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宫颈癌(cervical cancer, CC)是女性中最常见的癌症之一[1],全球诊断出527 600例新的CC病例,仅2012年就有265 700例CC相关死亡[2]。CC在15~44岁的女性中普遍存在,是第8位最常见的女性癌症[3]。在全球范围内,中国占新CC病例的11.9%,每年死亡率为11.1%[4]。流行病学评估在无干预的情况下,中国新发CC的发生率可能会从2010年到2050年增加40%~50%[5]。
人乳头瘤病毒(human papillomavirus, HPV)属于高度异质性的DNA病毒,可引起皮肤和黏膜上皮内细胞内瘤变。大约40种HPV基因型感染生殖道黏膜,这已被证明是宫颈鳞状上皮内瘤变(CIN)和CC的主要原因[6]。HPV可根据其与癌前病变的关联性分为高危型(high-risk, HR)和低危型(low-risk, LR),有报道指出HPV高危亚型的持续性或反复性感染是CC及其癌前病变进展的重要危险因素[7]。目前共18种HPV亚型(包括-16, -18, -26, -31, -33, -35, -39, -45, -51, -52, -53, -56, -58, -59, -66, -68, -73和-82等)被归类为能促进宫颈病进展为CC的高危亚型[7]。生殖道高危型HPV感染情况由于地域、气候条件和种族的差别等因素的影响,HPV亚型的分布在全球范围内具有差异性。一项覆盖五大洲数百万病例的研究[8]表明,HPV-16是世界上最流行和致癌的基因型,其次是HPV-18。然而,在巴西排名第二的是HPV-31和HPV-33,在非洲排名第二的是HPV-52[8-9],以上表明在某些地区非HPV-16/18亚型的重要性。有研究[11-13]表明CIN病人中最常见的三种HR HPV亚型是HPV-52、HPV-16和HPV-58[10]。
在我国,HPV的基因型分布也存在地理上的差异[14-19]。因此,为了有效使用HPV疫苗以及优化CC预防策略,HR HPV亚型在特定区域分布以及相关宫颈癌前病变(CPLs)与CC病人中流行特征有必要进行深入的了解。本研究中对安徽北部地区HPV感染女性病人中高危亚型的流行及其CPLs与CC分布特征进行分析,旨在为该地区有效接种HPV疫苗预防CC提供参考依据。
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本研究中6 382例样本基因分型检测显示HR HPV感染率为13.16%(840/6 382)。HR HPV亚型感染包括高危单一型(530, 8.30%),高危混合型(122, 1.91%)以及高低危混合型(188, 2.95%)。
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HR HPV 15种亚型均被检出,所有高危亚型总频数为1 114,亚型的前5名依次为HPV-52(17.70%, 197/1 114)、HPV-16(14.54%, 162/1 114)、HPV-58(10.30%, 115/1 114)、HPV-51(7.00%, 78/1 114)、HPV-56(6.55%, 73/1 114)。HPV单一感染中高危亚型总频数为530,主要亚型依次为HPV-16(9.00%, 100/1 114)、HPV-52(8.20%, 91/1 114)、HPV-58(5.50%, 61/ 1 114)、HPV-39和HPV-51(3.14%, 35/1 114)以及HPV-68(3.10%, 34/1 114)等;HPV高危多重感染中高危亚型总频数为584,主要亚型依次为HPV-52(9.51%, 100/1 114)、HPV-16(5.57%, 62/1 114)、HPV-58和HPV-53(4.84%, 54/1 114)、HPV-51(3.86%, 43/1 114)以及HPV-56(3.77%, 42/1 114)等。
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不同年龄段女性病人人群HR HPV感染阳性占比以41~50岁年龄段为最高(38.30%),其次是51~60岁(24.40%),31~40岁(20.10%),≥61岁(9.10%),≤30岁(8.10%)。HR HPV感染病人的阳性占比随着年龄的增长而增大,在41~50岁年龄段达到最高,随后呈下降趋势,各年龄组感染差异无统计学意义(χ2=7.53,P>0.05);同时,41~50岁也是HR HPV亚型频数分布最多的年龄段(36.00%),其次是51~60岁(24.10%),31~40岁(19.74%),≥61岁(11.58%),≤30岁(8.61%)。其中主要的亚型依次是HPV-52(18.20%,106/584)、HPV-16(10.60%, 62/584)和HPV-58(9.20%, 54/584)。此外,HR HPV感染病人中宫颈病变的分布也主要集中在41~50岁(42.09%, 63/147),其次是51~60岁(27.20%, 40/147),31~40岁(17.00%, 25/147),≥61岁(11.60%, 17/147),≤30岁(1.40%, 2/147)。LSIL与HSIL分布随年龄段增大而增加,在41~50岁达到最高,随后降低;而CC分布则在41~50岁和51~60岁年龄段达到最高,随后呈下降趋势。
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840例HR HPV感染中病理诊断包括正常组693例,LISL组73例,HSIL组40例及CC组34例。HR HPV单一感染中正常组421例,LISL组52例,HSIL组28例及CC组29例,而多重感染中正常组272例,LISL组21例,HSIL组12例及CC组5例,HR HPV单一感染与多重感染在CPLs及CC分布上差异具有统计学意义(χ2=11.73,P < 0.01)。随着宫颈病变等级的增加,HPV感染阳性占比均逐渐降低。同样,随着宫颈病变程度的加重,HR HPV感染的阳性占比也基本呈现降低的趋势。此外,147例宫颈病变病人HR HPV亚型频数分布为:LSIL组分布有16种高危亚型,出现频率较高的亚型依次为HPV-16、HPV-52、HPV-58和HPV-56等;其中HSIL组分布有11种高危亚型,主要亚型依次为HPV-16、HPV-33、HPV-58以及HPV-52等;CC组分布有11种高危亚型,主要亚型依次为HPV-16、HPV-58、HPV-18和HPV-68、HPV-39等(见表 1)。
亚型 正常组 LSIL组 HSIL组 CC组 总计 阳性率/% HPV-16 109 18 18 17 162 32.7 HPV-18 38 2 3 4 47 19.1 HPV-31 39 5 3 1 48 18.8 HPV-33 35 5 7 2 49 28.6 HPV-35 23 3 0 2 28 17.9 HPV-39 58 4 1 3 66 12.1 HPV-51 74 3 1 0 78 5.1 HPV-52 172 19 4 2 197 12.6 HPV-56 61 10 1 1 73 16.4 HPV-58 95 10 6 4 115 17.4 HPV-59 33 3 0 0 36 8.3 HPV-68 54 1 1 4 60 10.0 HPV-82 19 1 3 0 23 17.4 HPV-26 5 2 0 0 7 28.6 HPV-53 59 4 2 0 65 9.2 HPV-66 43 3 1 2 49 12.2 表 1 HR HPV感染亚型中LSIL、HSIL及CC的分布
高危型HPV感染亚型分布及其与宫颈病变和宫颈癌的关系
Distribution of high-risk HPV infection subtypes and its correlation with cervical lesions and cervical cancer
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摘要:
目的分析高危型人乳头瘤病毒(HR HPV)感染亚型流行特征及其与宫颈癌前病变(CPLs)和宫颈癌(CC)的关系, 为该地区有效使用HPV疫苗以及优化CC预防策略提供理论依据。 方法收集女性病人(19~90岁)6 382例宫颈脱落细胞标本, HPV基因亚型采用PCR-反向点杂交法进行HPV基因亚型检测, 宫颈刮片通过细胞病理学和阴道镜检查指导的活组织进行检查。统计分析HR HPV感染型别, 不同年龄组的HR HPV亚型、CPLs和CC的分布以及HR HPV不同亚型与CPLs和CC的关系。 结果HR HPV感染率为13.16%(840/6 382), 其中高危单一型530例(8.30%), 高危混合型122例(1.91%)以及高低危混合型188例(2.95%)。HR HPV主要基因型为HPV-52、HPV-16、HPV-58。HR HPV感染、CPLs及CC的分布均集中于41~50岁年龄段。此外, 低度鳞状上皮内病变与高度鳞状上皮内病变的分布集中于41~50岁年龄段, 而CC的主要分布于41~60岁年龄段。HR HPV单一感染与多重感染在CPLs及CC分布上差异具有统计学意义(P < 0.05)。HPV-16、HPV-52和HPV-58是在CPLs及CC中主要基因型。 结论安徽北部地区HR-HPV的感染流行亚型主要是HPV-52、HPV-16和HPV-58, 41~50岁以及41~60岁年龄组女性分别是CPLs、CC发生的高危人群。HR HPV单一亚型(尤其HPV16单一亚型)感染是导致CPLs和CC的主要基因型。 Abstract:ObjectiveTo investigate the epidemiological characteristics of high-risk HPV infection and the correlation of high-risk human papillomavirus(HPV) and cervical precancerous lesions(CPLs) and cervical cancer(CC), for providing theoretical basis for effective using HPV vaccine and the prevention of CC in this area. MethodsA total of 6 382 cervical exfoliated cells were collected from female patients(19-90 years old) in Huaibei Miners General Hospital.HPV genotypes were detected by PCR-reverse dot blot hybridization.The cervical smears were examined by cytopathology and biopsy guided by colposcopy.SPSS19.0 software was used to analyze the distribution of HR HPV genotypes, CPLs and CC in different age groups, and the relationship between different types of HR HPV and CPLs and CC. ResultsThe HR HPV positive rate was 13.16%(840/6 382), containing high-risk single type(530, 8.30%), high-risk mixed type(122, 1.91%) and high-low-risk mixed type(188, 2.95%).The main genotypes of HR HPV were HPV-52, -16, and -58.The distribution of HR HPV infection, CPLs and CC were concentrated in the 41-50 age group.In addition, the distribution of LSIL and HSIL was also concentrated in the 41-50 age group, while CC was mainly distributed in the 41-60 age group.There was a statistically significant difference among the distribution of CPL and CC between HR HPV single infection and multiple infections(P < 0.05).HPV-16, -52 and -58 were the prominent types. ConclusionsThe prevalence of HR HPV infections is mainly HPV-52, -16 and -58 in northern Anhui province.The 41-50 years old and 41-60 years old women are high-risk groups of CPLs and CC, respectively.HR HPV single subtype(especially HPV16 single subtype) infection is the major genotype that leads to CPLs and CC. -
Key words:
- cervical neoplasms /
- high-risk human papillomavirus /
- genotype /
- cervical lesions
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表 1 HR HPV感染亚型中LSIL、HSIL及CC的分布
亚型 正常组 LSIL组 HSIL组 CC组 总计 阳性率/% HPV-16 109 18 18 17 162 32.7 HPV-18 38 2 3 4 47 19.1 HPV-31 39 5 3 1 48 18.8 HPV-33 35 5 7 2 49 28.6 HPV-35 23 3 0 2 28 17.9 HPV-39 58 4 1 3 66 12.1 HPV-51 74 3 1 0 78 5.1 HPV-52 172 19 4 2 197 12.6 HPV-56 61 10 1 1 73 16.4 HPV-58 95 10 6 4 115 17.4 HPV-59 33 3 0 0 36 8.3 HPV-68 54 1 1 4 60 10.0 HPV-82 19 1 3 0 23 17.4 HPV-26 5 2 0 0 7 28.6 HPV-53 59 4 2 0 65 9.2 HPV-66 43 3 1 2 49 12.2 -
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