宫颈上皮内瘤变的诊治进展：HPV感染与宫颈上皮内瘤变

宫颈上皮内瘤变（CIN）是与宫颈浸润癌密切相关的一组癌前病变,常可反映宫颈癌发生发展的连续过程。根据Richar的定义,CINⅠ相当于轻度不典型增生,CINⅡ相当于中度不典型增生,CINⅢ相当于重度不典型增生和原位癌。人乳头状瘤病毒（HPV）是宫颈鳞状上皮内病变或宫颈上皮内肿瘤和宫颈癌发病的重要因素。研究发现,99．7％以上的宫颈癌组织中可检测HPV,由高危型HPV感染引起的CIN易发生癌变。     

宫颈脱落细胞HPV E6/E7mRNA、HR-HPV DNA在宫颈病变筛查中的应用

目的 探讨HPV E6/E7 mRNA与高危型孔头瘤病毒（HR-HPV） DNA在宫颈病变筛查中的应用价值.方法 对301例宫颈病变疑似病例进行宫颈脱落细胞取样,分别检测慢性宫颈炎、宫颈癌前病变、宫颈鳞状细胞癌中HPV E6/E7 mRNA与HR-HPV DNA的表达,比较二者在不同年龄组及病变程度中表达的差异.结果 在宫颈癌前病变及宫颈鳞状细胞癌患者中HPV E6/E7 mRNA的特异性和阳性预测值高于HR-HPV DNA（P均＜0.05）,敏感性低于HR-HPV DNA（P ＜0.05）.30岁以下与30～39岁受检者中HPV E6/E7 mRNA的阳性率低于HR-HPV DNA（P均＜0.05）.CIN2、CIN3及宫颈癌患者HPV E6/E7 mRNA阳性率高于慢性宫颈炎患者,且CIN3者高于CIN2者（P均＜0.05）,CIN1、CIN2、CIN3及宫颈癌患者HR-HPV DNA阳性率高于慢性宫颈炎患者（P均＜0.05）.结论 对于宫颈癌及癌前病变,HPV E6/E7 mRNA的阳性率及其诊断的特异性高于HR-HPV DNA,可作为筛查和随访的指标.     

HPV DNA HCⅡ检测在宫颈病变筛查中的应用

目的探讨用第二代杂交捕获技术（HCⅡ）行HPV DNA检测在宫颈病变筛查中的价值。方法采用HCU对2153例宫颈疾病患者行宫颈脱落细胞HPV DNA检测。结果2153例受检者中701例（32．6％）检测出HPV DNA。其中宫颈癌患者检出率为93．9％,宫颈上皮内瘤变为54．6％,明显高于其他妇科良性疾患的31．5％,P均〈0．05。CIN Ⅰ、CINⅡ、CINⅢ宫颈病变中HPV检出率分别为29．9％、53．8％、80．2％,HPV检出率随着病变的严重程度增高而增高。结论HCⅡ技术检测HPV DNA是宫颈癌前病变筛查的重要手段。     

贵州地区宫颈上皮内瘤变和宫颈浸润癌患者HPV感染状态及其亚型分布

目的观察贵州地区宫颈上皮内瘤变（CIN）和宫颈浸润癌患者人乳头状瘤病毒（HPV）的感染状态及其亚型分布。方法采用导流杂交技术对30例CIN（CIN组）、33例宫颈浸润癌患者（宫颈癌组）、60例自愿接受宫颈HPV感染筛查的妇女（对照组）进行HPV分型检测,所有受检者均来自贵州地区。结果 CIN组HPV阳性13例（43.33%）,宫颈癌组19例（57.58%）,对照组5例（8.33%）。CIN组、宫颈癌组与对照组比较,P均〈0.01。CIN组共检出7种亚型HPV,均为高危型（HR-HPV）,无多型HPV感染（M-HPV）。其中HPV16 7例,HPV31、52各2例,HPV18、33、53、58各1例。宫颈癌组检出5种亚型,亦均为HR-HPV,M-HPV3例。其中HPV16 11例,HPV534例,HPV58 3例,HPV18、59各1例。对照组检出7种亚型,HR-HPV中的HPV16、18、31、39、53、58和低危型HPV的HPV6各1例;M-HPV 1例。CIN组、宫颈癌组HPV16感染率明显高于对照组,P均〈0.05。HR-HPV感染与CIN（OR=8.412,95%CI为2.62~26.99）和宫颈浸润癌（OR=14.929,95%CI为4.74~46.98）紧密相关,且主要与HPV16感染有关（CIN：OR=17.957,95%CI为2.09~154.15;宫颈浸润癌：OR=29.500,95%CI为3.60~242.07）,P均〈0.05。结论贵州地区CIN和宫颈浸润癌与HR-HPV感染密切相关,HPV16为主要感染亚型。     

p16~(INK4A)蛋白及HPV感染与宫颈上皮内瘤变和宫颈鳞癌的相关性分析

目的探讨宫颈上皮内瘤变和宫颈鳞癌中p16INK4A蛋白的表达及人乳头瘤病毒(HPV)感染率。方法收集2012年1月至2013年8月来该院就诊,并在妇产科门诊行宫颈活检和宫颈手术的患者122例,其中慢性宫颈炎22例宫颈上皮内瘤样变(CIN)Ⅰ28例、CINⅡ20例、CINⅢ29例,宫颈鳞癌23例。对其宫颈标本进行HPV DNA检测及p16INK4A蛋白的检测。结果 p16INK4A蛋白在慢性宫颈炎、CINⅠ、CINⅡ、CINⅢ、宫颈鳞癌中的表达率分别为0、46.43%、75%、82.86%、91.3%。随着宫颈病变的程度加重,p16INK4A蛋白的表达率逐渐上升,各级别宫颈病变中p16INK4A蛋白的表达率差异有统计学意义(P<0.05);HPV感染率在慢性宫颈炎、CINⅠ、CINⅡ、CINⅢ及宫颈鳞癌中分别为22.73%、39.29%、55%、55.17%、73.91%,随着宫颈病变的程度加重,HPV的感染率也越来越高。并且各级别宫颈病变之间HPV感染率差异有统计学意义(P<0.05)。并且宫颈病变HPV感染中以HPV16型最为常见,HPV的感染与p16INK4A蛋白的表达具有相关性(P<0.05)。结论在宫颈病变中,p16INK4A蛋白的表达与HPV感染率相关,若联合二者进行检测,对宫颈癌的早期筛查有重要意义。     

高危型HPV载量在人宫颈LSIL筛查中的应用

目的探讨子宫颈病变与高危型人乳头状瘤病毒（HR-HPV）感染和病毒载量的关系。方法对213例HR-HPV DNA载量≥1的低度鳞状上皮内病变（LSIL）患者的年龄进行分层,分析HR-HPV DNA载量与宫颈病理类型的关系。结果本组213例LSIL中,≤30岁者感染75例（35．2％）,〉30岁者感染138例（64．8％）;≤30岁患者的HR—HPV DNA载量明显高于〉30岁者（P〈0．05）。慢性宫颈炎27例,其病毒载量均低于CINⅠ级（135例）和CINⅡ级（47例）患者（P均〈0．05）。结论HR-HPV感染和病毒载量在LSIL中具有年龄分布特征,HR—HPV DNA载量与宫颈病变严重程度有关。     

HPV感染宫颈病变组织中IL-2、IL-4的表达变化及意义

采用原位杂交法检测高危型HPV16／18阳性的宫颈上皮内瘤变（CIN,55例）、宫颈癌（20例）及高危型HPV16／18阳性和阴性的宫颈炎（各15例）组织中的IL-2 mRNA、IL-4 mRNA。结果显示,与高危HPV阴性及阳性宫颈炎组织、高危HPV阳性CINⅠ、CINⅡ组织相比,高危型HPV16／18阳性的CINⅢ和宫颈癌组织中IL-4 mRNA的表达明显上升,IL-2 mRNA则明显下降,P均〈0．01。认为感染高危型HPV16／18的宫颈组织容易发展为CINⅢ甚至宫颈癌,其机制可能是局部细胞因子表达发生变化。     

与CO2冷冻治疗宫颈上皮内瘤变伴HPV感染疗效相关的影响因素分析

目的　探究CO2冷冻治疗宫颈上皮内瘤变（cervical intraepithelial neoplasia, CIN）伴人乳头瘤病毒（human papillomavirus, HPV）感染的疗效,并分析HPV持续感染的危险因素。方法　选取2018年1—11月期间在首都医科大学附属北京妇产医院治疗的CIN伴HPV感染患者560例作为研究对象,观察CIN和HPV感染的治疗效果,并采用Logistic回归分析方法探究治疗后HPV持续感染的危险因素。结果　治疗后6个月,CIN治疗的临床有效率为83.04%,HPV转阴率为73.75%;Logistic回归分析显示,年龄≥50岁、性伴侣个数≥2个、人流次数≥1次、生殖道炎症是CO2冷冻治疗后HPV持续感染的独立危险因素（P均＜0.05）。结论　CO2冷冻治疗对CIN和HPV感染清除均有一定的效果, HPV清除效果受到年龄、性伴侣个数、人流次数、生殖道炎症等因素的影响。     

宫颈上皮内瘤变组织中高危型HPV DNA的检测及意义

目的探讨宫颈上皮内瘤变（CIN）患者高危型人乳头瘤病毒（HPV）的感染情况。方法采用PCR技术检测CIN患者病变组织中高危型HPVDNA。结果Ⅰ、Ⅱ、Ⅲ级CIN组织中HPVDNA检出率分别为53．85％、72．73％、96．97％,χ^2=25．762,P〈0．01。CIN患者存在多重HPV感染的情况,Ⅰ、Ⅱ、Ⅲ级CIN多重HPVDNA感染率不同。结论不同级别CIN的高危型HPV感染率不同,同时存在多重感染的情况。     

Multiple Human Papilloma Virus (HPV) Infections Are Associated with HSIL and Persistent HPV Infection Status in Korean Patients

Infections with multiple human papilloma virus (HPV) types have been reported, but their role in cervical carcinogenesis has not been fully elucidated. In this study, 236 cases with multiple HPV infection were examined and compared to 180 cases with single HPV infection. HPV genotyping was performed with cervico-vaginal swab specimens using multiplex (real-time) polymerase chain reaction (PCR). In multiple HPV infection, the most prevalent HPV genotype was HPV 53, followed by HPV 16, 58, 52, and 68. HPV 33, 35, 39, 51, 52, 53, 58, and 68 were high-risk-HPV (HR-HPV) genotypes that were more frequently detected in multiple HPV infection compared to that in single HPV infection. The association between multiple HPV infection and high-grade SIL (HSIL) was significantly stronger compared to that of single HPV infection and HSIL (p = 0.002). Patients with multiple HPV infection displayed persistent and longer duration of the HPV infection compared to patients with single HPV infection. Multiple HPV infections have distinct clinicopathologic characteristics. Since it is associated with persistent HPV infection, HSIL, and different HR-HPV strains in contrast to single HPV infection, the presence of multiple HPV infection should be reported; close follow up is warranted.     

Effects of the Prophylactic HPV Vaccines on HPV Type Prevalence and Cervical Pathology

Vaccination programs with the current prophylactic HPV vaccines started in most countries around 2008 with introduction of the bivalent Cervarix HPV16/18 vaccine, rapidly followed by Gardasil (HPV6/11/16/18) and, finally, Gardasil 9 (HPV6/11/16/18/31/33/45/52/58), from 2015. Many studies have now confirmed their ability to prevent infection with vaccine-covered HPV types, and the subsequent development of either genital warts and/or cervical neoplasia, although this is clearly more effective in younger women vaccinated prior to sexual debut. Most notably, reductions in the prevalence of vaccine-covered HPV types were also observed in unvaccinated women at the same geographical location, presumably by sexual dissemination of these changes, between vaccinated and unvaccinated women. Furthermore, there are several studies that have demonstrated vaccine-associated HPV type-replacement, where vaccine-covered, high-risk HPV types are replaced by high-risk HPV types not covered by the vaccines, and these changes were also observed in vaccinated and unvaccinated women in the same study population. In light of these observations, it is not entirely clear what effects vaccine-associated HPV type-replacement will have, particularly in older, unvaccinated women.     

局部细胞中HPVl6基因表达量及突变与其宫颈持续感染的关系

目的探讨宫颈脱落细胞中人乳头瘤病毒（HPV）16基因的表达量及突变与其宫颈持续感染的关系。方法选取96例HPVl6感染患者,其中33例宫颈脱落细胞HPVl6持续阳性（持续感染组）,63例6个月后复查转为阴性（非持续感染组）。采用半定量PCR技术检测两组（宫颈脱落细胞中）HPVl6E5、E6、E7及长控制区（LCR）基因表达量,基因测序法检测HPVl6E5、E6、E7及LCR基因突变。结果持续感染组HP~16E5、E6、E7、LCR基因表达量分别为0．20±0．02、0．30±0．02、0．19±0．01、0．53±0．02,非持续感染组分别为0．17±0．02、0．27±0．03、0．16±O．06、0．504-0．04,两组比较P均〉0．05。持续感染组与非持续感染组3978A→c（144L）位点突变例数分别为33、63例,4041A→G（165V）位点突变例数分别为33、63例,4076A—T（同义突变）位点突变例数分别为28、31例;两组4076A→T突变例数比较,P〈0．01。持续感染组与非持续感染组E6基因178T→G（D25E）位点突变例数分别为10、4例,两组比较,P〈0．05;持续感染组与非持续感染组E7基因647A→G（N29S）与846T→c（同义突变）联合突变例数分别为9、8例,两组比较,P〉0．05;持续感染组与非持续感染组7761c→T位点突变例数分别为33、63例,P〉0．05;7727A→c位点突变例数分别为14、4例,两组比较,P〈0．01。结论宫颈脱落细胞中HPVl6基因表达量与持续性感染无密切关系,HPVl6E5、E6、LCR基因突变与宫颈持续性感染有关,其中HPVl6E54076A→T（同义突变）、E6178T→G（D25E）与LCR7727A→c突变点可能是导致HPVl6持续感染的关键突变位点。     

Evaluation of cervical length and optimal timing for pregnancy after cervical conization in patients with cervical intraepithelial neoplasia: A retrospective study

To evaluate the change of cervical length and the best timing for pregnancy after cervical conization in patients with cervical intraepithelial neoplasia (CIN).This was a retrospective study including patients under 40 years with fertility desire treated by cervical conization for CIN. To assess the cervical length, the patients were divided into 2 groups according to different surgery procedure: loop electrosurgical excision procedure (LEEP) and cold knife conisation (CKC). Patients with cervical length < 2.5 cm in CKC group were divided into 2 groups according to whether receiving cervical cerclage. Trans-vaginal ultrasound examination was used to measure cervical length by fixed professional sonographers.In LEEP group, the cervical length preoperative was significantly longer than 3 months postoperatively (3.03 ± 0.45 cm vs 2.84 ± 0.44 cm, P = .000). In CKC group, the cervical length preoperative was significantly longer than 3 and 6 months postoperatively (2.90 ± 0.41 cm vs 2.43 ± 0.43 cm and 2.68 ± 0.41 cm, respectively, P = .000). Cervical length was significantly longer at 12 and 9 months after cerclage compared to that without cerclage. Eighteen patients got pregnant in LEEP group, among which one was pregnant at 5 months postoperatively and had premature delivery. There was 1 inevitable abortion and 1 preterm birth among 39 pregnant patients from CKC group.Patients who have fertility desire with CIN were recommended for pregnancy at 6 and 9 months after LEEP and CKC, respectively. Cerclage effectively prolonged cervical length in patents with that less than 2.5 cm to prevent cervical incompetence.     

宫颈上皮内瘤变、宫颈癌中乙酰肝素酶的表达及意义

目的 探讨乙酰肝素酶在宫颈黏膜上皮内瘤变与宫颈癌中的表达及其意义.方法 采用免疫组化SP法检测乙酰肝素酶在56例宫颈黏膜上皮内瘤变(轻度12例,中度26例,重度18例)、54例宫颈癌(伴有淋巴结转移的20例,不伴淋巴转移34例)中的表达.结果 乙酰肝素酶在宫颈黏膜上皮轻、中、重度上皮内瘤变组织中表达率分别为33.33%,38.48%,44.44%,宫颈癌中表达率为48.14%.乙酰肝毒酶在宫颈黏膜上皮内瘤变与宫颈癌中的表达无统计学意义(P＞0.05).20例宫颈癌伴淋巴结转移者,乙酰肝素酶表达(70.00%)明显高于无转移组(35.29%),P＜0.01.结论 乙酰肝素酶表达与宫颈癌发生、发展无关,与宫颈癌组织淋巴结转移有关.