子宫内膜癌的分子病理分型及其研究进展

子宫内膜癌是一种在分子水平及组织学上存在显著异质性的恶性肿瘤,不同的病理类型具有不同的生物学行为及组织学特征。与其他组织学亚型的晚期癌症相类似,早期子宫内膜样癌通常采用辅助放射治疗,浆液性子宫内膜癌通常采用化疗。因此,正确的亚型分类是选择合适的辅助治疗方案的关键。目前,临床上子宫内膜癌的分型依旧引用Bokhman分型及世界卫生组织（World Health Organization,WHO）病理类型分型。随着精准医疗及分子诊疗技术的全面推广,传统子宫内膜癌分型方法在子宫内膜癌的个体化治疗、预后评估及相关遗传病筛查上的局限性逐渐凸显。临床上亟需一种优化的分型方法提供确切的理论及实践依据。2013年美国癌症基因组图谱（The Cancer Genome Atlas,TCGA）研究中心通过整合基因组特征的方法确定了子宫内膜癌的分子分型,该分型与Bokhman分型及WHO分型相比,取得了与子宫内膜癌患者预后更强的关联性,为子宫内膜癌的分子诊疗拉开了序幕。     

重视子宫内膜癌分子分型的开展及应用

本文简要介绍了子宫内膜癌分子分型的变迁, 强调了推广应用分子分型对于子宫内膜癌治疗及预后的重要性并结合本期重点号栏目发表的论著, 阐述了不同分子分型检测技术之间的一致性与差异性, 以及结果判读时需要注意的问题。正确应用分子分型除了可以很好地指导子宫内膜癌的预后判断, 近年在临床治疗中的一些新的拓展应用也值得关注, 例如:对于保留生育功能治疗、淋巴结转移情况以及临床手术入路等的评估价值。本文还强调, 分子分型并不完美, 在应用时传统的组织病理形态不能丢弃, 将传统的病理形态学诊断与现代分子技术相结合, 方能更好地为子宫内膜癌患者提供精准的诊断以及恰当的个体化治疗。随着分子分型的推广应用, 国内需要更大范围地开展多中心研究, 并应建立临床、病理以及相关学科等多学科团队协作的诊疗团队, 就分型特征、临床后续放化疗以及免疫治疗方案的选择等进行更深入的研究, 使分子分型能真正为子宫内膜癌的诊治带来进步, 让患者受益。     

子宫内膜癌的分子分型及其对治疗影响的研究进展

子宫内膜癌是常见的女性生殖系统恶性肿瘤,具有显著的异质性。随着基因组学的深入研究以及精准医疗的需求,开展子宫内膜癌的分子分型势在必行,2020年新出版的第5版WHO女性生殖系统肿瘤分类已经在子宫内膜样癌分型中将分子遗传学特征整合到病理形态学分型中,这一变化将会提供更多的肿瘤生物学信息,筛选出可接收保守治疗以及从靶向治疗中受益的患者。本文结合子宫内膜癌的传统病理形态学分型,对子宫内膜癌的分子分型及其对临床治疗的影响进行综述。     

细胞黏附分子L1在子宫内膜癌组织中的表达及其在预后评估中的作用

目的:研究子宫内膜癌组织中L1细胞黏附分子(L1CAM)的表达,探讨L1CAM表达与子宫内膜癌患者预后的相关性。方法:回顾分析2012年1月至2017年6月于南通大学附属丹阳医院妇产科行手术治疗的300例子宫内膜癌患者的临床病理资料。HE染色及免疫组化法检测子宫内膜癌组织中L1CAM表达,Log-rank检验方法进行单因素分析,采用Cox回归模型进行多因素分析。结果:300例子宫内膜癌患者中,L1CAM表达阳性者45例(15.0%)。单因素分析结果表明L1CAM表达阳性与子宫内膜癌宫外转移、淋巴结受累、组织分化差、淋巴血管间隙浸润、宫颈间质浸润及年龄大于65岁密切相关(P0.05),而与深肌层浸润(50%或以上)、肿瘤直径2cm以上、体重指数等无显著相关。多因素分析结果显示,L1CAM阳性、子宫内膜样腺癌分级、非子宫内膜样腺癌、肌层浸润≥50%及腹膜细胞学检查阳性与子宫内膜癌患者的生存预后相关(P0.05);而将L1CAM表达阳性作为独立变量分析,其与中危组和高危组的子宫内膜癌患者预后密切相关(P0.05)。结论:L1CAM表达可能与子宫内膜样腺癌的侵袭转移、腹腔外复发和低生存率密切相关,但L1CAM表达在子宫内膜癌患者治疗预后的作用需进一步研究。     

分子靶向药物用于晚期或复发子宫内膜癌的研究进展

子宫内膜癌是女性生殖系统常见的恶性肿瘤,晚期或复发子宫内膜癌患者往往失去了手术时机,治疗较为棘手,以药物治疗为主,因此药物治疗受到广泛的关注和研究。分子靶向药物是近年新兴的抗肿瘤药物,在一些恶性肿瘤的防治中已经彰显成效。近年晚期或复发子宫内膜癌药物治疗的新策略转向应用针对肿瘤发展特异性生物环节的分子靶向药物,其中一些药物已进入临床研究阶段,并证实在延长患者生存期、缓解症状、提高生活质量及耐受性方面优于传统的化疗。现就分子靶向药物在晚期或复发子宫内膜癌中的应用进展作一综述。     

13例子宫内膜癌合并多原发恶性肿瘤临床分析

目的 提高对子宫内膜癌合并多原发性恶性肿瘤认识;方法 采用回顾性分析方法。对1982年7月-1999年8月我院共收治201例子宫内膜癌患者中合并多原发性恶性肿瘤患者的临床资料及治疗结果进行分析;结果13/201例子宫内膜癌合并多原发性恶性肿瘤(6％),其中同时性多原发恶性肿瘤6例(2.98％),平均发病年龄51.4岁,发生部位在卵巢、结肠及乳腺;异时性多原发恶性肿瘤7例(3.5％),第一恶性肿瘤年龄46.4岁,子宫内膜癌发病年龄54.5岁,发生部位乳腺、肾脏、卵巢、脑及结肠。治疗均以手术为主的综合治疗;结论 重视子宫内膜癌合并多原发性恶性肿瘤,高危患者定期复查,早发现,早治疗。     

二甲双胍用于子宫内膜癌预防和治疗的研究进展

随着代谢性疾病发病率不断升高,子宫内膜癌的发病率不断增长,发病年龄趋于年轻化。前期研究发现,二甲双胍在多种生殖道恶性肿瘤的预防和治疗中发挥着重要作用。流行病学显示,二甲双胍可降低糖尿病患者子宫内膜癌的发病风险,提高子宫内膜癌患者的总生存率和无瘤生存期。本文就二甲双胍在子宫内膜癌预防和治疗方面的研究进展做一综述。     

窖蛋白1及p38丝裂原活化蛋白激酶在良、恶性子宫内膜组织中的表达及其临床意义

子宫内膜癌是女性生殖系统三大恶性肿瘤之一,而目前子宫内膜癌的发病机制还不是十分清楚,因此研究子宫内膜癌发病的分子途径、寻找以分子为靶点的治疗途径成为焦点.     

子宫内膜癌术后可否应用绝经激素治疗

关于子宫内膜癌患者绝经激素治疗(MHT)的研究尚有限,大部分医生考虑到雌激素是子宫内膜癌的重要发病因素之一,并不建议给予子宫内膜癌患者术后MHT。目前认为子宫内膜癌并不是MHT的绝对禁忌证,选择恰当的剂量和药物种类不会引起子宫内膜癌术后复发以及病死率增加,并可提高子宫内膜癌患者治疗后生存质量和起到适当保护作用。由于数据大部分来自具有选择偏差的回顾性研究或小型前瞻性非随机研究。因此,医生在评估子宫内膜癌患者术后是否需要MHT时一定要充分考虑利弊,个体化治疗。     

子宫内膜癌分子分型特征及治疗价值的探讨

子宫内膜癌是最常见的女性生殖道恶性肿瘤,其发病率及病死率逐年提高且呈年轻化的趋势。既往子宫内膜癌的分类主要根据形态学特征,但由于此分类方式主观性大,可重复性低,对预后的预测价值有限。现提出子宫内膜癌的分子分型,它不仅可以协助诊断林奇综合征(Lynch综合征),而且可以辅助子宫内膜癌患者进行风险分层、指导预后并提供精准治疗,应用前景良好。本文就子宫内膜癌从传统分类到新型分子分型的进展、治疗价值及其面临的挑战、前景等方面进行综述。     

子宫浆液性癌的分子学特征及靶向治疗研究进展

子宫浆液性癌（uterine serous carcinoma,USC）是一种特殊类型的子宫内膜癌。有别于常见的子宫内膜样腺癌,USC较为少见,且恶性程度高,侵袭转移风险高,临床上预后较差。随着子宫内膜癌分子学研究的不断深入,分子学特征被应用于子宫内膜癌的病理分型诊断、治疗和预后评价中。研究发现USC中存在多种基因的突变,这些相关基因的突变对该病的诊断和预后具有重要的指导意义。同时,特异性的分子学改变为USC的靶向治疗提供了潜在的治疗靶点。目前,多种靶向治疗手段包括人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）抑制剂、免疫检查点抑制剂、抗血管生成治疗、磷脂酰肌醇3激酶（phosphoinositide 3-kinases,PI3K）通路抑制剂和多腺苷二磷酸核糖聚合酶[poly(ADP-ribose) polymerase,PARP]抑制剂等被应用于USC的临床治疗研究中,针对性的靶向治疗有望成为USC治疗的新突破。     

子宫内膜癌分子特征指导术后辅助治疗选择

子宫内膜癌是女性生殖道常见的恶性肿瘤,在我国发病率仅次于宫颈癌,治疗方式包括手术治疗及辅助治疗（放疗、化疗和内分泌治疗等）,通常应用于Ⅰb～Ⅳ期患者。然而,过度治疗和无效治疗会导致部分Ⅰ～Ⅱ期患者治疗后复发,并导致高级别（grade 3,G3）子宫内膜样腺癌（endometrial endometroid carcinoma,EEC）临床结局差异显著。分子特征评价可指导病理疑难型和罕见型子宫内膜癌患者精准治疗,多聚酶ε基因（POLE）突变型子宫内膜癌铂类化疗耐药性高,部分抗细胞毒性T淋巴细胞相关抗原4/细胞程序性死亡蛋白1（CTLA4/PD1）及磷脂酰肌醇3激酶/有丝分裂原活化蛋白激酶（PI3K/MEK）治疗有效;错配修复基因表达缺陷型子宫内膜癌常规放化疗耐药性高,部分抗细胞程序性死亡蛋白配体1/融合蛋白（PD-L1/B7-H4）治疗有效;高拷贝数变异型子宫内膜癌PI3K及周期蛋白依赖性激酶（CDK）抑制剂联合应用效果较好,还可考虑降低区域扩增基因表达水平相关靶向治疗;低拷贝数变异型子宫内膜癌鼠双微体蛋白4（MDM4）抑制剂治疗可能有效。通过层次聚类分析发现预后相关基因与子宫内膜癌预后显著相关,检测其表达水平可与分子分型相结合预测患者预后。现就美国癌症基因组计划（The Cancer Genome Atlas,TCGA）分子分型与本课题组发现的预后相关基因在子宫内膜癌精准辅助治疗中的临床意义作一总结。     

子宫内膜癌分型的研究进展

子宫内膜癌(endometrial carcinoma)是妇科三大恶性肿瘤之一,以手术联合放、化疗为标准治疗方式;部分渴望保留生育能力的患者可经咨询后行保守治疗,待生育后进行手术。1983年,Bockman提出子宫内膜癌临床分型,将其分为Ⅰ型(雌激素依赖型)和Ⅱ型(非雌激素依赖型);1994年,Poulsen将子宫内膜癌按组织病理学分为腺癌、浆液性腺癌、黏液性腺癌、透明细胞癌、鳞状细胞癌、混合性癌和未分化癌;2013年,癌症基因组图谱(The Cancer Genome Atlas,TCGA)根据不同突变方式和拷贝数将子宫内膜癌分为4种,即POLE(DNA polymerase epsilon)突变型、微卫星不稳定高突变型、低拷贝数型和高拷贝数型。该分子分型对不同亚型患者的精准化治疗与预测患者预后具有重要指导意义。本文总结了子宫内膜癌的3种分型的优势与局限性及其临床意义。子宫内膜癌分型的不断完善,将有助于理解其预后的个体差异,指导治疗策略的选择,为精准医疗时代规范化、个体化、人性化的治疗奠定理论基础。     

Molecular carcinogenesis of endometrial cancer

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.     

Molecular genetic characterization of tamoxifen-associated endometrial cancer

OBJECTIVES: The non-steroidal, selective estrogen receptor modulator tamoxifen is currently the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical trials have shown an increased risk of endometrial cancer with tamoxifen exposure; however, few studies have examined these tumors on a molecular level. We sought to elucidate the molecular genetic alterations found in tamoxifen-associated endometrial cancer. METHODS: Twenty-nine breast cancer patients with a history of tamoxifen use who subsequently developed endometrial cancer were retrospectively identified and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumor tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PTEN, K-RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher's Exact Test was utilized for statistical analyses. RESULTS: Of 29 tamoxifen-associated cancers, 10 (34.5%) contained PTEN mutations compared to 13 (44.8%) of the non-tamoxifen-associated cancers (P = 0.59). All PTEN mutations were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite instability were present in similar frequencies between the two breast cancer groups, and moreover, these were similar to mutational frequencies found in sporadic endometrial cancer. CONCLUSION: Tamoxifen and non-tamoxifen-associated endometrial carcinomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.     

Recurrent fallopian tube carcinoma: TP53 mutation and clinical course.

Primary fallopian tube carcinoma is a rare, aggressive gynecological cancer; little is known about its cause. Previous studies have indicated that p53 immunopositivity is correlated with short-term survival in primary fallopian tube carcinoma. We examined p53 and p21/WAF1 immunostaining and TP53 mutation in exons 5 to 8 by single-stranded conformation polymorphism and constant denaturant gel electrophoresis in nine cases of primary fallopian tube carcinoma and their metastases/recurrences from patients who survived for between a few months and more than 20 years after diagnosis. We found that 1.) p53 immunopositivity without detectable p21/WAF1 immunostaining did not correlate with TP53 mutations in the conserved domains; 2.) mutations in TP53 occurred in two metastases/recurrences but not in their corresponding primary tumors; 3.) in two cancers, a TP53 mutation was observed in the primary tumor but not in the metastases/recurrences; 4.) constant denaturant gel electrophoresis seems to be more sensitive than single-stranded conformation polymorphism in detecting TP53 mutations; and 5.) in the nine cases studied, p53 immunoreactivity and/or TP53 mutation analysis did not correlate with tumor progression, survival, or response to treatment.     

Molecular Pathogenesis of Uterine Serous Carcinoma

Uterine serous carcinoma (USC) is a biologically aggressive cancer with a high relapse rate and poor prognosis. USC is characterized by frequent TP53 gene mutations. Identical TP53 mutations are conserved during progression from precursor lesions, indicating that mutation of the TP53 gene plays an important role in USC progression and is considered a key event in the initiation of USC. A high frequency of HER2/neu overexpression has also been reported, suggesting the possibility of therapeutic targeting of HER2/neu. In addition, USC is reported to have a high frequency of genomic alterations affecting PIK3CA, PPP2R1A, FBXW7, CHD4/Mi2b, and TAF1. Recent studies investigating microRNAs have presented new information on tumor progression. The molecular genetic profiles of USC differ from those of endometrioid subtypes; thus, understanding genetic alterations in USC will help to explain differences in the behaviors of these cancers and may provide possible novel therapeutic targets for USC.     

Dualistic model of molecular pathogenesis in endometrial carcinoma

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.     

Hypoxia contributes to development of recurrent endometrial carcinoma

Tumor hypoxia can trigger the induction of angiogenesis. High microvessel density (MVD) as well as hypoxia-inducible factor-1alpha (HIF-1alpha) have been related to recurrent disease and tumor aggressiveness, respectively. In this study, MVD and hypoxic status were investigated in primary and recurrent endometrial carcinomas. A total of 65 primary tumors of patients with recurrent endometrial carcinoma (n = 40), and without recurrent endometrial carcinoma (n = 25) were studied. Immunohistochemical analysis was performed on paraffin-embedded tumor tissue. MVD was determined by quantitative analysis of CD31/FVIII positive vessels. Tumor hypoxia was estimated by evaluating the expression of the hypoxia-regulated gene HIF-1alphaand its target gene carbonic anhydrase IX (CA-IX). An additional 23 recurrent tumors were available for determination of MVD and HIF-1alpha expression. Effects of hypoxia on tumor protein p53 (TP53) expression were evaluated in the endometrial cancer cell lines (ECC-1), Ishikawa (derived from adenocarcinomas), and AN3CA (derived from a lymph node metastasis). MVD, CA-IX, and HIF-1alpha expression were not significantly different in primary tumors of patients with recurrence compared to the control tumors. The MVD was significantly lower, and HIF-1alpha expression was significantly higher in recurrent tumors when compared with their primary tumors (paired t test, P < 0.05). HIF-1alpha expression correlated well with TP53 expression levels in primary tumors, but not in recurrences. TP53 protein levels were highest in AN3CA cells. Hypoxic conditions induced TP53 protein in ECC-1 and Ishikawa, but not AN3CA cells. We conclude that MVD, CA-IX, and HIF-1alpha expression are not independent prognostic markers for recurrent endometrial carcinoma. The low MVD, increased HIF-1alpha protein levels, dissociation of hypoxia, and TP53 protein induction in the metastatic tumor cells (AN3CA) support a role for hypoxia in the development of recurrent endometrial carcinoma.