Successful conservative treatment of endometrial carcinoma permitting subsequent pregnancy: report of two cases

Two women with endometrial carcinoma who wished to preserve their childbearing ability received conservative treatment by medroxyprogesterone acetate (MPA, 600 mg/day for 22 weeks and 29 weeks, respectively). Following regression of endometrial lesions, their infertility was treated by inducing ovulation. Intact pregnancy was diagnosed 13 months and 11 months after completion of the MPA treatment, respectively. One patient had a twin pregnancy and delivered two infants at 35 weeks of gestational age. The other patient delivered a full-term baby. They had no evidence of recurrence 60 months and 31 months after the conservative treatment, respectively. We believe this conservative treatment with progestin may be safely performed for young patients with endometrial cancer who wish to preserve their fertility.     

Pregnancy outcomes of women who received conservative therapy for endometrial carcinoma or atypical endometrial hyperplasia

Case

Approximately 3%‐25% of cases of endometrial carcinoma (EC) or atypical endometrial hyperplasia (AH) occur in women aged <40 years and conservative treatment with high‐dose medroxyprogesterone acetate (MPA) is administered to women who wish to preserve their fertility. Here is reported the pregnancy outcomes of patients with EC or AH who received MPA therapy at Tokushima University Hospital, Tokushima, Japan. The frequency of pregnancy and live births among the patients with EC or AH who received conservative treatment, followed by fertility treatment, were analyzed retrospectively.

Outcome

Twelve patients underwent fertility examinations and received fertility treatment immediately after the completion of conservative treatment for EC or AH. One patient had the complication of severe diabetes and total embryo cryopreservation was performed before her diabetes was treated. Among the other 11 patients, 8 (72.7%) became pregnant at least once and 6 (54.5%) experienced at least 1 live birth. Three patients (25.0%) suffered disease recurrence during or after the infertility treatment and all of the recurrences occurred in the EC cohort.

Conclusion

When patients with EC or AH wish to preserve their fertility, it is recommended that prompt and effective fertility treatment, including assisted reproductive technology, should be initiated just after conservative treatment because EC and AH exhibit relatively high recurrence rates among conservatively treated patients.     

Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma

OBJECTIVE: Progestin is an effective endocrine treatment for patients with atypical hyperplasia or with endometrial carcinoma that is estrogen receptor (ER) positive and progesterone receptor (PR) positive. However, long-term progestin treatment may lead to resistance. We have studied the progestin resistance phenotype that frequently develops in endometrial carcinoma. METHODS: Ishikawa endometrial carcinoma cells were cultured for a long period (10 months) in the presence of the synthetic progestin medroxyprogesterone acetate (MPA), thereby generating a subline refractory to the growth-suppressive effects of MPA. RESULTS: The MPA-resistant subline showed growth stimulation rather than inhibition after MPA treatment. Immunocytochemical analysis showed reduced ER alpha and PR-B expression and increased ER beta expression in this subline compared with parental Ishikawa cells. Progestin-resistant Ishikawa cells also showed increased expression of transforming growth factor alpha (TGFalpha), the epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK); MPA treatment further stimulated the expression of TGFalpha in these cells. Additionally, progestin-resistant Ishikawa cells were highly sensitive to growth stimulation by TGFalpha and to growth inhibition by the EGFR-TK-specific inhibitor AG1478, and they showed increased dependence on TGFalpha-EGFR signaling. CONCLUSIONS: Our results suggest that prolonged treatment of endometrial carcinoma cells with MPA induces resistance to the growth-suppressive effects of MPA and enhances cancer cell proliferation. The downregulation of ER alpha and PR-B, the upregulation of ER beta, and highly activated TGF-EGFR signaling are thus likely to contribute to progestin resistance in endometrial carcinoma. Therefore, an EGFR-TK-specific inhibitor might be useful in the treatment of progestin-resistant endometrial carcinoma.     

Young women with atypical endometrial hyperplasia or endometrial adenocarcinoma stage I: will conservative treatment allow pregnancy? Results of a French multicentric survey

OBJECTIVES: To analyse the carcinological and obstetrical results of young women with atypical endometrial hyperplasia or endometrial adenocarcinoma, treated in a conservative way to allow pregnancy. PATIENTS AND METHODS: A retrospective analysis of 13 cases (5 adenocarcinomas and 8 atypical hyperplasias) followed in 8 French centers between 1997 and 2004. RESULTS: After 4.6 months of conservative treatment, there were no residual lesions in 61.5% of the cases. Progestatives seem to be the most effective treatment. Tumoral regression makes it possible to plan a pregnancy, with childbirth in 25% of the cases. In these frequently infertile patients, all the techniques of assisted reproduction can be used. Recurrences are not rare after hormonal treatment (37.5%), so, total hysterectomy is justified after delivery. DISCUSSION AND CONCLUSION: Conservative treatment for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma stage I can be considered in some cases to enable pregnancy.     

高分化子宫内膜样癌及子宫内膜重度不典型增生患者孕激素治疗的临床分析

目的探讨35岁以下高分化子宫内膜样癌及子宫内膜重度不典型增生患者采用孕激素治疗以保留患者子宫的疗效,并随访其治疗后的生育情况.方法采用回顾性分析的方法对1991年至2005年北京协和医院收治的35岁以下、接受孕激素治疗（以醋酸甲羟孕酮为主）的25例高分化子宫内膜样癌及子宫内膜重度不典型增生患者的临床病理资料进行研究.其中,子宫内膜样癌8例（内膜癌组）,子宫内膜重度不典型增生17例（不典型增生组）.孕激素治疗前对患者进行全面的分期评估,治疗后每1～6个月诊刮以评价疗效,对有生育要求者随访其生育情况.结果内膜癌组患者孕激素治疗前经全面的分期评估,证实为早期、高分化子宫内膜样癌.除1例子宫内膜样癌患者尚未评估疗效外,内膜癌组其他7例及不典型增生组17例患者治疗后有效者分别为6例（6/7）、17例（100%）;缓解者分别为5例（5/7）、14例（82%）;缓解后复发者分别为1例（1/5）、3例（21%）,复发时间为缓解后6～30个月;随访缓解后要求生育的14例患者中,内膜癌组4例患者尚未生育,不典型增生组10例患者中4例妊娠共7次.1例自然受孕后失访;3例经促排卵治疗后受孕并足月分娩,其中1例产后人工流产3次.结论对于要求保留子宫的高分化子宫内膜样癌及子宫内膜重度不典型增生的年轻患者,孕激素治疗是一种治疗选择.孕激素治疗前应对子宫内膜样癌患者进行详细全面的分期评估,辅助生殖措施的介入有望提高治疗后的妊娠率.     

Pregnancy following intracytoplasmic sperm injection and preimplantation genetic diagnosis after the conservative management of endometrial cancer

A rare case of a patient with conservatively treated endometrial carcinoma who conceived and delivered a healthy baby after the transfer of embryos with intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD) is presented. A 41-year-old woman had an office hysteroscopy in the infertility work-up and stage I endometrial adenocarcinoma was diagnosed. After conservative treatment, the patient underwent ICSI and PGD. She achieved pregnancy with two normal embryos. Two gestational sacs were observed but one of them was blighted. The patient subsequently delivered a healthy female infant. Repeated office hysteroscopy and endometrial sampling was performed after delivery. The appearance of the endometrium was normal on hysteroscopy, and the histology report was normal. The principal concern with medical therapy is that the lesion cannot be fully evaluated until the hysterectomy is performed, the nodes palpated, and the uterus is sectioned. The patient was referred to a gynaecological oncologist for definitive surgery.     

Endometrial carcinoma in septate uterus detected 6 months after full-term delivery: case report and review of the literature

BACKGROUND: Endometrial carcinoma associated with pregnancy is rare. We present the case of a 39-year-old woman with endometrial carcinoma in the septate uterus detected 6 months after normal delivery. CASE: The patient complained of vaginal bleeding from 32 weeks' gestation, and had a spontaneous vaginal delivery at 37 weeks. The bleeding continued after the delivery, but repeated endometrial cytology and biopsy did not reveal evidence of malignancy. An exploratory laparotomy was performed 6 months postpartum with suspicion of uterine myoma. A histological diagnosis of endometrial carcinoma was made based on examination of frozen sections from the hysterectomy specimen, and bilateral salpingo-oophorectomy and pelvic/para-aortic lymphadenectomy were also performed. Histological examination revealed G3 endometrioid adenocarcinoma with squamous differentiation, which arose in the septum of the uterus and deeply invaded the myometrium. The patient received postoperative chemotherapy and is healthy with no evidence of disease 3 years after the treatment. CONCLUSIONS: Although pregnancy-associated endometrial carcinoma is rare, careful examinations are needed when unexplained vaginal bleeding continued.     

宫腔镜联合孕激素治疗年轻患者早期子宫内膜癌的疗效及预后分析

目的:探讨宫腔镜联合孕激素治疗年轻早期子宫内膜癌患者的疗效及预后。方法:回顾性分析四川大学华西第二医院2008年1月至2014年12月自愿接受宫腔镜联合孕激素治疗的年轻早期子宫内膜癌16例患者的临床资料,且随访资料完整。所有患者行宫腔镜下刮宫或宫腔镜下病灶切除+刮宫,其中7例联合口服醋酸甲羟孕酮(250 mg/d,MPA组),9例联合醋酸甲地孕酮(160 mg/d,MA组)治疗。比较两组患者缓解、复发及生育等情况。结果:随访中位时间为54个月(17~90个月),其中12例(75.0%)完全缓解,3例(18.8%)部分缓解,1例(6.2%)无反应,MPA组和MA组的完全缓解率分别为71.4%(5/7)和77.8%(7/9),差异无统计学意义(P0.05)。16例患者中有3例在完全缓解后复发(MPA组1例,MA组2例),复发平均时间为42个月。16例患者中有8例(50.0%)完成了妊娠(其中1例2次妊娠),有6次(66.6%)妊娠顺利生产,3次(33.3%)流产。结论:宫腔镜联合孕激素治疗对于年轻早期子宫内膜癌患者保守治疗是有效的,其中MPA和MA的治疗效果无明显差异,但均存在着一定的复发风险,所以应对其进行严格的筛选和严密的随访。     

Case of atypical polypoid adenomyoma that possibly underwent a serial progression from endometrial hyperplasia to carcinoma

Atypical polypoid adenomyoma is a rare uterine tumor composed of atypical endometrial glands, which often exhibit squamous metaplasia, and a cellular smooth muscle stroma. Although atypical polypoid adenomyoma is categorized as a benign lesion, it is reportedly associated with endometrial cancer, and it shows persistence and recurrence even after conservative medical treatment. We present a rare case of atypical polypoid adenomyoma that possibly underwent a serial pathological change from endometrial hyperplasia to carcinoma in a 40-year-old woman with no history of pregnancy. She was diagnosed with atypical polypoid adenomyoma during polypectomy surgery. After resecting the atypical polypoid adenomyoma, endometrial hyperplasia complex was detected. This condition eventually progressed from atypical hyperplasia complex to endometrial adenocarcinoma, and total abdominal hysterectomy was performed. A patient with atypical polypoid adenomyoma who wishes to preserve her fertility should be carefully monitored for endometrial carcinoma. If endometrial hyperplasia is detected in such a patient, a meticulous follow-up examination by performing endometrial biopsy is mandatory.     

Ovarian metastasis in a nulliparous woman with endometrial adenocarcinoma failing conservative hormonal treatment

BACKGROUND: There have been several reports about successful fertility-preserving treatment of endometrial carcinoma with subsequent pregnancy. However, conservative hormonal treatment for early-stage endometrial cancer still entails some risk. CASE: We present a 36-year-old nulliparous woman, initially diagnosed as clinical stage IA, grade 1 endometrial adenocarcinoma, receiving 6-month conservative treatment with remission achieved at 4 months from diagnosis. Recurrence at the endometrium was documented at the end of treatment. She underwent a definitive surgery including total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node dissection. The final pathology revealed well-differentiated endometrioid adenocarcinoma with inner one-third myometrial invasion and right ovarian metastasis. CONCLUSION: This case report signals a warning that negative preoperative imaging studies are not reassuring for a relapsing low-grade, early-stage endometrial carcinoma failing conservative treatment.     

Tratamiento conservador del cáncer de endometrio en una pareja estéril

Successful conservative management for early-stage low-grade endometrial cancer in young women wishing to preserve fertility has been reported in small series. Although few data are available on assisted reproductive technology (ART) outcomes after conservative management of endometrial carcinoma, ART does not seem to worsen prognosis. We report the case of a 29-year-old woman with a history of primary infertility, who was diagnosed with a well-differentiated endometrial adenocarcinoma (stage Ia), which was treated with high doses of oral progesterone. A successful pregnancy was achieved after ART.     

Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger

To clarify what constitutes the adequate management of uterine endometrial carcinoma in young women, we reviewed clinicopathologically 31 patients aged 40 years and younger between January 1991 and June 2004. As a primary treatment, 12 cases chose hormonal treatment with medroxyprogesterone acetate (MPA; 600 mg/day) due to no findings of myometrial invasion and diagnosis of a grade 1, well-differentiated adenocarcinoma. In remaining 19 cases, surgery was performed. All the 19 patients who received surgery as a primary treatment are alive, with no evidence of a recurrence of the disease. In the 12 patients who received hormonal treatment, 8 patients eventually received a hysterectomy because of recurrence or no response to MPA. Of these eight patients, myometrial invasion was recognized in three patients. One of the eight patients died of the metastasized disease to the liver and brain after hysterectomy. After hormonal treatment, 4 of the 12 patients were exempted from surgery and showed no evidence of recurrence. Two patients had viable children. Progesterone receptor was negative in one case that died. Careful consideration should be given to hormonal treatment with MPA for the conservative management of endometrial carcinoma in young women. Moreover, MPA is not always a consistent management for every patient.     

Two successful pregnancies after in vitro fertilization and embryo transfer in a patient with endometrial atypical hyperplasia bordering on adenocarcinoma treated conservatively with high-dose progesterone

Women suffering from anovulatory infertility may develop endometrial hyperplasia and adenocarcinoma due to the unopposed estrogen effect. We present the case of a young infertile woman with endometrial atypical hyperplasia bordering on adenocarcinoma who refused hysterectomy and bilateral salpingo-oophorectomy and achieved two successful pregnancies after conservative treatment with high-dose progesterone followed by in vitro fertilization and embryo transfer. It is concluded that conservative treatment with high-dose progesterone for endometrial hyperplasia and well-differentiated early-stage adenocarcinoma followed by assisted reproductive technologies is an appropriate means for achieving pregnancy. However, the issue of hysterectomy and bilateral salpingo-oophorectomy after delivery or after fertility being no longer required is controversial. If surgery is not performed, close observation with endometrial sampling every 6 months is advisable.     

The fertility-sparing treatment in patients with endometrial atypical hyperplasia and early endometrial cancer: A debated therapeutic option

Fertility-sparing treatment may represent a realist option for accurately selected young patients with endometrial atypical hyperplasia or well differentiated, early endometrial cancer. Oral progestins, and especially medroxyprogesterone acetate (MPA) and megestrol acetate with different doses and schedules, represent the most commonly used hormone agents in this clinical setting. Approximately three fourths of the women achieve a histologically documented complete response, with an mean response time of 12 weeks, but about one third of these subsequently developed a recurrence after a mean time of 20 months. The expression of receptor for progesterone receptor (PR), PTEN gene, DNA mismatch repair gene MLH1 and phospho-AKT on tissue specimens may be useful for selecting patients fit for a conservative management. Several successful pregnancies have occurred after a fertility-sparing treatment of endometrial atypical hyperplasia or endometrial cancer, more frequently with assisted reproductive technologies. The implementation of in vitro fertilisation techniques not only increases the chance of conception, but it may also decrease the interval to conception. The opportunity of a demolitive surgery after delivery or after childbearing being no longer required is a still debated issue. Large multicenter trials are strongly warranted to better define the selection criteria for a conservative treatment, endocrine regimen of choice, the optimal dosing, the duration of treatment and follow-up protocols. In any case, the patient should be accurately informed about the relatively high recurrence rates after complete response to hormone treatment and expectations for pregnancy.     

子宫内膜非典型增生18例保守治疗结局分析

目的探讨孕激素治疗子宫内膜非典型增生的结局及适宜的辅助生育策略。方法回顾性分析2002年1月～2007年4月18例不孕合并子宫内膜非典型增生的患者应用大剂量孕激素保守治疗的结果及妊娠结局。结果①14例患者在应用大剂量孕激素治疗3～36个月后病灶消退，4例病灶持续存在；②3例患者在停止治疗5～15个月后发展为子宫内膜癌。内膜非典型增生病变的再现率为33．3％；③8例患者接受了辅助生育治疗．5例分别经CC＋HMG促排卵治疗3～6周期无优势卵泡发育．1例在第6个促排卵周期获宫内单胎妊娠。4例（包括1例CC＋HMG促排卵未孕者）患者接受了5个周期IVF助孕，1例输卵管妊娠。1例自然流产。另2例冻存胚胎等待移植。结论多数子宫内膜非典型增生的患者对大剂量孕激素治疗有效。对这类患者．一旦内膜病变消退，应积极助孕．可以适当放宽IVF—ET指征。     

Fertility after conservative treatment of placenta accreta

OBJECTIVE: To report a pregnancy with vaginal delivery after a preceding pregnancy complicated by placenta accreta that was managed conservatively.DESIGN: Case report.SETTING: University medical center.PATIENT(S): A patient with placenta accreta that was managed conservatively.INTERVENTION(S): The placenta was left in situ and both uterine arteries were embolized.MAIN OUTCOME MEASURE(S): Preservation of reproductive capacity.RESULT(S): The patient had a term pregnancy with uncomplicated vaginal delivery.CONCLUSION(S): Pregnancy is possible after conservative treatment of placenta accreta. This treatment should be considered in the appropriate circumstances to preserve reproductive capacity.     

Immunohistological localization of pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG) in endometrial adenocarcinoma and effect of medroxyprogesterone acetate

Endometrium from postmenopausal women with endometrial adenocarcinoma was examined immunohistochemically using a monoclonal antibody to pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the glandular epithelium during the late luteal phase of the menstrual cycle and early pregnancy. Specimens were obtained at initial diagnostic curettage and at hysterectomy after medroxyprogesterone acetate (MPA) therapy. alpha 2-PEG was not detected in any malignant tissue irrespective of histological differentiation. Non-malignant endometrium obtained in association with malignant tissue was negative for alpha 2-PEG before treatment although after MPA therapy all specimens obtained exhibited marked alpha 2-PEG localization in glands. In four specimens endogenous alkaline phosphatase was observed consistently only in the malignant endometrium. Malignant endometrium does not appear to synthesize alpha 2-PEG nor is its synthesis induced by an oral progestogen, so that it does not represent a useful marker for endometrial carcinoma. Non-malignant endometrium in postmenopausal women appears to be fully capable of alpha 2-PEG production after stimulation with an oral progestogen.     

A patient with stage 1a endometrial carcinoma in whom a solitary recurrent lesion was detected in the external iliac lymph node after MPA therapy

BACKGROUND: In the treatment of endometrial carcinoma, young patients desire the preservation of the uterus, and therefore hormonal therapy has been administered. CASE REPORT: The patient was a 39-year-old nullipara diagnosed with stage 1a endometrial carcinoma. The patient desired the preservation of the uterus, and oral administration of MPA was prescribed for 18 weeks, which after the cancer tissue disappeared. However, about 1 year and 6 months later, the patient was diagnosed as having recurrent endometrial carcinoma in the left external iliac lymph node. CONCLUSION: In the literature, there is no patient with relapse at another site in the absence of endometrial relapse after MPA therapy for stage 1a endometrial carcinoma, as performed in the present patient.     

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。     

Assisted reproductive technologies in conjunction with conservatively treated endometrial adenocarcinoma. A case report

This case report illustrates the successful use of assisted reproductive technologies (ARTs) in a patient receiving conservative treatment for endometrial adenocarcinoma. A 31-year-old infertile woman, diagnosed as FIGO stage Ia endometrial adenocarcinoma (grade 1), received oral medroxyprogesterone acetate 400 mg/day for 12 weeks. Endometrial curettage was performed and the absence of endometrial carcinoma was confirmed. A single pregnancy was achieved with in vitro fertilization and embryo transfer. A healthy female infant was born via cesarean section at 42 weeks' gestation. The carcinoma has not recurred, and the patient now desires a second child. We conclude that ART combined with progesterone treatment might be a powerful option for the treatment of infertile patients with early stage, well-differentiated endometrial adenocarcinoma.