Arends M J, Buckley C H, Wells M
Department of Pathology, University of Edinburgh, Medical School, UK.
J Clin Pathol. 1998 Feb;51(2):96-103. doi: 10.1136/jcp.51.2.96.
Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs.
早期关于宫颈肿瘤的流行病学研究表明其与性活动存在因果关系，人乳头瘤病毒（HPV）已成为主要的性传播致癌嫌疑因子。HPV分为两大类：低风险型，与宫颈湿疣和CIN 1相关；高风险型（主要是16型和18型），在50% - 80%的CIN 2和CIN 3病变以及90%的癌症病例中被发现。这种与癌症的关联非常强烈，在方法合理的病例对照研究中，优势比大于15（通常更高）。一组不常被检测到的中等风险型HPV与各级CIN相关，偶尔也与癌症相关。在大量无症状对照中也检测到了HPV，这表明肿瘤发生还需要其他事件，如病毒持续存在和/或病毒基因表达改变，这通常发生在病毒基因组整合之后。这使得两个主要的病毒癌基因E6和E7直接与病毒增强子和启动子相连，从而在整合后能持续表达。高风险HPV的E7蛋白结合并使Rb蛋白失活，而E6蛋白结合p53并导致其快速降解。一系列假定的辅助因子与疾病进展有关：HLA类型、免疫抑制、性类固醇激素和吸烟；这些辅助因子大多似乎影响向CIN 3的进展。其自然病程包括10%的CIN 1病例和20%的CIN 2病例进展为CIN 3，而至少12%的CIN 3病例进展为浸润癌。宫颈腺上皮内瘤变（CGIN）常与鳞状CIN共存，高级别CGIN的癌前潜能毋庸置疑，但低级别CGIN的自然病程仍不确定。高比例的CGIN病变和腺癌HPV呈阳性，HPV18在腺性病变中比在鳞状病变中涉及更多。对于从宫颈刮片中获取的细胞进行HPV分型应用有充分的临床依据；然而，将HPV分型引入宫颈筛查项目需要进行严格的成本效益分析。预防性和治疗性HPV疫苗正在研发中。本文综述了宫颈肿瘤的病因、发病机制和病理学，重点强调了HPV的作用。
