Management of Endometrial Cancer in Young Women SHAH, MONJRI M. MD; WRIGHT, JASON D.

MD Keywords: endometrial cancer; young women; ovarian preservation; progesterone; fertility-conserving surgery Author Information Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York Correspondence: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Ave, 8th Floor, New York, NY. e-mail: jw2459@columbia.edu 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 endometrial cancer, causes loss of fertility and ovarian function, both of which can significantly negatively impact a young woman's physical and mental well-being. Recently, conservative management with progestational agents has been reported with success from both oncologic and reproductive perspectives. However, there are no randomized trials comparing conservative versus surgical therapy. Patients who are candidates for conservative therapy must be extensively counseled regarding the risks and must comply with close surveillance. Introduction Cancer of the uterine corpus is the fourth most common cancer diagnosed in women in the United States. In the United States, an estimated 43,470 women will be diagnosed in 2010 and approximately 7950 will die of the disease. The average age of women diagnosed with endometrial cancer is 62 years. Although the majority of women with endometrial cancer are postmenopausal, approximately 9% are under the age of 44 years, and another nearly 20% are between 45 and 54 years of age. Young women with endometrial cancer are traditionally thought to have early-stage, low-grade cancers and thus an improved survival.1 With rising rates of obesity in women of childbearing age, it can be assumed that the incidence of endometrial cancer in premenopausal women will only increase. Risk Factors A number of investigators have endeavored to delineate risk factors for endometrial cancer in young women. It is generally agreed that increasing body mass index (BMI), nulliparity, and irregular menstrual cycles are associated with an increased risk of uterine cancer.2 The mechanism behind many of these risk factors is thought be excessive estrogen leading to unopposed endometrial stimulation. It has been reported that obesity increases risk of

In their retrospective cohort study examining risk factors in young endometrial cancer patients.4 The largest study. pointing perhaps to inflammation as an exacerbating factor. Most investigators agree that young women with a personal history of another HNPCC cancer. endometrium.endometrial cancer up to 10-fold. Clinical and Pathologic Characteristics The majority of women with endometrial cancer will have endometrioid histology. Matthews et al5 retrospectively examined women under the age of 50 years diagnosed with endometrial adenocarcinoma and found immunohistochemical evidence of mismatch repair defects in 34% of these patients. and 7% had stage IV endometrial cancer at the time of diagnosis.5 Hereditary nonpolyposis colorectal cancer (HNPCC. Some investigators have shown a high proportion of young women present with advanced stage cancer and lymph node involvement but most studies report either no difference in stage or earlier stage at presentation. In contrast. either synchronous or metachronous.0 and who were older than 45 years than their respective counterparts with normal BMIs. and hepatobiliary system. Lee et al1 found that while endometrioid adenocarcinoma was by far the most common histologic type in both age groups. Some data suggest that diabetes is an independent risk factor in the development of endometrial carcinoma even after controlling for obesity. and then the Amsterdam criteria to test for a germline mutation (Tables 1. Soliman et al2 did not find an increased rate of HNPCC mutations a conclusion that is supported by other invesigators. others have found no difference in the prevalence of high-risk histologies in women younger than 45 years compared with older women.8 As there is some controversy in the literature. ovary.7 The precise risk of a HNPCC mutation in young women with endometrial cancer is difficult to define.5. although these diseases may be proxies for obesity. In the largest study to date comparing women under 40 years of age to those who are older. or those women with a suggestive family history should be offered genetic counseling and testing. 2).2 Thomas et al3 found an almost 22-fold increase in risk in women with BMIs ≥35. and End Results registry by Lee et al.2. Women who test positive for HNPCC should undergo regular. although there is no demonstrated benefit. Epidemiology.6 Several retrospective studies have been published which suggest that young women diagnosed with either colon or endometrial cancer are at significantly elevated risk for HNPCC. an analysis of the Surveillance.0 who were younger than 45 years at last menstrual period versus an almost 4-fold increase in women with BMIs ≥35. but also age at menopause are important risk factors. suggesting that not only obesity.1 found that in women 40 years or younger. 5% had stage III.6 . it is reasonable to triage young women with endometrial cancer first by the revised Bethesda criteria to test for microsatellite instability. frequent colonoscopic surveillance. including those of the large and small intestine. 79% had stage I cancer. also known as Lynch syndrome) is a genetic autosomal dominant disorder caused by mutations in a family of DNA mismatch repair genes. Lindor et al6 delineated an algorithm for testing for HNPCC.1 Several retrospective studies suggest that young women diagnosed with endometrial cancer are at increased risk of having a genetic predisposition to cancer. 7% had stage II at diagnosis. Other risk factors include diabetes and hypertension. Women with HNPCC are susceptible to multiple different kinds of cancers. women under 40 years of age were more likely than older women to have a sarcoma but less likely to present with uterine papillary serous carcinomas. experts also recommend yearly urinalysis in those women diagnosed with those women with a genetic predisposition.

MEDICAL THERAPY Progestin therapy for treatment of endometrial cancer was proposed as early as the 1960s but in general was limited to women who were not operative candidates. there is no consensus on dosing or delivery (Table 3) . Although no randomized controlled trials have been conducted comparing hormonal therapy to definitive surgical therapy. The majority of patients in the literature have been treated with either medroxyprogesterone acetate or megestrol acetate. Hysterectomy results in loss of fertility. 23% of the women did not respond and a further 19% of patients who initially responded to progestin therapy recurred. The authors concluded that while fertility-sparing treatment is effective.TREATMENT The mainstay of treatment for women of any age with endometrial cancer or atypical hyperplasia is hysterectomy with bilateral salpingo-oophorectomy and consideration of lymphadenectomy. of the patients who achieved a complete response.10 Over the past decade. whereas oophorectomy not only results in loss of fertility but subjects young women to early onset menopause and its associated sequelae. Numerous investigators have published observational series describing experiences with hormonal therapy. Overall. 47% of them had a recurrence. However. There has been much recent interest in fertility-conserving therapies in selected young women with endometrial cancer. Of note. there has been a growing trend to attempt medical therapy in young. with a median duration of treatment of 24 weeks. Ushijimaet al11 conducted a prospective phase II trial looking at pathologic complete response of women younger than 40 years diagnosed with either stage IA endometrial cancer or atypical hyperplasia. close follow-up is necessary even in women with a complete response given the high rate of recurrence. with no evidence of extrauterine spread documented on imaging. In a systematic review that included 81 patients treated from 1966 to 2003. most investigators agree that uterine-conserving therapy should only be offered to women who have not completed childbearing and have well-differentiated endometrioid adenocarcinomas.11 Although there is no consensus on which women are appropriate candidates for progestational therapy. the complete response rate was 67%. However. well-selected patients in an effort to preserve fertility. Ramirez et al10 noted that approximately 60% of patients had a sustained complete response to hormonal therapy.9. Patients were treated with oral medroxyprogesterone acetate for up to 26 weeks with periodic pathologic surveillance.

there is a dearth of data to recommend or refute use of these tests in women undergoing conservative therapy. pregnancy was attempted. Most reports describe standard ovulation induction with either clomiphene citrate or gonadotropins followed by either intrauterine insemination or in vitro fertilization and embryo transfer. Gotlieb et al9 used CA-125 in the initial evaluation. but all values were within normal range. is used to monitor response to treatment. No case reports or studies have been conducted using an intrauterine progestin system in young. there is a large reported range (4 to 60 wks). Most women were treated with high-dose progestins and when pathologic remission was documented.. Although most women who respond to progestational therapy do so within 12 weeks. As Ramirez et al10 point out. and that other modalities would need to be used to differentiate these processes from metastatic disease. Even if a complete histologic response is noted after 12 weeks.12–15 Successful use of a progestin intrauterine device in women who are poor operative candidates has been reported. If at the time of reassessment patients have not achieved a response.16 In general. Magnetic resonance imaging has been used by many investigators to assess myometrial and cervical invasion as a proxy for surgical staging.12 The largest of these series followed 12 women diagnosed with grade I. The role of serum tumor markers such as CA-125 and routine pelvic imaging to evaluate extrauterine spread is unknown. which may preclude diagnosis of recurrence.13 However. stage I endometrial cancer who were deemed to have excessive surgical risk. Patients underwent periodic endometrial sampling. the dose of the progesterone can be increased or patients can be deemed a treatment failure and counseled for hysterectomy. otherwise healthy endometrial cancer patients who desire fertility. whether by biopsy or dilation and curettage. Some protocols allowed time for spontaneous conception. and a progestincontaining intrauterine device was placed. whatever they might be. Most investigators are in favor of definitive surgical management as “the predisposing factors. The role of hysterectomy after completion of childbearing remains largely unaddressed. do not disappear over time” and recurrence rate is not known. serial endometrial sampling is performed at variable intervals. Six of 8 patients at 12 months were histologically negative for disease. The authors acknowledged that an elevated CA-125 in this population may be difficult to interpret given the numerous other causes for elevation in young women. There are numerous case reports and small series involving women with endometrial carcinoma and subsequent pregnancies after conservative treatment. it is advocated to continue treatment for a minimum of 24 weeks. and optimal frequency has not been determined. . there are case reports of women who decline definitive management and continue with surveillance with or without progestin treatment. but magnetic resonance imaging has been shown to be poor at detecting deep myometrial invasion and pelvic lymph node infiltration. pregnancy rates are excellent (between 70% to 80%) and correlate to patients' age rather than the diagnosis or primary treatment.10 Typically.10 Endometrial sampling. further study is needed in this area. The ideal length of treatment also remains controversial.16 Length of follow-up is variable in these studies.16 Dilation and curettage and imaging were used to determine grade and stage. Clearly. but most investigators proceeded with assisted reproductive techniques to shorten time to conception.

early stage cancer with no evidence of ovarian involvement. Opponents of ovarian preservation argue that not only are the ovaries the source of estrogen that may stimulate occult endometrial cancer cells. Patients who are diagnosed with synchronous stage I endometrial and stage I ovarian cancer have a 5-year survival rate of 97%. In contrast.17 Of these women.4. By and large. these studies have suggested that ovarian preservation is safe.18 Despite the potential for either synchronous or metachronous ovarian disease. Epidemiology.18 There is wide variation in rates of synchronous ovarian cancer in patients with stage I endometrial cancer reported in the literature.19. but that young women with endometrial cancer are also at increased risk for the development of synchronous ovarian malignancies. hip fracture.OVARIAN PRESERVATION Bilateral salpingo-oophorectomy is traditionally included in surgical therapy for endometrial cancer to complete staging and remove the primary source of estrogen. and End Results database by Wright et al. and cognitive dysfunction.20 Ovarian preservation decreases not only the risk of osteoporosis and cardiovascular disease but also may have a direct effect on mortality. Ovarian preservation is associated with a number of benefits. which may still be desired.17. is a major determinant of survival. Studies of young women with endometrial cancer have shown a rate of concurrent ovarian malignancy in up to 29%. The authors of this series strongly advocated for visualization by laparoscopy or careful imaging of the adnexae before undertaking conservative therapy for endometrial cancer. the vast majority were found to have a stage I endometrioid ovarian cancer on final pathology. Menopause often results in vasomotor symptoms and vaginal atrophy. This poses a dilemma in premenopausal women for two reasons: surgical castration precludes fertility.17.20 Women who go through menopause before the age of 50 years have a higher all-cause mortality rate than women who . 19% of patients with a grade I endometrial cancer had malignant adnexal pathology. and there are data to suggest that young women who are subjected to surgical menopause may have an increased risk of cardiovascular disease.19. and psychosocial issues). osteoporosis. concluding that in a patient with low-grade.19 found no excess deaths with ovarian preservation. risk of recurrence is not increased and survival is not affected by ovarian preservation. ovarian pathology is most commonly consistent with a synchronous primary as opposed to metastasis.20 Several population-based studies suggest that age at menopause. and may predispose these patients to complications encountered by premature menopause (increased risk of osteoporosis. Women diagnosed with ovarian cancer as a single primary cancer most often have serous histology. women who have dual primary endometrial and ovarian cancers are more likely to have endometrioid histology for both. almost 10% of women with normal adnexae on preoperative imaging had ovarian involvement on final pathology review. several reports have examined the safety of ovarian preservation at the time of hysterectomy in young women with endometrial carcinoma. whether natural or surgical. and all of these women were found to have a second primary ovarian cancer.18 In women with grade 1 endometrial cancer. an analysis of the Surveillance. On final pathology. The largest of the studies.17 Walsh et al18 analyzed a population of 102 young women who were diagnosed with endometrial cancer who eventually underwent definitive therapy. increased incidence of cardiovascular events. These authors stated that while preoperative imaging was helpful in identifying women with abnormal adnexae.

Patients with a history suggestive of HNPCC or those with a family history of ovarian cancer should be strongly counseled to undergo oophorectomy... Prognostic factors for uterine cancer in reproductiveaged women Obstet Gynecol.105:575–580 3. et al. Emerging data suggests that in carefully selected women conservative medical management may be appropriate treatment..114:22–27 4.. As the survival rate for early stage endometrial cancer is high. Soliman PT.85:504–508 5. 2006. 2009. et al.296:1507–1517 7. Dolan MS. posing a challenge to the gynecologic oncologist. Endometrial cancer risk among younger. Although many questions remain unanswered. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome Obstet Gynecol.111:1161–1166 6. Risk factors for young premenopausal women with endometrial cancer Obstet Gynecol.105:569– 574 . Wingo PA. Hadley DW. in those women who do require surgery. Conclusions Although endometrial cancer is traditionally a disease of postmenopausal women. Lynch syndrome in women less than 50 years of age with endometrial cancer Obstet Gynecol. Jensen D. Gitsch G. et al. 2005. Hanzal E. 1995. 2005. Conner MG. Matthews KS. Ovarian conservation should be individualized. ovarian pathology may exist. Lee NK. Petersen GM. Shin JY. Lu KH. Estes JM.go through menopause after the age of 50 years. overweight women Obstet Gynecol. Schmeler KM. recent advances give young patients with endometrial cancer more treatment options and the hope of a normal life and reproductive function despite their diagnosis.109:655–662 2. Dinh M. an increasing number of premenopausal women are diagnosed every year. Those who choose ovarian preservation need to be counseled extensively that despite normal imaging or even visualization of the adnexae. et al. Endometrial cancer in premenopausal women 45 years and younger Obstet Gynecol. Oh JC. et al. there is significant rationale for ovarian conservation in young women. 2007. et al. Lindor NM. and continued adnexal surveillance will likely be necessary. 2008. Kohlmann W. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review JAMA. et al.. Thomas CC. Cheung MK. Young women with endometrial cancer face unique challenges including loss of fertility and premature menopause. References 1. ovarian preservation may be an option. The risks and benefits of ovarian preservation should be carefully discussed with women before surgical therapy.

91:569–572 17.27:1214–1219 20. Wu Y.94:456–462 18. 2003. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review Gynecol Oncol. Sood AK. Yahata H. Fertility-preserving treatment with progestin. Cooper BC.. Shah M. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer Obstet Gynecol.95:133–138 11. Hirai M. Shalmon B.111:231–241 .22:1953–1958 14.102:718–725 10. 2007.. Yamazawa K.25:2798–2803 12. et al. Coexisting ovarian malignancy in young women with endometrial cancer Obstet Gynecol. et al. Sijmons RH. 2010. Efficacy of megestrol acetate (megace) in the treatment of patients with early endometrial adenocarcinoma: our experience with 21 patients Int J Gynecol Cancer. and pathological criteria to predict responses. Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis J Clin Oncol. Frumovitz M. 2009.. Broaddus RR. . Beiner ME. 2004.. Bristow RE. ACOG Practice Bulletin No. Intrauterine progesterone treatment of early endometrial cancer Am J Obstet Gynecol.186:651–657 13. Bovicelli A. Montz FJ.. Quinn MA. Walsh C. et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases Gynecol Oncol. Izadi-Mood N. Hoang Y. Buck AM. 2008. 2007. Safety of ovarian preservation in premenopausal women with endometrial cancer J Clin Oncol. Berends MJ.. et al. et al. 2004.. Ramirez PT. 89. 2003. et al. Soliman PT. Proestogen treatment options for early endometrial cancer BJOG.117:879–884 15. Gotlieb WH. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women J Clin Oncol. Ushijima K.19:249–252 16. Yoshikawa H. Cade TJ. et al. et al. 2005. 2002.. in young women with endometrial cancer Hum Reprod.106:693–699 19.. Nishi H. et al. Implementation of assisted reproductive technologies following conservative management of FIGO grade I endometrial adenocarcinoma and/or complex hyperplasia with atypia Gynecol Oncol..8..21:4364– 4370 9. Rome RM. Slomovitz BM. et al.. Yarandi F. 2009. et al. et al. 2003. Elective and risk-reducing salpingo-oophorectomy Obstet Gynecol. Bodurka DC. Holschneider C. Eftekhar Z. Wright JD.. Lowe MP.

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