Conservative Management of Atypical Hyperplasia and Grade I Endometrial Carcinoma: Review of the Literature and Presentation of a Series

Abstract

Objective: The purpose of this study was to evaluate the safety of fertility-sparing treatment in young women with atypical hyperplasia (AH) or grade 1 endometrial cancer (EC). Design: This study was designed as a retrospective cohort study. Methods: All women ≤45 years of age with AH or grade 1 EC treated at Mayo Clinic between January 1, 1985 and December 31, 2005 were identified. Patient demographics, management, and follow-up data were retrospectively abstracted and analyzed . Results: Ninety-four women were treated for AH or grade 1 EC, 71 underwent immediate surgical treatment, and 23 elected to preserve fertility Among the latter, complete data were available for 21 patients (16 with AH and 5 with EC at initial diagnosis). During the first course, 11 received medroxyprogesterone acetate (MPA), 7 received megestrol acetate (MA), 1 received oral contraceptive pills, and 2 were observed. Response after the first course (median duration 6.1 months) was 71% overall; 81% in AH patients versus 40% in EC patients (p=0.11). All patients treated with MPA versus 43% treated with MA (p=0.01) responded. All 3 who did not respond after the first course responded to the second course with regression to benign endometrium (median duration 3.3 months). Overall response rate after two courses was 81% and 94.4% among those treated solely with progestins. Among those who continued fertility-preserving therapy after two courses, the recurrence rate was 39%; all patients with EC had a recurrence. All recurrences were confined to the uterus. Conclusions: Conservative management of AH and grade 1 EC appears to be an effective, but temporary alternative to hysterectomy for carefully selected, highly motivated women. Once childbearing is complete, women should be offered definitive surgical treatment. (J GYNECOL SURG 28:262)

Introduction

Endometrial cancer (EC) is the most common malignancy of the female reproductive tract in the United States, accounting for almost one half of all gynecologic cancers treated in this country. There were an estimated 43,470 new cases and 7,950 EC-related deaths in the United States in 2010.¹ The incidence of EC has been steadily increasing over the past two decades² and is the sixth most common cause of cancer death in women in the United States.¹ Although it is primarily a disease of perimenopausal and postmenopausal women, ∼ 25% of cases occur in premenopausal women and 2.5%–14.4% occur in women ≤40 years of age.^3–5 Among the latter group, >70% are nulliparous at the time of diagnosis.⁶ This holds true particularly in developed countries, where deferral of childbearing has led to higher pregnancy rates in women 35–49 years of age.⁷

Endometrioid (type I) EC is hormone dependent^8,9 and carcinogenesis stems from continuous stimulation of the endometrium by either endogenous or exogenous estrogens.^10,11 Younger women diagnosed with EC often have a history of estrogen excess or hormone-related disorders such as obesity, polycystic ovarian syndrome (PCOS), chronic anovulation, infertility, and/or ovarian dysfunction.^3,4,12–14 Such conditions appear to increase the risk of developing well-differentiated endometrioid EC and, in this age group, myometrial invasion (MI) and extrauterine spread is usually absent.^4,15 By virtue of these characteristics, such patients tend to have a more favorable prognosis. Cure rates of patients with early stage, low-grade endometrioid EC who undergo hysterectomy are excellent, with 5-year survival >90%.¹⁶

EC is believed to follow a continuum of histologically distinguishable lesions ranging from simple endometrial hyperplasia without atypia to complex atypical hyperplasia (CAH) and, ultimately, well-differentiated EC, a process that can follow a slow but unpredictable course.¹⁷ If atypical hyperplasia (AH), the direct precursor lesion of type I EC, remains untreated, the risk of progression to frank carcinoma is ∼25%. Moreover, up to 62% of endometrial biopsy specimens interpreted as AH are associated with coexisting invasive EC.^18–20 Therefore, it is recommended that patients with AH undergo a hysterectomy and tailored salpingo-oophorectomy.

However, young women with AH or EC are frequently nulligravid and may desire preservation of their fertility. Hence, the gynecologic oncologist may face a therapeutic dilemma with this patient population. Conservative treatment modalities that have been used include hormonal agents, selective estrogen receptor modulators, aromatase inhibitors and hysteroscopic endometrial resection/ablation.^12,21–30 Progestins, such as medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are particularly effective against progesterone receptor positive well-differentiated EC.^31,32 In addition to high regression rates following treatment,^{12,23,27,33–36} successful pregnancies after conservative management have also been reported.^27,37–46

Although the literature is growing in the area of fertility-preserving therapy for AH and EC, response and recurrence rates vary among studies. This may be because of disparities in dosage and duration of treatment, patient selection criteria, and follow-up surveillance. The purpose of this study was to report the Mayo Clinic's experience on the safety of fertility-sparing treatment in young women with AH or EC in terms of adequately identifying the patients who are suitable candidates for conservative management, as well as in terms of short-term and long-term oncologic outcomes.

Methods

All women ≤45 years of age with AH or grade 1 EC treated at Mayo Clinic in Rochester, Minnesota between January 1, 1985 and December 31, 2005 were included in this retrospective study. Following Institutional Review Board approval, both the surgical and medical indices were queried to identify all women who met criteria for inclusion, and data were abstracted from all cases. In accordance with the Minnesota Statute for the Use of Medical Information in Research, only those individuals who had previously provided informed consent for the use of their medical records were included.

Patient demographics, reproductive data, medical comorbidities, and specific AH or EC treatment(s) were abstracted and analyzed. Among women who had selected fertility-preserving management, regimens and length of treatment, time to follow-up endometrial sampling and subsequent treatments, including definitive surgical management when performed, were abstracted. Central pathology review was performed by a single gynecologic pathologist (GLK) on all specimens.

Response to the first course of conservative management was defined as regression to lower “grade” disease in follow-up biopsy compared with initial diagnosis. Lack of response to the first course was considered to indicate either persistent or progressive disease. Response to the second course of conservative management was defined as nonprogressive disease in the second follow-up biopsy compared with the first follow-up biopsy, which could mean either regression to a lower “grade” disease or no change. Lack of response to the second course was considered to indicate progressive disease in the second follow-up biopsy compared with the first follow-up biopsy. Overall response after two courses was defined as response to at least one course of conservative management, either the first or the second course, and nonprogressive disease at the second follow-up biopsy. Total time to last follow-up was defined as the time interval between initial diagnosis and last follow-up endometrial sampling.

Descriptive statistics were used to summarize patient and management characteristics. The median was reported as the measure of central tendency, given the skewed distribution of the variables “time to follow-up” and “dose of progestational agents.” Response rates were compared across the different histology and drug groups using the Fisher's exact test. For further details of statistical methods used, please refer to the tables. A level of p<0.05 was considered statistically significant. Statistical analyses were performed using the JMP software (version 8.0; SAS Institute, Inc.; Cary, NC).

Results

Patient demographics

A total of 94 women ≤45 years of age were treated at the Mayo Clinic for AH or grade 1 EC between January 1, 1985 and December 31, 2005. Out of the 94 women, 71 underwent definitive surgical treatment. In this group, 17 (24%) patients had AH and 54 (76%) had stage I, grade 1 EC (52 stage IA and 2 stage IB according to 2009 International Federation of Gynecology and Obstetrics [FIGO] staging⁴⁷). Among patients with EC, 21 (40%) had no MI and, therefore, would have been ideal candidates for conservative therapy.

There were 23 women who elected to preserve fertility; however, 2 patients in the fertility-preservation group had incomplete follow-up data and were therefore excluded from this study. The final cohort managed conservatively included 16 (76%) with an initial diagnosis of AH and 5 (24%) with grade 1 EC. Patient characteristics of the 21 conservatively managed and 71 surgically managed cases are summarized in Table 1.

Table 1.

Patient Characteristics in the Conservative and Surgical Treatment Groups

	Treatment Groups
Characteristic	Conservative (n=21) n^b	Surgical (n=71) n^b	p-value^a
Histology^c			<0.0001
Atypical hyperplasia	16 (76)	17 (24)
Endometrial cancer, grade 1	5 (24)	54 (76)
Stage IA	-	52 (96)
Stage IB	-	2 (4)
Estrogen receptors			0.1970
Yes	3 (14)	37 (52)
No	1 (5)	1 (1)
Unknown	17 (81)	33 (47)
Progesterone receptors			0.1970
Yes	3 (14)	35 (49.3)
No	1 (5)	1 (1.4)
Unknown	17 (81)	35 (49.3)
Age (years)			0.0024
Mean (SD)	36.6 (4.4)	39.79 (4.8)
Median (range)	36 (28–44)	41 (23–45)
BMI			0.6820
Mean (SD)	37.4 (13.2)	35.3 (11.1)
Median (range)	36.95 (19.3–66.7)	33.4 (18.2–60.2)
BMI categories			0.4458
Not obese (≤30)	6 (29)	28 (40)
Obese (>30)	15 (71)	42 (60)
Gravidity			0.1339
Mean (SD)	0.9 (1.3)	1.6 (1.6)
Median (range)	0 (0–4)	1 (0–8)
Nulligravida	12 (57)	29 (41)	0.2177
Parity			0.1013
Mean (SD)	0.8 (1.3)	1.3 (1.6)
Median (range)	0 (0–4)	1 (0–6)
Nulliparity	14 (67)	32 (45)	0.1350
Polycystic ovarian syndrome	9 (43)	11 (16)	0.0140
Dysfunctional uterine bleeding	21 (100)	65 (92)	0.3304
Diabetes mellitus type 2	4 (19)	12 (17)	1.00
Hypertension	2 (10)	13 (18)	0.5062

p-value for comparison of each variable between treatment groups; continuous variables (age, body mass index [BMI], gravidity, parity): Wilcoxon rank-sum test; dichotomous variables (histology, estrogen receptors, progesterone receptors, BMI categories-dichotomized as BMI >30 vs. ≤30 kg/m², nulligravida, nullipara, polycystic ovarian syndrome, dysfunctional uterine bleeding, diabetes mellitus type 2, hypertension): Fisher's exact test.

Values are expressed as number (%) unless otherwise indicated.

Conservative management group: central pathology review diagnosis; surgical management group: final pathology report diagnosis.

Outcomes after first course of fertility-preserving therapy

During the first course of conservative management, 11 (52%) were managed with MPA, 7 (33%) with MA, 1 (5%) with oral contraceptive pills (OCPs), and 2 (10%) were observed. The median duration of the first course of conservative management prior to repeat endometrial sampling was 6.1 months (interquartile range 3.7–12.4; range 3.2–24.4). Fifteen (71%) responded to their first course whereas 6 (29%) did not. None of the 6 nonresponders had progressive disease; all had stable histology. Within histologic subgroups, 13 patients (81%) with AH responded to treatment versus 2 (40%) with EC (p=0.11). The response rate was higher among those treated with MPA (11/11; 100%) compared with those treated with MA (3/7; 43%) (p=0.01). Type of treatment during the first course, dose of progestin, response per dose and final outcome are summarized in Table 2.

Table 2.

First Course of Fertility-Sparing Treatment: Type of Treatment, Dose of Progestin, Response per Dose and Final Outcome

Patient No.	Age (years)	Histology^a	Treatment^b (1st course)	Dose (mg/day)	Response after 1st course	Final Outcome	Last follow-up (months)
1	40	AH	MPA	10	Yes	Continued fertility-sparing mgmt.; alive with no disease at last follow-up	42
2	32	AH	MPA	20	Yes	Continued fertility-sparing mgmt.; alive with no disease at last follow-up	18
3	34	AH	MPA^c	150^c	Yes	Continued fertility-sparing mgmt.; alive with no disease at last follow-up	148
4	44	AH	MPA	10	Yes	Hysterectomy despite initial response	191
5	36	AH	MPA	unknown	Yes	Hysterectomy despite initial response	27
6	42	AH	MPA	10	Yes	Hysterectomy despite initial response	223
7	34	AH	MPA	10	Yes	Lost to follow-up during 2nd course	12
8	43	AH	MPA	10	Yes	Long-term response after 2 cycles; hysterectomy for menorrhagia	231
9	38	AH	MPA	10	Yes	Long-term response after 2 cycles; hysterectomy (without recurrent disease) after infertility mgmt.	158
10	34	AH	MPA	10	Yes	Long-term response after 2 cycles; hysterectomy (without recurrent disease) after infertility mgmt.	225
11	41	EC	MPA	10	Yes	Continued fertility-sparing mgmt.; recurrent CAH at 137months: hysterectomy	139
12	30	EC	MA	160	Yes	Continued fertility-sparing mgmt.; alive with no disease at last follow-up	36
13	35	AH	MA	160	Yes	Continued fertility-sparing mgmt.; alive with no disease at last follow-up	64
14	28	AH	MA	160	Yes	Lost to follow-up during 2nd course	21
15	34	EC	MA	160	No^d	Hysterectomy after 1st follow-up	8
16	34	AH	MA	160	No^d	Response after 2nd course; continued fertility-sparing mgmt.; alive with no disease at last follow-up	45
17	38	AH	MA	320	No^d	Response after 2nd course; continued fertility-sparing mgmt.; recurrent CAH at 69 months: levonorgestrel-IUD; stable disease at last follow-up	74.5
18	32	EC	MA	Unknown	No^d	Response after 2nd course; recurrent EC at 60 months: hysterectomy	100
19	38	EC	OCPs	-	No^d	Hysterectomy after 1st follow-up	142
20	42	AH	Observed	-	Yes	Continued fertility-sparing mgmt. (progestins); recurrent CAH at 33.7months: levonorgestrel-IUD; alive with CAH at last follow-up	39
21	39	AH	Observed	-	No^d	Hysterectomy after 1st follow-up	185

Atypical hyperplasia (AH); endometrial cancer (EC); central pathology review (GLK); all EC were grade 1.

Medroxyprogesterone acetate (MPA); megestrol acetate (MA).

Depo-provera.

Persistent disease (stable histology).

After the first follow-up endometrial sampling, 3 responders and 3 nonresponders underwent definitive surgical treatment. Among the nonresponders (1 AH and 2 EC), all had persistent disease; 1 had stage IA, grade 1 EC with a primary tumor diameter (PTD) of 4 cm and MI of 13%, and 1 had stage IA, grade 1 EC with a PTD of 5.6 cm and MI of 35%. Among the responders (all 3 initially diagnosed with AH), 1 had benign endometrium, 1 had simple hyperplasia, and 1 persistent AH not identified on first follow-up endometrial biopsy. The remaining 15 patients continued conservative management.

Outcomes after the second course of fertility-preserving therapy

Among the 15 patients who received a second course of conservative treatment, 2 responders underwent ovulation induction at an outside institution and were lost to follow-up. Thirteen women (10 with an initial diagnosis of AH and 3 with EC) completed a second course of conservative therapy. Median duration of the second course was 4.8 months (interquartile range 3.3–8.7; range 1.1–91.4). All three of the prior nonresponders, all with EC, responded to the second course with regression to benign endometrium. One patient with AH was observed at diagnosis, regressed to normal endometrium initially, but then recurred with CAH on progesterone. Among the 13 patients who completed two courses of conservative management, 1 patient was observed, 3 patients pursued infertility treatment (none of which was successful in attaining pregnancy) and 9 patients continued medical treatment for a median of 30 months (interquartile range 12–57.5 months; range 5–120 months).

Overall response and recurrence after fertility-preserving therapy

The overall response rate after two courses was 81% (17/21). When excluding the 3 patients who did not receive a progestin during the first course, the response rate after two courses was 94.4% (17/18) with the response in AH patients being 100% (14/14) and the in EC patients being 75% (3/4) (p=0.222).

The overall recurrence rate in the group of patients who continued conservative management after having completed two courses was 39% (5/13). Those with EC were more likely to have a recurrence (3/3; 100%) compared with those with AH (2/10; 20%) (p=0.035). Median time to recurrence was 60 months (range 32.4–137.3) in those initially diagnosed with EC, and 56 months (range 33.8–69.3) in the AH cohort (p=1.00). All recurrences were confined to the uterus. All 3 EC cases underwent hysterectomy. Surgical diagnoses were: 1 with CAH (completed 11 years of progestin treatment), 1 stage IA, grade 1 endometrioid EC (completed 5 years of progestin treatment), and 1 stage IA, grade 3 mixed clear cell and endometrioid EC (initial endometrial biopsy was grade 1 endometrioid EC; completed 2.5 years of progestin treatment). Both patients initially diagnosed with AH who had a recurrence refused definitive surgical treatment and were treated with a levonorgestrel-containing intrauterine device (IUD). Endometrial sampling revealed stable disease (complex hyperplasia without atypia and CAH) at last follow-up (75 months and 39 months from initial diagnosis, respectively).

Among those who continued medical management after completing two courses, 3 responders (all with initial AH) underwent hysterectomy. Despite benign endometrial biopsies, 1 had complex hyperplasia without atypia and 1 had microscopic grade 1 EC with a synchronous primary stage IA, grade 3 endometrioid ovarian cancer in the left ovary. In the initial cohort of 21 patients treated conservatively, 12 (57%) ultimately underwent hysterectomy (either for oncologic or nononcologic indications). Among those who had EC, none had a recurrence following hysterectomy.

Of the remaining 7 patients who continued conservative management after completing two courses and did not undergo definitive treatment, all had enduring regression of disease as per last follow-up. Median total time to last follow-up for these patients was 45 months (interquartile range 33.8–74.5 months; range 18.3–148.1 months).

Discussion

Conservative management of AH and EC has been described since the early 1960s^48,49 and particular interest has grown recently because of the increasing number of younger women with EC who wish to preserve fertility. However, no consensus exists regarding patient selection criteria, management guidelines, and long-term follow-up recommendations.

This study, as well as the growing body of literature, has suggested that medical management is an acceptable initial alternative to hysterectomy for well-informed women motivated to preserve fertility. In 2004, Ramirez et al.⁵⁰ performed a meta-analysis that included a combined total of 81 patients with grade 1 EC, which was followed up in 2008 by a second meta-analysis published by Chiva et al.⁵¹ who updated the Ramirez series for a total of 133 patients. The most common progestins used were MPA and MA. An overall response rate of 76% was observed and 40% of patients achieved at least one pregnancy following treatment; however, the recurrence rate of EC among initial responders was 34%. Furthermore, EC-related deaths following conservative treatment were first reported only after January 2004.^14,52–54 With regard to AH, regression of the lesion has been reported in 60%–95% of patients.^27,55 However, most of these studies were retrospective with small series of cases. In 2007, Ushijima et al. published a multicenter prospective study on the use of MPA for EC and AH in young women.²⁹ The overall response rate was 67%, with 55% of EC and 82% of AH patients responding to treatment. During the 3 year follow-up period, 7 live deliveries were achieved and only 1 death occurred, which was attributed to a synchronous primary peritoneal carcinoma. Among responders, however, 57% of EC and 38% of AH cases eventually recurred.

Although progestins offer the option of fertility-preserving therapy, they are not the standard treatment for AH and grade 1 EC; conservative management is not without risk. Apart from not negligible recurrence rates, potential MI and/or nodal metastases cannot be ruled out with imaging alone. Moreover, whereas the incidence of synchronous primary cancers of the endometrium and ovary among all women with EC is ∼5%,⁵⁶ premenopausal women with EC appear to have an increased risk of synchronous ovarian cancer with reported rates of 5%–29%.^3,57–60 In a recent population-based study, it was observed that among women ≤50 years of age diagnosed with EC, 9.4% had a synchronous epithelial ovarian cancer (unpublished data). Therefore, careful assessment of the adnexa is imperative in this subset of patients, and high resolution pelvic imaging could be helpful when assessing the patient who desires fertility-preserving therapy for her EC.

The response rates for AH and presumed early-stage EC ranges from 83 to 94% and from 57 to 76%, respectively. In this series, the response rate after two courses of progestins was similar at 94.4%, with a trend toward a higher response rate in AH (100%) compared with EC patients (75%). A higher response rate was also observed after the second course (92.3%) compared with the response rate after the first course (71.4%). This observation may indicate that a longer duration of treatment is required for some to achieve disease regression, and continued medical management despite initial failure may be an option. Similar data have previously been reported, and complete regression has been observed in nonresponders or partial responders after prolonging treatment for >1 year.^{13,23,27,33,61} Also, as suggested by the relatively long-term disease regression among the 13 patients in this cohort who continued medical management beyond two courses, prolonged medical treatment may consolidate the initial response and maintain disease regression.

However, the optimal progestin, dose, and duration of treatment remain unclear. There is no existing literature supporting the superiority of one progestin over another. In this study, MPA yielded a higher response rate than did MA (100% vs. 43%, respectively; p=0.01). However, as a not significantly higher proportion of those with EC received MA, this may have biased the response rates. The optimal dose of progestins required to achieve disease regression is also unknown. Varying doses have been used with MA ranging from 10 to 400 mg/day and with MPA ranging from 200 to 800 mg/day. Ushijima et al.²⁹ treated both EC and AH with 600 mg/day of MPA based on the results of one of their previous studies in which they observed better response with 600 mg/day compared with 200 mg and 400 mg.¹² Of note, in this study, 8 out of 9 patients treated with MPA received 10 mg/day and 1 received 20mg/day; all but 1 patient had a long-term response to treatment and remained without disease as of last follow-up. This suggests that lower doses of MPA may achieve similar results to those achieved with higher doses. Considering the potential side effects associated with high dose progestin treatment (thrombophlebitis, weight gain, headaches, sleep disorders, mood and libido changes, and leg cramps^12,25,62), using the lowest dose is important to minimize these potential side effects and ensure compliance.

As for duration of therapy, Randall and Kurman²⁷ reported that the median length of treatment required to achieve disease regression was 9 months, which is similar to the experience with this study. Similarly, Perri et al.⁶³ concluded that prolonged progestin treatment is a feasible treatment alternative that could allow women to conceive more than once. Conversely, Ramirez et al.⁵⁰ reported a shorter median time to response of 12 weeks. Ushijima et al.²⁹ administered MPA for a maximum of 26 weeks; patients who had no change or progressive disease at 8, 16, or 26 weeks were withdrawn from the study and offered definitive treatment. It is unknown whether these initial nonresponders would have responded with a longer duration of treatment. Whereas the ideal duration of treatment to see a response remains unclear, it appears that those who do not respond after 9–12 months of progestins may be true nonresponders.

Conservative management carries risks that have been demonstrated in recent literature. These include the risk of clinically understaging a more advanced cancer, persistence or progression of disease while on medical treatment, disease recurrence after initial response, and the risk of synchronous ovarian malignancy. The reported recurrence rates of AH is 13% and from 11 to 50% for EC. Recurrences tend to occur within 1 year of completing conservative treatment and are generally confined to the uterus.^50,62,64 However, longer times to recurrence have been reported (up to 87 months after therapy initiation), and in this study the longest was 137 months. Given that hyperestrogenic states such as obesity and PCOS are often persistent and are linked to endometrial cancer, it is not surprising that the risk for disease recurrence and progression also persists, even decades after therapy. Although no EC-related deaths occurred in this series, Yasuda et al. reported the first EC-related death associated with fertility-preserving therapy in 2004;⁵⁴ 3 additional cases have now been reported.^14,52,53 Furthermore, cases of local disease progression and distant metastasis while on treatment and after treatment completion have also been reported.^{23.41,65–67}

The high local failure rate indicates that conservative management should be considered a temporary alternative to hysterectomy. Once the woman has completed her childbearing, definitive surgical treatment with hysterectomy, at a minimum, should be recommended. In the patient who refuses definitive treatment, maintenance therapy should be offered followed by a long-term surveillance with endometrial sampling and imaging. OCPs, cyclic progestins, Depo-Provera, and progestin-IUDs have been used as maintenance therapy.^13,23,33 In 2002, Montz et al.²⁵ evaluated the efficacy of levonorgestrel-IUDs in managing stage IA, grade 1 EC in women at high risk for perioperative complications, and concluded that disease regression can be achieved in some cases. Vereide et al.⁶⁸ and Ørbo et al.⁶⁹ concluded that the levonorgestrel-IUD is a more effective treatment for endometrial hyperplasia than is oral MA. In accordance with these findings, both AH patients treated with levonorgestrel-IUDs in this study after recurrence to CAH despite initial response remained without disease at last follow-up, of 39 months and 75 months, respectively. Therefore, the levonorgestrel-IUD may be a reasonable long-term option for patients who decline hysterectomy.

Strengths of this study include central pathology review of all specimens performed by a single gynecologic pathologist and the fact that all consecutive cases of AH or grade 1 EC treated conservatively at the Mayo Clinic within a 20-year period were reported. This is a retrospective study, and the various treatment regimens limit direct progestin comparison. Additionally, during the study period, infertility services were inconsistent, and those women who sought advanced reproductive assistance were lost to follow-up, as they sought their infertility treatment at outside institutions.

Conclusions

In conclusion, a growing body of evidence indicates that conservative management is a reasonable and effective alternative to surgical treatment, with high response rates and long-term disease regression for women who desire fertility preservation. A thorough pretreatment evaluation with assessment of the adnexae should be performed to identify those candidates best suited for conservative management. Select AH and clinical stage I, grade 1 EC patients motivated to preserve fertility could be offered this alternative. However, counseling on the limitations of clinical staging, the high rate of eventual failure of conservative treatment, the risk of disease recurrence or progression even after initial response, and the risk of EC-related death are essential. Given these not negligible risks, a high level of treatment compliance and monitoring is also required.

Footnotes

Acknowledgment

This work was partially supported by the Office of Women's Health Research Building Interdisciplinary Careers in Women's Health (BIRCWH award K12 HD065987).

Disclosure Statement

No competing financial interests exist.

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