Endometrial Carcinoma Can Fertility Be

Preserved?
T. Levy
Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, Holon and
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Introduction
Endometrial carcinoma is the most common gynecologic
malignancy in women. It is estimated by the American Cancer Society that
approximately 36,000 women will develop endometrial cancer yearly in
the United States, making it the fourth most common cancer in women
(1).
Endometrial cancer is primarily a disease of postmenopausal women,
although 25% of these cancers occur in premenopausal patients and 5%
occur in patients younger than 40 years (1). In the young women, the
adenocarcinoma is usually a well differentiated, endometrioid type lesion,
associated with minimal myometrial invasion, early-stage disease and
good prognosis. These patients often have a history of obesity, irregular
menses, polycystic ovarian disease (PCOD) with chronic anovulation and
infertility (2).
These young women, particularly the infertile patients, present a
therapeutic dilemma. The standard treatment for early endometrial
carcinoma is hysterectomy with bilateral salpingo-oophorectomy, pelvic
and para-aortic lymph node sampling followed by adjuvant radiotherapy
for intermediate and high-risk patients. However, young, nulliparous
women will lose any chance for future pregnancy by this treatment
approach.
Endometrial cancer is considered to be a hormone dependent tumor.
Estrogen, progesterone and androgen receptors have been identified in
these lesions and their expression is correlated with favorable prognosis.
In the endometrial glandular epithelium, estrogen can increase
proliferation and continuous exposure was shown to exert a carcinogenic
effect on the endometrium. Additionally, clinical findings of endometrial
hyperstimulation by unopposed estrogen solidified the evidence of a
positive association between estrogen and endometrial hyperplasia and
carcinoma. Progesterone, on the other hand, inhibits these estrogenic
effects and has led to its therapeutic use in endometrial carcinoma.
Young patients who develop endometrial cancer usually have risk
factors that are related to unopposed estrogen stimulation. Thus, primary
hormonal therapy with progesterone, as an alternative treatment for
surgery, offers them the only option to preserve their fertility.

61 Levy
Progestin Therapy
Conservative treatment with high-dose progesterone has been attempted in
premenopausal women with endometrial cancer who had a strong desire to
preserve their fertility. A Medline literature search revealed 62 such
patients (3-8) that were treated with various progestins at different doses
and for a variable duration of time. Randall and Kurman (3) reported that
12 patients with well-differentiated carcinoma were treated with
progestins, nine of them (75%) had disease regression and three patients
delivered five healthy babies. Kim et al (4) evaluated their results in 7
women treated with megestrol acetate at 160 mg/day for 3 months,
together with 14 patients retrieved from the literature. Thirteen of these 21
women (62%) had an initial response and three of them delivered six
healthy babies. Kaku et al (5) described 12 patients with endometrial
cancer treated with medroxyprogesterone acetate (MPA) at 200-800
mg/day for 2-14 months. In 9 patients (75%) initial response was
achieved. Two of them became pregnant and one delivered a full-term
infant. Of the 62 women found in the literature search, 17 women (27%)
delivered at least one healthy baby. However, these figures have a
dangerous publication bias. It is possible that those patients published in
the medical literature actually represent mostly good outcomes that are
reported. It is possible that there are other patients with less successful
outcome that were not reported or published.
Conservative treatment with progestins is not free of risk. In 14 patients,
persistent or recurrent disease was present in the uterus at the time of
hysterectomy (3-8). In 3 of these women there was an extrauterine disease
(4-6) and in another one, involvement of the isthmus was discovered (8),
necessitating further adjuvant therapy. These figures are probably an
underestimation since not all published reports specified in details the
outcome of all patients. Thus, the true magnitude of the risk of disease
progression occurring during or after progestin therapy is unknown.
Nonetheless, in 3/61 (5%) women an extrauterine disease was found that
presents either progression of disease or missed metastases in the primary
evaluation. For these women, progestin therapy delayed definitive surgical
treatment and may have adversely affected their prognosis.
In the last 4 years the author treated 136 patients with endometrial cancer.
As expected most women were postmenopausal. Eight patients desired
future fertility preservation. In 3 women suspicious ovarian mass was
diagnosed in the pretreatment evaluation, and they were found to have
concomitant ovarian cancer. Five women received megestrol acetate 160
320 mg/day for 6-9 months. In only one patient complete regression was
achieved. This woman conceived after 5 IVF cycles and delivered a

61 Levy
healthy baby. The same woman underwent 3 more IVF cycles and she is
currently on the 16th week of her second gestation.
Patient Selection
The optimal criteria for patients who can be candidates for
conservative progestin therapy are unknown. Good prognostic factors
include: well differentiated lesion, endometrioid type tumor, no or
minimal myometrial invasion and early stage disease. However, staging of
endometrial cancer is surgical and in patients selected for conservative
treatment such valuable information cannot be achieved. Thus, a thorough
pretreatment evaluation is mandatory in these patients. Dilatation and
curettage (D&C) is usually part of the initial evaluation. In recent years,
hysteroscopy became a widely accepted procedure for the evaluation of
the uterine cavity. Though it is claimed that hysteroscopy has a higher
sensitivity and specificity compared to D&C, its role in diagnosing
endometrial cancer has not been established. Furthermore, an association
between hysteroscopy and peritoneal dissemination of malignant cells was
observed (9). Whether positive peritoneal cytology affects the prognosis of
patients, with otherwise stage I endometrial cancer, is unknown. Currently,
it is not clear if this procedure should be offered to patients who are
candidates for conservative treatment.
Preferably only patients with well-differentiated (grade 1)
endometrioid lesions should be selected for conservative progestin
therapy. Only in such cases can we assume that the lesion is probably
estrogen related and contains estrogen and progesterone receptors. Tumors
of a higher grade or of unfavorable histology will less likely contain
progesterone receptors and respond to progestin treatment. Nevertheless,
literature search (3-8) does show that there are at least 5 women with
moderately differentiated (G2) lesions that were treated conservatively.
Only one had initial response that was durable. The other patients failed
treatment and underwent hysterectomy. Although none of the patients
were apparently affected by the delay, the risk of treating less favorable
tumors is unknown and thus may be prohibitive.
Myometrial invasion is one of the most important prognostic
factors in endometrial cancer. Deep invasion is related to metastatic
disease, lymph node involvement and to lower survival rates. Evidence of
deep myometrial invasion will prohibit the option of conservative
treatment. Probably contrast-enhanced magnetic resonance imaging (MRI)
has the most promising results in preoperative evaluation of endometrial
cancer patients (10). This test shows an overall accuracy for deep
myometrial invasion is about 90% with a sensitivity of 88%-91% and
specificity of 88%-97% in large studies. Furthermore, MRI can also
visualize the cervix and estimate its involvement with an accuracy of 90%.

61 Levy
 An alternative for MRI in estimating myometrial invasion is
transvaginal sonography (TVS). Recently, a sensitivity of 90% with
specificity of 85% and overall accuracy of 90% was reported (10). TVS
can also demonstrate pathological ovarian appearance. Some authors
reported a relatively high incidence (29%) of coexisting ovarian
neoplasms (11). In our series, 3/8 (37.5%) patients had a suspicious
ovarian mass that was found to be epithelial ovarian cancer.
Helical CT has much lower sensitivity and specificity (83% and
42% respectively) compared to MRI (12). However, CT does have some
theoretical importance in excluding intraabdominal and lymph node
metastasis, which is important information before deciding to continue
with the conservative treatment.
Other tests that might be helpful in the pretreatment assessment are
evaluation of the progesterone receptor status in the endometrial biopsy
specimen and measurement of serum concentrations of CA 125 and CA
15-3 as predictors of extrauterine spread (13). Recently, microsatellite
instability was found to be an independent prognostic factor in early stage
disease (14). Patients with stable microsatellites had significantly longer
5-year survival rate compared to patients with microsatellite instability
(96% and 63% respectively). In the future such tests can be relevant to a
prognostic characterization of early stage endometrial cancer and help in
individualization of treatment options.
Treatment and Follow-up
Because of the limited experience reported so far, the optimal
approach to the treatment and surveillance of patients with endometrial
carcinoma treated conservatively is unknown. There are no strict
guidelines regarding the type of progestin used, the dosage or treatment
duration. Most authors treated their patients for at least 3 months and than
reevaluated the uterine cavity. Some reached final decisions at that point
(4) while others continued therapy for more than one year until complete
regression was achieved. After an initial response, many patients were
treated with maintenance therapy to prevent recurrence. This treatment
was either oral contraceptives or cyclic progestins. The optimal
surveillance method and schedule is also unknown. Most authors carry a
combination of sonography and D&C every 3-6 months.
Other unresolved issues are when to allow these patients to
become pregnant? Should ovulation induction be considered since the
extremely high estrogen concentrations can be detrimental? Can in vitro
fertilization be offered to these women? Should these patients undergo
hysterectomy after the delivery?
Another intriguing question is whether hysterectomy without
oophorectomy should be offered to patients that did not respond favorably

61 Levy
to the progestin therapy. This surgical option will give them a chance to
achieve a child through surrogacy, however, as previously mentioned,
there is a 30% risk for concomitant ovarian cancer.
Conclusions
Conservative treatment of endometrial cancer with progestins is an
option that should be offered to a selected, highly motivated group of
women. These patients should be informed of the limited experience and
data in the literature, as well as of the risks entailed in this approach. Only
compliant women who understand the consequences of this treatment
modality should be allowed to continue with treatment and follow-up.
Moreover, these women should also be informed of the low overall
pregnancy rate that in part can be related to their primary infertility
problem and in part to their cancer treatment. However, in current times
when fertility is also offered to elderly women, such conservative
treatment should be investigated more thoroughly.
References

1. Barakat RR. Contemporary issues in the management of

endometrial cancer. CA Cancer J Clin 48: 299-314, 1998.
2. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium
in women 40 years of age or younger. Obstet Gynecol 64: 417-
419, 1984.
3. Randall TC, Kurman RJ. Progestin treatment of atypical
hyperplasia and well-differentiated carcinoma of the
endometrium in women under age 40. Obstet Gynecol 90: 434-
440 1997.
4. Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz
FJ. Progestin alone as treatment of endometrial carcinoma in
premenopausal women. Cancer 79: 320-327, 1997.
5. Kaku T, Yoshikawa H, Tsuda H et al. Conservative therapy
for adenocarcinoma and atypical endometrial hyperplasia of
the endometrium in young women: central pathologic review
and treatment outcome. Cancer Letters 167: 39-48, 2001.
6. Mitsushita J, Toki T, Kato K, Fuigii S, Konishi I.
Endometrial carcinoma remaining after term pregnancy
following conservative treatment with medroxyprogesterone
acetate. Gynecol Oncol 79: 129-132, 2000.
7. Ogawa S, Koike T, Shabahara H, Ohwada M, Suzuki M,
Araki S, Sato I. Assisted reproductive technologies in
conjunction with conservative treated endometrial
adenocarcinoma. Gynecol Obstet Invest 51: 214-216, 2001.

61 Levy
 8. Vinker S, Shani A, Open M, Fenig E, Dgani R.
Conservative treatment of adenocaecinoma of the endometrium
in young patients. Is it appropriate?
9. Obermair A, Geramou M, Gucer F et al. Does hysteroscopy
facilitate tumor cell dissemination? Cancer 88: 139-143, 2000.
10. Kinkel K, Kaji Y, Yu KK, Segal MR, Lu Y, Powell CB,
Hricak H. Radiologic staging in patients with endometrial
cancer: a meta-analysis. Radiology 212: 711-718, 1999.
11. Gitch G, Hanzal E, Jensen D, Hacker NF. Endometrial
cancer in premenopausal women 45 years and younger. Obstet
Gynecol 85: 504-508, 1995.
12. Hardesty LA, Sumkin JH, Hakim C, Johns C, Nath M. The
ability of helical CT to preoperatively stage endometrial
carcinoma. AJR 176: 603-606, 2001.
13. Scambia G, Gadducci A, Benedetti Panici P et al.
Combined use of CA 125 and CA 15-3 in patients with
endometrial carcinoma. Gynecol Oncol 54: 292-297, 1994.
14. Fiumicino S, Ercoli A, Ferrandina G et al. Microsatellite
instability is an independent indicator of recurrence in sporadic
stage I-II endometrial adenocarcinoma. J Clin Oncol 19: 1008-
1014, 2001.

61 Levy