Medical Treatment of Endometrial Carcinoma for the Premenopausal Woman Wanting to Preserve her Ability to Have Children

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1 Medical Treamen of Endomerial Carcinoma for he Premenopausal Woman Waning o Preserve her Abiliy o Have Children Marie Claude Renaud, MD Marie Plane, MD Gynaecologic Oncology Service, L'Hoel-Dieu de Quebec. Cenre Hospialier Laval Universiy Quebec Ciy QC Absrac: Endomerial cancer occurs in less han five percen of paiens younger han 40 years of age. The sandard reamen is o surgically sage wih a hyserecomy and bilaeral salpingo-oophorecomy wih or wihou Iymph node biopsies. However, some of hese young paiens may wish o reain heir feriliy poenial. Well-differeniaed adenocarcinoma can regress wih high dose progesin herapy in 62 o 75 percen of cases. However, due o he rare occurrence of his condiion in ha age group, daa on he opimal progesional agen, dose or duraion of reamen is scarce. Cauion should be exercised because of he documened occurrence of coexising early sage endomerial carcinoma wih early sage ovarian carcinoma in some of hese paiens. Addiionally, paiens have recurred afer iniial successful medical reamen; hus, rigorous follow-up should be performed. Physicians should hus be aware of he high dose progesin herapy opion for he reamen of endomerial carcinoma in young paiens waning o preserve heir feriliy poenial, bu should also counsel hese paiens on he poenial failure of his reamen and of he risk o worsen a poenially curable disease. Resume : Le cancer de I'endomere affece moins de cinq pour cen des paienes de moins de 40 ans, Le raiemen normal consise a eablir le sade par chirurgie, au moyen d'une hyserecomie e d'une salpingo-ovariecomie bilaerale, avec ou sans biopsies des ganglions Iymphaiques. Cependan, ceraines des paienes encore jeunes pourraien vouloir conserver leur capacie de concevoir. Dans 62 a 75 pour cen des cas, on peu faire regresser un adenocarcinome bien differencie au moyen d'une herapie comporan une fore dose de progeserone. Touefois, ean donne que ces cas se presenen raremen dans cee caegorie d'äge, il es difficile de rouver des donnees sur le choix opimal de I'agen progesaif, de la dose e de la duree du raiemen. 11 fau faire res aenion parce qu'il a ee eabli que, chez quelques-unes de ces paienes, il y a eu co-exisence d'un carcinome de I'endomere a un sade precoce e d'un carcinome ovarien au sade precoce. De plus, ceraines paienes on subi une recurrence apres un raiemen medical iniial reussi. Pour cee raison, un suivi rigoureux s'impose. Le medecin doi ere au couran de la possibilie d'uiliser une herapie progesaive a fore dose pour le raiemen du carcinome de I'endomere chez les jeunes paienes qui veulen conserver leur capacie de concevoir, mais il doi aussi informer ces paienes de la possibilie d'un echec du raiemen e du risque de voir une maladie poeniellemen curable s'aggraver pluö. J Soc Obse Gynaecol Can 200 I :23(3):213-9 KeyWords Endomerial carcinoma, premenopausal, hormonal reamen Compeing ineress: none declared Received on May 26h, Revised and acceped on December I I eh, INTRODUCTION Endomerial careinoma is a disease rarely seen in he premenopausal paien. Indeed, less han hree o flve pereen of endomerial careinomas oeeur in women less han 40 years of age. I Despie his low ineidenee under 40 years of age, endomerial eareinoma now poses areal reamen dilemma, as many women are delaying ehildbearing in order o pursue heir career. As physieians, we may have o eounsel paiens faeed wirh diffieul reamen deeisions. JOURNAL SOGe

2 Currenly, he sandard of care for endomerial carcinoma is o surgically sage paiens, removing he uerus along wih bilaeral salpingo-oophorecomy and lymph node biopsy when indicaed. 2,3 However, he advances in reproducive echnology make i imporan for us o be aware of and discuss oher opions. We review here he medical reamen of endomerial carcinoma in premenopausal paiens waning o preserve heir abiliy o have children. METHODS A lieraure review was done using he PubMed search engine. All perinen arides found in he English lieraure during he pas wo decades were reviewed. The major headings used for his review were: "endomerial carcinomal cancer," "uerine cancer/carcinoma," "medical reamen," "premenopausal paiens," "endomerial hyperplasia", and "reamen of." Arides reviewed were mosly case repors, rerospecive reviews, and more rarely, prospecive sudies wihou conrols or randomizaion, and hus according o he Periodic Healh Exam 4 were level II or III evidmce. PATHOLOGY The diagnosis of endomerial carcinoma during he reproducive age should be viewed wih cauion because of he rare occurrence of his condiion in his age group. The pahology should be revised byan experienced pahologis in gynaecological cancers o ensure ha he lesion is no only aypical endomerial hyperplasia, which has been shown o respond weil o hormonal manipulaions, or ha he umour does no originae from he cervix, as cervical cancers are more frequen in ha age group. Aypical endomerial hyperplasia can be difficul o disinguish from weil-differeniaed adenocarcinoma. Lee and Scully5 have demonsraed a high frequency of aypical endomerial hyperplasia misdiagnosed as well-differeniaed endomerial adenocarcinoma. Aypical endomerial hyperplasia is considered a precursor of endomerial adenocarcinoma and is characerized by endomerial glands wih cyological aypias and back o back crowding wihou any sromal invasion. Iflef unreaed, i can progress o carcinoma in up o 25 o 29 percen of cases. 2,6 Progesin herapy has been repored o cause regression of aypical hyperplasia in as high as 94 percen of cases, whereas regression of well-differeniaed endomerial carcinoma wih progesins occurs in 62 o 75 percen ofwomen. 2 Ir has been suggesed ha here are wo disinc caegories of endomerial carcinoma in premenopausal women. In 1983, Bokhman developed his heory of esrogen-dependen and esrogen-independen umours o explain why some paiens fare beer han ohers?,8 The firs group shows evidence of prolonged exposure o unopposed esrogen: obesiy, nullipariy, polycysic ovarian syndrome (PCOS), chronic anovulaion, irregular menses, and inferiliy.9 The second group does no show evidence ofhyperesrogenism: women may be hin, have regular menses, and have had generally no gynaecological problems in he pas. IO The firs group of paiens ends o have a generally good prognosis, showing lesions wih well-differeniaed umours wih no or minimal myomerial invasion which are more likely o respond o progesin herapy. The second group ends o have less well-differeniaed umours wih a endency o invade deeply ino he myomerium and o be progesin insensiive. 8,10 A review aride by Sardi e al 3 saed ha grade I umours were more likely o regress wih high dose progesin herapy. In heir small series, a paien wih grade 11 umour did no respond o conservaive hormonal reamen. Ohers have combined chemoherapy o high dose progesins in grade 11 umours o enhance he response rae. 6 The grade of he umour is an imporan elemen in deciding wheher o choose conservaive reamen of endomerial carcinoma in young women.3,7,11 CLlNICAL PRESENTATION The age of presenaion is variable, wih paiens as young as 15 years of age having been diagnosed wih endomerial carcinoma. 1 Because of young age, he diagnosis is ofen delayed. Indeed i migh occur during an inferiliy invesigaion. Abnormal vaginal bleeding was he major presening sympom in more han 80 percen of paiens in Crissman's series: 11 The diagnosis of endomerial carcinoma a a young age may indicae he possibiliy of an inheried suscepibiliy, and i is imporan o invesigae he poenial risk, alhough rare, of Lynch 11 syndrome, which includes familial colon cancer and oher adenocarcinomas. Crissman e al. 11 and Gisch e al 12 found an incidence of coexising ovarian neoplasm in 19 and 29 percen of heir cases respecively. Ir has been hypohesized ha paiens wih PCOS migh be a greaer risk for boh endomerial and ovarian carcinoma. 13,14 The high levels of gonadoropins found in PCOS migh be he principal miigaing facor o explain he associaion of PCOS and ovarian carcinomas. 14 The high levels of gonadoropins also disrup ovulaion and he producion of progeserone, hence leading o he high levels of unopposed esrogen causing endomerial carcmoma. ENDOMETRIAL CANCER AND PREGNANCY There have been 24 cases of endomerial carcinoma associaed wih pregnancy repored in he lieraure The diagnosis mos frequenly occurred on cureage specimen evaluaion following sponaneous aborion or pregnancy erminaion. More rarely, he diagnosis was made during Caesarean secion. 12,17 Pregnancy is usually hough o be a proecive facor for endomerial carcinoma. Human chorionic gonadoropin (hcg)

3 and progeserone may be linked o ha proecion, or indeed i may be ha ovulaory women are less likely o develop endomerial carcinoma. Anoher mechanism migh involve he heoreical aniproliferaive effec ofhcg on he endomerium. 15,18 Local regulaory sysems for proliferaion of endomerial cells are usually under he conrol of lueinizing hormone-releasing hormone (LHRH ) and epidermal growh facor (EGF); however, hcg migh ac on hese recepors, downregulaing limour proliferaion in hormone-dependen umours. 15 For unknown reasons, hese mechanisms migh no work properly in cases involving he associaion of early pregnancy and endomerial carcinoma. Anoher hypo hesis migh be ha some localized areas of he endomerium migh be refracory o progeserone, causing umours in ha area no o respond weh o hormonal reamen. INVESTIGATION The diagnosic seps in younger paiens should be he same as for posmenopausal women invesigaed for abnormal bleeding, commencing wih office endomerial biopsy and endocervical cureage (ECC).19 According o arecen Sociey of Obsericians and Gynaecologiss of Canada (SOGC) dinical guideline, he qualiy of specimens obained from office endomerial biopsy approached hose obained hrough dilaaion and cureage (D&C). However, if he iniial biopsy is impossible o do, incondusive or negaive, and sympoms persis, a formal D&C should be done. 19 During he reamen period, he response or lack hereof should be documened every hree monhs. 6,9 To rule ou more advanced disease, diagnosic ools such as ransvaginal ulrasonography or magneic resonance imaging (MRI) have been proposed o evaluae he risk of TABLE I myomerial invasion. 9,20 Pelvic ulrasound could be performed, as i can be helpful o rule ou adnexal pahology in view of he risk of coexising ovarian carcinoma. ll - 13 Some auhors propose a diagnosic laparoscopy o evaluae he ovaries and perioneal caviy.3 Laparoscopy has he advanage of no delaying definiive surgical herapy if more advanced disease is presen or if concomian ovarian carcinoma is found. The use of umour markers such as CA-125 or CA-19-9 alone or in combinaion wih imaging modaliies mayalso be ofhelp in deermining more advanced disease. 9,20 Hyseroscopic assessmen of he uerine caviy has been suggesed,3,9 bu here is curren concern ha his procedure may cause ransubal cancer ceh disseminaion, which mayworsen he prognosis If possible, hormonal recepor assessmen should be obained, as i may be helpful in deermining which unloufs are more likely o respond o hormonal reamen? MEDICAL TREATMENTS Once a pahologis experienced in gynaecologic oncology confirms he diagnosis of endomerial cancer, horough discussion of reamen opions should ake place wih he paien. Given he in frequen occurrence of his condiion, i migh also be helpful o obain a consulaion wih a gynaecologic oncologis. Also before he paien decides on her herapy sraegy, i would be helpful o enlis a mulidisciplinary eam, induding a counsehor, o ascerain ha he paien really undersands and appreciaes he implicaions of her choice. If for reasons of feriliy preservaion he paien wans o avoid a hyserecomy and bilaeral salpingo-oophorecomy, he opion ofhigh dose hormonal herapy should be forwarded. Because of he rare occurrence of his condiion in his age group, exensive daa or large prospecive rials are lacking. Table 1 summarizes four sudies uilizing high dose progesional agens. 3,6,7,9 Regression of well-differeniaed adenocarcinoma afer a shor course of progesins given preoperaively has been documened on final pahology in 24.1 percen of cases? Bokhman e ap used oxyprogeserone caproae (Delaluin ) in 19 paiems under 40 years of age wih clinical sage I endomerial carcinoma, COMPARISON OF MEDICAL TREATMENT OF PREMENOPAUSAL ENDOMETRIAL CARCINOMA Auhor # Progesin Treamen Regression Persisencel Paien Paiens (dose) duraion (mo) (%) recurrence (# pregnancies) Sardi 4 Provera I 2 (3) ( 1998) ( mg) (75) Randall 12 Megace (5) ( 1997) ( mg)*** (75) Kim 7 Megace ( 1997) (160 mg) (57) Bokhman 19* Delaluin ** ( 1985) (500 mg) (79) * Grade 11 umour ** 2 paiens wih no residual umour 2 microfoci *** I paien 400 mg self disconinued I paien adenosquamous, I paien failed, I paien disconinued --

4 a a dose of 500 mg inramuscularly per day for hree monhs. Afer hree monhs, a biopsy or cureage was carried our. If he process had no regressed, paiens wen on o have surgical saging. If he biopsy showed no evidence of adenocarcinoma, he reamen was coninued for anoher hree monhs a he same dosage bu he frequency was reduced o wice a week. Afer six monhs, paiens who had responded o he progescional reamen were pu on oral conracepives unil hey were ready o conceive. Using his reamen sraegy, 15 ou of 19 paiens were considered cured (Table 1). Twelve paiens had compiee regression of umour afer hree monhs of reamen and in hree cases regression was obained afer six monhs. Four paiens had a cureage earlier (1.5-2 monhs) and showed no regression, and hus underwen a hyserecomy. Pahological examinaion revealed no residual umour in wo paiens and microfoci of adenocarcinoma in he oher wo. Of noe in he Bookman sudy were four paiens wih FIGURE 1 ALGORITHM FOR SUSPICION OF ENDOMETRIAL CANCER IN PREMENOPAUSAL PATIENTS Adenoca cervix Managemen Cervical Ca OEB ECC / Suspicion of endomerial cancer in premenopausal paiens If ECC or endomerial sampling done i Complex Unsaisfacory Endomerial Ca Hyperplasia Unable o Dx / Managemen Hyperplasia No wish o preserve feriliy Sandard Surgical Treamen D&C "" Revise pahology Gyn Oncology consulaion Wish o reain feriliy 1 nvesigaion Ches X-ray TV or pelvic US or MRI Tumour markers (Ca-125. Ca 19-9) Tumour recepors (esrogen/progeserone) Laparoscopy Clinical sage la disease. Grade 1 umour Clinical sage 1 b or higher grade 11 or 111. unfavorable hisology Sandard Sx reamen Medical reamen Sandard Sx reamen OEB: Office Endomerial Biopsy ECC: Endocervical Cureage TV: ransvaginal

5 FIGURE 2 ALGORITHM FOR MEDICAL TREATMENT OF ENDOMETRIAL CARCINOMA IN PREMENOPAUSAL PATIENTS f Regression o Hyperplasia Pursue same Tx 3-6 mo Medical Treamen F/U q 3 monhs D&C/OEB Pelvic examinaion Complee regression * Longer ~ F/U q 3-6 mo D&C/OEB OC unil ready o conceive Family compleed Consider TAH BSO Or coninue rigorous F/U OEB: Office endomerial biopsy OC: oral conracepives Persisance afer 6 mo reamen Failure Medical Treamen ~ Sandard Sx reamen grade II lesions who were given chemoherapy in addiion o oxyprogeserone caproae, bu daa on response or lack of i was no analyzed separaely. Follow-up in ha series ranged from hree o nine years, wih eigh paiens having been followed for more han five years wih no evidence of recurren disease. In Randall's sudy of hormonal reamen of premenopausal women wih aypical complex endomerial hyperplasia and well-differeniaed adenocarcinoma of he uerus, 14 paiens had well-differeniaed adenocarcinoma. 6 Of hese, 12 were reaed wih high dose megesrol aceae (Megace ) 40 o160 mg per day. Nine of hese paiens (75%) had documened regression afer a median lengh of reamen of nine monhs (range 3-18 monhs). Three paiens had persisen lesions: one paien declined furher herapy and surgery; while he oher wo were found o have coexisen sage I ovarian endomerioid umours afer hree and six monhs of reamen and persisen carcinoma in he uerus. These las wo paiens were considered free of disease afer a follow-up of 61 and 72 monhs afer definiive surgery. One paien in he regression group recurred and was rereaed wih progesins, and laer conceived. No paiens reaed conservaively had progression. Follow-up in his series ranged from nine o 78 monhs in he responder group (median of 38 monhs). Paiens wih persisen disease underwen definiive surgery, induding one paien who was reaed only wih oral conracepives. Of he hree paiens wih persisen lesions, wo were found o have coexisen ovarian carcinomas and were operaed accordingly, and he hird paien declined furher reamen (Table 1). Sardi e al3 repored four cases of endomerial carcinoma reaed wih hormonal herapy. Their paiens had endomerial sampling and hyseroscopies every wo monhs unil regression was documened. Two paiens had regression documened afer wo monhs, bu were reaed for a oal of hree monhs. One paien had regression o aypical hyperplasia afer four monhs and o normal afer nine monhs. The las paien did no show regression afer four monhs and was reaed by surgery, and was found o have measaic disease o he ovary a surgery. Follow-up of he responders ranged from 17 o 72 monhs wih a median of 34 monhs. Three ou of he four paiens received 500 mg of medroxyprogeserone aceae (MPA) Provera and one paien in he early regression group received 200 mg MPA per day. Kim e al9 used a hree monh course of megesrol aceae (Megace ) 160 mg per day for seven premenopausal women wih well-differeniaed endomerial carcinoma. Four paiens had no evidence of disease in he endomerial sampling done afer hree monhs of reamen bu wo of hese four paiens laer recurred, one a 21 monhs and he oher a 12 monhs. They were boh rereaed wih megesrol aceae. The firs one responded o reamen again and endomerial sampling was negaive. She laer developed heavy bleeding and underwen surgery: endomerial adenocarcinoma was found on final pahology. The second paien was hough o respond bu here was no furher sampling o prove i. The hree oher paiens underwen surgery: he firs because he medicaion was no oleraed, he second because of anxiey over a medical reamen insead of surgery, and he hird had persisence of he neoplasm. Follow-up of responders ranged horn seven o 46 monhs, alhough hree of he responders were followed for 12 monhs or less. Oher hormonal agens, such as gonadoropin-releasing hormone analogues and danazol, have been used wih so me response in endomerial hyperplasia, bu experience in endomerial cancer is lacking and hey canno be recommended a his momen. A few auhors have used amoxifen in combinaion o a progesional agen o enhance response; however, here is lile daa available o suppor is use. 24 Oral conracepives have been used in only a few paiens wih deceiving resuls because of persisence of he pahologic process, and hus are no recommended as primary hormonal herapy. They are, however, useful in paiens who are no ready o conceive afer regression of heir endomerial cancer, as an ongoing herapy o ry o preven recurrence of he cancer cells. 9

6 OBSTETRICAL OUTCOME Afer successful medical reamen of endomerial cancer, here have been several case repors of successful pregnancies. 15,24-29 Since a majoriy of young women wih endomerial carcinoma had an underlying feriliy problem before he diagnosis of heir cancer, i is no surprising ha mos women required some form of ovulaion inducion wih domiphene cirae, menoropins, and even in viro ferilizaion Alhough he number of cases is limied and follow-up is shor, i would seem ha hormonal manipulaion o assis reproducion does no have a negaive impac on umour recurrence, provided ha he paien is carefully followed during he period of ovulaion inducion and afer pregnancy o rule ou recurrence. As a precauion, Muechler e al recommended posparurn cureage o rule ou recurren disease. 27,30 FOLl.OWUP During follow-up, cases of hyperplasia and frank carcinoma have been demonsraed. 6,9,30 Kim e al.,9 based on a small series, suggesed ha he risk of progression during or afer progesin herapy is probably around five percen. Any abnormal bleeding should be horoughly invesigaed, and hese paiens should be moniored dosely wih cervical cyology, pelvic exarninaion, ulrasound, and endomerial sampling every hree o six monhs for an undeermined period of ime. 3,9 Lai e al 24 and Kimming e al29 recommend definiive hyserecomy afer compleion of he family in hese paiens because he risk of recurrence in he fuure is unknown and because he underlying cause for cancer developmen has no been resolved in he majoriy of cases. RECOMMENDATIONS Alhough he bes reamen modaliies are sill undear, megesrol aceae 160 mg per day orally (Megace ), medroxyprogeserone aceae 500 mg per day orally (Provera ) or oxyprogeserone caproae 500 mg per day inramuscularly (Delaluin ) for six o nine monhs would seem o be equivalen. (11-2 B) To preven recurrence, a mainenance regimen wih low dose progesins or oral conracepives should be used while awaiing he ime o conceive. (11-2, III B) A hyserecomy would be a wise sraegy once he family is compleed because of documened recurrences. I is also advisable o remove he ovaries given he non-negligible percenage of ovarian carcinomas in hese paiens. (11-3 B) The issue of hormonal replacemen herapy in hese paiens has no been addressed and should be discussed wih he paien and wih he emerging lieraure on he subjec. Clinical saging of endomerial carcinoma has been shown o underesimae he sage of disease; however, radiological ools such as MRI and ulrasonography may aid in deermining myomerial invasion or adnexal pahology. (II-3 B) Laparoscopy can be used o rule ou more advanced disease and hus no delay definiive surgical reamen. (III B) The use of assised reproducion echnology in hese paiens does no seem o adversely affec he prognosis once he disease has regressed. (11-3, III C) Finally and mos imporancly, no all paiens are suiable candidaes for medical reamen of endomerial carcinoma: grade 1 endomerioid llmours are mos likely o respond o hormonal reamen. (11-1 A) SUMMARY Prospeccive rials on he opimal dosage, reamen duraion, and hormonal agen o use are lacking. Medroxyprogeserone aceae 500 mg per day orally (Provera ), megesrol aceae 160 mg per day orally (Megace ), and oxyprogeserone caproae 500 mg per day inramuscularly (Delaluin ) have been he mos widely used regimen. Opimal duraion of reamen is no known and should probably be in he range of six o nine monhs, alhough regressions have been documened afer wo monhs. During he reamen period, he response or lack hereof should be documened wih endomerial sampling every hree monhs. 6,9 Medical reamen of well-differeniaed endomerial carcinoma in young paiens wishing o reain heir feriliy poenial seems possible. However, clear recommendaions or guidelines are lacking because his is a rare disease in premenopausal women and preservaion of feriliy is imporan only o a minoriy of paiens. Hisologie grade differeniaion is imporan o predic probabiliy of regression. Paiens wih higher-grade lesions should no be offered his reamen. Moreover, paiens wih adverse hisologie ypes such as carcinosarcomas, adenosquamous, papillary serous, and dear cell umours should no be offered a conservaive reamen opion. The paien should undersand ha alhough daa available seems encouraging, delay in he definiive reamen of a disease ha is more han 95 percen curable wih surgical reamen may jeopardize he oucome. If he opion of medical reamen of endomerial carcinoma is considered, careful paien counselling along wih a mulidisciplinary approach induding pahology and gynaecologic oncology consulaions should be sough and available. Medical reamen of endomerial carcinoma in his special group of paiens should be viewed as a emporary measure o allow compleion of he family. REFERENCES I. Farhi DC. Nosanchuk J. Silverberg SG. Endomerial adenocarcinoma in women under 25 years of age. Obse Gynecol 1986;68: Morrow CP, Curin JP. Synopsis of Gynecologic Oncology. 5h ediion. NewYork:Churchili Livingsone.1998;p.179.

7 3. Sardi J,Anchezar Henry JP. Paniceres G, Gomez Rueda N,Vighi S. Primary hormonal reamen for early endomerial carcinoma. Eur J Gynaecol Oncol 1998; 19: Woolf SH, Baisa RN,Anderson GM, Logan AG, Wang E. Assessing he clinical effeciveness of prevenive maneuvers: analyic principles and sysemic mehods in reviewing evidence and developing clnical pracice recommendaions. Arepor by he Canadian Task Force on he Periodic Healh Examinaion. J CHn Epidemiol 1990;43(9): Lee KR, Scully RE. Complex endomerial hyperplasia and carcinoma in adolescens and young women 15 o 20 years of age: arepor of 10 cases. In J Gynecol Pahol 1989;8: Randall TC, Kurman RJ. Progesin reamen of aypical hyperplasia and well-differeniaed carcinoma of he endomerium in women under age 40. Obse Gynecol 1997;90: BokhmanJV,Chepick DF,VolkovaAT,VishnevskyAS. Can primary endomerial carcinoma sage I be cured wihou surgery and radiaion herapy? Gynecol Oncol 1985;20: Scurry J, Brand A, Sheehan P. Planner R. High-grade endomerial carcinoma in secreory endomerium in young women: arepor of five cases. GynecolOncol 1996;60: Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Monz FJ. Progesin alone as primary reamen of endomerial carcinoma in premenopausal women. Cancer 1997;79: Honore LH, Davey SJ. Endomerial carcinoma in young women: arepor of four cases. J Reprod Med 1989;34: Crissman JD,Azoury RS, Barnes AE, Schell ras HF. Endomerial carcinoma in women 40 years of age or younger. Obse Gynecol 1986;57: Gisch G, Hanzal E,Jensen D, Hacker NF. Endomerial cancer in premenopausal women 45 years and younger. Obse Gynecol 1995;85: Hoffman MS, Cavanagh D, Waler TS,lonaa F, Ruffolo EH. Adenocarcinoma of he endomerium and endomerioid carcinoma of he ovary associaed wih pregnancy. Gynecol Oncol 1989;32: Schildkrau JM, Schiwingl PJ, Basos E, Evanoff A, Hughes C. Epihelial ovarian cancer risk among women wih polycysic ovary syndrome. Obse Gynecol 1996;88: AyhanA, Gunalp S, Karaer C, GokozA, Oz U. Endomerial adenocarcinoma in pregnancy. Gynecol Oncol 1999;75: Schneller JA, Nicasri AD. Inrauerine pregnancy coinciden wih endomerial carcinoma: a case sudy and review of he lieraure. Gynecol Oncol 1994;54: Schammel Dp' Mial KR, Kaplan K, Deligdisch L, Tavassoli FA. Endomerial adenocarcinoma associaed wih inrauerine pregnancy.ln J Gynecol Pahol 1998; 17: Suzuki A, Korishi I, Okamura H, Nakashima N. Adenocarcinoma of he endomerium associaed wih inrauerine pregnancy. Gynecol Oncol 1984;18: Brand A, Dubuc-Lissoir J, Ehlen TG, Plane M. Diagnosis of endomerial cancer in women wih abnormal vaginal bleeding.j Soc Obse Gynaecol Can 2000;86: Schneider J, Ceneno M, Saez F, Genolla J, Ruibal A. Preoperaive CA- 125, CA-I 9-9 and nuclear magneic resonance in endomerial carcinoma: correlaion wih surgical sage. Tumor Biol 1999;20: Rose PG, Mendessohn G, Kornbluh I. Hyseroscopic disseminaion of endomerial carcinoma. Gynecol Oncol 1998;71: Leveque J, Goya F, Dugas J, Locille L, Grall JY, LeBars S. Value of perioneal cyology afer hyseroscopy in surgical saging of adenocarcinoma of he endomerium. Oncol Rep 1998;5: Zerbe MJ, Zhang J, Brisow RE, Grumbine FC,Abularach SM, Monz FJ. Rerograde seeding of malignan cells during hyseroscopy in endomerial cancer. Absrac presened SGO Meeing, Lai CH, Hsueh S, Chao AS, Soong YK. Successful pregnancy afer amoxifen and megesrol aceae herapy for endomerial carcinoma. Br J Obse Gynecol 1994; I 0 I : Niwa K,Yokoyama Y,Tanaka T, e al. Successful pregnancy in a paien wih endomerial carcinoma reaed wih medroxyprogeserone aceae. Arch Gynecol Obse 1994;255: Kowalczyk CL, Malone J, Peerson EP.Jacques SM, Leach RE. Well-differeniaed endomerial adenocarcinoma in an inferiliy paien wih laer concepion. J Reprod Med 1999;44: Paulson RJ, Sauer MV, Lobo RA. Pregnancy afer in viro ferilizaion in a paien wih sage I endomerial carcinoma reaed wih progesins. Feril Seril 1990;54: Muechler EK, Bonglio T, Choae J, Huang KE. Pregnancy induced wih menoropins in a woman wih polycysic ovaries, endomerial hyperplasia and adenocarcinoma. Feril Seril 1986;46: Kimmig R, Srowizki T, Muller-Hocker J, Kurzl R, Korell M, Hepp H. Conservaive reamen of endomerial cancer permiing subsequen riple pregnancy. Gynecol Oncol 1995;58: Misushia J, Toki T, Kao K, Fudgii S, Konishi I. Endomerial carcinoma remaining afer erm pregnancy following conservaive reamen wih medroxyprogeserone aceae. Gynecol Oncol 2000;79: A Guide for Healh Professionals Working wih Aboriginal Peoples This issue of he Journal SOGe includes a Self-Direced Learning Module on he guide for healh professionals working wih Aboriginal peoples. This module qualifies for credis under Secion 2 of he Mainenance of Cerificaion Program of he Royal College of Physicians and Surgeons of Canada. Don' miss his valuable selfdireced learning module on he guide for healh professionals working wih Aboriginal peoples. Suppored by an unresriced educaional gran from JA' WYETH-AYERST CANADA INC