ANTICANCER RESEARCH 35: 6799-6804 (2015)

Cancer Incidence in Patients with Atypical Endometrial Managed by Primary or Fertility-sparing Treatment

CLÉMENTINE GONTHIER1, BRUNO PIEL2, CYRIL TOUBOUL2, FRANCINE WALKER3, ANNIE CORTEZ4, DOMINIQUE LUTON1, EMILE DARAÏ2,5 and MARTIN KOSKAS1

Departments of 1Obstetrics and Gynecology, and 3Pathology, Bichat University Hospital, Paris, France; Departments of 2Obstetrics and Gynecology, and 4Pathology, Tenon University Hospital, Paris, France; 5Research Unit S938, Pierre and Marie Curie University, Paris, France

Abstract. Aim: To compare the risk of developing of childbearing age. Over the past 40 years, the fertility- endometrial carcinoma (EC) in young women with atypical sparing management of AEH has been reported in the endometrial hyperplasia (AEH) undergoing fertility-sparing literature (6, 7). management compared to women treated by primary Oral progestin appears to be a good alternative to hysterectomy. Patients and Methods: In this multicentric hysterectomy, with a regression of the lesions in 75 to 95% retrospective study, 111 patients with a diagnosis of AEH by of patients with AEH. After a complete response, the were included. EC incidence was recurrence rate varies from 20 to 38% of the cases, compared in two groups: 32 patients treated with fertility- depending on the follow-up period (8-10). Other medical sparing management and 79 older patients treated with treatments [levonorgestrel-releasing intrauterine system, and primary hysterectomy. Results: The rates of EC diagnosed by gonadotropin-releasing hormone (GnRH) agonist] have been of hysterectomy specimens were comparable reported to produce similar results (11). The medical between the groups. The probability of developing EC at 12, treatment should not be considered curative because 24 and 36 months were 14%, 21% and 26%, respectively, in recurrence is always possible. Obtaining remission with patients managed conservatively, and 29%, 37% and 37%, medical treatment allows one or several pregnancies before a respectively, in patients treated with primary hysterectomy. more radical treatment is required. One of the most Conclusion: Fertility-sparing management of AEH does not important factors that patients with AEH (and their increase the risk of diagnosing EC from the hysterectomy practitioners) should know is whether they are at an specimen. increased risk of during this period. The aim of our study was to evaluate whether the rate of Atypical endometrial hyperplasia (AEH) is a precursor to EC is increased in women with AEH who undergo fertility- endometrial carcinoma (EC), an -dependent cancer sparing management compared with women who receiving that presents itself along a continuum (1). The co-existence non-conservative treatment. of EC or the progression to EC in patients diagnosed with AEH has been shown in several studies; EC was detected at Patients and Methods the final histological analysis in 10% to 59% of AEH cases (2-4). Patients. We conducted a multicenter retrospective analysis that included two groups of patients diagnosed with AEH between 2001 Approximately 5% of patients with EC are diagnosed and 2013. The first group consisted of patients extracted from the before the age of 40 years (5). The standard treatment for National Registry, which collects cases of AEH and EC managed AEH is hysterectomy, which is often unacceptable to women conservatively. The patients with AEH were referred to our Center from 17 French Gynecological Units. The second group of patients did not have conservative disease management (primary hysterectomy group) and came from two French gynecological units Correspondence to: Martin Koskas, Department of Obstetrics and (including the referral center for fertility preservation in cases of Gynecology, Bichat University Hospital, Paris, France. AEH). For the two groups, we included only patients who met the following inclusion criteria: Diagnosis of AEH was confirmed Key Words: Fertility-sparing management, atypical endometrial independently by two pathologists (including a reference hyperplasia, progression risk, . pathologist); minimum follow-up period of six months or until a

0250-7005/2015 $2.00+.40 6799 ANTICANCER RESEARCH 35: 6799-6804 (2015) hysterectomy was performed; radiological examination was cases for which hysterectomy was not performed, we considered conducted with at least an ultrasound examination. there to be no progression if neither the endometrial biopsy nor the Patients who underwent fertility-sparing management were hysteroscopy showed AEH or EC, and the was preserved. The selected for this procedure if they were 42 years old [age limit for log-rank test was used to compare the probability of a diagnosis of assisted reproductive technology (ART) reimbursement by the EC in the hysterectomy sample between the two groups. National Insurance system in France] or younger and had a strong When analyzing the outcomes of patients, we used the intention- desire to preserve fertility. We excluded all cases that received to-treat (ITT) principle. Even when treated conservatively, patients conservative management due to any concern other than fertility sometimes undergo early hysterectomy (within three months) sparing (e.g. medical contraindication to surgery) from the study. because they change their mind or because of persistent disease, 3 Patients with conservatively treated EC have been reported in other months after the beginning of hormone therapy. In contrast, even studies (12,13). Patients who met the criteria were counseled when primary surgery is decided upon in the management of AEH, extensively regarding the risk of recurrence or progression if they it is sometimes delayed because of anesthetic risks to the patient chose medical therapy and gave informed consent for the treatment. related to age, obesity, the patient’s treatment or because of the Patients who underwent non-conservative treatment were patient’s wishes concerning the date of surgery. In such cases, the included in the study if the first option of treatment was surgery for delay between the diagnosis and hysterectomy is similar to the the treatment of AEH. delays usually seen in patients who undergo a fertility-sparing This study was approved by the Ethics Committee of the College management. The discrepancy between the decisions made to plan a National des Gynécologues Obstétriciens Français (Institutional patient’s treatment and what is actually done in real practice is the Review Board number: 2012-GYN-07-02). cornerstone of ITT. The data were analyzed with the R software package, version Patient management. The patients in the fertility-sparing 2.13.0, using the Design, Hmisc and Verification libraries management group were scheduled to receive the medical treatment (http://lib.stat.cmu.edu/R/CRAN/). for a minimum of three months. Given that a higher incidence of synchronous has been reported in young patients Results with EC (14,15), a diagnostic laparoscopy was performed prior to medical treatment in the last 22 patients. In no case did the Patients’ characteristics. One hundred and eleven patients laparoscopic findings modify the disease staging. diagnosed with AEH on endometrial biopsy were included All patients included in this study were assessed for in the study, including 32 patients with fertility-sparing prior to conservative management. Treatment response was assessed management and 79 with a primary hysterectomy. The using pathological specimens obtained by curettage or endometrial patient age was significantly different between the groups, biopsy after 3-6 months of medical therapy. Remission was indicated if the last endometrial sample or hysterectomy specimen ranging from 23 to 42 years for the conservative treatment showed normal without hyperplasia. Persistence was group and from 38 to 87 for the non-conservative treatment defined if the last biopsy showed AEH. Recurrence was defined if a group (p<0.001). The diagnosis of AEH was made during lesion that had initially regressed following treatment reappeared in infertility investigations in 20 vs. 0 cases and during an the form of AEH or EC. investigation of irregular bleeding in 11 vs. 70 cases in the For patients showing no response to medical therapy, total fertility-sparing management and non-conservative treatment hysterectomy with or without bilateral salpingo-oophorectomy was groups, respectively (Table I). proposed. If the patient wished to continue the fertility-sparing management and if no progression was diagnosed, a secondary medical therapy different from the first was attempted. For example, Patients’ management and follow up. Among the 32 patients if no remission occurred after 3-6 months of progestin therapy, a treated with conservative management, 23 patients received GnRH agonist could then be given. After the documentation of progestin, four received a GnRH agonist, and five did not complete remission, women had a follow-up visit every 3-6 months receive any medical treatment (one became pregnant before with diagnostic hysteroscopy and endometrial biopsy. Patients were starting treatment, and hysteroscopic resection was considered encouraged to conceive spontaneously. ART could be attempted complete in four cases). Twenty-five (78%) out of the 32 after complete remission and was based on a couple's fertility parameters. Women who failed in their attempts to conceive or who patients managed conservatively had remission after a mean successfully completed their desired childbearing were encouraged time of 5 months (2 to 12 months), 22 following the first to undergo definitive surgery. treatment and three after the second-line treatment. Four out Patients were counseled to undergo hysterectomy if EC was of these 25 patients (16%) had a recurrence, with a mean found during the follow-up or if AEH persisted despite two different delay of 20 months between remission and recurrence. treatments. Twelve women (38%) achieved 14 pregnancies, four of which were spontaneous. A total of 11 live births were recorded. Statistical analysis. Fisher’s exact test, the Chi-square test and the Among the patients belonging to the primary surgery two-sided t-test were employed for statistical analyses. Significance was set at the standard value of p<0.05. Kaplan–Meier curves were group, 60 (76%) had undergone an outpatient diagnostic generated to examine the probability of finding EC in the hysteroscopy or an operative hysteroscopy before surgery. hysterectomy specimens. The endpoint was the last known disease The mean delay to hysterectomy was 3.2 months, ranging status, and patients who were lost to follow-up were censored. In from 1 to 23 months.

6800 Gonthier et al: Safety of Preservation for Atypical Endometrial Hyperplasia

Table I. Comparison of patient characteristics according to the Table II. Comparison of outcomes and follow-up according to management of atypical endometrial hyperplasia. management of atypical endometrial hyperplasia (AEH).

Fertility-sparing Primary p-Value Fertility-sparing Primary p-Value management hysterectomy management hysterectomy n=32 n=79 n=32 n=79

Age at diagnosis, years Hysterectomy Median (mean) 34 (33.6) 59 (60.2) <0.001 Yes 13 (41%) 79 (100%) <0.001 Range 23-42 38-87 No 19 (59%) - BMI (kg/m2) 31.2 32.2 0.81 Final diagnosis on hysterectomy Obesity Non AEH 2 (6%) 0 Yes 10 31 AEH 2 (6%) 60 (76%) No 13 42 0.93 Stage IA EC 6 (19%) 15 (19%) Unknown 9 6 Stage IB EC 0 2 (3%) <0.001 Infertility Stage IIIA EC 2 (6%) 0 Yes 27 0 <0.001 Stage IIIC EC 1 (3%) 2 (3%) No 5 79 Delay from diagnosis to Diagnosis circumstances hysterectomy, months Bleeding 11 70 Average (median) 24.1 (24) 3.2 (2) <0.001 Infertility 20 0 <0.001 Range 6-47 1-23 Follow-up, months Other 1 9 Average (median) 47.9 (32) 15.4 (12) <0.001 Histologic diagnosis Range 7-121 1-93 Operative hysteroscopy 8 43 Endometrial biopsy 1 27 EC: Endometrial carcinoma. Endometrial curettage 22 7 <0.001 Cervical polyp 0 2 Unknown 1 0

BMI: Body mass index. The final histopathologyical evaluation obtained from the two performed after pregnancy showed non- atypical hyperplasia. Three stage IA, one stage IIIA and one Outcome. The mean follow-up was 48 months for patients stage IIIC ECs were diagnosed in patients who underwent treated conservatively and 15 months for patients whose hysterectomy for persistent AEH. One AEH, two stage IA primary treatment was hysterectomy (p<0.001). Thirteen and one stage IIIA ECs were diagnosed in the patients who patients (41%) with fertility-sparing management ultimately underwent hysterectomy for disease recurrence. Stage IA EC underwent hysterectomy, with a mean delay of 24 months after was founded in the patient who underwent hysterectomy for the diagnosis of AEH. The risk of finding EC was comparable progression, and AEH was found in the one who underwent between the groups: 28% in women with fertility-sparing hysterectomy after ART failure. management and 24% in patients with initial hysterectomy The probability of a diagnosis of EC in the hysterectomy (p=0.64). All patients who were managed conservatively and sample over time is shown in Figure 1. For patients treated did not undergo hysterectomy had no evidence of AEH or EC conservatively, the probability of EC at 12, 24 and 36 months on the last endometrial biopsy sample. Among the patients who was 14%, 21% and 26%, respectively. For the patients underwent fertility-sparing management, the mean follow-up treated by primary hysterectomy, the probability of EC at 12, was 52 months for patients who ultimately underwent 24 and 36 months was 29%, 37%, and 37% (p=0.08). hysterectomy and 49 months for those who did not (p=0.79). The risk of finding stage IB or more EC was comparable Discussion between the groups: 9% (three cases) for women with fertility- sparing management and 5% (four cases) in the primary In the present study, we compared the risk of developing EC hysterectomy group (p=0.68) (Table II). in women with AEH undergoing a fertility-sparing Of the 13 patients treated with conservative management management and older women treated by primary who ultimately underwent a hysterectomy, two were hysterectomy. The oncological outcomes were comparable performed after pregnancy, five were performed for between the groups, and the only difference between the persistence of AEH, four for recurrence, one for disease groups concerned the delay in diagnosis of EC. The highest progression, and one underwent hysterectomy after ART probability of finding EC was observed later in women failure. treated conservatively. This finding suggests that medical

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undergo primary surgery probably did not request a fertility- sparing management strategy because they were 45 years or older and were unable to achieve pregnancy or did not wish to. Despite this limitation, several patients in the primary surgery group still had childbearing potential. The impact of age on the prognosis of AEH remains debated. In a study of 773 women who underwent hysterectomy for AEH, EC was found in 38% of pre- menopausal patients and 64% of the post-menopausal patients (p<0.001) (2). In another study of 824 patients diagnosed with AEH, the probability of finding EC in hysterectomy specimens was independently correlated with age (18). Based on these studies, one could expect that EC would be less likely to occur in the conservatively-treated group. However, in studies reporting a higher rate of EC Figure 1. Kaplan–Meier curve of the probability of progression to among older women, the reported rates of EC in endometrial cancer (p=0.08) in patients with atypical endometrial hysterectomy specimens are particularly elevated and are hyperplasia stratified by fertility-sparing management (dotted line) and higher than the rates of EC observed in our population. A primary hysterectomy (solid line). randomized study with two populations comparable in age would be impossible because it would involve fertility- sparing interventions. Even a retrospective study is unlikely because young women with AEH are often willing to treatment permits a delay in the occurrence of EC, but does preserve their fertility and most cases in young woman are not prevent it from occurring. diagnosed during explorations of infertility (19). Although this study is one of the largest to report the Interestingly, infertility and AEH are both associated with the fertility-sparing management of AEH only, the number of following conditions: estrogen exposure, obesity, chronic patients included might seem too low to draw strong , and polycystic ovarian syndrome. conclusions. However, AEH is rarely diagnosed in young None of the patients who achieved pregnancy had a women and in order to limit recruitment bias, all the women recurrence of AEH. This finding can be explained by the included in the present study were selected only if they met high levels of progesterone produced during pregnancy, that criteria that are not systematically checked when the could have played a role in the treatment itself (20). diagnosis of AEH is made. Importantly, because we did not Gynecologists treating such patients should advise women to find any significant difference between the two groups in conceive rapidly and resort to ART if necessary (21). terms of cancer probability (analyzing the outcome of more Similarly, to improve the chances of pregnancy in an obese than 100 well-selected women), it is unlikely that fertility- patient diagnosed with AEH, weight loss is part of the sparing management significantly increases EC incidence. conservative management (22) but once pregnancy has been Most studies of fertility preservation in women with achieved, hysterectomy should be proposed. Postpartum EC endometrial lesions concern both AEH and early EC. We cases have been described (23). believe that AEH and EC outcomes should be analyzed In both study groups, we recorded unfavorable outcomes separately. Recently, two meta-analyses of fertility-sparing concerning advanced EC. The underlying question is: Was treatment suggested that these diseases have different this finding due to the conservative management or was this prognoses (16, 17). advanced-stage disease present from the time of diagnosis of Importantly, the current study is the first to include a AEH? Our study is a retrospective multicentric study control group of patients (who underwent primary surgery) reflecting real life rather than the best possible standard. treated at the same time and at the same institutions to Since unfavorable outcomes occurred in both groups, an compare the risk of EC in patients with conservatively optimal follow-up with histology is indispensable in patients managed AEH. The aim of the present study was not to managed conservatively. Similarly, in the pre-therapeutic compare oncological outcomes between young and older evaluation of patients diagnosed with AEH, systematic women treated for AEH, but rather to compare women who magnetic resonance imaging is mandatory. received fertility-sparing treatment versus women who The principal obstacle to the fertility-sparing management elected to undergo primary surgery. Consequently, one of the of AEH relates to the difficulty of initially obtaining a underlying limits of this study is the significant difference in specific diagnosis. There is neither a very reliable clinical age between the groups. Most patients who elected to parameter nor an imaging feature which distinguishes

6802 Gonthier et al: Safety of Preservation for Atypical Endometrial Hyperplasia between AEH and EC. Endometrial biopsy has a low 7 Cade TJ, Quinn MA, Rome RM and Neesham D: accuracy (55%) for differentiating AEH from EC compared treatment options for early endometrial cancer: BJOG Int J with dilatation plus curettage (73%) (24) or hysteroscopy- Obstet Gynaecol 117(7): 879-884, 2010. directed biopsy (92%) (25). Moreover, there is poor 8 Simpson AN, Feigenberg T, Clarke BA, Gien LT, Ismiil N, Laframboise S, Massey C and Ferquson SE: Fertility sparing reproducibility in the pathological diagnosis of AEH (26). treatment of complex atypical hyperplasia and low-grade Only the pathological analysis of the hysterectomy specimen endometrial cancer using oral progestin. Gynecol Oncol 133(2): is able to exclude the need for concurrent EC at the time of 229-233, 2010. diagnosis. 9 Minig L, Franchi D, Boveri S, Casadio C, Bocciolone L and Fertility-sparing management of women diagnosed with Sideri M: Progestin intrauterine device and GnRH analogue for AEH is conceivable because this lesion has a slow evolution. uterus-sparing treatment of endometrial precancers and well- In fact, 20% of patients are cured spontaneously (28). differentiated early endometrial carcinoma in young women. Ann Oncol Off J Eur Soc Med Oncol ESMO 22(3): 643-649, 2011. This study confirms that hormonal treatment does not 10 Randall TC and Kurman RJ: Progestin treatment of atypical preclude the development of EC but instead delays the hyperplasia and well-differentiated carcinoma of the occurrence of EC without increasing its risk. endometrium in women under age 40. Obstet Gynecol 90(3): 434-440, 1997. Acknowledgements 11 Jadoul P and Donnez J: Conservative treatment may be beneficial for young women with atypical endometrial The Authors would like to thank Pr Benifla, Dr Marchand (Paris), hyperplasia or endometrial adenocarcinoma. Fertil Steril 80(6): Dr Challan Belval, Dr D’Argent (Paris), Pr Poncelet (Bondy), Pr 1315-1324, 2003. Dauplat, Dr Bergzoll, Dr Bourdel (Clermont Ferrand), Pr Fernandez 12 Koskas M, Yazbeck C, Walker F, Clouqueur E, Agostini A, Ruat (Le Kremlin Bicêtre), Pr Deffieux (Clamart), Pr Raudrant, Pr S, Lucot JP, Lambaudie E, Luton D and Madelenat P: Fertility- Golfier (Lyon), Pr Morice, Dr Uzan, Dr Gouy (Villejuif), Dr sparing management of grade 2 and 3 endometrial Fourchotte (Paris), Dr Le Tohic, Dr Panel (Versailles), Pr Collinet, adenocarcinomas. Anticancer Res 31(9): 3047-3049, 2011. Dr Boyon, Dr Clouqueur, Dr Lucot (Lille), Dr Villefranque 13 Koskas M, Bendifallah S, Luton D, Daraï E and Rouzier R: (Pontoise), Dr Debiolles (Beaumont), Pr Graesslin, Dr Derniaux Safety of uterine and/or ovarian preservation in young women (Reims), Dr Vincens (Montpellier), Pr Lecuru, Dr Hauser Douay, with grade 1 intramucous endometrial adenocarcinoma: a Dr Fournier (Paris), Pr Haddad, Dr Boujenah (Créteil), Dr Mabrouk comparison of survival according to the extent of surgery. Fertil (Amilly), Dr Ohl (Schiltigheim), Dr Faller, Dr Schindler, Pr Wattiez Steril 98(5): 1229-1235, 2012. (Strasbourg), Dr Parmentier (Rang-du-Fliers), Dr Grynberg 14 Walsh C, Holschneider C, Hoang Y, Tieu K, Karlan B and Cass (Bondy), Dr Lambaudie (Marseille), Pr Brun, Dr Conri, Dr Legrand I: Coexisting ovarian malignancy in young women with (Bordeaux) and Pr Agostini (Marseille) for providing us with details endometrial cancer. Obstet Gynecol 106(4): 693-699, 2005. of patients under their care. 15 Zivanovic O, Carter J, Kauff ND and Barakat RR: A review of the challenges faced in the conservative treatment of young References women with endometrial carcinoma and risk of ovarian cancer. Gynecol Oncol 115(3): 504-509, 2009. 1 Sherman ME: Theories of endometrial carcinogenesis: a 16 Koskas M, Uzan J, Luton D, Rouzier R and Daraï E: Prognostic multidisciplinary approach. Mod Pathol Off J US Can Acad factors of oncologic and reproductive outcomes in fertility- Pathol Inc 13(3): 295-308, 2000. sparing management of endometrial atypical hyperplasia and 2 Antonsen SL, Ulrich L and Høgdall C: Patients with atypical adenocarcinoma: systematic review and meta-analysis. Fertil hyperplasia of the endometrium should be treated in oncological Steril 101(3): 785-794, 2014. centers. Gynecol Oncol 125(1): 124-128, 2012. 17 Gunderson CC, Fader AN, Carson KA and Bristow RE: Oncologic 3 Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke and reproductive outcomes with progestin therapy in women with JJ, Alberts D and Curtin J: Concurrent endometrial carcinoma in endometrial hyperplasia and grade 1 adenocarcinoma: a systematic women with a biopsy diagnosis of atypical endometrial review. Gynecol Oncol 125(2): 477-482, 2012. hyperplasia: a Gynecologic Oncology Group study. Cancer 18 Suh-Burgmann E, Hung Y-Y and Armstrong MA: The value of 106(4): 812-9 15, 2006. additional pathology comments indicating suspicion of 4 Kurman RJ, Kaminski PF and Norris HJ: The behavior of adenocarcinoma among women diagnosed preoperatively with endometrial hyperplasia. A long-term study of «untreated» complex atypical endometrial hyperplasia. Int J Gynecol Pathol Off hyperplasia in 170 patients. Cancer 56(2): 403-412, 1985. J Int Soc Gynecol Pathol 31(3): 222-226, 2012. 5 Navarria I, Usel M, Rapiti E, Neyroud-Caspar I, Pelte M-F, 19 Wethington SL, Herzog TJ, Burke WM, Sun X, Lerner JP, Lewin Bouchardy C and Petignat P: Young patients with endometrial SN and Wright JD: Risk and predictors of malignancy in women cancer: How many could be eligible for fertility-sparing with endometrial polyps. Ann Surg Oncol 18(13): 3819-3823, treatment? Gynecol Oncol 114(3): 448-451, 2009. 2011. 6 Signorelli M, Caspani G, Bonazzi C, Chiappa V, Perego P and 20 Ichinose M, Fujimoto A, Osuga Y, Minaguchi T, Kawana K, Mangioni C: Fertility-sparing treatment in young women with Yano T and Kozuma S: The influence of infertility treatment on endometrial cancer or atypical complex hyperplasia: a the prognosis of endometrial cancer and atypical complex prospective single-institution experience of 21 cases. BJOG Int J endometrial hyperplasia. Int J Gynecol Cancer Off J Int Gynecol Obstet Gynaecol 116(1): 114-118, 2009. Cancer Soc 23(2): 288-293, 2013.

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21 Elizur SE, Beiner ME, Korach J, Weiser A, Ben-Baruch G and 26 Zaino RJ, Kauderer J, Trimble CL, Silverberg SG, Curtin JP, Dor J: Outcome of in vitro fertilization treatment in infertile Lim PC and Gallup DG: Reproducibility of the diagnosis of women conservatively treated for endometrial adenocarcinoma. atypical endometrial hyperplasia: a Gynecologic Oncology Fertil Steril 88(6): 1562-1567, 2007. Group study. Cancer 106(4): 804-811, 2006. 22 Gonthier C, Walker F, Luton D, Yazbeck C, Madelenat P and 27 Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba Koskas M: Impact of obesity on the results of fertility-sparing T, Muderspach LI and Roman LD: Time interval between management for atypical hyperplasia and grade 1 endometrial endometrial biopsy and surgical staging for type I endometrial cancer. Gynecol Oncol 133(1): 33-37, 2014. cancer: association between tumor characteristics and survival 23 Vaccarello L, Apte SM, Copeland LJ, Boutselis JG and Rubin outcome. Obstet Gynecol 125(2): 424-433, 2015. SC: Endometrial carcinoma associated with pregnancy: A report 28 Horn L-C, Schnurrbusch U, Bilek K, Hentschel B and Einenkel of three cases and review of the literature. Gynecol Oncol 74(1): J: Risk of progression in complex and atypical endometrial 118-122, 1999. hyperplasia: clinicopathologic analysis in cases with and without 24 Suh-Burgmann E, Hung Y-Y and Armstrong MA: Complex progestogen treatment. Int J Gynecol Cancer Off J Int Gynecol atypical endometrial hyperplasia: the risk of unrecognized Cancer Soc 14(2): 348-353, 2004. adenocarcinoma and value of preoperative dilation and curettage. Obstet Gynecol 114(3): 523-529, 2009. 25 Ørtoft G, Dueholm M, Mathiesen O, Hansen ES, Lundorf E, Møller C, Marinvskij E and Petersen LK: Preoperative staging Received July 29, 2015 of endometrial cancer using TVS, MRI, and hysteroscopy. Acta Revised October 19, 2015 Obstet Gynecol Scand 92(5): 536-545, 2013. Accepted October 23, 2015

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