大剂量孕激素治疗子宫内膜不典型增生及早期子宫内膜癌的疗效及妊娠结局分析

目的:探讨大剂量孕激素治疗子宫内膜不典型增生及早期子宫内膜癌的疗效及妊娠结局。方法:选择2014年1月至2018年12月广州医科大学附属第三医院就诊的年轻且有生育要求的子宫内膜不典型增生患者24例及早期子宫内膜样腺癌患者6例,分析应用大剂量孕激素保守治疗的临床效果及妊娠结局。结果:24例子宫内膜不典型增生患者中完全缓解20例(83.33%),部分缓解0例,疾病稳定1例(4.17%),疾病进展1例(4.17%),疾病复发2例(8.33%);20例完全缓解中1例未婚,余19例中成功妊娠10例(52.63%),其中4例足月分娩,3例孕中期双胎流产,2例孕早期流产,1例孕早期随访中;2例疾病复发患者继续药物治疗后均完全缓解,其中1例自然受孕后足月分娩。6例早期高分化子宫内膜样腺癌完全缓解3例(50.00%),部分缓解0例,疾病稳定2例(33.33%),疾病进展0例,疾病复发1例(16.67%);疾病稳定2例最终行子宫内膜癌全面分期手术,余4例保留生育功能患者目前未成功妊娠。结论:密切随访下,大剂量孕激素治疗子宫内膜不典型增生和早期子宫内膜癌是安全有效的。     

子宫内膜增生并发子宫内膜癌的高危因素及预后分析

目的:研究子宫内膜增生患者并发子宫内膜癌的高危因素及其预后的分析。方法:回顾性分析2014年1月至2015年1月行全子宫切除术,且术前诊断性刮宫(诊刮)提示子宫内膜增生的74例患者的临床资料。根据全子宫切除术后的病理结果分为子宫内膜癌组(28例)和子宫内膜增生组(46例),对两组的临床特征进行比较,并分析发生子宫内膜癌的高危因素。结果:①74例患者中37.8%(28/74)并发子宫内膜癌。单因素和多因素分析结果均提示:年龄≥48岁和诊刮病理为重度子宫内膜不典型增生(重度AEH)为发生子宫内膜癌的高危因素(P0.05)。②不伴任何高危因素、伴有1个高危因素和2个高危因素的患者并发子宫内膜癌的几率分别为5.0%(1/20)、46.2%(12/26)和81.8%(9/11),差异有统计学意义(P0.05),且随着高危因素数目的增加发生子宫内膜癌的风险显著升高(OR 16.3,95%CI 1.9~140.3,P=0.011;OR 85.5,95%CI 6.8~1071.3,P=0.001)。③28例并发子宫内膜癌患者均为早期子宫内膜样癌,25例为高分化,3例为中分化。平均随诊13.3±6.3月,没有患者复发或死亡。结论:子宫内膜增生患者并发子宫内膜癌的发生率较高,特别是对于高龄(≥48岁)、诊刮病理为重度AEH的患者并发风险显著增加,但并发的子宫内膜癌多为分化较好的早期子宫内膜样癌,近期预后良好。     

子宫内膜不典型增生患者的内膜癌漏诊因素分析

目的:探讨子宫内膜不典型增生患者子宫内膜癌漏诊的因素及合理治疗方案。方法:回顾分析132例子宫内膜不典型增生子宫切除前后的临床病理资料。根据术前内膜取样方式分为宫腔镜组与诊刮组,比较两种方式的诊断符合率。比较术前病理与术中冰冻病理、术后常规病理,分析其主要临床病理资料。结果:132子宫内膜不典型增生患者中,术后证实为子宫内膜癌者42例(31.82%)。诊刮组的内膜癌漏诊率为32.99%(32/97),高于宫腔镜组28.75%(10/35),但无统计学差异(P0.05)。42例内膜癌患者中,95.24%(40/42)为子宫内膜样腺癌,ⅠA期38例(90.48%),高分化癌34例(80.95%)。术中行冰冻病理检查者115例,其中11例子宫内膜癌漏诊。长期月经紊乱、未生育患者子宫内膜癌漏诊的风险增高。结论:子宫内膜病理诊断为不典型增生的患者有子宫内膜癌漏诊的风险,尤其是长期月经紊乱、未生育的女性。子宫内膜不典型增生的治疗应采取个体化治疗方案。     

生育年龄妇女子宫内膜不曲型增生与复合增生的诊…

本文研究对生育年龄妇女中的１７例不典型增生和４例复合增生的初诊和随诊时的刮宫标本，以及其中１２例经手术切除手术切除的子宫标本进行观察与分析。本组中除１例在短期内切除子宫外，２０例均经反复的孕激素治疗，随衣２～３８年。２例重度不典型增生发展为浸润癌，４例复合增生和２例轻度不典型增生分别于初诊后一年内受孕，足月分娩。本文对子宫内膜不典型增生和复合增生的组织形态学诊断及预后进行了讨论。     

子宫内膜增生性疾病患者内膜细胞凋亡的研究

目的 :研究凋亡在子宫内膜增生性疾病中的作用。方法 :用改良原位末端标记技术检测 15例正常月经周期的增生期、分泌期、月经期子宫内膜 ,11例增殖性子宫内膜 ,12例子宫内膜癌 ,以及术前用孕激素治疗的 13例异常增生子宫内膜中的凋亡细胞 ,并计算其凋亡指数 (AI)。结果 :分泌期、月经期子宫内膜、增殖性子宫内膜、子宫内膜癌AI均比正常增生期子宫内膜AI高 (P <0 .0 1)。增殖症患者内膜不典型增生组AI比单纯增生、复杂增生组AI高 (P <0 .0 5 ) ;内膜癌患者低分化组AI比高分化组、中分化组AI高 (P <0 .0 5 )。结论 :细胞凋亡与正常子宫内膜周期性变化有关 ,而在增殖性和癌变子宫内膜中的异常表达可能与子宫内膜的良恶性病变有关     

早期高分化子宫内膜癌及子宫内膜不典型增生患者保留生育功能治疗的结局分析

目的:探讨早期高分化子宫内膜癌及子宫内膜不典型增生患者保留生育功能治疗的结局。方法:回顾性分析2010年1月至2017年12月就诊于北京大学第三医院要求保留生育功能的早期高分化子宫内膜癌患者43例及不典型增生患者77例的临床病理资料及治疗结局。结果:保守治疗的完全缓解(CR)率为96.67%(116/120),不典型增生组患者保守治疗3个月CR的比例显著高于子宫内膜癌组(74.03%vs 41.86%,P0.05)。109例患者有妊娠要求,妊娠率为43.12%(47/109)、活产率为33.03%(36/109)。分析显示,体质量指数(BMI)、是否癌变及合并有糖尿病或胰岛素抵抗与治疗缓解后能否成功妊娠有关(P0.05),而治疗获得CR的时间及缓解后维持治疗与妊娠无关(P0.05)。复发率为32.76%(38/116),中位复发间隔为17月,是否癌变(RR 5.624)是影响复发的独立危险因素(P0.05),达CR后的维持治疗(RR 0.385)及妊娠(RR 0.382)是影响复发的保护性因素(P0.05)。子宫内膜癌组的中位复发间隔为13月,子宫内膜不典型增生组为24月,两组差异有统计学意义(P0.05)。复发后重复孕激素治疗的有效率为100.00%(31/31)。结论:早期高分化子宫内膜癌和不典型增生的有生育要求的患者,保守治疗安全有效。保守治疗3个月子宫内膜不典型增生疗效好于子宫内膜癌。BMI、是否合并糖尿病和胰岛素抵抗及癌变与其妊娠有关,治疗达CR后的维持治疗并不影响妊娠,但治疗后复发率较高,妊娠和维持治疗是预防复发的保护因素。复发后重复保守治疗仍然有效。     

孕激素与子宫内膜增生和子宫内膜癌

应用孕激素可以在一定程度上抑制子宫内膜增生及子宫内膜癌的发生.孕激素广泛应用于治疗部分子宫内膜增生患者和需保留生育能力以及晚期、复发等情况的子宫内膜癌患者,取得一定疗效.阐述孕激素与子宫内膜增生、子宫内膜癌发生的关系及其治疗机理和临床应用.     

子宫内膜增殖症诊治的研究进展

子宫内膜增殖症是子宫内膜腺体增生和（或）腺体间质比例增加的子宫内膜增生性病变，雌激素刺激子宫内膜而无孕激素抵抗被认为是主要的致病风险因素，其确切病因仍未完全明确。子宫内膜增殖症目前主要根据病理结果分类为子宫内膜增生不伴不典型和子宫内膜不典型增生，其中子宫内膜不典型增生被认为是Ⅰ型子宫内膜癌的癌前病变。诊断子宫内膜增殖症需结合病史、影像学、细胞学，以组织学结果为最终诊断依据。子宫内膜增殖症的治疗主要分为药物治疗和手术治疗，具体采用的治疗方法主要依据子宫内膜增生的类型和患者的生育要求。本文从子宫内膜增殖症的概念、分型、发病机制、诊断、治疗等几个方面进行综述。     

复发性子宫内膜增生症处理原则

文章对复发性子宫内膜增生的诊断和监测方法、管理及治疗等复发性子宫内膜增生的相关问题结合国内外最新指南进行了讨论。复发性子宫内膜增生最佳的保守性治疗根据子宫内膜组织学分类决定,对无不典型子宫内膜增生,可用随访和连续口服孕激素持续6个月,或放置左炔诺孕酮宫内缓释系统（LNG-IUS）。无生育要求者推荐应用LNS-IUS 5年;对随访中进展为内膜不典型增生、接受药物治疗12个月仍无组织学缓解、子宫不规则出血持续存在、绝经后复发性子宫内膜增生等,均应手术切除子宫治疗。     

孕激素与子宫内膜增生和子宫内膜癌

应用孕激素可以在一定程度上抑制子宫内膜增生及子宫内膜癌的发生。孕激素广泛应用于治疗部分子宫内膜增生患者和需保留生育能力以及晚期、复发等情况的子宫内膜癌患者，取得一定疗效。阐述孕激素与子宫内膜增生、子宫内膜癌发生的关系及其治疗机理和临床应用。     

40岁以下子宫内膜腺癌患者的孕激素治疗--附六例报告及文献复习

目的 评价孕激素治疗40岁以下高分化、早期子宫内膜腺癌患者的有效性和安全性.方法回顾性分析复旦大学附属肿瘤医院1996年至2004年以孕激素治疗作为初次治疗的6例 40岁以下的高分化、早期子宫内膜腺癌患者的临床病理资料;同时检索近10年的国内外相关研究报道,发现相关病例56例,对以上两组资料进行综合分析.结果本组6例患者中,4例孕激素治疗有效,2例无效者行手术治疗.4例有效者中,2例分别于治疗后10个月和12个月出现复发而行手术治疗,故共有4例行子宫切除术,术后病理检查均未发现子宫外转移.6例患者随访至今均无瘤生存.文献报道的56例患者中,46例孕激素治疗有效,其中11例复发者中7例再次采用孕激素治疗,且5例再次获得完全缓解.此56例中,共有16例行手术治疗,15例无瘤生存,1例术后出现盆腔复发.本组6例患者治疗后无妊娠和分娩;文献报道的56例患者中,共有41次妊娠,并分娩40个婴儿,其中双胎4例,三胎2例.结论孕激素治疗40岁以下高分化、早期子宫内膜腺癌我们的经验尚少,虽难作评价,但国内外文献报道是安全可行的,并可达到妊娠和分娩的目的.     

PTEN、bcl-2/Bax表达预测子宫内膜增生孕激素治疗反应的研究

目的:研究孕激素治疗前后子宫内膜增生组织中PTEN基因、bcl-2/Bax的表达,结合临床治疗效果探讨其在预测孕激素治疗反应中的作用。方法:回顾分析子宫内膜增生患者56例(复杂性增生31例,非典型性增生25例),孕激素治疗3个月,留取治疗前后子宫内膜组织,取石蜡切片进行免疫组化染色,应用H-score评价孕激素治疗前后子宫内膜腺体中PTEN、bcl-2/Bax的表达。结果:(1)56例患者治疗3个月后,44例(78.57%)缓解,7例(12.50%)有效,1例(1.79%)治疗后复发,4例(7.14%)治疗无效,平均随访(33.49±9.62)个月。复杂性增生、轻度非典型性增生和中重度非典型性增生3组缓解+有效率的差异无统计学意义(P=0.245)。(2)子宫内膜增生组织中PTEN基因表达缺失率为16.07%(9/56),PTEN表达阳性组缓解+有效率为97.87%(46/47),PTEN表达阴性组缓解+有效率为55.56%(5/9),两组间比较差异有统计学意义(P<0.05)。(3)56例患者孕激素治疗前后子宫内膜腺体中bcl-2及Bax表达均阳性。缓解和有效组与复发和无效组治疗前bcl-2/Bax的H-score值无明显差异(P=0.486),两组治疗前后H-score差值亦无明显差异(P=0.368)。结论:子宫内膜增生组织中PTEN基因表达阳性组对孕激素治疗反应较好,PTEN基因表达缺失可能提示病变对孕激素抵抗,因此治疗前检测子宫内膜腺体细胞中PTEN基因的表达可以预测疗效;bcl-2/Bax不能作为预测孕激素治疗反应的指标。     

Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review

OBJECTIVE: We reviewed reported cases of grade 1 endometrial adenocarcinoma that were conservatively managed with hormonal therapy in an effort to identify the most effective treatment regimen. METHODS: We searched MEDLINE and other databases for English-language articles describing patients with grade 1 endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and December 2003. The following key words were used: endometrial cancer, uterine cancer, adenocarcinoma, hormones, progesterone, medroxyprogesterone acetate, megestrol acetate, conservative therapy, fertility, and female. A total of 79 articles were found. Studies were excluded for the following reasons: advanced stage, metastatic or recurrent disease, progestin use after radiation, chemotherapy, or surgery, concurrent with radiation therapy or chemotherapy, administration of progestin other than orally or intramuscularly, tumor confined to a polyp, grade 2 or 3 disease, undocumented grade, nonendometrioid histology, progestin use in conjunction with ovarian wedge resection or other hormones, and hyperplasia. Our study ultimately included 81 patients in 27 articles. RESULTS: Sixty-two patients (76%) responded to treatment. The median time to response was 12 weeks (range, 4-60 weeks). Fifteen patients (24%) who initially responded to treatment recurred. The median time to recurrence was 19 months (range, 6-44 months). Ten (67%) of the patients with recurrence ultimately underwent total abdominal hysterectomy. Residual endometrial carcinoma was found in six patients (60%). Nineteen patients never responded. Twenty patients were able to become pregnant at least once after completing treatment. The median follow-up was 36 weeks (range, 0 weeks-30 years). No patients died of their disease. CONCLUSION: The majority of patients reported with well-differentiated endometrial adenocarcinoma who undergo conservative treatment with a progestational agent respond to treatment. When an initial response is not achieved or when disease recurs, carcinoma extending beyond the uterus is rare.     

Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review

Objective

The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy.

Methods

A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fisher's exact test was used to calculate statistical differences.

Results

Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p = .002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p = .03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p = .02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p = .39), with 117 live births reported.

Conclusion

Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.     

Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma

OBJECTIVE: To evaluate whether an alternative treatment to radical hysterectomy exists for young women with endometrial adenocarcinoma. DESIGN: A review of the literature (70 articles) plus personal results. SETTING: University hospital. PATIENT(S): Women with atypical endometrial hyperplasia or adenocarcinoma. MAIN OUTCOME MEASURE(S): The recurrence rate and the pregnancy rate after conservative therapy. CONCLUSION(S): Conservative treatment of well-differentiated stage I endometrial adenocarcinoma can be considered in young patients, with close surveillance to diagnose any possible recurrence.     

Expression of cyclin D1 in normal,hyperplastic and neoplastic endometrium and its correlation with Ki-67 and clinicopathological variables

Methods We investigated cyclin D1 expression in proliferative endometrium, endometrial hyperplasia and endometrioid adenocarcinoma, and examined the correlation of cyclin D1 expression with Ki67 as a cell proliferation associated marker. Immunohistochemical expression of cyclin D1 and Ki67 were studied in 30 cases with endometrial carcinoma, 14 cases with atypical hyperplasia, 15 cases with simple hyperplasia and 30 cases with proliferative endometrium.Results One out of 30 patients (3.3%) with proliferative endometrium, 1 out of 14 patients (7.1%) with atypical hyperplasia, and 8 out of 30 patients (26.6%) with endometrial carcinoma were found to have immunoreactivity to cyclin D1. All cases of simple hyperplasia had negative staining for cyclin D1. A positive immunoreaction for Ki67 was obtained in all cases. Statistically significant difference was found in cyclin D1 immunoreactivity between both proliferative endometrium and adenocarcinoma, and simple hyperplasia and adenocarcinoma (p<0.05). In patients with adenocarcinoma, cyclin D1 immunoreactive cases had higher mean Ki67 values compared with the non-immunoreactive ones (p<0.05). Ki67 and cyclin D1 immunoreactivity had no impact on overall survival. Univariate analysis revealed a significant relationship between survival and grade and stage (p<0.01). Cyclin D1 expression was not correlated with age, depth of myometrial invasion, lymphovascular space involvement, grade, lymph node metastasis and stage.Conclusion Cyclin D1 expression in endometrial carcinoma is higher than proliferative endometrium and simple hyperplasia. These findings support that cyclin D1 may play a role in endometrial carcinogenesis.     

Development of metastatic endometrial endometrioid adenocarcinoma while on progestin therapy for endometrial hyperplasia

BACKGROUND: Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. CASE: A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. CONCLUSION: Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.     

45岁以下子宫内膜癌患者的临床分析

目的　总结 45岁以下子宫内膜癌患者的临床特点。方法　回顾性分析北京协和医院52例 45岁以下子宫内膜癌患者的临床资料 ,并将其分为≤ 3 5岁年龄组 (A组 ,17例 )与 3 5～ 45岁年龄组 (B组 ,3 5例 )进行比较分析。结果　 45岁以下内膜癌患者占内膜癌总数的 12 7% ,随年龄的增加 ,发病人数有增加的趋势 ,约 50 %的患者合并未产、不育、月经失调、子宫内膜增生 ,2 9%合并肥胖 ,2 3 %合并多囊卵巢 ,其中A组合并多囊卵巢的比例为 53 % ,合并内膜不典型增生的比例为 59% ,较B组明显增高 (分别为 9%、2 6% ) ,差异有显著性 (P <0 0 5)。按国际妇产科联盟 (FIGO)标准手术病理分期Ⅰ期占 82 % ,其中A组均为Ⅰ期子宫内膜样腺癌 ;B组有高危因素的患者比例占 2 6% ,但除了分期有升高的趋势 (P <0 0 5)外 ,其余差异均无显著性 (P >0 0 5)。治疗以手术为主 ,另有 2例患者采用孕激素治疗保留生育功能 ,获得缓解。 2例复发。结论　 45岁以下子宫内膜癌患者多合并不育、月经失调、内膜增生、肥胖、多囊卵巢 ,表明其发生与雌激素有关 ;期别以Ⅰ期为主 ,尤其是≤ 3 5岁者 ,高危因素少 ,预后较好。对于早期 (Ⅰa期 ) 45岁以下内膜癌患者可考虑保留生育功能或卵巢     

Reevaluating the safety of fertility-sparing hormonal therapy for early endometrial cancer

OBJECTIVE: To evaluate the safety of fertility-sparing hormonal therapy for endometrial cancer in young patients. METHODS: Six patients diagnosed with endometrial adenocarcinoma grade I and had undergone progestin treatment were reviewed. Four patients failed progestin treatment and were then found at surgery to have both endometrial and ovarian cancers. A clonality assay using the human androgen receptor gene as the X-linked polymorphic marker and immunohistochemistry for steroid hormone receptor expression were used to delineate the relation between the endometrial and ovarian lesions and to explore possible causes of treatment failure. RESULTS: The patients were followed for a mean of 48.8 months. Four of the six responded to the treatment at a mean of 3.5 months. Two of these patients had a recurrence within a mean of 4.5 months after their initial response. Two patients did not respond to progestin treatment. At surgery in those 4, both endometrial and ovarian tumors were found. All 6 are still alive, and 2 successfully delivered healthy infants. The clonality assay revealed an independent cell origin for the endometrial and ovarian lesions in 2 of the 4 women who failed progestin treatment. Progesterone receptors were absent in both endometrial and ovarian tumors in 2 of these 4 patients. CONCLUSION: The absence of progesterone receptors may relate to the failure of progestin treatment. The use of progestin treatment for well-differentiated early endometrial carcinoma should be cautious and requires very careful clinical evaluation before and after treatment.