年轻子宫内膜癌及不典型增生患者孕激素保留生育功能治疗的疗效及妊娠分析

发布时间：2018-02-08 13:12

本文关键词： 子宫内膜样腺癌子宫内膜非典型增生保留生育功能辅助生殖技术妊娠　出处：《天津医科大学》2017年博士论文　论文类型：学位论文

【摘要】：研究背景和目的:子宫内膜癌常见于围绝经期及绝经后的女性,近些年来,子宫内膜癌的发病率呈现逐年上升并且显现出年轻化的趋势,40岁以下的患者所占比例上升可以达到14%,其中年龄小于40岁的患者中有约80%以上的患者未曾生育或者仍然有再生育的愿望。因此尝试保留年轻并且有生育要求的子宫内膜癌患者的生育功能,是目前妇科临床和生殖医学领域的热点问题。由于子宫内膜癌常常较早出现临床症状,被诊断时多数处于疾病早期,预后相对较好,并且多数病例对激素治疗敏感,这为年轻的子宫内膜癌患者进行保留生育功能的治疗提供了依据。子宫内膜癌保留生育功能的治疗目前仍缺乏大样本的随机对照临床试验,2012年NCC N指南首次提到年轻子宫内膜癌患者保留生育功能治疗,直到2016年NCCN指南仍只是建议年轻子宫内膜癌保留生育功能的治疗的适应症,在治疗的诸多方面尚未取得共识,如孕激素治疗的用量、治疗时间、治疗后的后续治疗及随访仍未明确,目前尚没有预测孕激素治疗效果的相关分子指标。本研究采用前瞻性的研究方法,采用大剂量口服孕激素为主同时配合口服二甲双胍、他莫昔芬及宫腔镜下子宫内膜病灶切除术治疗早期子宫内膜癌及子宫内膜非典型增生的患者,对符合纳入标准的就诊于天津市中心妇产科医院的早期子宫内膜癌及子宫内膜非典型增生患者共36例进行调查分析,总结临床资料,分析治疗效果、妊娠结局、生存结局及相关影响因素。本研究的目的在于进一步验证早期子宫内膜癌及子宫内膜非典型增生患者保留生育功能治疗的安全性及有效性,并尝试为预测影响妊娠率的相关因素提供参考指标。研究对象和方法::研究对象的入选标准:(1)年龄≤40岁并有强烈的保留生育功能的愿望及要求;(2)组织病理学诊断为高分化子宫内膜样腺癌或子宫内膜非典型增生;(3)免疫组织化学染色测定孕激素受体阳性。(4)无血清CA125的升高;(5)经阴道彩色多普勒超声检查(T VS)和/或核磁共振(MRI)检查未发现有肌层浸润以及宫颈实质的受累,未发现子宫外转移的证据;(6)无应用相关药物的禁忌症;(7)具备密切随访的条件,依从性良好;(8)理解保留生育功能治疗的利弊,强烈要求进行保留生育功能的治疗并签署知情选择同意书。研究方法:所有患者保守治疗前均行宫腔镜检查+全面清宫术,既能达到明确诊断又能减少肿瘤负荷的目的。从月经或宫腔镜检查诊刮后的第五天开始周期性(21天)口服醋酸甲地孕酮(MA)160 mg/天,停药来月经后第五天再开始下一周期的治疗,停药2周不来月经者为避免无治疗间隔的延长,则改为连续性口服醋酸甲地孕酮160 mg/天治疗,免疫组化测定孕激素受体(P R)指数低于50%者加枸橼酸他莫昔芬20 mg/天口服,治疗前有糖尿病或胰岛素抵抗者加二甲双胍750 mg/天口服。治疗过程中如T VS或MRI检查提示有宫腔占位性病变,则行宫腔镜下子宫内膜病灶电切术,术后再继续口服M A160 mg/日治疗。每3个周期治疗后行宫腔镜检查及全面诊刮术获得子宫内膜组织送病理检查评估子宫内膜的变化。子宫内膜获得病理完全缓解后即转入辅助生殖中心助孕,争取早日妊娠。结果:研究共纳入17例子宫内膜样腺癌(E C)和19例子宫内膜非典型增生(AE H)患者,中位年龄31岁。大剂量口服孕激素为主的保守治疗有31例患者(86.1%)获得完全反应(CR),2例患者(5.6%)获得部分反应(PR),2例患者(5.6%)病情稳定(SD),1例患者(2.8%)疾病进展(PD)。获得病理完全反应的平均时间为8.26±0.87个月。其中有1例患者因发生严重不良反应(双下肢静脉血栓)而终止治疗,最终因并发腹膜癌而行手术治疗。平均随访26.17±2.60个月,复发率为19.4%(6/31),平均复发时间为29.5±5.64个月,6例复发患者中2例患者接受手术治疗,4例患者再次进行保留生育功能治疗,其中2例患者获得病理完全反应,2例患者仍在保守治疗中。截至最后一次随访全部保守治疗的患者有32例患者无疾病生存,4例患者带病存活。进行保留生育功能治疗后子宫内膜病理获得完全反应并且有迫切生育愿望的患者共25例,9例患者妊娠11次,妊娠率为36%,获得活产儿4名,生育率为16%。从停止保守治疗到获得妊娠的时间平均为7.33±0.83个月。结论:本课题采用前瞻性的研究方法,应用口服大剂量孕激素为主配合口服二甲双胍、他莫昔芬及宫腔镜下子宫内膜病灶切除术保留生育功能治疗早期子宫内膜癌和子宫内膜非典型增生的患者,多种方式联合保守治疗的方案国内外报道少见。获得了较满意的逆转率和一定的妊娠率,86.1%获得完全反应,36%妊娠,人工辅助生殖技术显著提高了妊娠率。1 9.4%的患者出现复发,全部患者32例无疾病生存,4例带病存活。
[Abstract]:Background and objective: endometrial cancer is common in perimenopausal and postmenopausal women, in recent years, the incidence of endometrial cancer has been rising and showing the trend of younger patients under the age of 40, the proportion reached 14%, of which less than 40 years of age with more than about 80% patients not birth or still have fertility desire. So try to keep young and endometrial cancer patients with fertility requirements of reproductive function, is a hot issue in clinical gynecology and reproductive medicine at present. Due to endometrial cancer often appears early clinical symptoms, was diagnosed at most in the early stage of the disease, the prognosis is relatively good, and most a case sensitive to hormone therapy, which provides a basis for endometrial carcinoma in young patients with the fertility sparing treatment. The treatment of endometrial cancer with reproductive function preserved There is still a lack of randomized controlled clinical trials of large sample, the 2012 NCC N guide was first mentioned in the young patients with endometrial carcinoma fertility preserving treatment, treatment until the 2016 NCCN guidelines still recommend young endometrial cancer to preserve fertility indications, no consensus in many aspects of treatment, such as the dosage of progestin therapy, treatment time, follow-up treatment and follow-up after treatment is not clear, there is no related molecular markers to predict the effect of progesterone treatment. This study used a prospective research method, with large doses of oral progesterone hormone mainly with oral metformin, tamoxifen and hysteroscopic endometrial resection in treatment of patients with early endometrial cancer and endometrial atypical hyperplasia, met the inclusion criteria from Tianjin Central Obstetrics and Gynecology Hospital during early endometrial cancer and Endometrial atypical hyperplasia patients with a total of 36 cases were investigated and analyzed, summarized the clinical data, analysis of the treatment effect, pregnancy outcome and related factors of survival outcomes. The purpose of this study is to further verify the early endometrial cancer and endometrial atypical hyperplasia patients with preserved fertility safety and effectiveness of treatment, and try to predict the impact of related factors of pregnancy rate and provide reference index. The research object and methods: the inclusion criteria: (1) the desire and requirement of older than 40 years of age and have strong reproductive function preserved; (2) the histopathological diagnosis was well differentiated endometrioid adenocarcinoma or atypical endometrial hyperplasia (3); Determination of progesterone receptor positive immunohistochemical staining. (4) elevated serum free CA125; (5) transvaginal color Doppler ultrasound (T VS) and / or nuclear magnetic resonance (MRI) examination found no myometrial invasion and The essence of cervical involvement, no evidence is found outside the uterus transfer; (6) no contraindications to application related drugs; (7) with close follow-up, good compliance; (8) to understand the advantages and disadvantages of fertility treatment, strong demand for fertility sparing treatment and signed informed consent. The method of selection conservative treatment all patients underwent hysteroscopy and curettage can achieve comprehensive, clear diagnosis and reduce the tumor burden. Starting from menstrual periodic or hysteroscopy curettage after fifth days (21 days) oral megestrol acetate (MA) mg/ 160 days, fifth days after stopping menstruation before the start of the next cycle of treatment, drug withdrawal for 2 weeks to avoid prolonged menstruation does not come without the treatment interval, instead of continuous oral megestrol acetate 160 mg/ days of treatment, immunohistochemical determination of progesterone receptor (P R) index of less than 50% with citric acid Tamoxifen 20 mg/ day orally, have diabetes or insulin resistance plus metformin 750 mg/ day oral before treatment. The treatment process such as T VS or MRI examinations showed uterine cavity lesions, underwent hysteroscopic endometrial lesion resection, M A160 mg/, and then continue to oral therapy after operation. 3 cycle treatment by hysteroscopy and curettage was full of endometrial tissue for pathological examination to assess the changes of the uterine endometrium. Endometrial pathological complete remission after moving into the center of assisted reproduction pregnancy, early pregnancy. Results: there were 17 cases of endometrioid adenocarcinoma (E C) and 19 cases of endometrial atypical hyperplasia (AE H) with a median age of 31 years. Large dose of oral progesterone conservative treatment of 31 patients (86.1%) achieved a complete response (CR), 2 patients (5.6%) received partial response (PR), 2 patients stable disease (SD (5.6%) ), 1 patients (2.8%) disease progression (PD). The average time of pathological complete response was 8.26 + 0.87 months. There were 1 patients due to serious adverse reaction (deep vein thrombosis) and eventually discontinued treatment due to complicated peritoneal carcinoma treated surgically. The average follow-up was 26.17 + 2.60 months and the recurrence rate was 19.4% (6/31), the average recurrence time was 29.5 + 5.64 months, 6 cases of recurrence in 2 patients who underwent surgical treatment, 4 patients again fertility preserving treatment, including 2 cases of patients with pathological complete response, 2 patients were still in the conservative treatment at the end of follow-up. All the patients were treated conservatively and 32 cases were disease-free survival, 4 patients living with the disease. To preserve fertility after treatment of endometrial pathology obtained complete response and there is an urgent desire to procreate with a total of 25 cases, 9 patients with 11 pregnancies, the pregnancy rate was 36%, achieved live Children 4, the fertility rate is obtained from the 16%. to stop pregnancy conservative treatment for an average of 7.33 + 0.83 months. Conclusion: this topic using prospective research method, the application of high-dose oral progesterone combined with oral metformin, tamoxifen and hysteroscopic endometrial resection to preserve the fertility of the treatment of early endometrial cancer and endometrial atypical hyperplasia patients, the combination of various methods of conservative treatment scheme is rarely reported at home and abroad. The reversal rate is satisfactory and the pregnancy rate was 86.1%, achieved a complete response, 36% pregnancy, assisted reproductive technology can significantly improve the pregnancy rate of 9.4% patients with.1 recurrence, all 32 patients with disease-free survival. 4 patients living with the disease.

【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.33

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