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.     

Medroxyprogesterone acetate therapy for patients with adenocarcinoma of the endometrium who wish to preserve the uterus-usefulness and limitations

BACKGROUND: To determine the effectiveness of medroxyprogesterone acetate therapy for women with endometrial adenocarcinoma who wish to preserve their uterus. STUDY DESIGN: Fifteen patients with endometrial carcinoma (12 with grade 1 endometrioid adenocarcinoma. 2 with grade 2 adenocarcinoma and 1 with adenoacanthoma) were treated with high-dose medroxyprogesterone acetate alone as primary therapy and their clinical responses evaluated. RESULTS: Seven of the 12 cases (58%) with grade I adenocarcinoma and one of the two (50%) with grade 2 carcinoma responded initially to medroxyprogesterone acetate. The median length of treatment required for regression was 29 weeks. Three patients who initially responded relapsed. Thirteen patients are alive without evidence of disease as of December 1999 (10 to 146 months, median; 4 years and 11 months) and one is continuing medroxyprogesterone acetate therapy as a final follow-up. One patient was lost to follow-up. Two patients have conceived having three healthy infants. CONCLUSION: Treatment of endometrial carcinoma with high-dose medroxyprogesterone acetate could be an alternative to hysterectomy, although the successful rate is limited.     

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.     

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.     

Fertility-sparing treatment in young women with endometrial cancer or atypical complex hyperplasia: a prospective single-institution experience of 21 cases

We conducted a prospective study of conservative treatment in 21 young nulliparous women with grade (G)1 endometrial cancer stage IA (11) or atypical complex hyperplasia (10). All were treated with a low-dose cyclic natural progestin therapy (200 mg/day from day 14–25) and encouraged to attempt pregnancy immediately. No adverse therapy-related effects were recorded. Overall response rate to progestin therapy was 57%. Nine women conceived (43%). There were 13 pregnancies, of which 13 were spontaneous and 8 were in women with persistent disease or partial response to hormonal treatment. Three additional complete responses were observed after delivery. Only women with known primary infertility or severe polycystic ovary syndrome showed inadequate pregnancy rate. Fifteen women underwent definitive surgery after enrolment (median 27 months, range 3–56 months). All 21 women are alive and disease free after a median follow up of 98 months.     

Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer

OBJECTIVE: To evaluate the safety of fertility-sparing hormonal therapy for endometrial cancer in young patients. METHODS: We reviewed the clinical and pathologic records of patients diagnosed with endometrial adenocarcinoma before the age of 40, who were treated and followed over a 30-year period in the Division of Gynecologic Oncology. All patients who underwent conservative management with progestins (n = 13) are the subjects of this study. RESULTS: Follow-up was available for all 13 patients, with a mean follow-up of 82 months. All patients responded to treatment within a mean period of 3.5 months, with normal pathology on follow-up endometrial samplings. Six patients had a recurrence within a period extending between 19 and 358 months (median 40 months). Four patients were treated with a second course of progestins, and all had a histologic complete response. As of the time of preparation of this report, nine healthy infants had been born, and all the patients remained without evidence of disease. CONCLUSION: Conservative management of well-differentiated endometrial carcinoma in young patients, combined with assisted reproductive technologies, if needed, does not seem to worsen the prognosis. This approach also provides the possibility of conceiving and carrying a normal pregnancy.     

Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors

Eleven cases of endometrial stromal sarcoma were obtained from the files of Yale New Haven Hospital from 1969 to 1981 for clinicopathologic correlation and determination of the outcome after hormonal therapy with progestational agents. Histologically, nine of the tumors were classified as low grade stromal sarcomas, and two were of a high grade. All of the patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy as the main modality of treatment. Two patients received radiation, three adjuvant chemotherapy, two hormonal therapy (Megace 160 mg qd), three received no therapy at all, and the treatment is not known in one case. Two of the patients who received no therapy had recurrences and were placed on hormonal therapy. The remaining patient was a stage IV and died of disease 3 months after diagnosis. All four of the patients who were treated with hormonal therapy are alive, free of disease, or with stable tumor from 2 to 6 years after diagnosis. The presence of estrogen receptors (ER) and progestin receptors (PR) was demonstrated in the tumor in some of the cases; this may explain the sensitivity of this neoplasm to hormonal therapy.     

Chemotherapy plus Sequential Hormonal Therapy for Advanced and Recurrent Endometrial Carcinoma: A Phase II Study

We evaluated the therapeutic value of sequential cyclical hormonal therapy (megestrol acetate, and tamoxifen citrate) plus single-agent chemotherapy (carboplatin) in the outpatient management of advanced or recurrent endometrial cancer. Carboplatin (300 mg/m²) was administered every 4 weeks for six courses or until disease progression. In addition, patients alternated megestrol acetate (80 mg orally twice daily) with tamoxifen citrate (20 mg orally twice daily) every 3 weeks. Thirteen of 18 (72.2%) patients were considered evaluable. Four patients (30.8%) had a complete response, six (46.2%) had a partial response, one (7.7%) had stable disease, and two patients (15.4%) progressed. Six of seven patients with vaginal disease responded. The median progression-free interval was 14 months for complete responders. Two patients (15.4%) are alive with no evidence of disease at 41 and 59 months. Seven of 13 patients experienced a hematologic toxicity (six grade 2, one grade 3); all resolved within 2 weeks. Dose reduction of carboplatin to 200 mg/m²was required in one patient. No other toxicities were encountered. The median survival for all patients is 11 months, and is 33 months for complete responders. We conclude that a regimen of carboplatin plus sequential hormonal therapy shows promise in this pilot study for the treatment of advanced or recurrent endometrial cancer.     

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.     

The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer

PURPOSE OF REVIEW: Hormone therapy has been palliative for advanced/ recurrent endometrial cancer. High remission rates are seen in well-selected stage I, grade 1 endometrial cancer of young women using hormone therapy (usually progestins) as fertility-preserving treatment. Many other hormones, such as gonadotropin-releasing hormone analogs (GnRHa), selective estrogen receptor modulators, aromatase inhibitors, intrauterine progestins, and others are potential modalities. This review updates the recent publications in this area. RECENT FINDINGS: Two reports investigating different scheduling of tamoxifen and progestins indicated that tamoxifen may be a valuable adjunct to progestin therapy. GnRHa has been used adjunctively to tamoxifen as second-line hormone therapy for fertility sparing after progestin failed. Aromatase inhibitors have shown their potential in treating endometrial cancer and endometrial hyperplasia as single agent or in combination with progestins. Intrauterine progestins seem efficacious in treating endometrial hyperplasia; its applications on endometrial cancer patients, however, have been limited to postmenopausal women with poor surgical risk. SUMMARY: Translational research based on molecular mechanisms is mandatory to a more appropriate utilization of hormone therapy. The role of dose, scheduling, route of administration of progestins as well as the addition of other hormonal agents should be further explored by well designed randomized controlled trials.     

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. METHODS: Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given. RESULTS: Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17-38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors (n = 16), 24% in those with grade 2 disease (n = 17), and 22% among patients with grade 3 disease (n = 23). Women less than or equal to 60 years (n = 16) appear to have a better response rate than those >60 years (n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease (n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease (n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. CONCLUSION: A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.     

Fertility-preserving treatment of stage IA,well-differentiated endometrial carcinoma in young women with hysteroscopic resection and high-dose progesterone therapy

Objective

The standard treatment for endometrial cancer is surgery with hysterectomy. However, this procedure will cause infertility in young women who desire to preserve pregnant ability. Conservative management with hormone therapy has been shown to be satisfactory in both tumor control and fertility preservation. Recently, hysteroscopic tumor resection followed by progestin therapy has been reported to be an alternative strategy. In this study we present our experience with this approach.

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.     

Fertility-sparing management of endometrial adenocarcinoma

Approximately 15% of patients with endometrial cancer are premenopausal. Previous studies largely support the conservative treatment of endometrial cancer in women desiring future fertility. From these studies, 75% to 80% of patients demonstrate a complete response to progestin therapy and the average recurrence rate is 30% to 35%. Conservative therapy should be reserved for women with International Federation of Gynecology and Obstetrics grade I tumors. Before conservative management, patients should be informed of the elevated risk (11%-29%) of concurrent ovarian cancer in cases of premenopausal endometrial cancer, and screening and ongoing surveillance during the treatment period is mandatory. A suggestion of myometrial invasion or metastatic disease is a contraindication to conservative management. Individuals meeting criteria for Lynch syndrome testing should be referred to genetic counseling. Fertility treatment should be individualized, and close surveillance is required during treatment. Staging hysterectomy is recommended after the completion of the childbearing period. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to select appropriate candidates with endometrial cancer for fertility-sparing treatment. Educate patients with endometrial cancer regarding the risks and benefits of standard of care therapy and conservative therapy and screen appropriate patients for Lynch syndrome.     

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.     

External pelvic radiation therapy in stage IC endometrial carcinoma

OBJECTIVE: To evaluate outcomes of patients with stage IC endometrial carcinoma treated with external whole pelvic radiation but not vaginal brachytherapy. METHODS: Sixty-one women with stage IC endometrial carcinoma had postoperative pelvic radiation without vaginal brachytherapy. The median age was 69 years (range 44-87 years). Most subjects had histologic findings of adenocarcinoma (71%) and grade 2 or 3 disease (74%). The median pelvic irradiation dose was 48.6 Gy (range 43.2-50.4 Gy). No patients received adjuvant chemotherapy or hormonal therapy. The median follow-up time was 69.5 months (range 7-196 months). RESULTS: The 5-year actuarial disease-free and overall survivals of the entire group were 86.7% and 97.6%, respectively. No patient developed local (vaginal) recurrence. One patient had recurrent disease in the lateral pelvis. Ten patients (16.4%) had distant (extrapelvic) metastases. No serious sequelae were noted, including vaginal necrosis, small bowel obstruction, proctitis, or fistulae. CONCLUSION: Local control was excellent in stage IC endometrial carcinoma treated with adjuvant radiation therapy alone. Attention needs to be focused on efforts to control extrapelvic recurrence in patients with this disease.     

Implementation of assisted reproductive technologies following conservative management of FIGO grade I endometrial adenocarcinoma and/or complex hyperplasia with atypia

OBJECTIVE: The objective was to report a series of infertility therapy outcomes following conservative management of endometrial adenocarcinoma and/or complex hyperplasia with atypia. METHODS: A retrospective review of the University of Iowa assisted reproductive technology database was performed. All women presenting with International Federation of Obstetrics and Gynecology (FIGO) grade I uterine adenocarcinoma and/or complex hyperplasia with atypia were assessed for type and duration of medical management, initial, interim treatment, and preinfertility treatment endometrial biopsy (BX) findings. Assessment of infertility treatment outcomes and postinfertility endometrial biopsy findings were performed. All of the pathology samples were re-reviewed at the Gynecologic Oncology Tumor Board to confirm the diagnosis by a pathologist with a particular expertise in gynecologic pathology. RESULTS: Four infertile women, three nulligravid and one primigravid, were evaluated with the diagnosis of FIGO grade 1 endometrial adenocarcinoma and/or complex hyperplasia with atypia desiring to preserve fertility. Two women with FIGO grade 1 endometrial adenocarcinoma were successfully treated with high-dose progestational agents resulting in normal proliferative endometrium. In addition, both women with complex hyperplasia with atypia were successfully treated with progestins and/or ovulation induction. Successful pregnancy outcomes were achieved for three of the four women with assisted reproductive technology. A total of five successful pregnancies and eight healthy live-born infants were achieved among three women. One of the four women was unable to conceive despite three cycles of in vitro fertilization. Hysterectomy was performed for recurrent complex hyperplasia with atypia. In our series, we found it can take 3-10 months (mean, 6.25 months; median, 6 months) to obtain benign endometrium preceding infertility therapy. CONCLUSION: This report demonstrates that conservative management of well-differentiated endometrial adenocarcinoma and/or complex hyperplasia with atypia followed by aggressive assisted reproduction is an option to highly motivated and carefully selected women.     

Endometrial carcinoma remaining after term pregnancy following conservative treatment with medroxyprogesterone acetate

BACKGROUND: Successful pregnancies after conservative progestin treatment to young women with endometrial carcinoma have recently been reported. However, it is not known for certain whether the lesion is completely eradicated in such patients. We present a case of residual endometrial carcinoma after term pregnancy which had been treated conservatively before the pregnancy began. CASE: A 28-year-old woman with endometrial carcinoma received conservative treatment with high-dose medroxyprogesterone acetate (MPA) and then conceived. After delivery at term, atypical cells were found in the endometrial curettage specimen. A hysterectomy was performed 6 months after delivery and revealed the presence of a small focus of intramucosal, grade 1, endometrioid-type adenocarcinoma. Immunohistochemically, the tumor cells were positive for estrogen and progesterone receptors. CONCLUSION: We concluded that while MPA treatment had been effective, it had not completely eradicated the carcinomatous lesion, which remained during and after the term pregnancy.     

Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study

Objective

For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry.