目的：

探讨乌鲁木齐市宫颈高级别鳞状上皮内病变（high-grade squamous intraepithelial lesion，HSIL）患者利普术（loop electrosurgical excision procedure，LEEP）后高危人乳头瘤病毒持续性感染及病灶复发的相关影响因素，并评估其预测价值。

方法：

对2018年7月至2021年7月在新疆维吾尔自治区人民医院因确诊为HSIL接受LEEP术的516例患者的临床资料及两年随访记录进行回顾性分析，于术后第6个月、12个月、18个月、24个月进行随访检查，选取相关因素分别对术后HR-HPV持续性感染和病灶复发进行单因素和多因素分析，并绘制受试者工作特征（receiver operating characteristic，ROC）曲线评估预测价值。

结果：

1.516例患者中，术后持续感染率为6.78%（35/516）；复发者24人，复发率为4.65%（24/516）。单因素分析显示术后持续性感染与患者的年龄、绝经状态、术前HPV载量及多重HR-HPV感染、转化区类型、术前及术后阴道炎等密切相关（P＜0.05）；术后病灶复发与民族、年龄、经阴分娩次数、绝经状态、术前HPV载量、活检病理级别、转化区类型、累腺情况、锥切深度、切缘状态、高级别病变累及范围密切相关（P<0.05）。多因素分析显示，术前多重HR-HPV感染、HPV载量≥1000RLU、术后患阴道炎是HSIL患者LEEP术后HR-HPV持续感染的独立危险因素（P＜0.05）；而术前活检III型转化区、切缘阳性、术前HPV载量≥1000RLU是HSIL患者LEEP术后病灶复发的独立危险因素（P＜0.05）。

2.术前HPV载量、多重HR-HPV感染、术后患阴道炎分别单独预测LEEP术后HR-HPV持续性感染时，曲线下面积分别为0.583（P＞0.05）、0.608（P＜0.05）、0.610（P＜0.05）。

3.切缘状态、术前HPV载量、转化区类型单独作为LEEP术后病变复发的预测因素时，曲线下面积分别为0.649（P＜0.05）、0.631（P＜0.05）、0.723（P＜0.05）。

结论：

1.术前多重HR-HPV感染、术前HPV载量≥1000RLU、术后患阴道炎是HSIL利普术后HR-HPV持续感染的独立危险因素；III型转化区、切缘阳性、术前HPV载量≥1000RLU是病灶复发的独立危险因素。

2.术前HPV载量对HSIL利普术后HR-HPV持续性感染无预测价值，多重HR-HPV感染、术后患阴道炎的预测价值均较低，三者联合可提高预测价值；切缘状态、术前HPV载量对复发的预测价值均较低，转化区类型的预测价值较高，三者联合可提高预测价值。

Objective:

To investigate the associated influencing factors of persistent high-risk human papillomavirus (HR-HPV) infection and lesion recurrence in patients with cervical high-grade squamous intraepithelial lesions (HSIL) following loop electrosurgical excision procedure (LEEP) in Urumqi, and to assess their predictive significance.

Methods:

A retrospective analysis was conducted on the clinical data and two-year follow-up records of 516 patients who underwent LEEP surgery for HSIL at the Xinjiang Uygur Autonomous Region People's Hospital between July 2018 and July 2021. Follow-up examinations were scheduled at 6, 12, 18, and 24 months post-surgery. Relevant factors were selected for both univariate and multivariate analyses to investigate postoperative HR-HPV persistent infection and lesion recurrence. Furthermore, receiver operating characteristic (ROC) curves were generated to evaluate the predictive value.

Results:

1. Among the 516 patients, the postoperative persistent infection rate was 6.78% (35/516); 24 patients experienced recurrence, with a recurrence rate of 4.65% (24/516). Univariate analysis showed that postoperative persistent infection was closely related to patient age, menopausal status, preoperative HPV load and multiple HR-HPV infections, transformation zone type, and preoperative and postoperative vaginitis (P < 0.05). Postoperative lesion recurrence was significantly associated with ethnicity, age, number of vaginal deliveries, menopausal status, preoperative HPV load, biopsy pathology grade, transformation zone type, involvement of glands, depth of conization, margin status, and extent of high-grade lesions (P < 0.05). Multivariate analysis revealed that preoperative multiple HR-HPV infections, HPV load ≥1000 RLU, and postoperative vaginitis were independent risk factors for HR-HPV persistent infection after LEEP in HSIL patients (P < 0.05). Preoperative biopsy type III transformation zone, positive margins, and preoperative HPV load ≥1000 RLU were independent risk factors for lesion recurrence after LEEP in HSIL patients (P < 0.05).

2. When predicting postoperative HR-HPV persistent infection after LEEP individually, the areas under the curve (AUC) were 0.583 (P > 0.05) for preoperative HPV load, 0.608 (P < 0.05) for multiple HR-HPV infections, and 0.610 (P < 0.05) for postoperative vaginitis.

3. When predicting postoperative lesion recurrence after LEEP individually, the areas under the curve were 0.649 (P < 0.05) for margin status, 0.631 (P < 0.05) for preoperative HPV load, and 0.723 (P < 0.05) for  transformation zone type.

Conclusions:

1. Preoperative multiple HR-HPV infections, preoperative HPV load ≥1000 RLU, and postoperative vaginitis are independent risk factors for persistent HR-HPV infection after LEEP in patients with HSIL. Type III transformation zone, positive margins, and preoperative HPV load ≥1000 RLU are independent risk factors for lesion recurrence after LEEP in patients with HSIL.

2. When predicting postoperative HR-HPV persistent infection following LEEP, the preoperative HPV load alone does not show significant predictive value. While multiple HR-HPV infections and postoperative vaginitis have lower predictive values, combining them improves the overall predictive value. When predicting postoperative lesion recurrence, the margin status and the preoperative HPV load have lower predictive values, but the predictive value of the transformation zone type is higher. Combining all three factors can enhance the predictive value.

[1]王静馥,史志萍,于海凤,等.派特灵联合重组干扰素α-2b栓治疗持续高危型人乳头瘤病毒感染患者的效果及对血清炎症细胞因子水平的影响[J].中国妇幼保健,2021,36(05):1012-1014.

[2]沈丹华.宫颈鳞状细胞前驱病变命名及其相应临床处理原则-基于<第四版世界卫生组织女性生殖系统肿瘤分类>[J].中华妇幼临床医学杂志(电子版),2016,12(04):379-382.

[3]蔡明翠,张荣.宫颈上皮内病变术后复发及残留的危险因素分析[J].现代实用医学,2018,30(9):1204-1206.

[4]陈绍正.宫颈上皮内瘤变锥切术后病理升级及复发的高危因素分析[J].中国妇幼保健,2019,34(7):1523-1527.

[5]王玲伟,王秀秀,柴泽英.宫颈高级别鳞状上皮内病变患者LEEP手术后复发的相关因素分析[J].中国妇幼健康研究,2020,31(07):965-968.

[6]尹燕娜,艾星子·艾里,丁岩.新疆维吾尔族宫颈癌发病特征及进展[J].现代妇产科进展,2012,21(05):404-405.

[7]曾艳华,何文丽,孟存仁.乌鲁木齐地区不同民族女性HPV感染基因亚型分布分析[J].国际检验医学杂志,2020,41(14):1769-1772.

[8]陈丽梅,刘莉,陶祥,等.1005例子宫颈HSIL患者行LEEP术后24个月内的复发及其影响因素分析[J].中华妇产科杂志,2019,54(08):534-540.

[9]蔡礼仲,姚锐.高级别宫颈上皮内病变患者环形电切术后HPV持续感染及病变残留复发的危险因素[J].中国妇幼保健,2024,39(19):3775-3780.

[10]王琳,韩莉莉,玛依努尔·尼牙孜,隋霜.人乳头状瘤病毒E6/E7蛋白在维吾尔族及汉族宫颈癌发展中的表达及意义[J].中国医药导报,2015,12(21):75-78.

[11]古丽加那提·毛吾列提,纪莎,玛依努尔·尼牙孜.HPV病毒载量与宫颈病变及宫颈癌的相关性研究[J].新疆医学,2015,45(02):182-187.

[12]孔蕊,姚群,吴晓博,等.高危型人乳头状瘤病毒感染类型及载量与子宫颈癌前病变严重程度及病变范围的相关性[J].中华临床医师杂志(电子版),2020,14(05):376-379.

[13]陶佳,朱艳,刘雷,等.高级别宫颈上皮内瘤变患者阴道微生态对HPV感染转归的影响因素分析[J].中华医院感染学杂志,2020,30(04):581-585.

[14]赵慧芳,张凤格,朱丹,等.宫颈上皮内瘤变患者宫颈锥切术后发生高危型HPV持续感染的影响因素分析[J].实用妇科内分泌电子杂志,2022,9(29):9-12.

[15]张菲菲,高广云,张海燕,等.宫颈上皮内瘤变患者宫颈环形电切术后HPV持续感染的高危因素分析及其对阴道微生态和免疫调节功能的影响[J].现代生物医学进展,2022,22(15):2854-2859.

[16]董世庆,陈萃.不同类型宫颈转化区在高危型人乳头瘤病毒感染后的转归比较[J].重庆医学,2023,52(18):2780-2784.

[17]郝春雪,齐智慧,刘丽娜,等.宫颈上皮内瘤变患者术后高危型HPV持续感染危险因素及其预测模型评价[J].中华医院感染学杂志,2023,33(20):3117-3121.

[18]周佳怡,张跃明,何静,吴蕾,姜飞洲,侯文杰.高级别宫颈鳞状上皮内病变患者宫颈锥切术后高危型人乳头瘤病毒持续感染的相关因素分析[J].肿瘤预防与治疗,2021,34(05):408-413.

[19]陈娜娜,韩松筠,商文金,等.宫颈高级别鳞状上皮内病变患者经锥切术后切缘阳性的危险因素及锥切高度的相关分析[J].中国临床医生杂志,2023,51(10):1226-1229.

[20]王爽,袁学华,柯盈月,等.阴道微生态异常与高危型人乳头瘤病毒感染及宫颈病变的关系[J].中国微生态学杂志,2018,30(08):959-963.

[21]魏至瑶,代荫梅.子宫颈环形电切术后子宫颈上皮内病变复发的相关影响因素及对策研究[J].中国妇产科临床杂志,2021,22(04):352-355.

[22]王雅卉,郑颖龄,周丽.子宫颈鳞状上皮内病变子宫颈环形电切术术后病变残留或复发情况及影响因素研究[J].中国妇幼保健,2020,35(19):3567-3571.

[23]李英,王金桃.高危型人乳头瘤病毒载量与宫颈病变的相关性研究[J].基层医学论坛,2015,19(35):4903-4905.

[24]刘莉,陈丽梅,陶祥,等.1502例子宫颈HSIL患者行LEEP锥切术后随访半年的临床结局及术后病灶残留的危险因素分析[J].中华妇产科杂志,2017,52(11):751-756.

[25]王明宇,程广艳,张雯雯,等.宫颈锥切术后病变残留的危险因素分析[J].肿瘤预防与治疗,2020,33(05):423-427.

[26]李飞.宫颈上皮内病变术后复发及残留高危因素分析[D].大连医科大学,2017:1-43.

[27]金屏.CINⅡ~Ⅲ级患者宫颈锥切术后病变残留的高危因素探讨[J].中国性科学,2020,29(03):36-38.

[28]曾燕,卢爱妮,廖予妹.宫颈上皮内瘤变锥切术后复发的相关预测因素[J].实用医学杂志,2015,31(04):601-603.

[29]刘静云,刘艳秋,吕志红.CIN2-CIN3宫颈电环锥切术后病变残留/复发的危险因素及预测指标[J].中国计划生育学杂志,2022,30(03):699-702.

[30]焦桢,陆萍,隋霜,等.新疆维吾尔族妇女宫颈癌高危型人乳头瘤病毒负荷量与宫颈病变的相关性研究[J].中国生育健康杂志,2014,25(01):14-17.

[31]郑鹏涛,张琳,闫璐,等.宫颈锥切术后病变残留危险因素分析[J].实用妇产科杂志,2018,34(02):131-134.

[32]杨扬,殷新明,袁霞.切缘阴性宫颈锥切术后影响宫颈上皮内肿瘤残留/复发的因素[J].中国性科学,2019,28(08):36-40.

[33]李宁,佐晶,黄婴,等.HPV分型检测在子宫颈高级别鳞状上皮内病变治疗后随访中的临床意义[J].中华妇产科杂志,2015,50(04):258-262.

[34]王丽萍,景晓兰.宫颈上皮内瘤变患者行宫颈锥切术后病变残留的危险因素分析[J].临床医学研究与实践,2020,5(12):6-8.

[35]王淑玲,拜莹,李嘉荣,等.宫颈病变冷刀锥切术后切缘阳性及病变残留的危险因素分析[J].现代肿瘤医学,2022,30(23):4303-4308．

[36]赵超,刘军,李明珠,等.子宫颈锥形切除术操作规范[J].中国妇产科临床杂志,2021,22(02):218-219．

[37]刘慧慧.高级别宫颈鳞状上皮内病变患者宫颈锥切术后复发的预测因素分析[J].航空航天医学杂志,2022,33(02):138-140.

[38]张倩,金影.宫颈冷刀锥切深度对育龄女性高级别宫颈上皮内瘤变疗效及预后的影响[J].中国医刊,2022,57(11):1239-1243.

[39]汪美容,王艺,邓潇,等.宫颈上皮内瘤变锥切术后切缘阳性的相关危险因素及其复发情况分析[J].微创医学,2022,17(5):555-559.

[40]袁博,王武亮,赵虎,等.HSIL宫颈冷刀锥切术后切缘阳性的临床处理及转归[J].医学研究杂志,2022,51(01):84-87.

[41]张辉.采用宫颈锥切术治疗的宫颈上皮内瘤变患者的预后及相关因素分析[D].山东大学,2016:1-139.

[42]林俊.高级别宫颈上皮内瘤变宫颈锥切术后高危型人乳头瘤病毒转归影响因素[J].中国计划生育学杂志,2022,30(05):1098-1101.

[43]Ouh YT,Cho HW,Kim SM,et al.Risk factors for type-specific persistence of high-risk human papillomavirus and residual/recurrent cervical intraepithelial neoplasia after surgical treatment[J].Obstet Gynecol Sci,2020,63(5):631-642.

[44]So K A,Lee I H,Kim T J,et al.Risk factors of persistent HPV infection after treatment for high-grade squamous intraepithelial lesion[J].Arch Gynecol Obstet,2019,299(1):223-227.

[45]Vänskä S,Luostarinen T,Lagheden C,et al.Differing age-specific cervical cancer incidence between different types of human papillomavirus: implications for predicting the impact of elimination programs[J].Am J Epidemiol,2021,190(4):506-514.

[46]Liao G,Jiang X,She B,et al.Multi-infection patterns and co-infection preference of 27 human papillomavirus types among 137943 gynecological outpatients across China[J].Front Oncol,2020,10(9):449.

[47]Giannella L,Fodero C,Boselli F,et al.Age-related changes in pre-and post-conization HPV genotype distribution among women with high-grade cervical intraepithelial neoplasia[J].Int J Gynecol Obstet,2017,137(1):72-77.

[48]Zhang G,Lang J,Shen K,et al.High-risk human papillomavirus infection clearance following conization among patients with cervical intraepithelial neoplasm grade 3 aged at least 45 years[J].Int J Gynecol Obstet,2017,136(1):47-52.

[49]Koyanagi Y,Kubo C,Nagata S,et al.Detection of pagetoid urothelial intraepithelial neoplasia extending to the vagina by cervical screening cytology:a case report with renewed immunochemical summary[J].Diagn Pathol,2019,14:1-5.

[50]Ylitalo N,Sørensen P,Josefsson A M,et al.Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ:a nested case-control study[J].The Lancet,2000,355(9222):2194-2198.

[51]Rasmussen C L,Thomsen L T,Aalborg G L,et al.Incidence of vulvar high-grade precancerous lesions and cancer in Denmark before and after introduction of HPV vaccination[J].Gynecol Oncol,2020,157(3):664-670.

[52]Oyervides-Muñoz M A,Pérez-Maya A A,Sánchez-Domínguez C N,et al.Multiple HPV infections and viral load association in persistent cervical lesions in Mexican women[J].Viruses,2020,12(4):380.

[53]Spinillo A,Dominoni M,Boschi A C,et al.The relationship of human papillomavirus infection with endocervical glandular involvement on cone specimens in women with cervical intraepithelial neoplasia[J].Gynecol Oncol,2020,159(3):630-635.

[54]Cheng W,Xu F,Gao L,et al.The correlation between the determination of vaginal micro-ecological composition and the outcome of HPV infection by high-throughput metagene sequencing information technology on the illumina platform[J].J Infect Public Heal,2020,13(12):1961-1966.

[55]Lara-Peñaranda R,Rodríguez-López P M,Plitt-Stevens J,et al.Does the trend toward less deep excisions in LLETZ to minimize obstetric risk lead to less favorable oncological outcomes?[J].Int J Gynecol Obstet,2020,148(3):316-324.

[56]Baser E,Ozgu E,Erkilinc S,et al.Risk factors for human papillomavirus persistence among women undergoing cold-knife conization for treatment of high-grade cervical intraepithelial neoplasia[J].Int J Gynecol Obstet,2014,125(3):275-278.

[57]Wiik J,Sengpiel V,Kyrgiou M,et al.Cervical microbiota in women with cervical intra-epithelial neoplasia,prior to and after local excisional treatment,a Norwegian cohort study[J].BMC women's Health,2019,19:1-9.

[58]Bilibio JP,Monego HI,Binda MLA,et al.Menopausal status is associated with a high risk for residual disease after cervical conization with positive margins[J].PLoS One,2019,14(6):e0217562.

[59]Ordi J,Alonso I,Torné A,et al.Human papillomavirus load in Hybrid Capture II assay:does increasing the cutoff improve the test?[J].Gynecol Oncol,2005,99(2):313-319.

[60]Güdücü N,Sidar G,Başsüllü N,et al.Endocervical glandular involvement,multicentricity,and extent of the disease are features of high-grade cervical intraepithelial neoplasia[J].Ann Diagn Pathol,2013,17(4):345-346.

[61]Kim Y T,Kim J W,Kim D K,et al.Loop diathermy and cold-knife conization in patients with cervical intraepithelial neoplasia:a comparative study[J].J Korean Med Sci,1995,10(4):281-286.

[62]Paraskevaidis E,Lolis E D,Koliopoulos G,et al.Cervical intraepithelial neoplasia outcomes after large loop excision with clear margins[J].Obstet Gynecol,2000,95(6):828-831.

[63]Kim Y B,Kim Y T,Cho N H,et al.High-dose-rate intracavitary radiotherapy in the management of cervical intraepithelial neoplasia 3 and carcinoma in situ presenting with poor histologic factors after undergoing excisional procedures[J].Int J Radiat Oncol Biol Phys,2012,84(1):e19-e22.

[64]Papoutsis D,Rodolakis A,Mesogitis S,et al.Appropriate cone dimensions to achieve negative excision margins after large loop excision of transformation zone in the uterine cervix for cervical intraepithelial neoplasia[J].Gynecol Obstet Invest,2013,75(3):163-168.

[65]DAVIDESKO S,MEIROVITZ M,SHACO-LEVY R,et al.Positive pathological margins after loop electrosurgical excision procedure-Management and outcome[J].Eur J Surg Oncol,2023,49(5):1031-1036.

[66]Ghaem-Maghami S,Sagi S,Majeed G,et al.Incomplete excision of cervical intraepithelial neoplasia and risk of treatment failure:a meta-analysis[J].Lancet Oncol,2007,8(11):985-993.

[67]Cuello M A,Espinosa M E,Orlandini E J,et al.The value of endocervical curettage during loop electrosurgical excision procedures in predicting persistent/recurrent preinvasive cervical disease[J].Int J Gynecol Obstet,2018,141(3):337-343.

[68]KILIC D,GULER T,ATIGAN A,et al.Predictors of Human papillomavirus (HPV) persistence after treatment of high grade cervical lesions;does cervical cytology have any prognostic value in primary HPV screening?[J].Ann Diagn Pathol,2020,49:151626.

[69]JING X,DU T,CHEN K,et al.Icariin protects against iron overload-induced bone loss via suppressing oxidative stress[J].J Cell Physiol,2019,234(7):10123-10137.