|Year : 2019 | Volume
| Issue : 1 | Page : 24-29
Clinicopathological evaluation of ovarian juvenile granulosa cell tumor: Is fertility-sparing surgery safe?
Lu Guo, Xiao-Cheng Liu, Xiu-Ying Chen, Xi-Rong Xiao, Yu-Qing Qu, Bin Li
Department of Obstetrics and Gynecology; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases; Department of Obstetrics and Gynecology of Shanghai Medical School, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
|Date of Submission||15-Jan-2019|
|Date of Web Publication||11-Apr-2019|
Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road, Shanghai 200090
Source of Support: None, Conflict of Interest: None
Objective: To retrospectively investigate the clinicopathological characteristics of ovarian juvenile granulosa cell tumors (JGCTs) and to evaluate the safety of fertility-sparing surgery.
Methods: In this study, surgically treated patients with JGCTs diagnosed between January 2004 and October 2018 in our center were identified. Clinicopathological data, survival outcomes, and recurrence rates were examined in these patients.
Results: A total of 8 patients were included. All patients were premenarchal girls or young women (age range, 9–32 years). Irregular vaginal bleeding was the most common presenting symptom. Of them, seven patients were classified with Stage I JGCTs, and they underwent fertility-sparing surgery. One patient who had Stage IIIC JGCT and had completed childbearing underwent complete surgery. Seven patients received adjuvant chemotherapy. The median follow-up duration in the total cohort was 64 months (range, 2–117 months). The overall survival rate in the fertility-sparing group was 100%, whereas the patient with Stage IIIC JGCT died 1 month after the treatment.
Conclusions: Fertility-sparing surgery might not show a negative impact on oncologic outcomes. Fertility sparing could be considered a modified option for patients with Stage I JGCTs. However, due to the limited number of patients, the conclusion must be interpreted with caution, and larger or multicenter studies are needed before conclusions can be drawn.
Keywords: Adjuvant Chemotherapy; Complete Surgery; Fertility-Sparing Surgery; Ovarian Juvenile Granulosa Cell Tumor
|How to cite this article:|
Guo L, Liu XC, Chen XY, Xiao XR, Qu YQ, Li B. Clinicopathological evaluation of ovarian juvenile granulosa cell tumor: Is fertility-sparing surgery safe?. Reprod Dev Med 2019;3:24-9
|How to cite this URL:|
Guo L, Liu XC, Chen XY, Xiao XR, Qu YQ, Li B. Clinicopathological evaluation of ovarian juvenile granulosa cell tumor: Is fertility-sparing surgery safe?. Reprod Dev Med [serial online] 2019 [cited 2019 Aug 26];3:24-9. Available from: http://www.repdevmed.org/text.asp?2019/3/1/24/255993
| Introduction|| |
Ovarian sex cord–stromal tumors are rare neoplasms, accounting for about 1.2% of primary ovarian tumors, among which ovarian granulosa cell tumors (GCTs) are the most common sex cord–stromal tumors, comprising 2%–5% of ovarian carcinomas. Ovarian GCTs are classified into juvenile and adult type. Ovarian adult GCTs (AGCTs) are more common and usually observed in perimenopausal and postmenopausal women. Ovarian juvenile GCTs (JGCTs) are rare, representing 5% of all GCTs and occurring in premenarchal girls and young women. In contrast to AGCTs, JGCTs exhibit a high mitotic index and more aggressive tumor growth.
Ovarian cancer is often a deadly disease because most patients are diagnosed at an advanced stage. Despite the high mitotic activity, most JGCTs, with the 5-year survival rate of approximately 90%, are detected in the International Federation of Gynaecology and Obstetrics (FIGO) Stage I. Due to the current social trends, childbearing is increasingly postponed, and the number of young women who present with JGCTs and have not yet completed their family-building plans may increase. It is, therefore, necessary to consider fertility preservation in these patients.
According to the FIGO and the National Comprehensive Cancer Network, complete surgery is recommended, encompassing bilateral salpingo-oophorectomy, hysterectomy, omentectomy, pelvic and para-aortic lymphadenectomy, and removal of all visible peritoneal carcinomatosis, as well as visceral metastases. However, this approach also results in permanent sterility and estrogen deficiency, thus eliminating the possibility of future pregnancies and leading to some perimenopausal symptoms. For women with FIGO Stage I ovarian carcinoma who have a desire to preserve fertility, fertility-sparing surgery may be possible. The procedure consists of a unilateral salpingo-oophorectomy, with or without pelvic and para-aortic lymphadenectomy, peritoneal biopsies, and omentectomy, but leaves the contralateral ovary and uterus in situ. It has previously been demonstrated that fertility-sparing surgery does not lead to an increase in mortality, poorer overall survival, or shorter disease-free survival in patients with Stage I epithelial ovarian cancer.,
However, the experience with JGCTs is limited, and it is unknown whether the previously reported survival results apply to patients with JGCTs. Few published reports revealed the clinicopathological characteristics and safety of fertility-sparing surgery in JGCTs. Thus, the aim of this study was to evaluate the clinicopathological characteristics of JGCTs and determine the safety of fertility-sparing surgery.
| Methods|| |
In the present retrospective study, patients with histopathologically confirmed JGCTs diagnosed between January 2004 and October 2018 who underwent primary surgery in the Obstetrics and Gynecology Hospital of Fudan University were identified. The institutional review board or ethical committee approved this study. Medical charts and surgical pathology reports were reviewed; data on the clinical presentation, surgery, laboratory investigations, tumor size, location, mitotic activity, follow-up, and the outcomes were extracted. Recurrence-free survival was measured as the number of months from the primary surgery to the date of recurrence or censored at the date of the last follow-up. The 2009 FIGO staging system was used for tumor staging. All pathological data had been previously reviewed by gynecological pathologists, and surgical staging was performed after the diagnosis was confirmed. The immunohistochemical analysis was performed by the pathologists to detect the expression of inhibin A, calretinin, cluster of differentiation (CD) 99, and epithelial membrane antigen in the ovaries. All sections were incubated at 60°C for 1 h, deparaffinized in xylene, and rehydrated in a graded series of ethanol routinely. Antigen retrieval was performed in 0.01 mol/L citrate buffer (pH 6.0) and high microwave irradiation for 30 min. Endogenous peroxidase activity was eliminated with 3% H2O2 for 10 min and then nonspecific binding was blocked with 10% normal goat serum for 30 min at room temperature. Afterward, the sections were separately incubated with primary antibodies against inhibin A (1:1,000), calretinin (1:1,000), CD99 (1:1,000), and epithelial membrane antigen (1:1,000) overnight at 4°C and then placed for 45 min at room temperature. The sections were rinsed with phosphate-buffered saline (PBS) and then secondary antibodies were added for 10 min. After washed with PBS, all sections were incubated with horseradish peroxidase (HRP) for 10 min at room temperature. Following, the washed sections were incubated with 3,3-diaminobenzidine to visualize the final product and counterstained. Negative control was treated by substituting PBS for a primary antibody.
| Results|| |
A total of 8 patients were included in this study [Table 1]. All patients were premenarchal girls or young women (age range, 9–32 years). The mean follow-up duration was 64 months. The presenting symptoms were irregular vaginal bleeding in six patients and an abdominal mass and abdominal pain in two patients. About 62.5% (5/8) of patients harbored a large pelvic mass with a tumor diameter >10 cm. All tumors were unilateral. Seven patients had ruptured tumors, and only one tumor remained intact. Five patients underwent cytology examinations and the results were negative. Seven patients were classified with Stage I JGCTs and underwent fertility-sparing surgery, whereas the remaining patients with Stage IIIC JGCT who had delivered children before underwent complete surgery. Specific immunohistochemical staining was performed [Figure 1] and [Table 2]. Patients with Stage I JGCTs had inhibin A positivity, whereas patients with Stage IIIc JGCTs had no expression of inhibin A. Calretinin in patient number 1–3, 6, 7 and CD99 and vimentin in patient number 1, 2–8 tested positive, whereas epithelial membrane antigen in patient number 1, 2–8 tested negative. Among the patients in the fertility-sparing surgery group who underwent unilateral salpingo-oophorectomy with or without pelvic lymphadenectomy and omentectomy, six patients had Stage IC disease with the main symptoms of irregular vaginal bleeding and abdominal mass, and one had Stage IA disease with the symptom of irregular vaginal bleeding. The median age at diagnosis in the fertility-sparing surgery group was 17 years (range 9–31 years). Three patients had mitotic count data, and only one had a mitotic count >20/10 high-power fields (HPFs). Eighty-eight percent (n = 7) of all evaluated patients received adjuvant chemotherapy, which included the bleomycin, etoposide, and carboplatin in four patients and bleomycin, vincristine, and carboplatin (BVP) in three patients. The rate of adjuvant treatment was 86% (n = 6) in the fertility-sparing surgery group and 100% (n = 1) in the complete surgery group. The median follow-up duration in the total cohort was 64 months (range 2–117 months). No recurrence occurred in patients who underwent fertility-sparing surgery, and none had intended pregnancies. Those who survived had normal menstruation after treatment. The overall survival rate in the fertility-sparing surgery group was 100%, whereas the only patient with Stage IIIC disease had recurrence and died 1 month after the initial treatment.
|Figure 1: HE and immunohistochemical staining of JGCT. (a) HE of JGCT (×40); (b) HE of JGCT (×200); (c) immunoreactivity for inhibin-a in JGCT (×200); (d) immunoreactivity for CD99 in JGCT (×200). HE: Hematoxylin and eosin; JGCT: Juvenile granulosa cell tumor.|
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| Discussion|| |
About 92 patients were diagnosed with GCTs between January 2004 and October 2018 in our center; AGCTs accounted for 91.3% (84/92), and JGCTs accounted for 8.7% (8/92), the latter of which is slightly higher than the previously reported incidence of 5%. Unlike epithelial ovarian tumors, JGCTs occur in a younger age group, are usually detected at an early stage, and often have features of hyperestrogenism. In the prepubertal age group, hyperestrogenism resulting in breast development, increased pubic hair, vaginal bleeding, and increased growth is observed. In the reproductive age group, altered menstrual patterns such as menorrhagia, intermenstrual bleeding, or amenorrhea may manifest. In our study, the main symptoms were irregular vaginal bleeding.
Preserving fertility is an important issue when considering cancer treatment in younger patients. It was found that patients undergoing fertility-sparing surgery for early-stage JGCTs did not have poor survival, which indicates oncological safety in selected patients., To our knowledge, few studies have focused on the safety of fertility-sparing surgery for women with JGCTs. In this study, patients treated with fertility-sparing surgery were younger and had a lower FIGO Stage (IA or IC). Colombo et al. concluded that fertility-sparing surgery is a reasonable approach if the disease is limited to one ovary. In addition, wedge biopsy from the contralateral ovary and chemotherapy is not recommended. Zhang et al. reported that the 5-year survival rates of standard surgical treatment and uterine-sparing procedures are 97% and 98%, respectively. Lee et al. also concluded that no statistically significant differences in recurrence or survival are exhibited between patients who underwent fertility-sparing surgery and those who underwent complete surgery. Powell et al. treated a patient who had Stage III JGCT with fertility-sparing surgery and adjuvant chemotherapy; the patient recurred twice during the follow-up period, achieved pregnancies, and survived. In our study, seven patients with Stage I JGCTs underwent fertility-sparing surgery and had no recurrence. As they had no intended pregnancy at present, no data on their fertility were available.
It has been reported that large tumor size, high mitotic index, tumor rupture, and lymphatic metastasis have strong correlations with the prognosis of JGCTs.,, In our study, in the fertility-sparing surgery group [Table 3], four patients had tumor masses larger than 10 cm in diameter, whereas three patients had tumor masses smaller than 10 cm in diameter. Six patients had ruptured tumors. Three patients underwent mitotic activity examinations, and only one patient had mitotic counts >20/HPF, but no recurrence was found. Compared to the four patients who underwent pelvic lymphadenectomy, three patients did not undergo lymphadenectomy, and no differences were found in the recurrence-free survival. Because lymph node metastasis is rarely observed in patients with sex–cord stromal tumors, pelvic and para-aortic lymphadenectomy may not be included in the staging surgery.,
|Table 3: High risk factors of patients treated with fertility-sparing surgery|
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There is no standard protocol for adjuvant chemotherapy because of the relatively low incidence and late recurrence of the disease. No evidence has been found that postoperative adjuvant chemotherapy prevents recurrence. There are reports of advanced-stage tumors successfully treated with platinum-based chemotherapy. Schneider et al. determined that chemotherapy should be administered for Stage IC tumors with preoperative rupture or malignant ascites, especially those with high mitotic activity. The clinical significance of postoperative adjuvant chemotherapy for high-risk patients has not been demonstrated through prospective randomized trials, but the administration of adjuvant chemotherapy and radiation therapy has sometimes been associated with prolonged disease-free survival in high-risk patients. Children with advanced JGCTs appear to benefit from long-term complete remission following adjuvant chemotherapy. Thus, chemotherapy is generally recommended for children with Stage IC JGCTs with high mitotic indices (20/10 HPFs or higher) or more advanced stages.,, In our study, seven of the eight patients received 2–7 courses of postoperative adjuvant chemotherapy.
Moreover, to reduce the noxious effect that chemotherapy might have on the ovaries, the suppression of ovulation activity and protection of the ovarian reserve by gonadotropin-releasing hormone agonist (GnRH-a) has been suggested. However, the efficacy and clinical application of this strategy has been highly debated recently. Several randomized controlled trials have revealed the benefits of concomitant GnRH analog therapy, whereas others have shown contradictory results. Studies have demonstrated that the administration of goserelin with chemotherapy appears to protect against ovarian failure, reducing the risk of early menopause and improving fertility in patients with breast cancer., Three recent meta-analyses demonstrated that the administration of luteinizing hormone-releasing hormone agonist during chemotherapy reduces the risk of amenorrhea and that the administration of GnRHa is associated with a higher rate of recovery of regular menses after chemotherapy.,, However, another meta-analysis showed that the protective effect of GnRHa against premature ovarian insufficiency is present in patients with breast cancer, but unclear in patients with ovarian cancer and lymphoma.
Poor prognosis and early recurrence should be expected in cases of advanced disease. Patients with Stage I GCTs are reported to have a 5-year survival rate of 94% and a 10-year survival rate of 82%. The 5-year disease-free survival rates are 92%, 89%, and 50% in patients with Stages I, II, and III GCTs, respectively. Wu et al. found that, among patients who died of JGCTs, 3.4% of the patients had Stage I JGCTs, 50% of the patients had Stage II JGCTs, and 10% of the patients had Stage III JGCTs. In our study, patients with Stage I JGCTs were alive, and the only one who died had Stage III JGCT, which was in accordance with previous findings. Although recurrence would not be expected after treatment in a short time, late recurrence was reported.
Moreover, inhibin B is thought to be a reliable marker to detect recurrence during the follow-up period, which was not exhibited by any of the patients in our study. In our study, inhibin A was positive in patients with Stage I JGCTs, whereas it was negative in the patient with Stage IIIC JGCT. Advanced-stage disease is associated with weaker expression of inhibin, demonstrating a lesser degree of normal cellular function. It has also been reported that a low-expression pattern or the extinction of an ovarian-determination gene, FOXL2, is related to poor prognosis in patients with JGCTs. Calretinin, CD99, Mullerian-inhibiting substance, vimentin, Wilms' tumor-1, steroidogenic factor-1, cytokeratin, S-100, and SMA usually test positive, but they are not specific to sex cord–stromal tumors.
In conclusion, tumor prognosis has a strong correlation with tumor aggressiveness. Fertility-sparing surgery seems to be a safe option for patients with Stage I JGCTs. The surgery should only be performed by specialists in gynecological oncology. Patients should be carefully selected and thoroughly informed. Complete surgery with hysterectomy and removal of the contralateral ovary should strongly be considered after delivery. However, there are some limitations in the present study. The relatively small number of cases makes it difficult to draw definitive conclusions; larger or multicenter studies may be sought to draw a definitive conclusion regarding oncological safety when performing fertility-sparing surgery.
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[Table 1], [Table 2], [Table 3]