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Endometrial Carcinoma Associated with Ovarian Granulosa Cell Tumors – a Case Report

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Endometrial Carcinoma Associated with Ovarian Granulosa Cell Tumors – a Case Report ANTICANCER RESEARCH 35: 5547-5550 (2015) Endometrial Carcinoma Associated with Ovarian Granulosa Cell Tumors – A Case Report NICOLAE BACALBASA1, CLAUDIA STOICA2, ILEANA POPA3, GRATIELA MIREA2 and IRINA BALESCU4 1Obstetrics and Gynecology Department Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 2General Surgery Department, Ilfov County Hospital, Bucharest, Romania; 3Pathology Department Coltea Clinical Hospital, Bucharest, Romania; 4General Surgery Department, Ponderas Hospital, Bucharest, Romania Abstract. Ovarian granulosa cell tumors represent patients, abnormal vaginal bleeding, abdominal swelling and uncommon neoplasms with estrogen-secreting capacity. Due even abnormal palpable masses in the lower abdomen can be to their association with persistently increased levels of seen (4). Most tumors are large, solid or cystic, with slow estrogen, modifications of the endometrial tissue ranging growth and tendency for late recurrence (1, 4, 6). When it from hyperplasia to malignant degeneration may be comes to their hormonal activity, estradiol has been encountered. We present the case of a 65-year-old patient advocated as a true tumor marker for these neoplasias (4, 7). who presented for post-menopausal vaginal bleeding. The However, the estradiol concentration is not a reliable marker endometrial biopsy raised the suspicion of an atypical of disease activity, no significant correlation has been endometrial hyperplasia and the patient was submitted to established between it and the presence of bulky disease (8, surgery. Histopathological studies of the specimen of total 9). Despite this, high hormonal levels can be associated with hysterectomy with bilateral adnexectomy revealed the other significant modifications of estrogen-sensitive tissues, presence of a well-differentiated endometrial carcinoma such as endometrial tissues. Prolonged endometrial exposure associated with a granulosa cell tumor of the ovary. In to high estrogen levels are responsible for pathological conclusion whenever a modified aspect of the endometrium modifications ranging from endometrial hyperplasia to is found preoperatively, attention should be given on other endometrial cancer (10, 11). Most often, malignant possible underlying modifications and a radical approach endometrial degeneration will comprise well-differentiated should be taken in consideration. endometrioid adenocarcinoma; in rare cases, another pathological pathway might be incriminated, unrelated to Ovarian granulosa cell tumors represent uncommon estrogen stimulation, leading to development of serous neoplasms arising from the ovarian sex-cord stromal cells, carcinoma. The differential diagnosis between the two and account for 2-5% of all ovarian cancer (1-3). Based on hystopathological sub-types can be provided by the presence clinical and histopathological studies, these tumors are of mutation of the p53 tumor-suppressor gene, which is classified as juvenile and adult granulosa cell tumors (4). The uncommon in endometrial carcinoma but is usually main characteristic of these tumors is their hormone- associated with serous carcinoma (12). secreting capacity, nearly all of them being capable of synthesizing estradiol (4). Due to this particularity, ovarian Case Report granulosa cell tumors are responsible for the iso-sexual precocious pseudopuberty in young girls (5), while in older A 65-year-old patient presented for pelvic pain and reported two episodes of vaginal bleeding. The local examination showed no modifications of the uterine cervix; however, the vaginal tract revealed the presence of a tumor at the level of This article is freely accessible online. the left Douglas pouch. Papanicolau test excluded any microscopic modification of the uterine cervix, while Correspondence to: Nicolae Bacalbașa, Dimitrie Racoviţă Street, transvaginal ultrasonography revealed the presence of an no. 2, Bucharest, Romania. Tel: +40 723540426, e-mail: [email protected] enlarged left adnexa measuring 12×8 cm, with a solid aspect associated with an enlarged endometrium. Laboratory tests Key Words: Endometrial carcinoma, granulosa cell tumor of the including carcinoembryonic antigen and α-fetoprotein were ovary, total hysterectomy with bilateral adnexectomy. normal. The patient was submitted to endometrial biopsy, 0250-7005/2015 $2.00+.40 5547 ANTICANCER RESEARCH 35: 5547-5550 (2015) which confirmed the presence of an endometrial hyperplasia In order to determine the most important prognostic with rare atypia; the patient was submitted to surgery. factors which might predict the association with Intraoperatively, a large solid ovarian tumor entirely endometrial cancer, Ottolina et al. conducted a deforming the left adnexa was found, with no other retrospective study involving 150 patients with adult macroscopic modifications. The patient was submitted to granulosa cell tumors of the ovary. They demonstrated that radical hysterectomy with bilateral adnexectomy, and pelvic endometrial carcinoma was most often present in and para-aortic lymph node dissection. symptomatic patients (p=0.001) over 40 years of age or The histopathological studies revealed the presence of post-menopausal (p<0.001) (19). an adult ovarian granulosa cell tumor (Figure 1A) in the However, it seems that not only estrogen synthesis is left ovary associated with a well-differentiated responsible for the endometrial cancer in these patients. endometrioid adenocarcinoma (Figure 2). Microscopical Another associated factor is the presence of steroid hormones evaluation revealed a diffuse growth pattern of adult (20, 21), while the presence of progesterone has an granulosa cell tumor, with low mitotic activity of 1-2 antagonistic action by down-regulating estrogen receptors mitoses per 10 high-power fields, with no surface and enhancing the conversion of estradiol to the less active involvement. The uterine body presented lesions of estrone by increasing the activity of 17β-hydroxysteroid complex hyperplasia with cellular atypia associated with dehydrogenase (19). the presence of a locally well-differentiated invasive When it comes to the most important prognostic factors glandular process involving less than 50% of the of women diagnosed with ovarian granulosa cell tumors, it myometrial depth. Estrogen receptors were present in up seems that prognosis is strongly influenced by the initial to 50% of tumoral cells, while progesterone receptors were stage at diagnosis, followed by the integrity of the ovarian found in 15%. The ovarian tumor stained positively for capsule and the dimensions of the tumor. For patients calretinin and inhibin (Figure 1B and C). diagnosed with early stages of the disease, one of the most The postoperative course was uneventful, the patient being important factors predicting the recurrence rate and overall discharged on the sixth postoperative day. Postoperatively, survival remains the presence of nuclear atypia. A the patient received no adjuvant treatment and remains free significant association between the presence of nuclear of recurrent disease at two-year follow-up. atypia and time to recurrence also exists: tumors which develop early recurrence usually have a higher rate of Discussion nuclear atypia, of up to 77%, while those with late recurrence present nuclear atypia in up to 33% of cases (4, Ovarian granulosa cell tumor represents the most common 22, 23). estrogen-secreting ovarian tumor followed by thecoma, both Regarding the most adequate therapeutic protocol, being considered as feminizing mesenchymomas of the endometrial biopsy should be a rule in order to determine if ovary (13). In pre-pubertal patients, the main modifications any endometrial modifications have already occurred. In consist of iso-sexual pseudoprecocity, with early patients younger than 40 years with normal-appearing development of secondary sexual characteristics, while in endometrium, desiring preservation of reproductive function, adults, the most common manifestation consists of unilateral adnexectomy and close follow-up can be menometrorraghia, and only in isolated cases, amenorrhea. attempted, while in patients older than 40 years, total The adult tumor sub-type is most often found in post- abdominal hysterectomy with bilateral adnexectomy should menopausal women and is responsible for vaginal post- be the rule (4). menopausal bleeding, associated with breast tenderness and For the use of adjuvant radiotherapy, results are still diffuse pelvic pain (4, 5, 14, 15). In order to reach the right conflicting. Irradiation has been used both as adjuvant diagnosis, an endometrial biopsy is required; most treatment following surgery, and for recurrent disease. commonly, endometrial hyperplasia exists; however, it seems However, there is no randomized study assessing the role of that up to one-third of the specimens are associated with the adjuvant radiotherapy; although there are studies which presence of endometrial atypia. The natural progression of demonstrate an improved rate of survival in newly-diagnosed the disease is through low-grade endometrial endometrioid patients or those with recurrent disease, others failed to adenocarcinoma, which is reported in 5% up to 20% of demonstrate any benefit (6, 10, 24, 25). Concerning the cases. Less commonly, a serous adenocarcinoma will necessity for performing adjuvant chemotherapy, the main develop; however, it seems that is more likely to be related to indications for patients diagnosed with an early stage of the the presence of p53 mutation than
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