/CO认定为低病毒载量,病毒载量≥ 10.0 RLU/CO为高病毒载量。对hrHPV 结果阴性或病理诊断为CIN 1 的2 211 例妇女行24个月无干预随访。根据随访分别评价hrHPV 载量和HybriMax 分型两种检测方法预测宫颈鳞状上皮高级别病变（CINgrade2 orworse,CIN 2 +）的效果。结果:纳入基线、随访数据完整的女性共1 636 例。2 年内采用HC- 2 检测的132 例基线高病毒载量妇女中CIN 2 +的发生率为3.03%（4/ 132）,其相对危险度（RR）值为42.24（95%CI 为4.76～375.2）;采用HybriMax 分型检测的159 例基线分型HPV 16或18型阳性妇女中CIN 2 + 的发生率为2.51%（4/ 159）,RR值为33.06（95%CI 为3.72～293.9）。 对2 年内HC- 2 检测中高病毒载量例数和HybriMax 分型检测中HPV 16/ 18型别阳性例数进行比较,CIN 2 + 的发病率差异无统计学意义（P > 0.05）。 结论:HPV高载量和HPV 16/ 18型别阳性妇女人群进展为CIN 2 + 的风险均较高。在不具有持续监测hrHPV 条件的农村地区,HC- 2 检测的病毒载量≥ 10.0 RLU/CO阈值设定,与HybriMax 分型检测HPV 16/ 18型别均对hrHPV 初筛有分流作用,并对CIN 2+ 发生有预测作用。      

粤东地区妇女 人乳头瘤病毒感染 情况和亚型分布 及其与宫颈癌的关系

目的：检测粤东地区妇女人乳头瘤病毒（HPV）感染情况及亚型分布,探讨其与宫颈癌的关系。方法：选取2015年10月-2016年9月粤东地区7家三级医院30 000例行宫颈筛查的妇女作为研究对象。收集所有对象宫颈脱落细胞,采用HybriMax方法对HPV感染情况进行检测。对8 739例宫颈病变患者进行宫颈组织活检与HPV分型。比较分析不同病变类型以及年龄段HPV感染率与亚型分布。结果：脱落细胞检查个体中,HPV阳性者9 000例,感染率为30.00%。在8 739例行宫颈活检的宫颈病变患者中,HPV感染率为58.29%（5 094/8 739）,慢性宫颈炎中HPV感染率为40.00%（1 088/2 720）,CINⅠ中为53.59%（1 396/2 605）,CINⅡ/Ⅲ中为71.61%（1 647/2 300）,宫颈癌中为86.45%（963/1 114）。在各种宫颈病变中,HPV 16、18、33、58、52是最常见的高危亚型,感染率依次是14.02%、6.28%、5.23%、4.46%、3.71%。在宫颈癌患者中,最常见的亚型是HPV 16; ≥ 60岁的人群中HPV感染率最高,达到49.92%。结论：粤东地区HPV感染最常见的亚型为16、18、33、58、52型,宫颈病变程度越重,HPV的感染率越高。在宫颈癌患者中,HPV 16是最为常见的亚型,中老年患者的HPV感染率高于年轻人,单一感染可能更易导致宫颈癌的发生。     

高度鳞状上皮内病变患者宫颈细胞学检测结果及其人乳头状瘤病毒基因高危亚型分析

目的分析高度鳞状上皮内病变（HSIL）患者人乳头状瘤病毒（HPV）感染亚型的分布特点,探讨HPV分型检测在宫颈高度病变筛查中的作用。方法对137例患者进行HPV分型检测,并对HPV基因高危亚型进行分析,分析HPV亚型的检出情况,并比较HPV分型与病理结果。结果 31～40岁组和41～50岁组的阳性率分别为92.2%和89.6%,均高于≤30岁组（73.3%）和≥51岁组（82.6%,P〈0.05）;单型感染者62例,多重感染者58例,差异无统计学意义（P〉0.05）。HPV各类型中,以16及58型感染为多,其次是52、33和18型。单型感染和多重感染均主要以16、58和52型感染为主。高危型阳性的检出率为3.3%（4/120）,高于高危型阴性中宫颈癌的检出率（0,P〈0.05）;高危型阳性炎症、疣症及疣、CINⅠ、CINⅡ和CINⅢ的检出率分别为25.0%（30/120）、28.3%（34/120）、25.0%（30/120）和18.3%（22/120）,均高于高危型阴性的检出率（P〈0.05）。结论高危型HPV感染以16和58型感染为多,在宫颈病变进行高危型HPV检测对宫颈病变诊治和癌变预防起到指导性的作用。     

人乳头瘤病毒感染亚型与宫颈病变的关系

目的探讨HPV感染与宫颈病变发生的关系。方法将病理检查确诊宫颈有病变的187例患者分为3组:慢性炎症组(n=41)、宫颈上皮瘤变(CIN)组(n=62)和宫颈癌组(n=84)。采用人乳头瘤病毒核酸扩增分型技术对患者宫颈脱落细胞样本作HPV基因分型检测,分析HPV感染状况及HPV基因型在各组疾病中的分布。结果 1187例患者中共检出HPV阳性者136例,阳性率为72.72%(136/187),其中高危型HPV感染阳性率为95.58%(130/136)。在被测的21个HPV亚型中最常见的6个类型依次为16型(46.32%、63/136),58型(21.32%、29/136),52型(15.44%、21/136),18型(12.50%、17/136),33型(9.56%、13/136),31型(8.09%、11/136),未检测出44型、43型及6型。2慢性炎症组HPV阳性率为14.63%(6/41);CIN组HPV阳性率为85.48%(53/62)、其中CINⅠ组、CINⅡ组、CINⅢ组中HPV感染率分别为62.50%(10/16)、90.47%(19/21)、96.00%(24/25);宫颈癌组HPV阳性率91.67%(77/84)。CIN及宫颈癌组HPV阳性率均高于炎症组,而CINⅡ~CINⅢ组及宫颈癌组HPV阳性率又明显高于CINⅠ组。3组阳性表达率差异有统计学意义(P<0.05)。3HPV阳性者中单一感染率为67.65(92/136),多重感染率为32.35%(44/136),其中以双重感染为主,占79.55%(35/44)。4HPV感染患者年龄以30~59岁最高,但各年龄段HPV感染检出率比较无统计学差异(P>0.05)。5慢性炎症组、CIN组和宫颈癌组的16型感染率分别为16.67%(1/6)、47.16%(25/53)、48.05%(37/77)。CIN组和宫颈癌组的16型感染率高于慢性炎症组,差异具有统计学意义(P<0.05)。结论 HPV感染与宫颈病变发生、发展密切相关,HPV基因分型诊断对宫颈病变高危人群的筛查、预防、临床诊断、治疗可提供重要的理论依据。     

国产HPV杂交捕获技术在农村宫颈癌筛查中的应用

目的 人乳头瘤病毒(human papillomavirus,HPV)检测是国内外公认的宫颈癌筛查有效方式.近年来,我国研发了低成本、快速、简单的HPV检测方法,为HPV检测应用到人群筛查提供了希望.本研究分析国产HPV杂交捕获技术(hybrid capture 2,HC2)初筛不分流及DH2初筛HPV16/18分型检测分流检出宫颈癌前病变与宫颈癌的情况,评价此种检测技术应用于农村地区宫颈癌筛查的可行性.方法 按整群抽样的方法,对新密市7个乡镇35～64岁的农村妇女使用DH2检测进行宫颈癌筛查,阳性者召回做阴道镜,对镜下发现的可疑病变取活组织检查,病理诊断作为金标准,宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)≥2级(CIN2+)患者需手术治疗.对DH2阳性者同时进行HPV16/18分型检测,探索DH2初筛和HPV16/18分型检测分流策略对宫颈疾病的检出情况 .结果 DH2筛查阳性率为12.23％(1 512/12 358),其中≥50岁组HPV感染率和＜50岁组HPV感染率分别为13.40％(749/5 588)和11.27％(763/6 770),比值比(odds ratio,OR)=1.22(1.09～1.36),差异有统计学意义,x2=12.98,P＜0.001.共检出CIN2+ 87例(0.72％),CIN3+ 50例(0.41％),达到新密市近年最高水平.采用HPV16/18分型检测分流策略的阳性率为2.66％(319/11 981),检出CIN2+ 62例(0.52％),CIN3+ 37例(0.31％).HPV16/18分流检出CIN2+占总病例的73.81％(62/84),检出CIN3+占总病例的77.08％(37/48).结论 DH2检测对宫颈癌前病变及宫颈癌的检出率较高,可作为宫颈癌筛查方法使用.HPV16/18分流策略虽然可以降低阴道镜转诊率,但是会漏诊部分CIN2+患者,漏诊患者的基因型别有待进一步分析.     

Human papillomavirus types in 115,789 HPV-positive women: A meta-analysis from cervical infection to cancer

Genotyping may improve risk stratification of high-risk (HR) human papillomavirus (HPV)-positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta-analysis of cross-sectional HR HPV-type distribution in 115,789 HPV-positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low-grade squamous intraepithelial lesions (LSIL) and 6,616 high-grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR-based studies worldwide. No strong differences in HPV-type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20-28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios = 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios = 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV-positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV-based screening programs.     

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.     

Human papillomavirus infections among Japanese women: age-related prevalence and type-specific risk for cervical cancer

To obtain baseline data for human papillomavirus (HPV) screening and vaccination in Japan, we analyzed HPV DNA data from 2282 Japanese women (1517 normal cytology, 318 cervical intraepithelial neoplasia [CIN] grade 1, 307 CIN2–3, and 140 invasive cervical cancer [ICC]) that visited the University of Tsukuba Hospital or Ibaraki Seinan Medical Center Hospital for screening or treatment of cervical diseases between 1999 and 2007. An L1-based PCR method was used for individual HPV genotyping. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16 (40.5%), HPV18 (24.4%), HPV52 (8.4%), HPV58 (3.1%), and HPV33 (3.1%). Based on the comparison of HPV type distributions between normal cytology and CIN2–3 and ICC, estimated risk of disease progression varied considerably by genotype: HPV16, HPV18, HPV31, HPV33, HPV35, HPV52, and HPV58 (prevalence ratio, 1.92; 95% confidence interval 1.58–2.34); other oncogenic types (0.31, 95% confidence interval 0.19–0.50); and non-oncogenic types (0.09, 95% confidence interval 0.03–0.43). HPV16 and/or HPV18, including coinfections with other types, contributed to 67.1% of ICC and 36.2% of CIN2–3 among Japanese women. More importantly, the overall prevalence of HPV16 and/or HPV18 varied greatly according to the women's age: highest in women aged 20–29 years (ICC, 90.0%; CIN2–3, 53.9%), decreasing with age thereafter, and lowest in women aged 60 years or older (ICC, 56.3%; CIN2–3, 25.0%). In conclusion, type-specific HPV testing may help identify Japanese women at high risk of progression to CIN2–3 and cancer. In Japan, current HPV vaccines are estimated to provide approximately 70% protection against ICC and may be more useful in reducing the incidence of cervical cancer and precancer in young women of reproductive age. ( Cancer Sci 2009; 100: 1312–1316)     

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.     

Analysis of E6 variants of human papillomavirus type 33, 52 and 58 in Japanese women with cervical intraepithelial neoplasia/cervical cancer in relation to their oncogenic potential.

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC): 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs I/II than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P=0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific.     

人乳头状瘤病毒感染与宫颈病变的相关性分析？

目的：分析宫颈上皮内瘤变（ CIN）及宫颈癌（ CC）中人乳头状瘤病毒（ HPV）亚型,探讨HPV感染与宫颈病变的相关性。方法：慢性宫颈炎或液基细胞学异常的妇女检测21种HPV基因亚型和阴道镜下宫颈定位活检,分析2481例CC和CIN患者的HPV感染情况。结果：在2481例CIN和CC患者中,HPV感染率85．0%,HPV感染与宫颈组织学结果有较强的相关性（P〈0．001,Pearson列联系数=0．648）。 CC及CINⅢ、CINⅡ患者以HPV16、18感染最多见,其次见HPV58、33、31、52、45、59、68等亚型。304例患者宫颈感染HPV16、18、58、52、33等亚型后,发生高度鳞状上皮内病变（HSIL）、不明意义的非典型鳞状细胞（ASCUS）及低度鳞状上皮内病变（LSIL）的频率增加,TCT分型与HPV分型有较弱的相关关系（P=0．002,Pearson列联系数=0．322）。细胞学结果提示HSIL、AS-CUS,宫颈组织学诊断以CC、CINIII和CINII为多,TCT分型与组织学分型也有较弱的相关性（ P=0．026,Pearson列联系数=0．172）。结论：HPV16、18、58、33、52、31、45等高危型HPV感染是宫颈癌（ CC）及癌前病变（ CIN）最常见的风险因素。高危型HPV单独或混合感染宫颈后,细胞学检测HSIL、ASCUS及LSIL的发生率增加,细胞学结果与组织学分型的相关性促进了CC和CIN的及时诊治。     

Long‐term HPV type‐specific risks of high‐grade cervical intraepithelial lesions: A 14‐year follow‐up of a randomized primary HPV screening trial

Quantitative knowledge of the long‐term human papillomavirus (HPV) type‐specific risks for high‐grade cervical intraepithelial neoplasias Grades 2 and 3 (CIN2 and CIN3) is useful for estimating the effect of elimination of specific HPV types and clinical benefits of screening for specific HPV types. We estimated HPV type‐specific risks for CIN2 and CIN3 using a randomized primary HPV screening trial followed up for 14.6 years using comprehensive, nationwide registers. Poisson regression estimated cumulative incidences, population attributable proportions (PAR) and incidence rate ratios (IRRs) of high‐grade lesions by baseline HPV type, with censoring at date of first CIN2/3 or last registered cytology. Multivariate analysis adjusted for coinfections. IRRs were highest during the first screening round, but continued to be high throughout follow‐up (IRRs for CIN3 associated with high‐risk (HR) HPV positivity were 226.9, 49.3, 17.7 and 10.3 during the first, second and third screening round and for >9 years of follow‐up, respectively). Increased long‐term risks were found particularly for HPV Types 16, 18 and 31 and for CIN3+ risks. HPV16/18/31/33 had 14‐year cumulative incidences for CIN3+ above 28%, HPV35/45/52/58 had 14 year risks between 14% and 18% and HPV39/51/56/59/66/68 had risks <10%. HPV16 contributed to the greatest proportion of CIN2+ (first round PAR 36%), followed by Types 31, 52, 45 and 58 (7–11%). HPV16/18/31/33/45/52/58 together contributed 73.9% of CIN2+ lesions and all HR types contributed 86.9%. In summary, we found substantial differences in risks for CIN2 and CIN3 between different oncogenic HPV types. These differences may be relevant for both clinical management and design of preventive strategies.     

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.     

Human papillomavirus type specific risk of progression and remission during long‐term follow‐up of equivocal and low‐grade HPV‐positive cervical smears

The prevalence of clinically relevant HPV types and their specific risk for progression and regression in women with atypical squamous cells of uncertain significance (ASCUS) and low‐grade squamous intraepithelial lesions (LSIL) were studied in a routine screening population. A 4‐year cohort of women (n = 820) with ASCUS/LSIL and a positive HPV test in triage were followed for 6–9 years. The progression risks for CIN2+/CIN3+ were determined for single (71.2%) and multiple HPV infections (28.8%). The CIN2+ progression risk for all HPV 16, all HPV 35, single HPV 16 and single HPV 35 infections were 65.3% (95% CI: 59.6–71.0), 64.4% (95% CI: 50.4–78.4), 63.8% (95% CI: 56.2–71.4) and 73.7% (95% CI: 53.9–93.5), respectively. Based on CIN2+ progression risks four main groups were defined; the HPV 16 group, the HPV 31/33/35 group, the HPV 18/45/51/52 group and the HPV 39/56/58/59/66/68 group with progression risks of 65.3% (95% CI: 59.6–71.0), 62.1% (95% CI: 54.8–69.4), 52.6 (95% CI: 45.9–59.3) and 39.5 (95% CI: 33.0–46.0), respectively. In multivariate analyses, women in the age group 40–49 years had an increased risk of CIN2+ progression. As for CIN3+, HPV 16 had a higher progression risk than other HPV risk groups (p < 0.05). In multiple infections only HPV 16 had a significant additive CIN3+ progression risk (p < 0.05) as compared to other HPV risk groups. In summary, HPV types 16 and 35, including the HPV risk group 31/33/35, had a similar CIN2+ progression risk, but only HPV 16 had a higher risk for CIN3+ progression.