Fractal Analysis of Cervical Intraepithelial Neoplasia

Introduction

Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed.

Methods

Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist''s neoplasia grades with the predicted groups obtained by fractal methods.

Results

Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist''s grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia.

Conclusion

Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia.     

阴道镜检查在宫颈上皮内瘤样病变诊断中的价值

目的：探讨阴道镜检查在宫颈上皮内瘤样病变诊断中的价值。方法：回顾性分析我院自2004年10月至2006年6月528例阴道镜检查结果。结果：528例中行阴道镜和病理检查的有321例,阴道镜下诊断宫颈上皮内瘤样病变（CIN）76例,经病理确诊CIN51例,诊断符合率为67.11%;这两组用t检验,P〉0.05无统计学意义。同时行阴道镜检查和宫颈新柏氏膜式液基层细胞学检测（简称TCT）的324例患者进行分析表明,随着细胞学诊断分级的升高,阴道镜正常图像比例逐渐减少,异常图像比例逐渐增多。结论：阴道镜作为一种宫颈癌前病变和早期癌的重要方法之一,越来越受到临床医师的重视,它具有不与患者直接接触,对患者无任何损害,不造成任何不良影响,价格适中等优点,阴道镜可作为我国目前CIN和早期宫颈癌筛查的最佳方法,但最后确诊仍依靠病理学检查。     

Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer and Cervical Intraepithelial Neoplasia: A Meta-Analysis

Background

A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies.

Methods

Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models.

Results

A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59–0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49–0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population.

Conclusions

This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis.     

多个生物标志物预测宫颈上皮内瘤和宫颈癌的风险

目的:研究生物蛋白指标是否可以作为宫颈癌和高分级宫颈上皮内瘤样病变(CIN)的肿瘤标志物。方法:采用免疫组织化学方法检测包括宫颈内皮瘤和宫颈癌在内的292例标本中9个蛋白指标的表达,包括E-钙粘素(E-cadherin),细胞外信号调节激酶-1(ERK-1),基质金属蛋白酶-2(MMP-2),nm23-H1,核因子NF-κB,p16INK4A,存活素(survivin),人端粒酶逆转录酶(hTERT),血管内皮生长因子(VEGF-C),然后采用统计方法进行分析,构建变量模型,计算反映指标,与靶受体反应的特征曲线进行比较,确定上述蛋白标记物在预测宫颈癌存活率以及高分级CIN的作用。结果:所有个标记物中,nm23-H1及p16 INK4a对宫颈癌的生存率的单变量分析有明显的意义,在对所有标记物做细致详尽的分析后发现,其中3个标记物(E-钙粘素、VEGF-C、survivin)可对高分级的CIN进行预测。宫颈癌的生存率的有效的预测因子中,只有nm23-H1可以作为有效的预测因素。结论:联合检测多个生物蛋白,如E-钙粘素、VEGF-C、survivin指标可以有效的预测高危CIN的恶变风险,同时nm23-H1则可以为宫颈癌的预后提供参考。     

LEEP治疗宫颈上皮内瘤变疗效的临床研究

目的：探讨LEEP在宫颈上皮内瘤变（CIN）临床应用的安全性及有效性。方法：回顾性分析45例CIN患者治疗的临床资料。结果：45例LEEP手术过程中,患者无特殊不适,手术时间平均10±5 min,术中出血平均15±5 mL。术后病理报告与术前诊断相比完全符合18例,一致率为40%;病理升级13例,比率为28.89%;病理降级14例,比率为31.11%。其中16例LEEP患者再次行筋膜外子宫全切术,术后病检均未见到CIN的残留。1年后随访发现,16例经LEEP及筋膜外子宫全切术后,复查无异常,达到治愈。29例经单纯LEEP治疗后,27例治愈,2例治疗无效,再次行LEEP手术及药物治疗好转。结论：LEEP治疗CIN,安全有效,价格实惠,手术时间短,患者疼痛小,出血少,并且能够保留完整、连续的标本进行病检,明显降低CIN的漏诊率,值得临床应用。     

宫颈特殊染色技术对子宫颈癌及宫颈上皮内瘤变初筛的临床研究

目的:探讨宫颈特殊染色技术筛查方法对宫颈癌及癌前病变的筛查意义。方法:本研究通过对1963例就诊我院妇科门诊的患者进行宫颈特殊染色检查(FRD),以组织病理学检查结果为标准,分析FRD宫颈特殊染色的临床意义。结果:1963例患者行宫颈特殊染色检查及对初筛阳性患者行阴道镜下活检,根据活检病理结果进行分析,CINI阳性率80.77%℅,CINII81.25%,CINIII100%℅,侵润癌100%,总阳性率90.50%。结论:利用亚甲蓝显色和醋酸白化反应双重定位及指示,不仅可提高宫颈癌及癌前病变的检出率,而且操作简便,判读容易,结果快速,成本低廉。     

p16和bcl-2在宫颈上皮瘤样病变及宫颈癌中的表达

目的探讨p16和bcl-2表达产物在宫颈上皮瘤样病变及宫颈癌中表达的意义。方法对正常宫颈鳞状上皮、宫颈上皮内瘤变(CIN)和宫颈癌组织共69例,采用免疫组织化学EliVision法,对宫颈癌变过程中p16和bcl-2蛋白进行研究,将结果进行统计分析。结果p16蛋白在CIN中的表达高于正常宫颈上皮(P<0.01),在宫颈癌中的表达也高于正常宫颈上皮(P<0.01),且高于CIN中的表达(P<0.05);bcl-2蛋白在CIN中的表达高于正常宫颈上皮(P<0.01),在宫颈癌中的表达也高于正常宫颈上皮(P<0.01),但与CIN中表达无差异。p16和bcl-2两种蛋白在CIN和宫颈癌中的表达无明显差异。结论p16和bcl-2蛋白的表达与宫颈癌的发生有关,提示这两种蛋白有可能作为高危人群早期筛查的一种免疫组化指标。     

The Cytological Prediction of Cervical Intraepithelial Neoplasia In Colposcopically Directed Biopsies

The tissue sections and preceding cervical smears of 1262 women who had colposcopic cervical biopsies were reviewed and the reports correlated. Close correlation between the cytological and histological findings, to within one histological grade of cervical intraepithelial neoplasia (CIN), was noted in 86% of cases. However, the biopsy was negative, or contained evidence of wart virus infection only, in 24% of cases where dyskaryotic cells had been observed in the cervical smear. Of particular concern was the fact that negative histological findings were recorded in 13% of cases where the smear contained cells showing a moderate dyskaryosis and in 1.26% of cases where the smear showed severe dyskaryosis. This suggests that colposcopically directed biopsies do not always reflect the underlying pathological changes in the cervix. Management of these cases is discussed. In 45 women with a normal cervical smear prior to biopsy, histology revealed seven cases of CIN 3 and one case of invasive squamous carcinoma. This indicates that referral for colposcopy is advisable whenever there is clinical suspicion of cancer, even if the cervical smear report is normal.     

Cytology and Human Papillomavirus Co-Test Results Preceding Incident High-Grade Cervical Intraepithelial Neoplasia

Objective

High-risk HPV (hrHPV) and cytology co-testing is utilized for primary cervical cancer screening and for enhanced follow-up of women who are hrHPV-positive, cytology negative. However, data are lacking on the utility of this method to detect pre-cancer or cancer in community-based clinical practice. This study describes cytology and hrHPV results preceding high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer (i.e., CIN2+) in an integrated health system employing routine co-testing among women aged 30 years and older.

Methods

We conducted a cross-sectional analysis of adult female members of Kaiser Permanente Northern California (KPNC) with incident CIN2+ between July 2008 and June 2009. The primary outcome was the proportions of cytologic diagnoses and hrHPV co-test results preceding a diagnosis of CIN2+. Cervical cytology and hrHPV testing results were abstracted from electronic medical records.

Results

Of 1283 CIN2+ cases among adult women, 880 (68.5%) were among women aged 30 years and older and 145/880 (16.5%, 95% CI 14.1–19.1) had only normal cytology during the 12 months prior to diagnosis. Furthermore, 133/880 (15.1%, 95% 12.9–17.7) were preceded by only normal cytology and persistent hrHPV infection (at least 2 positive hrHPV tests) during the 6–36 months preceding CIN2+ diagnosis.

Conclusions

Incident CIN2+ is frequently preceded by normal cytology and persistent hrHPV infection among women aged 30 years and older; screening strategies that employ HPV testing and cytology may improve the detection of CIN2+ compared with cytology alone.     

Prevalence and Predictors of Colposcopic-Histopathologically Confirmed Cervical Intraepithelial Neoplasia in HIV-Infected Women in India

Background

Prevalence estimates of cervical intraepithelial neoplasia (CIN) among HIV-infected women in India have been based on cervical cytology, which may have underestimated true disease burden. We sought to better establish prevalence estimates and evaluate risk factors of CIN among HIV-infected women in Pune, India using colposcopy and histopathology as diagnostic tools.

Methodology

Previously unscreened, non-pregnant HIV-infected women underwent cervical cancer screening evaluation including standardized diagnostic colposcopy by a gynecologist. Histopathologic confirmation was conducted among consenting women with clinical suspicion of CIN. The prevalence of CIN was evaluated by a composite diagnosis based on colposcopy and histopathology results. Multivariable ordinal logistic regression analysis was conducted to determine independent predictors of increasing severity of CIN.

Results

The median age of the n = 303 enrolled HIV-infected women was 30 years (interquartile range, 27–34). A majority of the participants were widowed or separated (187/303, 61.7%), more than one-third (114/302, 37.7%) were not educated beyond primary school, and nearly two-thirds (196/301, 64.7%) had a family per capita income of <1,000 Indian Rupees (∼US$22) per month. Cervical high-risk HPV-DNA was detected in 41.7% (124/297) of participants. The composite colposcopic-histopathologic diagnoses revealed no evidence of CIN in 220 out of 303 (72.6%) women, CIN1 in 33/303 (10.9%), CIN2 in 31/303 (10.2%), CIN3 in 18/303 (5.9%) and 1 (0.3%) woman was diagnosed with ICC. Thus, over a quarter of the participants [83/303: 27.7% (95% CI: 22.7–33.1)] had ≥CIN1 lesions and a sixth [50/303: 16.5% (95% CI: 12.2–21.9)] had evidence of advanced (≥CIN2) neoplastic disease. The independent predictors of increasing severity of CIN as revealed by a proportional odds model using multivariable ordinal logistic regression included (i) currently receiving antiretroviral therapy [adjusted odds ratios (aOR): 2.24 (1.17, 4.26), p = 0.01] and (ii) presence of cervical high-risk HPV-DNA [aOR: 1.93 (1.13, 3.28), p = 0.02].

Conclusions

HIV-infected women in Pune, India have a substantial burden of cervical precancerous lesions, which may progress to invasive cervical cancer unless appropriately detected and treated. Increased attention should focus on recognizing and addressing this entirely preventable cancer among HIV-infected women, especially in the context of increasing longevity due to antiretroviral therapy.     

ProEx C 在宫颈癌及其癌前病变中的表达及意义

目的:探讨ProEx C在宫颈癌及其癌前病变中的表达及意义。方法:应用免疫组织化学SP法检测ProEx C在不同宫颈病变组织芯片中的表达。结果:ProEx C在宫颈炎、CINI、CINII、CINIII及宫颈癌中的阳性表达率分别是25%,51.7%,77.9%,90%,93.8%,且其表达在宫颈癌及CINIII级病变与宫颈炎及CINI级病变相比较差异具有统计学意义(P<0.05),ProEx C在CINI级组织中表达低于CINII级,差异具有统计学意义(P<0.05),ProEx C在浸润性宫颈癌中的表达与临床病理因素无关(P>0.05)。结论:ProEx C反映了细胞的增殖活性,促进宫颈癌的发生发展,可作为诊断及监测预后的指标。     

ProExC在宫颈癌及其癌前病变中的表达及意义

目的：探讨ProExC在宫颈癌及其癌前病变中的表达及意义。方法：应用免疫组织化学SP法检测ProExC在不同宫颈病变组织芯片中的表达。结果：ProExC在宫颈炎、C1NⅠ、CINⅡ、CINⅢ及宫颈癌中的阳性表达率分别是25％,51．7％,77．9％,90％,93．8％,且其表达在宫颈癌及CINⅡI级病变与宫颈炎及CINI级病变相比较差异具有统计学意义（P〈0．05）,ProExC在CINⅠ级组织中表达低于CINⅡ级,差异具有统计学意义（P〈0．05）,ProExC在浸润性宫颈癌中的表达与临床病理因素无关（P〉0．05）。结论：ProExC反映了细胞的增殖活性,促进宫颈癌的发生发展,可作为诊断及监测预后的指标。     

Immunohistochemical LRIG3 Expression in Cervical Intraepithelial Neoplasia and Invasive Squamous Cell Cervical Cancer: Association with Expression of Tumor Markers,Hormones, High-Risk HPV-Infection,Smoking and Patient Outcome

The novel biomarker LRIG3 is a member of the LRIG family (LRIG1-3). While LRIG1 has been associated with favorable prognosis and LRIG2 with poor prognosis in invasive cervical cancer, little is known about the role of LRIG3. The aim of this study was to investigate the expression of LRIG3 in invasive cancer and cervical intraepithelial neoplasia (CIN) for possible correlation with other tumor markers, to hormones and smoking, as a diagnostic adjunct in CIN, and prognostic value in invasive cancer. Cervical biopsies from 129 patients with invasive squamous cell carcinoma and 170 biopsies showing low grade and high grade CIN, or normal epithelium were stained for LRIG3 and 17 additional tumor markers. Among other variables the following were included: smoking habits, hormonal contraceptive use, serum progesterone, serum estradiol, high-risk HPV-infection, menopausal status and ten-year survival. In CIN, high expression of the tumor suppressors retinoblastoma protein, p53, and p16, and Ecadherin (cell-cell interaction), or low expression of CK10, correlated to LRIG3 expression. In addition, progestogenic contraceptive use correlated to high expression of LRIG3. In invasive cancer there was a correlation between expression of the major tumor promoter c-myc and high LRIG3 expression. High LRIG3 expression correlated significantly to presence of high-risk HPV infection in patients with normal epithelium and CIN. There was no correlation between LRIG3 expression and 10-year survival in patients with invasive cell cervical cancer. LRIG3 expression is associated with a number of molecular events in CIN. Expression also correlates to hormonal contraceptive use. The results on expression of other tumor markers suggest that LRIG3 is influenced by or influences a pattern of tumor markers in cancer and precancerous cells. Further studies are needed to elucidate if LRIG3 expression might be clinically useful.Key words: LRIG3, cervical cancer, cervical intraepithelial neoplasia, biological markers, human papillomavirus, hormonal contraceptives, smoking     

NFAT1和TWEAK在宫颈鳞癌及上皮内瘤变中表达的意义

目的：通过观察NFAT1和TWEAK在正常宫颈鳞状上皮、宫颈鳞状上皮上皮内瘤变、宫颈鳞癌中表达,探讨NFAT1和TWEAK表达情况在宫颈鳞癌发生和临床发展中的意义。方法：研究组织病例为档案病理蜡块,应用免疫组织化学技术检测NFAT1和TWEAK的表达;对宫颈鳞癌进行临床分期,分析NFAT1和Tweak表达与临床分期的相关性。结果：免疫组化结果显示,NFAT1阳性表达率在正常宫颈鳞状上皮、cINI级、CINII级、cINIIl级、鳞癌中分别为24．4％,24．5％,29．2％,72．7％,78．4％,各纽总体阳性表达率存在显著性差异,cINIII级与宫颈鳞癌中NFAT1表达率较宫颈正常上皮,CINI级,CINII级与cINIII级显著增高。TWEAK阳性表达率在正常宫颈鳞状上皮、CINI级、CINII级、cINⅢ级、鳞癌中分别为73．4％,66％,73．1％20．4％,19．6％,各组总体阳性表达率存在显著性差异。宫颈正常,CINI级,CINII级与CINIIIN．较CINⅢ与宫颈鳞癌中TWEAK表达率显著增高。NFATI和TWEAK表达相关性具有统计学意义。结论：NFAT1和TWEAK在正常宫颈上皮、宫颈上皮内瘤变、宫颈鳞癌中的表达存在差异且两者间表达存在相关性,NFAT1表达增加与宫颈鳞癌发生和肿瘤进展有关而TWEAK表达与宫颈癌发生呈负相关。     

宫颈上皮内瘤变治疗前后人乳头状瘤病毒载量的临床研究

目的:探讨宫颈上皮内瘤变(CIN)治疗前后人乳头状瘤病毒(HPV)载量与预后的意义.方法:从2006年6月～2009年9月间在新疆维吾尔自治区人民医院妇科门诊和妇科病房就诊的190例CIN患者,经宫颈环形电切术(LEEP)或宫颈冷刀锥切术治疗后进行1年随访,检测治疗前后HPV的载量,对病灶持续存在和复发进行分析.结果:CIN患者经LEEP或宫颈冷刀锥切术治疗后HPV平均载量较治疗前均显著降低(P＜0.01).随着HPV病毒载量持续时间越长,病变的持续存在率、复发率越高.结论:LEEP或宫颈冷刀锥切能显著降低CIN患者HPV载量,病毒载量影响疾病预后,其研究对随访和预后都有指导意义.     

TCT、阴道镜下活检和LEEP对CIN诊断价值的比较

目的：评价TCT检查、阴道镜活检和LEEP活检在宫颈上皮内瘤变（ClN）诊断中的价值,比较其差异。方法：对324例经TCT加阴道镜下活检诊断为CIN的患者进一步行LEEP,采用对比研究TCT、阴道镜下活检和IEEP活检病理结果。结果：TCT检查与阴道镜活检诊断结果的完全符合率为65．1％,TCT结果与LEEP活检病理学诊断结果的完全符合率为69．4％,诊断过度11．4％,诊断不足18．5％。阴道镜下宫颈活检结果与LEEP活检病理学诊断结果的完全符合率为68．2％,诊断过度21．9％,诊断不足9-3％,后两种方法的诊断结果差异有统计学意义（P〈O．01）。结论：TCT是辅助诊断CIN的有效方法;单独阴道镜下活检诊断CIN的准确性尚不够理想,阴道镜下活检不能替代LEEP活检;TCT诊断CIN者在初次治疗时可用LEEP一次完成诊断和治疗。     

TCT、阴道镜下活检和LEEP 对CIN 诊断价值的比较

目的:评价TCT检查、阴道镜活检和LEEP活检在宫颈上皮内瘤变(CIN)诊断中的价值,比较其差异。方法:对324例经TCT加阴道镜下活检诊断为CIN的患者进一步行LEEP,采用对比研究TCT、阴道镜下活检和IEEP活检病理结果。结果:TCT检查与阴道镜活检诊断结果的完全符合率为65.1%,TCT结果与LEEP活检病理学诊断结果的完全符合率为69.4%,诊断过度11.4%,诊断不足18.5%。阴道镜下宫颈活检结果与LEEP活检病理学诊断结果的完全符合率为68.2%,诊断过度21.9%,诊断不足9.3%,后两种方法的诊断结果差异有统计学意义(P<0.01)。结论:TCT是辅助诊断CIN的有效方法;单独阴道镜下活检诊断CIN的准确性尚不够理想,阴道镜下活检不能替代LEEP活检;TCT诊断CIN者在初次治疗时可用LEEP一次完成诊断和治疗。     

壮药金回合剂治疗宫颈上皮内瘤变、HPV 感染合并宫颈炎症 的疗效分析

目的:探讨壮药金回合剂治疗宫颈上皮内瘤变、HPV感染合并宫颈炎症的疗效。方法:将符合纳入标准的宫颈上皮内瘤变、HPV感染合并宫颈炎症患者,随机分为2组,各35例。观察组:壮药金回合剂宫颈上药,qod;对照组:安达芬拴宫颈上药,qod,比较两组临床疗效。结果:CINⅠ,观察组有效率为89.29%,对照组为65.38%,差异有显著性(P<0.05);而CINⅡ差异无显著性。HPV转阴,观察组转阴率为68.57%,对照组为45.71%,差异有显著性(P<0.05);宫颈炎改善情况比较,观察组有效率为94.29%,对照组为77.14%,差异有显著性(P<0.05)。全部患者在治疗过程中均未发现需要注意的不良反应。结论:壮药金回合剂治疗宫颈上皮内瘤变、HPV感染合并宫颈炎症,可恢复宫颈屏障功能,HPV转阴率高,疗效好。