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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).
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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
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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
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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.
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14. Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, et al. Oral
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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