Heritability and molecular genetic studies of endometriosis

Endometriosis is a common disease defined as the growth of endometrial tissue outside the uterine cavity that often results in a vast array of gynaecological problems including dyspareunia, dysmenorrhoea, pelvic pain and infertility. Despite the increasing evidence that supports a genetic component to this common gynaecological condition, the basic aetiology and pathogenesis of endometriosis remain unknown. It is likely that endometriosis is a common polygenic/multifactorial disease caused by an interaction between multiple genes as well as the environment. Such conditions do not have a clear Mendelian pattern of inheritance. Recent molecular cytogenetic studies on endometriotic tissue and an established endometriosis-derived cell line provide novel evidence that acquired chromosome-specific alterations may be involved in endometriosis, possibly reflecting clonal expansion of chromosomally abnormal cells. Molecular DNA studies examining the role of loss of heterozygosity in endometriotic lesions has identified candidate tumour suppressor gene loci, including 5q, 6q, 9p, 11q and 22q, that may play a role in the malignant transformation of endometriotic implants to endometrioid ovarian cancers. Evidence of mutations in the tumour suppressor PTEN gene in the endometrioid subtype of epithelial ovarian cancer further suggests that somatic genetic alterations represent early events in the transformation of benign endometriotic cells. Genetic factors are also likely to influence individual susceptibility to endometriosis. There is now evidence that heritable allelic differences in drug-metabolizing enzymes play an important role in the development of endometriosis. Further studies are warranted to identify major susceptibility gene(s) and the mechanism involved in endometriosis to assist in the development of better methods for early detection, diagnosis and prevention.     

子宫内膜癌合并多原发性肿瘤

【目的】探讨子宫内膜癌合并多原发癌的发生率、病因、诊断及预后。【方法】对45例子宫内膜癌合并多原发癌的临床及病理资料进行回顾性分析。【结果】本组子宫内膜癌合并多原发癌的发生率为3.2%(45/1389);异期癌两癌发生间隔时间最短8个月,最长19年;间隔5年以上者62%(16/26);子宫内膜癌合并生殖器官恶性肿瘤53%(24/45),其中大部分为同期癌(19/24);合并乳腺癌16%(7/45);合并大肠癌11%(5/45)。先期癌的临床分期中、早期者87%,治疗均采用相应的根治性治疗,其中31%(8/26)有放疗史,23%(6/26)有化疗史。本组多原发癌的治疗,全部为根治性治疗,5年生存率为63%。【结论】①必须警惕子宫内膜癌合并生殖器官、乳腺、大肠等器官多原发癌的发生;②子宫内膜癌合并多原发癌的病因可能与共同的胚胎来源、共同的雌激素受体、放射线、抗癌药物的使用等因素有关。     

PTEN、p53在子宫内膜浆液性癌和宫内膜样癌中的表达及临床病理意义

目的研究PTEN和p53在子宫内膜浆液性癌和宫内膜癌中的表达及临床病理意义。方法应用免疫组化方法检测26例宫内膜浆液性癌、42例宫内膜样癌和25例正常增生期宫内膜组织中PTEN、p53蛋白的表达。结果PTEN和p53蛋白在子宫浆液性癌、宫内膜样癌、正常增生期内膜中的阳性表达率分别为86.4%、28.6%、100%和76.9%、27.3%、0%。PTEN在子宫内膜样癌中阳性表达率明显低于浆液性癌(P<0.001)。p53蛋白表达与子宫内膜癌组织学类型、临床分期、病理分级、肌层浸润等因素有关(P<0.05)。结论PTEN突变和表达缺失与宫内膜样癌的发生、发展有关。p53基因突变和过表达与宫内膜浆液性癌发生发展关系密切。PTEN及p53蛋白检测对鉴别子宫浆液性癌与宫内膜样癌有重要价值。     

Expression of immunoreactivity of nuclear findings by p53 and cyclin a in endometrial cytology: Comparison with endometrial glandular and stromal breakdown and endometrioid adenocarcinoma grade 1

It is well known that “condensed cluster of stromal cells (CCSC)” and “metaplastic clumps with irregular protrusion (MCIP)” in endometrial glandular and stromal breakdown (EGBD) cases may simulate “clumps of cancer cells (CCC)” in endometrioid adenocarcinoma grade 1 (G1), leading to difficulty in cytological interpretation. The aim of this study was undertaken to clarify the cytological immunoreactivity of nuclear findings about CCSC and MCIP which may be recognized in EGBD cases by using p53 protein and cyclin A in liquid‐based cytologic (LBC) preparations. The material consists of cytologic smears of 20 cases of EGBD and 20 cases of G1 for which histopathological diagnosis was obtained by endometrial curettage at the JA Suzuka General Hospital. The evaluation of immunoreactivity was performed by using the intensity of nuclear staining and the nuclear labeling index (N‐LI). The intensity of nuclear staining was scored as negative (0), weak (1), moderate (2), or strong (3). The N‐LI was scored as less than 10% (0), from 10 to 25% (1), from 26 to 50% (2), or greater than 50% (3). The final score was calculated of the addition of both partial scores. Results are as follows: As for the p53 protein immunoreactivity, CCC (2.4 ± 1.4) was a significantly higher value in comparison with CCSC (0) and MCIP (0.8 ± 0.4), respectively. As for the cyclin A immunoreactivity, CCC (2.8 ± 1.1) was a significantly higher value in comparison with CCSC (0) and MCIP (0.6 ± 0.5), respectively. CCSC and MCIP in EGBD are misunderstood as cellular atypia and structural atypia on occasion; but, as for results of the immunoreactivity scores of p53 protein and cyclin A in our study, it seemed that those biochemical characters proved that the biological activity level was low (or degenerative). The results of the current study demonstrated that the cytological immunoreactivity of nuclear findings by p53 and cyclin A appear to be more useful for the LBC assessment of endometrial lesions, especially for the discrimination of EGBD and G1.Diagn. Cytopathol. 2013;41:303–307. © 2011 Wiley Periodicals, Inc.     

子宫内膜癌浸润肌层深度及原发灶体积预测其淋巴结转移

目的 观察依据术前MRI所示子宫内膜癌(EC)浸润肌层深度联合原发灶体积预测其淋巴结转移的价值。方法 回顾性分析255例经术后病理确诊的EC患者,以盆腔MRI评估EC浸润肌层深度(浸及深肌层或浅肌层),并测量原发灶体积。采用单因素及多因素logistic回归分析筛选EC淋巴结转移的独立预测因素,并建立联合模型回归方程;绘制各参数及联合模型的受试者工作特征(ROC)曲线,计算曲线下面积(AUC),评估其预测EC淋巴结转移的效能。结果 255例中,EC浸及深肌层91例、浅肌层164例; 25例淋巴结转移、230例无淋巴结转移。术前MRI显示EC浸润肌层深度及原发灶体积是淋巴结转移的独立预测因素(P均＜0.05),以之构建联合模型回归方程,即Logit(P)=－3.73+0.02×原发灶体积+2.06×MRI浸润肌层深度,以之预测EC淋巴结转移的AUC为0.83,高于单一EC浸润肌层深度及原发灶体积(AUC=0.77、0.78,Z=2.61、2.27,P均＜0.05)。结论 术前根据MRI所示EC浸润肌层深度联合原发灶体积可预测淋巴结转移。     

Uncommon ovarian epithelial tumours

Epithelial ovarian tumours represent the most common type of ovarian tumour. Most of malignant cases represent high-grade serous, clear cell and endometrioid carcinomas; borderline serous and mucinous tumours of intestinal type are less common. This review focuses on the uncommon or rare epithelial tumours of the ovary which include borderline and malignant Brenner tumours, the recently-described mesonephric-like carcinoma of the ovary, and primary ovarian neuroendocrine tumours, with emphasis on helpful and diagnostic features.     

Utility of Ki‐67, p53, Bcl‐2, and Cox‐2 biomarkers for low‐grade endometrial cancer and disordered proliferative/benign hyperplastic endometrium by imprint cytology

In this report, the authors examined the characteristic features of morphology and molecular biology of Ki‐67, p53, Bcl‐2, and cyclooxygenase‐2 (Cox‐2) immunocytochemistry in low‐grade endometrioid endometrial carcinoma (LG‐ENEC) and disordered proliferative (DP)/benign hyperplastic (BH) endometrium. We carried out a prospective study by collecting endometrial imprints from freshly resected uteri over a 20‐month period and finally 104 patients were evaluated with endometrial cytology. We focused on LG‐ENECs, as well as on BH endometrium and its precursor lesion, DP endometrium, firstly because of the overlapping cytomorphology of these pathologic entities and secondly because of the lack of agreement in the differential diagnosis of atypical hyperplasia from complex hyperplasia and well‐differentiated endometrial carcinoma, even in curettage specimens. Ki‐67 expression of LG‐ENEC showed predominance in comparison with DP/BH endometrium. Furthermore, high levels of Bcl‐2 (>50%) were expressed only in DP/BH endometrium. DP/BH endometrium was negative for p53 marker, except from two cases of BH endometrium. Cox‐2 expression ≥50% was found only in LG‐ENECs. Using Ki‐67, Bcl‐2, p53, and Cox‐2 markers, we managed to distinguish fully DP/BH endometrium from LG‐ENEC. Higher Ki‐67%/Bcl‐2% rate and also higher Cox‐2 expression were found in LG‐ENEC cases with FIGO stage ≥ IC, than in cases with FIGO stage < IC. The immunocytochemical findings from a combination of Ki‐67, p53, Bcl‐2, and Cox‐2, may differentiate LG‐ENEC from DP/BH endometrium with overlapping cytomorphology. Immunocytochemistry appeared to be useful also for the correlation between LG‐ENEC and FIGO stage. Diagn. Cytopathol. 2014;42: 134–142. © 2013 Wiley Periodicals, Inc.     

卵巢子宫内膜样腺癌组织中细胞角蛋白、CA125、抑制素α的表达及临床意义

目的:观察卵巢子宫内膜样腺癌组织中细胞角蛋白(CKpan)、糖类抗原125(CA125)、抑制素α(inhibinα)表达水平,探究其临床意义。方法:选取2012年1月至2015年1月河南科技大学第一附属医院收治的卵巢子宫内膜样腺癌患者73例,通过手术取其卵巢子宫内膜样腺癌组织。另选择73例因宫颈癌切除卵巢且无卵巢转移患者的正常卵巢组织作为对照。采用免疫组织化学染色法检测CKpan,CA125和inhibinα的表达水平,分析CKpan,CA125,inhibinα与卵巢子宫内膜样腺癌临床病理特征及预后关系。结果:正常卵巢组织、子宫内膜异位症卵巢组织、卵巢子宫内膜样腺癌组织中CKpan和CA125表达率依次升高,两两比较差异有统计学意义(P<0.05);正常卵巢组织、子宫内膜异位症卵巢组织、卵巢子宫内膜样腺癌组织中inhibinα表达率依次降低,两两比较差异有统计学意义(P<0.05);CKpan与CA125蛋白表达呈正相关(r=0.476,P<0.05),CKpan与inhibinα蛋白表达呈负相关(r=-0.493,P<0.05),CA125与inhibinα蛋白表达呈负相关(r=-0.473,P<0.05)。CKpan,CA125,inhibinα蛋白表达均与分化程度、肌层浸润、FIGO分期、淋巴结是否转移有关(P<0.05);CKpan,CA125高表达组3年存活率、中位生存时间均显著低于低表达组(P<0.05);inhibinα低表达组3年存活率、中位生存时间显著低于高表达组(P<0.05)。低分化、FIGO分期III^IV、淋巴结转移、CKpan高表达、CA125高表达是影响卵巢子宫内膜样腺癌患者预后的独立危险因素(均P<0.05);inhibinα高表达是独立保护因素(P<0.05)。结论:CKpan,CA125在卵巢子宫内膜样腺癌组织中高表达率高,inhibinα高表达率低,三者与卵巢子宫内膜样腺癌患者分化程度、肌层浸润、FIGO分期、淋巴结转移等临床病理参数及预后密切相关,可能参与卵巢子宫内膜样腺癌发生发展。     

CIP2A在子宫内膜样腺癌中的表达及临床意义

目的:探究蛋白磷酸酶2A(CIP2A)在子宫内膜样腺癌中的表达情况及临床意义。方法:选取2011年1月至2014年3月行手术切除并经病理证实的50例子宫内膜样腺癌(EAC)及同期行门诊刮宫术获取的40例正常增生期子宫内膜(NE)组织标本。应用RT-PCR、Western blot法检测EAC和NE组织中CIP2A mRNA及蛋白水平,免疫组化法检测CIP2A阳性表达情况。分析CIP2A在EAC和NE组织中的表达差异及与子宫内膜样腺癌临床病理特征的关系。采用Kaplan-Meier法分析CIP2A不同表达水平对患者预后生存的影响,通过COX分析预后独立危险因素。结果:免疫组化染色显示:CIP2A在子宫内膜样腺癌中呈高表达,阳性着色定位于细胞浆和细胞核中,EAC组织中CIP2A阳性表达率显著高于NE组织(P＜0.01)。RT-PCR和Western blot检测显示EAC组织中CIP2A mRNA及蛋白表达水平高于NE组织(P＜0.01)。CIP2A表达与EAC的组织学分级、FIGO分期、宫颈管受累情况、p53表达及Ki-67增殖指数有关（P＜0.05）。Kaplan-Meier法生存分析显示EAC患者5年无病生存率为92.0%、总生存率为88.0%;CIP2A表达、组织学分级、FIGO分期、肌层浸润深度、附件转移、脉管内癌栓及Ki-67增殖指数与患者预后不良相关（P＜0.05）。多因素分析显示,组织学分级、FIGO分期及脉管内癌栓是影响子宫内膜样腺癌患者预后生存的独立危险因素（P＜0.05）。结论:CIP2A在子宫内膜样腺癌中呈高表达,与患者总生存率下降相关,并非影响患者预后的独立危险因素。     

宫颈与宫体子宫内膜样腺癌的临床病理及免疫表型分析

目的探讨宫颈子宫内膜样腺癌和宫体子宫内膜样腺癌的临床病理和免疫表型差异。方法采用HE及免疫组化En-Vision两步法对8例宫颈内膜样腺癌和76例宫体内膜样腺癌的组织学形态和免疫表型进行比较观察。结果宫颈子宫内膜样腺癌和宫体子宫内膜样腺癌在组织学形态上相似。两组标本的免疫标记物阳性率分别为vimentin(0,95.45%)、CEA(100%,45.45%)、p53(12.50%,31.82%)、ER(0,54.54%)、PR(0,60.61%)、Ki-67(75.0%,12.12%)、HPV16/18(100%,3.03%)、p16(100%,46.97%)、Cam5.2(12.50%,62.12%)。两者相比,vimentin、CEA、ER、PR、p16、Ki-67、HPV16/18、PAS、Cam5.2的表达差异有显著性(P<0.05),而p53的表达差异无统计学意义(P>0.05)。结论应用免疫标记物vimentin、CEA、ER、PR、p16、Ki-67、HPV16/18、PAS、Cam5.2检测是鉴别宫颈和宫体子宫内膜样腺癌的一种重要的有效方法,p53可作为辅助鉴别的免疫标记物。