ISSN 0350-2899, 36(2011) br.1 p.39-42

Napomena: sažetak na srpskom
Note: Abstract in Serbian

INTRODUCTION

Endometrial cancer is one of the most frequent tumors affecting the female genital tract with the highest incidence rate in women aged between 53 and 60 years [1].
Increased exposure of the endometrium to unopposed estrogen stimulation is widely accepted as a major etiological factor. This hypothesis is supported by increased risk associated with estrogen replacement therapy but not with combined progestagens-estrogen therapy [2, 3]. Protective effect of combined estrogen-progestagens oral contraceptives is ascribed to the progestagens component [4].
Infertility and irregular uterine bleeding are associated with increased risk and are likely to be related to increased frequency of anovulation [5]. Hypertension, obesity and diabetes are important risks factors in peri and postmenopausal women [6]. Family history of endometrial carcinoma is an independent risk factor for the disease [7].
Although endometrial carcinoma is predominantly a disease that affects postmenopausal women, 3-5% of the tumors develop in women under 40 years of age [8]. Endometrial carcinoma is extremely rarely diagnosed in women under 25 years of age. In the very young it is often associated with polycystic ovarian disease, obesity, infertility, risk factors that are also associated with increased levels of estrogens [9]. In most cases it is diagnosed at an early stage, tumor is well differentiated with a favorable prognosis [8].
The use of progestins is mostly reported as the first option of medical treatment. Other drugs, such as gonadotropinreleasing hormone agonists, antiestrogens, and aromatase inhibitors have been rarely used [10].

CASE OUTLINE

A 21-year-old woman was evaluated for metrorrhagia in February 2000 in the Outpatient Clinic in the University Hospital of Obstetrics and Gynecology "Narodni Front" in Belgrade where the author of this paper works. A year before she was for the first time hospitalized at the Department for Conservative Gynecology in the same hospital and treated for metrorrhagia and adnexitis billateralis. The patient was virgo intact nulligravida. Menarche was at the age of 14, followed by irregular cycles. She had negative medical and family history and was not on medication. Her physical examination and bimanual gynecological exam was unremarkable, except that she had acyclic uterine bleeding. There was evidence of oligoovulation so clinical diagnosis of polycystic ovarian disease was made. The patient was not obese. Ultrasonography revealed slightly enlarged uterus, thickened endometrii of 13 mm, ovaries appeared polycystic. The bleeding episode was decreased on high estrogen-progestagens dose in few days. The patient didn’t follow up medical instructions and didn’t come for follow up visit, but continued the therapy with lower hormone dose on her own and consequently started to bleed again. After 11 days of bleeding she came in the Outpatient Clinic in bad physical condition and was hospitalized again at the Department for Conservative Gynecology, where she was treated with intramuscular estrogen therapy without progesterone. The patient left hospital without any advice for progesterone therapy. That is why bleeding started again after a few days. The patient decided to start contraceptive therapy on her own without any medical advice and bleeding stopped. In a few days, at the end of February, she came again to the Outpatient Department in good condition without any bleeding while on contraceptives. On this occasion, contraceptive therapy that she had already started on her own, was approved as a reasonable choice for her problem. After 15 days, in March 2000, she comes to the Outpatient Department because of another bleeding episode during contraceptive therapy.
Ultrasonography revealed endometrial thickness of 14 mm. Defloration and dilatation and curettage was suggested. The patient decided to have natural defloration. In April 2000 the patient underwent dilatation and curettage which showed adenocarcinoma endometrii in situ G1N1 with hyperplasia complex atypica and proliferative endometrium. Endometrial sample was reviewed by two independent pathologists.
The patient was extensively counseled and given the options of medical therapy vs. total abdominal hysterectomy. She desired to preserve her fertility potential and consented to progestagens therapy. The Consillium for Oncology Patients asked patient for results of hormonal tests and in generally agreed with suggested conservative therapy. All hormonal tests were within the normal range including prolactin and thyroid hormones.
The patient understood the importance of frequent evaluation of endometrial sampling and the chance of progression or recurrence of the disease.
Initial conservative hormonal therapy was gestonoroncapronat 200mg weakly started in April 2000 for 3 months until the first follow up dilatation and curettage was preformed. At the first follow up visit endometrii were 8 mm and endometrial samples after dilatation and curettage showed adenocarcinoma endometrii, hyperplasia complex atypica but also an atrophic endometrii. The therapy was changed. Gestonoroncapronat was cancelled and oral therapy-medroxyprogesteron acetate 500mg daily was introduced. On the second follow up visit (at the end of October 2000) endometrial thickness was 2.9-5.2mm with hyperechogen focus 2.6mm long and 2mm high. After dilatation and curettage endometrial atrophy was found in 50% of endometrial sampling. In other parts of endometrii adenocarcinoma endometrii and hyperplasia complex was found. Dosage of oral medroxyprogesteron was increased to 1000mg daily until next dilatation and curettage. From the end of December 2000, the patient was followed up at the Gynaecology and Obstetric Outpatient Clinic "Mošković" where the author was employed. In January 2001 hysteroscopy followed with dilatation and curettage was preformed in the University Hospital of Obstetrics and Gynecology "Narodni Front". Hysteroscopy showed atrophic endometrii with 3 mm isthmicus polypus. There were no signs of adenocarcinoma or hyperplasia in endometrial samples after dilatation and curettage. Thereafter the dosage of medroxyprogesteron acetate was decreased to 100mg daily. No related toxicity to hormonal therapy was observed. Finally hormonal therapy was discontinuited in March 2001. The patient didn not want pregnancy yet and was advised to be on carefully follow up monitoring including dilatation and curettage and cycle regulation until she decided to become pregnant. The patient did not follow medical advice strictly, after ten years of discontinuited therapy she had not major gynecological problems, had one pregnancy with pure outcome, and still is healthy young 30-year-old woman.

DISCUSSION

Between 3-5% of endometrial adenocarcinoma develop in women under 40 years [11]. These patients, especially younger and nulligravida are strongly motivated to preserve their fertility. The standard therapy for early endometrial carcinoma is total abdominal hysterectomy and bilateral salpingo-oophorectomy and when indicated, adjuvant radiation therapy is added. Surgical treatment results in the loss of fertility.
A conservative approach can offer reasonable oncological security and the opportunity of fulfilling their maternal desires in selected cases. However, consideration should be taken regarding the potential adverse outcomes. When a patient desires to retain her future fertility in the light of this diagnosis, choices of surgical vs. conservative medical therapy may present a dilemma for both the physician and the patient.
The first criterion for conservative treatment is an accurate diagnosis of a well-differentiated endometrial carcinoma by an expert pathologist. Taking advantage of this tumor's hormonal sensitivity, most authors have used hormone-based treatments as a conservative approach [12].
Fortunately, in patients under 40 years of age, most tumors are at the early stage and well-differentiated as it was in our case. But there are dilemmas about clinical tumor staging. Transvaginal sonography may help in the evaluation of myometrial invasion. Laparoscopy may be helpful in staging at the adnexal level. Recent publications warn us about the possibility of having ovarian metastasis or synchronic tumors in this group of young patients with endometrial cancer. [13]
Worldwide experience and data about conservative therapy of early endometrial cancer in young patients are lacking [11,14]. That is why it is difficult to acquire the necessary experience to offer recommendations regarding the conservative approach.
Progestin therapy for endometrial cancer has been used since the 60s. At first, this treatment was only confined to patients with hyperplasia with atypia, but nowadays patients with early endometrial carcinoma are also treated with this therapy. In literature it can be found out that seventy six percent of patients treated with hormonal therapy had a complete response and the other 24% never responded to treatment [15].
Medroxyprogesteron Acetate is the most frequently used progestin. The mayority of patients received progestin as the first treatment. A half of them were treated with 200 to 600 mg daily doses of Medroxiprogesterone Acetate [15]. We decided to start with gestonoroncapronat 200 mg weakly for 3 months, followed by Medroxiprogesterone Acetate of 500mg/a day. After 3 months and an incomplete respond, the dosage was increased to 1000 mg/a day. It is on average a higher dosage than in the mentioned studies.
Other reported cases were treated with 17 α hydroxyprogesteron caproate, megestrol and clomiphene. However, there is no consensus in the literature on the most appropriate progestin, the dose and length of treatment. [15].
According to literature, three out of four threated patients had an initial complete response, with an average response time of 12 weeks. The average duration of hormonal therapy was approximately 6 months [12]. In our case complete respond was 11 months what is, again, longer than average. The duration of therapy was also longer than average.
The follow up performed after regression of the disease should be very strict and should include periodic evaluation of cytology, sonographies, hysteroscopies and histopathologic examination of endometrial samples. Unfortunately, our patient didn not strictly followed our recommendations.
Many questions about the choice of appropriate therapy and follow up remain actual and unsolved. There is a dilemma about the treatment of irregular bleeding and stimulation of ovulation if necessary until the patient decides to have pregnancy. There is no consensus in literature for stimulation protocols. The patient must be informed that there is about 33% chance of progression or recurrence of the disease and a possible definitive surgical therapy [16].
This case illustrates that with close observation and follow up by endometrial sampling for histological diagnosis, conservative hormonal therapy may be a successful option for treating endometrial carcinoma in young women to allow future fertility.

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