人乳头瘤病毒类型与宫颈鳞状上皮内病变克隆状态之间的关联。

Association between human papillomavirus type and clonal status of cervical squamous intraepithelial lesions.

作者信息

Park T W, Richart R M, Sun X W, Wright T C

机构信息

Department of Pathology, College of Physicians and Surgeons of Columbia University, New York 10032, USA.

出版信息

J Natl Cancer Inst. 1996 Mar 20;88(6):355-8. doi: 10.1093/jnci/88.6.355.

DOI:10.1093/jnci/88.6.355

PMID:8609644

Abstract

BACKGROUND

Lesions that are histologically classified as precursors of cervical cancer, which are often referred to as squamous intraepithelial lesions (SILs), represent a heterogeneous clinical entity that can be associated with many different types of human papillomaviruses (HPVs) and have a variable biologic behavior. Approximately one half of low-grade SILs behave as non-neoplastic, productive viral lesions that frequently regress spontaneously, whereas the other half behave as neoplasms and either persist or progress to a histologically higher grade lesion. Identification of biomarkers that reliably differentiate those low-grade SILs with the properties of a non-neoplastic viral infection from those with the properties of neoplasia would provide a more rational basis for decisions about disease management. Since monoclonality is a hallmark of neoplasia irrespective or organ site, clonal status might represent one such biomarker.

PURPOSE

To better understand the pathobiology of SILs, we analyzed the clonality of low-grade and high-grade SILs and compared their clonal status with their associated HPV types.

METHODS

One hundred forty formalin-fixed, paraffin-embedded cervical biospy and loop electrosurgical specimens, originally diagnosed as SILs, were obtained from the pathology archives of both the Columbia-Presbyterian Medical Center and Kyto Diagnostics in New York. Clonality was determined with the use of a polymerase chain reaction (PCR) based method that detects nonrandom X-chromosome inactivation. This PCR-method amplifies a polymorphic region of the androgen receptor gene that is flanked by several differentially methylated enzyme sites. The same tissue was also analyzed for HPV DNA with the use of PCR and both L1 and E6 "consensus" primers.

RESULTS

All 25 evaluable cases of high-grade SILs were determined to be monoclonal. Although 54 (68%) of 79 evaluable low-grade SILs were monoclonal, 25 (32%) of 79 low-grade SILs were polyclonal. A strong association was observed between HPV type and clonal status, with a total of 71 (47 low-grade and 24 high-grade) SILs determined to be monoclonal and containing HPV types 16, 18, 31, 33, 35, 39, 45, 56, 58, or 65. In contrast, 22 (92%) of the 24 low-grade SILs that contained another type of HPV were polyclonal (Fisher's exact test, two-sided, P</-.001).

CONCLUSIONS

Our findings suggest that the histopathologic entity termed low-grade SIL consists of two different types of lesions that are biologically distinct. One lesion is monoclonal and is associated with HPV types 16, 18, 31, 33, 35, 39, 45, 56, 58, or 65. The second types of low-grade SIL is polyclonal and is associated with other types of HPV.

摘要

背景

组织学上被归类为宫颈癌前病变的病变，通常被称为鳞状上皮内病变（SILs），是一种异质性临床实体，可与多种不同类型的人乳头瘤病毒（HPV）相关，且具有可变的生物学行为。大约一半的低级别SILs表现为非肿瘤性、有病毒复制的病变，常可自发消退，而另一半则表现为肿瘤，要么持续存在，要么进展为组织学上更高等级的病变。识别能够可靠区分具有非肿瘤性病毒感染特征的低级别SILs与具有肿瘤特征的低级别SILs的生物标志物，将为疾病管理决策提供更合理的依据。由于单克隆性是肿瘤形成的标志，与器官部位无关，克隆状态可能就是这样一种生物标志物。

目的

为了更好地理解SILs的病理生物学，我们分析了低级别和高级别SILs的克隆性，并将它们的克隆状态与其相关的HPV类型进行比较。

方法

从纽约哥伦比亚长老会医学中心和京都诊断公司的病理档案中获取了140份经福尔马林固定、石蜡包埋的宫颈活检和环形电切标本，这些标本最初被诊断为SILs。使用基于聚合酶链反应（PCR）的方法检测非随机X染色体失活来确定克隆性。这种PCR方法扩增雄激素受体基因的一个多态性区域，该区域两侧有几个差异甲基化酶位点。同时使用PCR以及L1和E6“共识”引物对同一组织进行HPV DNA分析。

结果

所有25例可评估的高级别SILs均被确定为单克隆性。虽然79例可评估的低级别SILs中有54例（68%）为单克隆性，但79例低级别SILs中有25例（32%）为多克隆性。观察到HPV类型与克隆状态之间存在强关联，共有71例（47例低级别和24例高级别）SILs被确定为单克隆性且含有HPV 16、18、31、33、35、39、45、56、58或65型。相比之下，24例含有其他类型HPV的低级别SILs中有22例（92%）为多克隆性（Fisher精确检验，双侧，P<0.001）。