04 - management of en dome trial cancer in young women

8/6/2019 04 - Management of En Dome Trial Cancer in Young Women

1/7

Management ofEndometrial Cancerin Young Women

MONJRI M. SHAH, MD and JASON D. WRIGHT, MD

Division of Gynecologic Oncology, Department of Obstetricsand Gynecology, Columbia University College of Physiciansand Surgeons, New York, New York

Abstract: Endometrial cancer is the most common

gynecologic cancer and its incidence is rising among

premenopausal women. Hysterectomy and bilateral

salpingo-oophorectomy, traditional treatment for en-

dometrial cancer, causes loss of fertility and ovarian

function, both of which can significantly negatively

impact a young womans physical and mental well-being. Recently, conservative management with pro-

gestational agents has been reported with success from

both oncologic and reproductive perspectives. How-

ever, there are no randomized trials comparing con-

servative versus surgical therapy. Patients who arecandidates for conservative therapy must be exten-

sively counseled regarding the risks and must comply

with close surveillance.

Key words: endometrial cancer, young women, ovar-

ian preservation, progesterone, fertility-conserving

surgery

IntroductionCancer of the uterine corpus is the fourthmost common cancer diagnosed in wo-men in the United States. In the United

States, an estimated 43,470 women will bediagnosed in 2010 and approximately7950 will die of the disease. The averageage of women diagnosed with endome-trial cancer is 62 years. Although themajority of women with endometrial can-cer are postmenopausal, approximately9% are under the age of 44 years, andanother nearly 20% are between 45and 54 years of age. Young women withendometrial cancer are traditionallythought to have early-stage, low-gradecancers and thus an improved survival.1

With rising rates of obesity in women ofchildbearing age, it can be assumed thatthe incidence of endometrial cancer inpremenopausal women will only increase.

Risk FactorsA number of investigators have endea-vored to delineate risk factors for endo-metrial cancer in young women. It isgenerally agreed that increasing body

mass index (BMI), nulliparity, and irre-gular menstrual cycles are associated withan increased risk of uterine cancer.2 Themechanism behind many of these risk

www.clinicalobgyn.com | 219

Correspondence: Jason D. Wright, MD, Division ofGynecologic Oncology, Department of Obstetrics andGynecology, Columbia University College of Physi-cians and Surgeons, 161 Fort Washington Ave, 8thFloor, New York, NY. E-mail: [email protected]

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 54 / NUMBER 2 / JUNE 2011

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 54, Number 2, 219225r 2011, Lippincott Williams & Wilkins


2/7

factors is thought be excessive estrogenleading to unopposed endometrial stimu-lation. It has been reported that obesity

increases risk of endometrial cancer upto 10-fold.2 Thomas et al3 found an al-most 22-fold increase in risk in women withBMIs Z35.0 who were younger than 45years at last menstrual period versus analmost 4-fold increase in women with BMIsZ35.0 and who were older than 45 yearsthan their respective counterparts withnormal BMIs, suggesting that not onlyobesity, but also age at menopause are

important risk factors. Other risk factorsinclude diabetes and hypertension, al-though these diseases may be proxies forobesity. Some data suggest that diabetes isan independent risk factor in the develop-ment of endometrial carcinoma even aftercontrolling for obesity, pointing perhapsto inflammation as an exacerbatingfactor.

Clinical and PathologicCharacteristicsThe majority of women with endometrialcancer will have endometrioid histology.In the largest study to date comparingwomen under 40 years of age to thosewho are older, Lee et al1 found that whileendometrioid adenocarcinoma was by far

the most common histologic type in bothage groups, women under 40 years of agewere more likely than older women tohave a sarcoma but less likely to presentwith uterine papillary serous carcinomas.In contrast, others have found no differ-ence in the prevalence of high-risk histo-logies in women younger than 45 yearscompared with older women. Some inves-tigators have shown a high proportion of

young women present with advancedstage cancer and lymph node involvementbut most studies report either no differ-ence in stage or earlier stage at presenta-tion.2,4 The largest study, an analysis ofthe Surveillance, Epidemiology, and End

Results registry by Lee et al,1 found thatin women 40 years or younger, 79% hadstage I cancer, 7% had stage II at diag-

nosis, 5% had stage III, and 7% had stageIV endometrial cancer at the time ofdiagnosis.1

Several retrospective studies suggestthat young women diagnosed with endo-metrial cancer are at increased risk ofhaving a genetic predisposition to cancer.5

Hereditary nonpolyposis colorectal can-cer (HNPCC, also known as Lynch syn-drome) is a genetic autosomal dominant

disorder caused by mutations in a familyof DNA mismatch repair genes. Womenwith HNPCC are susceptible to multipledifferent kinds of cancers, including thoseof the large and small intestine, endome-trium, ovary, and hepatobiliary system.6

Several retrospective studies have beenpublished which suggest that young wo-men diagnosed with either colon or endo-metrial cancer are at significantly elevated

risk for HNPCC.7 The precise risk of aHNPCC mutation in young women withendometrial cancer is difficult to de-fine. Matthews et al5 retrospectively ex-amined women under the age of 50 yearsdiagnosed with endometrial adenocarci-noma and found immunohistochemicalevidence of mismatch repair defects in34% of these patients. In their retrospec-tive cohort study examining risk factors in

young endometrial cancer patients, Soli-man et al2 did not find an increased rate ofHNPCC mutations a conclusion that issupported by other invesigators.5,8

As there is some controversy in theliterature, it is reasonable to triage youngwomen with endometrial cancer first bythe revised Bethesda criteria to test formicrosatellite instability, and then theAmsterdam criteria to test for a germline

mutation (Tables 1, 2). Lindor et al6 deli-neated an algorithm for testing forHNPCC. Most investigators agree thatyoung women with a personal history ofanother HNPCC cancer, either synchro-nous or metachronous, or those women

220 Shah and Wright

www.clinicalobgyn.com


3/7

with a suggestive family history should beoffered genetic counseling and testing.Women who test positive for HNPCCshould undergo regular, frequent colono-scopic surveillance; although there is no

demonstrated benefit, experts alsorecommend yearly urinalysis in those wo-men diagnosed with those women with agenetic predisposition.6

TREATMENT

The mainstay of treatment for women ofany age with endometrial cancer or atypicalhyperplasia is hysterectomy with bilateral

salpingo-oophorectomy and considera-tion of lymphadenectomy. Hysterectomyresults in loss of fertility, whereas oophor-ectomy not only results in loss of fertilitybut subjects young women to early onsetmenopause and its associated sequelae.There has been much recent interest infertility-conserving therapies in selectedyoung women with endometrial cancer.

MEDICAL THERAPYProgestin therapy for treatment of endo-metrial cancer was proposed as early asthe 1960s but in general was limited towomen who were not operative candi-dates.9,10 Over the past decade, there has

been a growing trend to attempt medicaltherapy in young, well-selected patients inan effort to preserve fertility. Numerous

investigators have published observatio-nal series describing experiences with hor-monal therapy. In a systematic review thatincluded 81 patients treated from 1966 to2003, Ramirez et al10 noted that approxi-mately 60% of patients had a sustainedcomplete response to hormonal therapy,with a median duration of treatment of24 weeks. Of note, 23% of the women didnot respond and a further 19% of patients

who initially responded to progestin ther-apy recurred. Although no randomizedcontrolled trials have been conductedcomparing hormonal therapy to defini-tive surgical therapy, Ushijimaet al11 con-ducted a prospective phase II trial lookingat pathologic complete response of womenyounger than 40 years diagnosed with eitherstage IA endometrial cancer or atypicalhyperplasia. Patients were treated with

oral medroxyprogesterone acetate for upto 26 weeks with periodic pathologic sur-veillance. Overall, the complete responserate was 67%. However, of the patientswho achieved a complete response, 47%of them had a recurrence. The authorsconcluded that while fertility-sparingtreatment is effective, close follow-up isnecessary even in women with a completeresponse given the high rate of recur-

rence.11

TABLE 1. Revised Bethesda Guidelines6

Microsatellite Instability Testing Should bePerformed When 1 or More of the Following

Criteria are met:1. Colorectal cancer diagnosed in a patient who

is younger than 50 y2. Presence of colorectal cancers that are

synchronous or metachronous or other tumorsassociated with HNPCC, regardless of age

3. Colorectal cancer with a high amount ofmicrosatellite instability or histologydiagnosed in a patient who is younger than 60 y

4. Colorectal cancer or tumor associated withHNPCC diagnosed before the age 50 y in atleast 1 first-degree relative

5. Colorectal cancer or tumor associated withHNPCC diagnosed at any age in 2 first-degreeor second-degree relatives

HNPCC indicates hereditary nonpolyposis colorectal cancer.

TABLE 2. Amsterdam Criteria6

Assessing Family Risk for HNPCC: At least 3relatives have a HNPCC-related cancer:*One should be a first-degree relative of the other

2 relativesAt least 2 successive generations should be

affectedAt least 1 relative should be diagnosed before the

age of 50 y

Familial adenomatous polyposis should beexcluded

Tumors should be verified by pathologicexamination

* Colorectal, endometrial, small bowel, renal pelvis cancers.

HNPCC indicates hereditary nonpolyposis colorectal cancer.

Management of Premenopausal Endometrial Cancer 221



4/7

Although there is no consensus onwhich women are appropriate candidatesfor progestational therapy, most investi-

gators agree that uterine-conserving ther-apy should only be offered to women whohave not completed childbearing and havewell-differentiated endometrioid adeno-carcinomas, with no evidence of extra-uterine spread documented on imaging.The majority of patients in the literaturehave been treated with either medroxy-progesterone acetate or megestrol acetate.However, there is no consensus on dosing

or delivery (Table 3).1215

Successful useof a progestin intrauterine device in wo-men who are poor operative candidateshas been reported.12 The largest of theseseries followed 12 women diagnosed withgrade I, stage I endometrial cancer whowere deemed to have excessive surgicalrisk.16 Dilation and curettage and imagingwere used to determine grade and stage,and a progestin-containing intrauterine

device was placed. Patients underwentperiodic endometrial sampling. Six of 8patients at 12 months were histologicallynegative for disease. No case reports orstudies have been conducted using anintrauterine progestin system in young,otherwise healthy endometrial cancer pa-tients who desire fertility.

The ideal length of treatment also re-mains controversial. Although most women

who respond to progestational therapy doso within 12 weeks, there is a large re-ported range (4 to 60 wks).10 Endometrialsampling, whether by biopsy or dilationand curettage, is used to monitor responseto treatment. If at the time of reassess-ment patients have not achieved a re-

sponse, the dose of the progesterone canbe increased or patients can be deemeda treatment failure and counseled for

hysterectomy. Even if a complete histo-logic response is noted after 12 weeks, itis advocated to continue treatment for aminimum of 24 weeks.10 Typically, serialendometrial sampling is performed atvariable intervals, and optimal frequencyhas not been determined.

The role of serum tumor markers suchas CA-125 and routine pelvic imaging toevaluate extrauterine spread is unknown.

Gotlieb et al9

used CA-125 in the initialevaluation, but all values were withinnormal range. The authors acknowledgedthat an elevated CA-125 in this popula-tion may be difficult to interpret given thenumerous other causes for elevation inyoung women, and that other modalitieswould need to be used to differentiatethese processes from metastatic disease.Magnetic resonance imaging has been

used by many investigators to assess myo-metrial and cervical invasion as a proxyfor surgical staging, but magnetic reso-nance imaging has been shown to be poorat detecting deep myometrial invasionand pelvic lymph node infiltration. AsRamirez et al10 point out, there is a dearthof data to recommend or refute use ofthese tests in women undergoing conser-vative therapy.

The role of hysterectomy after comple-tion of childbearing remains largely un-addressed. Most investigators are in favorof definitive surgical management as thepredisposing factors, whatever they mightbe, do not disappear over time and re-currence rate is not known.13 However,

TABLE 3. Published Doses and Delivery of Progesterone Therapy1215

Reference Type and Dose of Progestogen ResultsMontz et al12 Levonorgestrel IUD 64% biopsy negative at 6 moYamazawa et al13 MPA 400 mg daily 78% complete response in 6 moEftekhar et al14 Levonorgestrel IUD MPA 200 mg twice daily 63% response rate over 6 moCade et al15 Megestrol acetate 160-320mg PO daily 86% response rate

MPA indicates medroxyprogesterone acetate.

222 Shah and Wright



5/7

there are case reports of women whodecline definitive management and con-tinue with surveillance with or without

progestin treatment.16

Length of follow-up is variable in these studies, which maypreclude diagnosis of recurrence. Clearly,further study is needed in this area.

There are numerous case reports andsmall series involving women with endo-metrial carcinoma and subsequent preg-nancies after conservative treatment. Mostwomen were treated with high-dose pro-gestins and when pathologic remission was

documented, pregnancy was attempted.Some protocols allowed time for sponta-neous conception, but most investigatorsproceeded with assisted reproductive tech-niques to shorten time to conception. Mostreports describe standard ovulation induc-tion with either clomiphene citrate or go-nadotropins followed by either intrauterineinsemination or in vitro fertilization andembryo transfer.16 In general, pregnancy

rates are excellent (between 70% to 80%)and correlate to patients age rather thanthe diagnosis or primary treatment.

OVARIAN PRESERVATION

Bilateral salpingo-oophorectomy is tradi-tionally included in surgical therapy forendometrial cancer to complete stagingand remove the primary source of estro-gen. This poses a dilemma in premeno-

pausal women for two reasons: surgicalcastration precludes fertility, which maystill be desired, and may predispose thesepatients to complications encountered bypremature menopause (increased risk ofosteoporosis, increased incidence of car-diovascular events, and psychosocial is-sues). Opponents of ovarian preservationargue that not only are the ovaries thesource of estrogen that may stimulate

occult endometrial cancer cells, but thatyoung women with endometrial cancer arealso at increased risk for the development ofsynchronous ovarian malignancies.

Studies of young women with endome-trial cancer have shown a rate of concur-

rent ovarian malignancy in up to 29%.4,17,18

In women with grade 1 endometrial can-cer, ovarian pathology is most commonly

consistent with a synchronous primary asopposed to metastasis. Women diagnosedwith ovarian cancer as a single primarycancer most often have serous histology.In contrast, women who have dual pri-mary endometrial and ovarian cancers aremore likely to have endometrioid histol-ogy for both.17,18 There is wide variationin rates of synchronous ovarian cancer inpatients with stage I endometrial cancer

reported in the literature.17

Of these wo-men, the vast majority were found to havea stage I endometrioid ovarian cancer onfinal pathology. Patients who are diag-nosed with synchronous stage I endome-trial and stage I ovarian cancer have a5-year survival rate of 97%.17

Walsh et al18 analyzed a population of102 young women who were diagnosedwith endometrial cancer who eventually

underwent definitive therapy. On finalpathology, 19% of patients with a gradeI endometrial cancer had malignant ad-nexal pathology, and all of these womenwere found to have a second primaryovarian cancer. These authors stated thatwhile preoperative imaging was helpful inidentifying women with abnormal adnex-ae, almost 10% of women with normaladnexae on preoperative imaging had

ovarian involvement on final pathologyreview. The authors of this series stronglyadvocated for visualization by laparo-scopy or careful imaging of the adnexaebefore undertaking conservative therapyfor endometrial cancer.18

Despite the potential for either syn-chronous or metachronous ovarian dis-ease, several reports have examined thesafety of ovarian preservation at the time

of hysterectomy in young women withendometrial carcinoma. By and large,these studies have suggested that ovarianpreservation is safe. The largest of thestudies, an analysis of the Surveillance,Epidemiology, and End Results database




6/7

by Wright et al,19 found no excess deathswith ovarian preservation, concludingthat in a patient with low-grade, early

stage cancer with no evidence of ovarianinvolvement, risk of recurrence is notincreased and survival is not affected byovarian preservation.

Ovarian preservation is associated witha number of benefits. Menopause oftenresults in vasomotor symptoms and vagi-nal atrophy, and there are data to suggestthat young women who are subjected tosurgical menopause may have an increased

risk of cardiovascular disease, osteoporo-sis, hip fracture, and cognitive dysfunc-tion.19,20 Ovarian preservation decreasesnot only the risk of osteoporosis andcardiovascular disease but also may havea direct effect on mortality.19,20 Severalpopulation-based studies suggest that ageat menopause, whether natural or surgi-cal, is a major determinant of survival.20

Women who go through menopause be-

fore the age of 50 years have a higher all-cause mortality rate than women who gothrough menopause after the age of 50years. As the survival rate for early stageendometrial cancer is high, there issignificant rationale for ovarian conser-vation in young women.

Ovarian conservation should be indivi-dualized. The risks and benefits of ovarianpreservation should be carefully discussed

with women before surgical therapy. Thosewhochooseovarian preservationneed to becounseled extensively that despite normalimaging or even visualization of the adnex-ae, ovarian pathology may exist, and con-tinued adnexal surveillance will likely benecessary. Patients with a history suggestiveof HNPCC or those with a family history ofovarian cancer should be strongly coun-seled to undergo oophorectomy.

ConclusionsAlthough endometrial cancer is tradition-ally a disease of postmenopausal women,an increasing number of premenopausal

women are diagnosed every year, posing achallenge to the gynecologic oncologist.Young women with endometrial cancer

face unique challenges including loss offertility and premature menopause. Emerg-ing data suggests that in carefully selectedwomen conservative medical manage-ment may be appropriate treatment; inthose women who do require surgery,ovarian preservation may be an option.Although many questions remain un-answered, recent advances give youngpatients with endometrial cancer more

treatment options and the hope of a nor-mal life and reproductive function despitetheir diagnosis.

References1. Lee NK, Cheung MK, Shin JY, et al.

Prognostic factors for uterine cancer inreproductive-aged women. Obstet Gyne-col. 2007;109:655662.

2. Soliman PT, Oh JC, Schmeler KM, et al.Risk factors for young premenopausalwomen with endometrial cancer. ObstetGynecol. 2005;105:575580.

3. Thomas CC, Wingo PA, Dolan MS, et al.Endometrial cancer risk among younger,overweight women. Obstet Gynecol. 2009;114:2227.

4. Gitsch G, Hanzal E, Jensen D, et al.Endometrial cancer in premenopausalwomen 45 years and younger. Obstet

Gynecol. 1995;85:504508.5. Matthews KS, Estes JM, Conner MG,

et al. Lynch syndrome in women less than50 years of age with endometrial cancer.Obstet Gynecol. 2008;111:11611166.

6. Lindor NM, Petersen GM, Hadley DW,et al. Recommendations for the care ofindividuals with an inherited predisposi-tion to Lynch syndrome: a systematicreview. JAMA. 2006;296:15071517.

7. Lu KH, Dinh M, Kohlmann W, et al.Gynecologic cancer as a sentinel cancerfor women with hereditary nonpolyposiscolorectal cancer syndrome. Obstet Gyne-col. 2005;105:569574.

8. Berends MJ, Wu Y, Sijmons RH, et al.Toward new strategies to select young

224 Shah and Wright



7/7

endometrial cancer patients for mismatchrepair gene mutation analysis. J ClinOncol. 2003;21:43644370.

9. Gotlieb WH, Beiner ME, Shalmon B,et al. Outcome of fertility-sparing treat-ment with progestins in young patientswith endometrial cancer. Obstet Gynecol.2003;102:718725.

10. Ramirez PT, Frumovitz M, Bodurka DC,et al. Hormonal therapy for the manage-ment of grade 1 endometrial adenocarci-noma: a literature review. Gynecol Oncol.2004;95:133138.

11. Ushijima K, Yahata H, Yoshikawa H,

et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogester-one acetate for endometrial carcinoma andatypical hyperplasia in young women.J Clin Oncol. 2007;25:27982803.

12. Montz FJ, Bristow RE, Bovicelli A, et al.Intrauterine progesterone treatment ofearly endometrial cancer. Am J ObstetGynecol. 2002;186:651657.

13. Yamazawa K, Hirai M, Nishi H, et al.

Fertility-preserving treatment with proges-tin, and pathological criteria to predict re-sponses, in young women with endometrialcancer. Hum Reprod. 2007;22:19531958.

14. Cade TJ, Quinn MA, Rome RM, et al.Proestogen treatment options for early

endometrial cancer. BJOG. 2010;117:879884.

15. Eftekhar Z, Izadi-Mood N, Yarandi F,

et al. Efficacy of megestrol acetate(megace) in the treatment of patients withearly endometrial adenocarcinoma: ourexperience with 21 patients. Int J GynecolCancer. 2009;19:249252.

16. Lowe MP, Cooper BC, Sood AK, et al.Implementation of assisted reproductivetechnologies following conservative man-agement of FIGO grade I endometrialadenocarcinoma and/or complex hyper-plasia with atypia. Gynecol Oncol. 2003;

91:569572.17. Soliman PT, Slomovitz BM, BroaddusRR, et al. Synchronous primary cancersof the endometrium and ovary: a singleinstitution review of 84 cases. GynecolOncol. 2004;94:456462.

18. Walsh C, Holschneider C, Hoang Y, et al.Coexisting ovarian malignancy in youngwomen with endometrial cancer. ObstetGynecol. 2005;106:693699.

19. Wright JD, Buck AM, Shah M, et al.

Safety of ovarian preservation in preme-nopausal women with endometrial can-cer. J Clin Oncol. 2009;27:12141219.

20. ACOG Practice Bulletin No. 89. Electiveand risk-reducing salpingo-oophorect-omy. Obstet Gynecol. 2008;111:231241.



04 - management of en dome trial cancer in young women

Documents