宫颈上皮内瘤变及其治疗对妊娠的影响

宫颈鳞状上皮内瘤变是一种和HPV感染有关的宫颈癌前病变。根据病变程度分为低度和高度鳞状上皮内病变,其中低度病变包括HPV感染和C IN1,高度病变包括C IN2~3。HPV感染和宫颈上皮内瘤变是一种生育年龄妇女常见的妇科疾病,HPV感染、宫颈病变本身及其治疗对妊娠的影响倍受关注。HPV感染在妊娠期间可能增加,经阴道分娩者新生儿暴露于HPV的机会增多,尚不能下结论对所有HPV感染者均采用剖宫产的分娩方式。妊娠期间发现C IN1,可以观察并产后随访。如果为C IN2~3,妊娠可能不会加重病变程度,但对阴道镜检查不满意者或高度怀疑浸润癌者应在孕期明确诊断,可于妊娠中期行宫颈锥切术。妊娠中期行宫颈锥切术可能使剖宫产率增加。C IN保守治疗对于患者受孕能力无显著的影响;宫颈冷刀锥切及LEEP锥切可能增加早产率,早产率的增加可能和胎膜早破的发生有关。     

Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or cervical intraepithelial neoplasia in Henan province,central China

To evaluate the prevalence of human papillomavirus (HPV) infection and its genotype among women with cervical lesions in Henan Province, central China. A total of 1317 cervical scrapes from patients with cervical intraepithelial neoplasia 1 (CIN1) (n = 91), CIN2/3 (n = 466), and cervical cancer (CC; n = 760) were collected from 2013 to 2018, and then tested for HPV genotypes using polymerase chain reaction followed by flow-through hybridization assay. The prevalence of HPV was 62.64% for patients with CIN1, 86.91% for patients with CIN2/3%, and 89.21% for patients with CC. In total, the HPV prevalence was 86.56%, and the most common HPV type was HPV16 (58.77%) followed by HPV58 (10.33%), 18 (7.67%), 52 (6.61%), and 33 (5.54%). In this study, the high-risk HPV cumulative attribution rate of nine-valent vaccine coverage was markedly higher than that of bivalent or quadrivalent vaccine coverage in each histopathological category or overall (P < .001). Single HPV infection was the main infection category in each histopathological diagnosis, and the total infection rate was 65.83% (867/1317; P < .001). The prevalence of HPV16 or single HPV infection increased with the severity of cervical lesions (P < .001). HPV16, 58, 18, 52, and 33 may be predominant high-risk factors for cervical lesions in Henan Province. The nine-valent prophylactic HPV vaccine is more effective than a bivalent or quadrivalent vaccine for protecting women from CC in the region.     

Type‐specific human papillomavirus prevalence in cervical intraepithelial neoplasia and cancer in Iran

In Iran, human papillomavirus (HPV) vaccination is not currently included in the national vaccination program and there are no comprehensive approaches to cervical screening program. Regional data on distribution of HPV types in women is important to predict the impact of current HPV vaccines. Although several studies on distribution of HPV types in cervical precancer and cancer have been conducted in Iran, in most of them HPV positive samples were subjected to specific‐primer genotyping (mainly 16 and 18), and leaving the other HPV genotypes almost undetermined. Therefore, the present study aimed to investigate the distribution of HPV types in cervical neoplasia from West and Northwest of Iran. A total of 112 women with atypia, cervical intraepithelial neoplasia, and invasive cervical cancer were included. A PCR assay was performed in all samples to detect the presence of the HPV genome using the GP5+/6+ L1 consensus primer set. All HPV positive samples were subjected for sequencing. In overall, HPV prevalence was 20% in atypica, 44.5% in cervical intraepithelial neoplasia I, 92.3% in cervical intraepithelial neoplasia II‐III, and 98.2% in invasive cervical cancer. The most frequent HPV type was HPV 16 (79.2%), which was followed by HPV types 18, 6, and 33 at the frequencies of 6.5%, 5.1%, and 2.7%, respectively. The least HPV types were found to be 31, 45, 53, 58, and 66. In conclusion, this study shows that the current HPV vaccines could have great impact to reduce the burden of cervical cancer in Iran.     

Distribution of human papillomavirus genotypes among cervical intraepithelial neoplasia and invasive cancers in Macao

Macao is a densely populated city situated in East Asia where a relatively high prevalence of human papillomavirus (HPV) types 52 and 58 has been reported in women with invasive cervical cancer. To provide data for a population‐specific estimation on the impact of HPV vaccines, paraffin‐embedded tissues collected from women with invasive cervical cancer or cervical intrapeitheilal neoplasia grade 2 or 3 confirmed histologically were examined for HPV using the INNO‐LiPa kit. Of the 35 HPV‐positive patients with invasive cancer, one HPV type was detected in 68.6%, and 31.4% were co‐infected with more than one HPV type. Overall, HPV 16, HPV 18, HPV 52, and HPV 54 were the most common types found respectively in 57.1%, 17%, 11.4%, and 8.5% of patients with invasive cervical cancer. Among the 59 HPV‐positive patients with cervical intraepithelial neoplasia grade 2/3, 55.9% hardbored one HPV type, and 44.1% had co‐infections. The common HPV types found included HPV 16 (52.5%), HPV 52 (23.7%), HPV 58 (18.7%), and HPV 33 (17%). Although HPV 11 (a low‐risk type) was also found commonly in invasive cervical cancers (14.3%) and cervical intraepithelial neoplasia grade 2/3 (15.3%), the fact that they all existed as co‐infections with another high‐risk type suggested HPV 11 was not the cause of the lesion. The current vaccines targeting HPV 16/18 are expected to cover 62.9–74.3% of invasive cervical cancers and 32.2–55.9% of cervical intraepithelial neoplasia 2/3 in Macao. Widespread HPV vaccination is expected to reduce substantially the disease burden associated with cervical neoplasia in Macao. J. Med. Virol. 82:1600–1605, 2010. © 2010 Wiley‐Liss, Inc.     

Factors affecting residual/recurrent cervical intraepithelial neoplasia after cervical conization with negative margins

To identify factors for predicting residual or recurrent cervical intraepithelial neoplasia (CIN) after cervical conization with negative margins. A total of 172 patients with histologically verified high‐grade squamous intraepithelial lesions who underwent conization with negative margins were recruited at the General Hospital of Tianjin Medical University from December 2006 to January 2016. Follow‐up comprised clinical examination, a liquid‐based cytology test, a human papillomavirus (HPV) DNA genotyping test, colposcopy assessment, and if indicated, colposcopy‐directed punch biopsy. The Kaplan‐Meier method was used to analyze the median recurrent time, whereas log‐rank tests and Cox regression models were used to determine the predictors of residual/recurrent CIN. Fourteen residual/recurrent cases (8.1%) were identified in 172 patients. In univariate analysis, cytologic abnormalities on follow‐up (P = .000), conization method (P = .017), HPV positivity at any visit (P = .000), persistent HPV infection postconization (P = .000), persistent infection with the same HPV genotype (P = .000), and HPV positivity at 18 months after conization (P = .000) were predictive factors of residual/recurrent CIN. The results of multivariate analysis further revealed that persistent HPV infection postconization (P = .035), HPV positivity at 18 months after conization (P = .017), and cytologic abnormalities on follow‐up (P = .000) had an increased risk of residual/recurrent CIN. During follow‐up, patients with persistent HPV infection or cytologic abnormalities were at high risk of residual/recurrent CIN and should be identified for close surveillance and monitoring. Meanwhile, patients with HPV who became negative within 18 months after treatment had a low risk of recurrence.     

Human papillomavirus type distribution in vulval intraepithelial neoplasia determined using PapilloCheck DNA Microarray

Vulval intraepithelial neoplasia is a precursor of vulval carcinoma, and is frequently associated with human papillomavirus (HPV) infection. Estimates of HPV prevalence in vulval intraepithelial neoplasia vary widely in the UK. The objective of this study was to assess HPV infection in a sample of women with vulval intraepithelial neoplasia, confirmed histologically, and determine the proportion of disease associated with HPV types targeted by prophylactic HPV vaccines. HPV infection was assessed in biopsies from 59 patients using the Greiner Bio‐One PapilloCheck® DNA chip assay. Valid results were obtained for 54 cases. HPV infection was present in 43 of the 54 cases (79.6%: 95% CI 67.1–88.2%). The most common HPV types were HPV 16 (33/54: 61.1%), HPV 33 (8/54: 14.8%), HPV 6 (5/54: 9.3%), and HPV 42 (3/54: 5.6%). The mean age of HPV positive women was significantly less than the mean age of HPV negative women. This is the largest UK series of vulval intraepithelial neoplasia in which HPV type has been investigated, and 34/54 (63.0%, 95% CI: 49.6–78.6%) cases were associated with HPV 16/18, which are targeted by current prophylactic HPV vaccines. J. Med. Virol. 83:1358–1361, 2011. © 2011 Wiley‐Liss, Inc.     

Anal canal neuroendocrine carcinoma associated with squamous intraepithelial neoplasia: a human papillomavirus 18-related lesion

Neuroendocrine carcinoma (NEC) of the anal canal is exceedingly rare and its histogenesis is poorly understood. We present a case of small-cell NEC of the anal canal in a 70-year-old woman. The NEC appeared as a submucosal tumor at the dentate line and was associated with squamous intraepithelial neoplasia (SIN). The NEC was positive for neuroendocrine markers including synaptophysin, chromogranin A and CD56, whereas the SIN component did not express any of these markers. Both components exhibited p16 overexpression. A PCR analysis revealed that both the SIN and NEC components were positive for human papillomavirus (HPV) 18 DNA. Our observations imply that SIN may be a precursor of anal canal NEC and that HPV18 may play an important role in the histogenesis of anal canal NEC, similar to its role in cervical NEC.     

Human papillomavirus genotyping as a predictor of high-grade cervical dysplasia in women with mildly cytologic abnormalities: a two-year follow-up report

High-risk human papillomavirus (HR-HPV) DNA testing has emerged as another testing modality for women with mildly cytologic abnormalities. We conducted a two-year follow-up study of 108 women with mildly abnormal cervical cytology for detection of CIN 2/3. A cervical swab sample was obtained for HPV genotyping by a HPV blot and histologic follow-up results were correlated with HR-HPV types. Of the 108 cases, 93 (86.1%) were positive for HR-HPV DNA. HPV-16 was detected in 45.1% of patients. CIN grade 2 or 3 was confirmed in 25 (23.1%) of the 108 women during the two-year follow-up period. The two-year cumulative incidence rates of CIN 2/3 were 38.6% (17/44) among HPV-16- positive women, but only 5.6% among HR-HPV-positive women without HPV-16 or HPV-18. The sensitivity of a positive HPV-16 test for CIN 2/3 was 68.0%, the specificity was 67.5%. Our results demonstrated that the type-specific HPV-16 test increased sensitivity of detecting high-grade cervical dysplasia for women who have mildly cytologic abnormalities. The implication of the present findings is that HPV genotyping may identify women with the greatest risk of high-grade CIN.     

Comparative evaluation of nm23 and p16 expression as biomarkers of high-risk human papillomavirus infection and cervical intraepithelial neoplasia 2(+) lesions of the uterine cervix

Benevolo M, Terrenato I, Mottolese M, Marandino F, Muti P, Carosi M, Rollo F, Ronchetti L, Mariani L, Vocaturo G & Vocaturo A
(2010) Histopathology 57 , 580–586
Comparative evaluation of nm23 and p16 expression as biomarkers of high‐risk human papillomavirus infection and cervical intraepithelial neoplasia 2⁺ lesions of the uterine cervix Aims: To investigate the clinical role of nm23 expression in identifying both high‐risk human papillomavirus (HR‐HPV) and high‐grade cervical lesions or carcinomas [cervical intraepithelial neoplasia 2⁺ (CIN2⁺)], and to compare it with p16 overexpression, as this latter biomarker has already been reported widely in HR‐HPV infected cervical lesions. Methods and results: Immunohistochemical evaluation of nm23 and p16 in 143 cervical biopsy specimens including negative, low‐ and high‐grade lesions and squamous carcinomas (SC). HR‐HPV testing by Digene hybrid capture 2 (HC2) and polymerase chain reaction (PCR) on the cervico‐vaginal samples of the same patients. In detecting CIN2⁺, p16 was significantly more sensitive and specific than nm23 (96.3% versus 81.8% and 66% versus 36.4%, respectively, both P < 0.0001). Concerning HR‐HPV detection by HC2, p16 showed a significantly higher specificity than nm23 (82% versus 47%, P <0.0001), although the sensitivities were comparable (71% versus 76%). We found a significantly direct correlation between nm23 and HC2 findings. However, nm23 expression did not correlate with HPV16/18 infection. In contrast, we observed a significant association between p16 overexpression and HPV16/18 genotypes. Conclusions: We confirm the diagnostic value of p16 overexpression. Moreover, despite in vitro data regarding the interaction with the HPV‐E7 protein, nm23 does not appear to be a more useful biomarker than p16 in identifying CIN2⁺ or HR‐HPV infection.     

Distribution of human papillomavirus genotypes in cervical intraepithelial neoplasia and invasive cervical cancer in Canada

Infection with high‐risk human papillomavirus (HPV) causes cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC). The distribution of HPV types in cervical diseases has been previously described in small studies for Canadian women. The prevalence of 36 HPV genotypes in 873 women with CIN and 252 women with ICC was assessed on cervical exfoliated cells analyzed with the Linear Array (Roche Molecular System). HPV16 was the most common genotype in CIN and ICC. The seven most frequent genotypes in order of decreasing frequency were HPV16, 51, 52, 31, 39, 18, and 56 in women with CIN1, HPV16, 52, 31, 18, 51, 39, and 33 in women with CIN2, HPV16, 31, 18, 52, 39, 33, and 58 in women with CIN3, and HPV16, 18, 45, 33, 31, 39, and 53 in women with ICC. HPV18 was detected more frequently in adenocarcinoma than squamous cell carcinoma (P = 0.013). Adjustment for multiple type infections resulted in a lower percentage attribution in CIN of HPV types other than 16 or 18. The proportion of samples containing at least one oncogenic type was greater in CIN2 (98.4%) or CIN3 (100%) than in CIN1 (80.1%; P < 0.001 for each comparison). Multiple type infections were demonstrated in 51 (20.2%) of 252 ICC in contrast to 146 (61.3%) of 238 women with CIN3 (P < 0.001). Adjusting for multiple HPV types, HPV16 accounted for 52.1% and HPV18 for 18.1% of ICCs, for a total of 70.2%. Current HPV vaccines should protect against HPV types responsible for 70% of ICCs in Canadian women. J. Med. Virol. 83:1034–1041, 2011. © 2011 Wiley‐Liss, Inc.     

High-risk human papillomavirus infection of the genital tract of women with a previous history or current high-grade vulvar intraepithelial neoplasia

Human papillomavirus (HPV) infection is associated with high-grade vulvar intraepithelial neoplasia (VIN-3). The prevalence of anogenital HPV infection in women with previously treated VIN-3 has not been documented yet. This cross-sectional study compared high-risk HPV DNA detection rates in women with past (n = 30) and current (n = 22) VIN-3 to those without current or past VIN (n = 86). HPV DNA was detected in vulvar and cervical samples with Hybrid Capture 2 (HC-2). Smoking was associated in multivariate analysis with current VIN-3 (odds ratio (OR) 8.3, 95% confidence interval (CI) 2.0-8.2) and any VIN-3 history (OR 6.5, 95% CI 2.5-16.5). High-risk HPV DNA was found on the vulva of 64%, 33%, and 20% of women with current VIN-3, past VIN-3, and without previous or current VIN, respectively. After controlling for age and smoking, high-risk HPV vulvar infection was associated with cervical high-risk HPV infection (OR 8.6, 95% CI 2.8-26.5; P = 0.001). After controlling for age, HPV infection was more often multifocal in women with current VIN-3 compared to women with previous but no current VIN-3 lesion (OR 17.6, 95% CI 1.4-227.2). Multifocal vulvar HPV infection was detected in women with previous or active VIN-3. Longitudinal studies are required to determine if the multifocality of HPV infection on the vulva could explain the high recurrence rate of VIN-3.     

Human papillomavirus infection and invasive cervical neoplasia: a study of prevalence and morphology

The prevalence of human papillomavirus (HPV) DNA sequences in 45 cervical cancer biopsies was examined with the hot-start polymerase chain reaction (PCR), employing HPV consensus primers from the L1 region. The cases comprised 38 squamous cell carcinomas, three adenosquamous carcinomas, and four adenocarcinomas. PCR products were typed with single-strand conformation polymorphism (SSCP) and the HPV types detected were correlated with tumour type. Forty-three biopsies were HPV-positive, HPV16 being the most prevalent type. HPV18/33/45/58 were also detected, but no low-risk or multiple types. Keratinizing squamous cell carcinoma was invariably associated with HPV16 and adenosquamous carcinoma and adenocarcinoma with HPVs 18/45. Non-keratinizing squamous cell carcinomas harboured all five detected types. Our data corroborate the view that malignant cervical tumours are almost invariably associated with high-risk HPV and that certain malignant cervical tumour phenotypes correlate with specific HPV types. © 1997 John Wiley & Sons, Ltd.     

The antigen-presenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium

The activation of HPV-specific T cells within the cervical microenvironment is likely to play an important part in the natural history of cervical intraepithelial neoplasia (CIN). The extent and the type of T cell activation will depend critically on the expression of MHC, costimulatory cell surface molecules and cytokines by keratinocytes and Langerhans cells within the cervical lesion. Expression of MHC class II (HLA-A-DR and -DQ), costimulatory/adhesion molecules (CD11a/18, CD50, CD54, CD58 and CD86) and cytokines (tumour necrosis factor-alpha (TNF-alpha) and IL-10) was therefore investigated by immunohistochemistry in normal squamous epithelium (n = 12), low-grade (n = 23) and high-grade (n = 18) squamous intraepithelial lesions of the cervix. CIN progression was associated with de novo expression of HLA-DR and CD54, and increased expression of CD58 by keratinocytes. However, significantly, there was no expression of any adhesion/costimulation molecule by epithelial Langerhans cells in any cervical biopsy studied. Furthermore, TNF-alpha, a potent activator of Langerhans cells, was expressed constitutively by basal keratinocytes in normal cervix (12+/12). but expression of this cytokine was absent in a number of CIN samples (20+/23 for low-grade, 12+/18 for high-grade CIN). Conversely, the suppressive cytokine IL-10 was absent in normal epithelium (0+/12), but was up-regulated in a number of CIN lesions (12+/23 for low-grade; 8+/18 for high-grade CIN). The restricted expression of costimulation/adhesion molecules and the nature of the cytokine microenvironment within the epithelium may act to limit effective immune responses in some CIN lesions.     

Detection of human papillomavirus in sanitary napkins: a new paradigm in cervical cancer screening

Human papillomavirus was successfully detected by polymerase chain reaction (PCR) in menstrual blood or vaginal discharge collected in sanitary napkins in 100% of 17 women having koilocytosis, cervical intraepithelial neoplasia, or squamous carcinoma. We advocate this form of cervical cancer screening because of its high sensitivity and acceptance by patients.     

LEEP术治疗宫颈上皮内瘤变的疗效分析

目的探讨高频电波刀环形电切除术（LEEP）治疗宫颈上皮内瘤变（CIN）的临床疗效。方法回顾性分析127例患者的临床资料,观察手术前后病理结果、手术时间、出血量和并发症等情况。每3-6个月及3个月后,每TCT或阴道镜复查的结果。结果手术平均时间3.5 min,术中平均出血10 mL;手术成功率91.3%,并发症发生率8.6%;术前与术后病理诊断结果一致占81.1%,所有手术标本切缘均阴性。结论 LEEP手术时间短,术中出血少,是治疗宫颈上皮内瘤变的首选方法。     

Genotyping of human papillomavirus in paraffin embedded cervical tissue samples from women in ethiopia and the Sudan

Cervical cancer is the most frequent female malignancy in most developing countries. Previous studies have demonstrated a strong association of human papillomavirus (HPV) infection with dysplasia and carcinoma of the uterine cervix. The objective of this study was to identify the prevailing HPV genotypes responsible for the development of cervical cancer among women in Ethiopia and the Sudan. A molecular characterization of HPV was done on 245 paraffin embedded cervical biopsy samples collected from the two countries. Amplification of HPV and subsequent genotyping was done using SPF10 primers and Line probe assay. Of samples collected from Ethiopian patients, 93% (149/160) and 13% (21/160) had high risk and low risk HPV genotypes, respectively. Among samples collected from the Sudan, 94% (80/85) harbored high risk and 11.7% (10/85) low risk HPV genotypes. Human papillomavirus 16 was the most frequent genotype identified in samples from Ethiopia (91%, 136/149) and the Sudan (82.5%, 66/80). HPV 52, 58, and 18 were the second, third and fourth common genotypes identified in Ethiopia, whereas HPV 18, 45, and 52 were the second, third, and fourth genotypes identified in samples collected from the Sudan. Thus, individuals living in different geographical localities should receive vaccines based on the specific genotypes circulating in the area and a vaccine targeting HPV 16, 18, 45, 52, and 58 may be optimal for the control of cervical cancer in the two countries. J. Med. Virol. 85:282–287, 2013. © 2012 Wiley Periodicals, Inc.