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582723823 Endometrial Cancer: Can Fertility Be Preserved? K. Podratz and W. Cliby Mayo Clinic, Rochester, MN, U.S.A. ©Copyright 2002 Mayo Foundation Endometrial cancer is the most common gynecologic malignancy. It accounts for 48% of all cancers of the female reproductive tract and, overall, is the fourth most frequently encountered neoplasm--exceeded only by breast, colon, and lung cancers. It has been estimated that approximately 39,300 new cases of endometrial cancer will be diagnosed in the United States during calendar year 2002 (1). The natural history of this disease generally includes clinical presentation during the sixth decade of life or beyond, with onset heralded by irregular menses or postmenopausal bleeding. Demographic characteristics of the at-risk patient population include obesity, nulliparity, unopposed exogenous estrogens, and late menopause. These characteristics suggest that the primary cause of endometrial cancer is the continuous exposure of the endometrium to estrogens. Confirmatory evidence has been provided by epidemiologic studies that have demonstrated decreased relative risks for women who smoke, have progestins in their hormone replacement regimen, or have a history of oral contraceptive pill use – all of which lower endogenous levels of estrogen. Pathogenetic type I, or estrogen-dependent, endometrial cancer characteristically is welldifferentiated, superficially invasive, and responsive to progestin therapy (2). The prediagnostic signs and symptoms are generally of long duration, and the long-term prognosis is very favorable. In contrast, type II or hormone-independent endometrial cancer is poorly differentiated, deeply invasive, and unresponsive to conventional therapy. The signs and symptoms are of short duration and the prognosis is guarded (2). Potentially unique clinical features of women who have endometrial carcinoma diagnosed before age 40 was emphasized by Dockerty et al. in 1951 (3). These authors reviewed the cases of 1,694 women with endometrial cancer examined at the Mayo Clinic between 1905 and 1944 and found that 36 women (2.1%) were of reproductive age. A well-differentiated carcinoma was diagnosed in 86% of these 36 young women, and an unexpected 20% presented with clinical features of Stein-Leventhal syndrome, currently known as polycystic ovarian syndrome (PCOS). According to contemporary reports, approximately 5% (3%-10%) of cases of endometrial cancer occur in women younger than 40 years. In addition to menometrorrhagia, these young obese women usually present with infertility and ovarian dysfunction or, rarely, a hormone-producing tumor. Invariably, the ovarian dysfunction reflects the physiologic alterations of prolonged intervals of anovulation or PCOS. Chronic anovulation is associated with a state of persistent progesterone hydroxysteroid dehydrogenase and an increase in estrogen receptors within the endometrium. In addition, PCOS is a hyperandrogenic state that results in increased bioavailability of unopposed estrogens through the peripheral conversion of increased endogenous levels of androstenedione and testosterone. These abnormalities are magnified further by the androgen-induced decrease in serum levels of hormone-binding globulin and decrease in tissue levels of dehydrogenases in the endometrium. The above conditions of unopposed estrogen excess predictably cause hyperplasia of the endometrium. If this hormonal milieu is not recognized and treated appropriately, the endometrium progresses through a continuum of hyperplastic histologic states. This histologic continuum appears to include the conversion of normal endometrium to simple hyperplasia, followed by complex hyperplasia, complex atypical hyperplasia (CAH), and well-differentiated adenocarcinoma. The possible reversibility of these histologic changes has been suggested by extended clinical surveillance of patients who had atypical hyperplasia. Kurman et al. (4) reported that of 48 women who were monitored prospectively after confirmation of atypical hyperplasia, 58% had regression and 23% had progression to endometrial cancer. Furthermore, Spiegel et al. (5) demonstrated that 60% of endometrioid carcinomas are associated with CAH. In addition to the histologic similarities, the clinical manifestations of CAH and endometrial cancer in young women are essentially identical (6). Also, the results of molecular analyses, including analyses of estrogen and progesterone receptors, K-ras mutations and PTEN gene anomalies are uniquely similar for both CAH and endometrial carcinoma (7,8). Page 2 Because of the significant risk that CAH can progress to endometrial cancer, hysterectomy is recommended as the definitive treatment of CAH in women who have completed childbearing. However, several investigators have reported various degrees of success in managing CAH with progestational agents in younger women (6,9,10). The results of three reports on women with documented CAH treated prospectively with progestins are summarized in Table 1. In 62% of these women, CAH showed regression, but in 11%, it ultimately progressed to endometrial cancer. The cytostatic agents most frequently used were medroxyprogesterone acetate, megestrol and 17αhydroxyprogesterone. Recent reports have suggested that either tamoxifen or gonadotropin-releasing hormone (GnRH) analogues plus progestins are as effective as progestins alone, and they may be more effective because of their direct and indirect effect of these agents on the endometrium (11,12). Outcome analysis has documented complete response to progestin in the majority of women with CAH. In addition, the clinical response rate is about 40% when grade 1 metastatic endometrial carcinoma is treated with progestins (13,14). In light of this, pilot trials have studied the agents listed above in the management of young women with localized, well-differentiated endometrial carcinoma in an attempt to preserve fertility. The composite results of three of these trials are summarized in Table 2 (6,10,15). The mean regression rate for the entire population of 45 women was 69% (31 women). Among the 31 women who initially experienced regression, the relapse rate was 19% (6 women), including a late failure that occurred at 87 months. Extrauterine neoplasms were subsequently discovered in 4 of the 45 women including 2 women with metastatic endometrioid carcinoma and 2 with cases of primary ovarian carcinoma that appeared to have originated in foci of ovarian endometriosis. The duration of therapy varied from a limited 3-month trial of progestin therapy to 1 year or longer of treatment. No appreciable adverse treatment effects were reported. However, extended therapy was judiciously monitored. Of the 31 women who initially had a response to progestin therapy, 7 (23%) delivered one or more viable infants. The following inclusion criteria should be met to determine whether a young woman who has endometrial cancer is eligible for conservative management: Desire to preserve reproductive function Well-differentiated carcinoma Minimal myometrial invasion No extrauterine spread Long-term surveillance Patient compliance Pretreatment evaluation should include pelvic imaging, thorough endometrial sampling, and assessment of tumor markers. To minimize the possibility of adnexal or pelvic wall involvement and to estimate the depth of myometrial invasion, imaging studies including ultrasonography, computed tomography, or magnetic resonance imaging (or a combination of these), are recommended. Furthermore, a well-differentiated (grade 1) homogeneous endometrioid carcinoma should be verified with formal dilatation and curettage (D&C). Also, an increase in tumor markers such as CA 125 or 15-3 potentially indicates the presence of endometriosis, or less likely, metastatic disease. As noted above, ovarian carcinoma has been observed in association with endometriosis in young women with endometrial cancer managed conservatively with progestins. The analysis of estrogen and progesterone receptors in the D&C specimen may influence whether recommendations could be made to patients with grade 2 histologic lesions. Finally, it should be kept in mind that an infrequent cause of early-age endometrial cancer is hereditary non-polyposis colon cancer (HNPCC). Because the etiology of carcinogenesis is secondary to gene mutations due to defective DNA mismatch repair, rather than estrogen excess, the data regarding fertility-sparing treatment cannot be applied to the HNPCC subgroup of endometrial cancer patients. Judicious surveillance and patient compliance are extraordinarily important to minimize the risk of untoward sequelae. The doses of the progestational agents alone or in combination with tamoxifen or GnRH analogues depend on the specific progestin administered. Furthermore, the duration of administration is a function of the clinical response. If the patient has a partial response, the treatment period can be a year or longer with appropriate monitoring. Monitoring should include Page 3 curettage and transvaginal ultrasonography every 3 to 4 months until complete resolution is documented. Thereafter, maintenance therapy is recommended, with options predicated on individual circumstances. These options may include continued progestin therapy, use of oral contraceptive agents, or consideration of ovulation induction. The prolonged use of progestational agents is associated with several potential adverse side effects. For example, weight gain, hypertension, thrombophlebitis, and pulmonary embolism have been reported with the use of progestin in the management of advanced or recurrent endometrial cancer,. Finally, patients should be counseled about the option of definitive surgical treatment after completion of childbearing. In summary, the cause and biologic features of endometrial cancer that occurs in women younger than 40 years appear to be different from those of the disease that commonly occurs during or after the sixth decade of life. On the basis of the results of limited studies, conservative management of endometrial cancer is acceptable in appropriately selected young women. Eligibility criteria should be determined by the characteristics of the disease and the anticipated compliance of the patient. Careful monitoring during therapy is obligatory, as is long-term surveillance. Patients should be counseled about assisted reproductive technologies or maintenance therapy after successful resolution of the disease. References 1. Jemal A, Thomas A, Murray T, Thun M. Cancer Statistics, 2002. CA Cancer J Clin 2002; 52:23-47. 2. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15:10-17. 3. Dockerty MB, Lovelady SB, Foust GT Jr. Carcinoma of the corpus uteri in young women. Am J Obstet Gynecol 1951; 61:966-81. 4. Kurman RJ, Kaminski PE, Norris HJ. The behavior of endometrial hyperplasia: A longterm study of “untreated” hyperplasia in 170 patients. Cancer 1985; 56:403-12. 5. Spiegel GW. Endometrial carcinoma in situ in postmenopausal women. Am J Surg Pathol 1995; 19:417-32. 6. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and welldifferentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90:434-40. 7. Mutter GL, Wada H, Faquin WC, Enomoto T. K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis. Mol Pathol 1999; 52:257-62. 8. Mutter GL, Lin MC, Fitgerald JT, Kum JB, Baak JP et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-30. 9. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progesteronetreated endometrial hyperplasia. Am J Obstet Gynecol 1989: 160:126-31. 10. Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: Central pathologic review and treatment outcome. Cancer Letters 2001; 167:3948. 11. Nola M, Jukic S, Ilic-Forko J, Babic D, Uzarevic B, et al. Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma. Gynecol Oncol 1999; 72:331-36. 12. Perez-Medina T, Bajo J, Folgueira G, Haya J, Ortega P. Atypical endometrial hyperplasia treatment with progestogens and gonadotropin-releasing hormone analogues: Long-term follow-up. Gynecol Oncol 1999; 73:299-304. 13. Podratz KC, O’Brien PC, Malkasian GD Jr, Decker DG, Jefferies JA, Edmonson JH. Effects of progestational agents in treatment of endometrial carcinoma. Obstet Gynecol 1985; 66:106-110. Page 4 14. Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: A dose-response study by the Gynecologic Oncology Group. J Clin Oncol 1999; 17:1736-44. 15. Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Cancer 1997; 79:320-7. Table I. Comparison of Three Studies on the Response of Complex Atypical Hyperplasia To Progestin Treatment. Table 2.--Comparison of Three Trials of Progestin Therapy for Well-differentiated Endometrial Cancer in Women Younger Than 40 Years