Gynandroblastoma With Juvenile Granulosa Cell Tumor and Concurrent Renal Cell Carcinoma

Introduction

Gynandroblastoma is an extremely rare ovarian tumor with only 26 cases reported in the English literature thus far.^1,2 Gynandroblastoma is characterized by mixed elements of testicular Sertoli or Sertoli–Leydig differentiation and ovarian granulosa cell differentiation with at least 10% of the lesser component. Clinically, they occur in women aged 10 to 60 years with a mean age of 30 years. ² Patients often present with symptoms caused by increased hormone, mainly androgen, production by these tumors. In most of cases, following surgical removal of the tumor, testosterone levels have been shown to fall to normal. ³ Although most gynandroblastomas are unilateral and often behave as low-grade malignancy, recurrence has been reported in one case. ¹ Gynandroblastoma with juvenile type of granulosa cell tumor (GCT) is even rarer, with only 4 cases reported in the English literature.^{4 -7} Concurrent gynandroblastoma with another malignant neoplasm has not been reported in the literature. We hereby report a case of gynandroblastoma with juvenile GCT and also a clear cell carcinoma of the kidney.

Case Report

A 32-year-old gravida 0 woman presented with hirsutism, oligomenorrhea, and morbid obesity with a body mass index of 37 kg/m². Family history was negative for known genetic syndromes, including Von Hippel–Lindau and Lynch syndromes. A computed tomography of her abdomen and pelvis revealed a right adnexal mass and a right kidney mass. The adnexal mass was described as a large cystic and solid mass arising from the right ovary measuring up to 18.5 cm. The solid area counted approximately 60% of the tumor mass. The renal mass was located in the upper pole of the right kidney and measured up to 4.2 cm. It was mainly solid with areas of hemorrhage and small cystic changes.

Laboratory tests revealed elevated DHEA-S (601.1 µg/dL), testosterone (198 µg/dL), free testosterone (68.9 pg/mL), free testosterone percentage (3.5%), Inhibin A (1004 pg/mL), and Inhibin B (5370 pg/mL). CA 125 (43 U/mL) was only mildly elevated. CEA (0.3 ng/mL), AFP (7.0 ng/mL), and hCG (0.1 mU/mL) were all within normal limits.

Given patient’s young age, she underwent unilateral right salpingo-oopherectomy and right partial nephrectomy. Frozen sections on the ovarian mass were read as a “malignant sex cord stromal tumor representing either a juvenile GCT or poorly differentiated Sertoli–Leydig cell tumor.” Therefore, the surgeon proceeded with ovarian cancer staging via bilateral pelvic and para-aortic lymphadenectomy with partial omentectomy.

Grossly the right ovarian mass measured 26 cm and had a smooth surface with no papillations or excrescences. Sectioning revealed tan-pink solid areas with foci of necrosis, myxoid degeneration, and hemorrhage as well as cystic cavities filled with serous fluid (Figure 1). Histologically the ovarian tumor contained elements of juvenile GCT (45%) and Sertoli–Leydig cell tumor (55%). The juvenile GCT displayed solid and cystic growth patterns with follicles of varying shapes and sizes. Cytologically the granulosa cells contained abundant cytoplasm, round to oval nuclei, open chromatin, but less prominent nuclear grooves than those seen usually in adult type GCT. Mitosis was brisky with mitotic figures in a range of 3 to 6 per 10 high power fields (Figure 2). The Sertoli–Leydig cell tumor consisted of intermediately differentiated spindle-shaped Sertoli cells that formed lobulated solid nodules. Some cells with cytoplasmic vacuoles were encountered (Figure 3A and B). Focally, large polygonal Leydig cells with abundant eosinophilic cytoplasm aggregated in cords and tubules in fibrous and edematous stroma (Figure 3C and D). There was no evidence of heterologous elements. Ovarian surface, pelvic and para-aortic lymph nodes, and omentum were negative for neoplasm. Pelvic washing was also free of neoplastic cells.

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Figure 1.

The sectioned surface of this 26 cm unilateral ovarian mass is composed of both cystic and solid areas. The latter part has grey-yellow tissue with nodular and lobulated appearance.

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Figure 2.

The juvenile granulosa cell tumor cells are growing in solid and lobulated patterns and punctured by follicles differing in size and shape (A). Tumor cells are relatively uniform, have abundant pale to eosinophilic cytoplasm, and round nuclei with open chromatin. Nuclear grooves are seen in some but not all tumor cells. Several mitotic figures are seen (B).

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Figure 3.

Sertoli–Leydig cell tumor has predominantly solid lobulated growth pattern (A). Most Sertoli cells are spindle shaped with intermediate differentiation, and some cells show prominent cytoplasmic vacuolization (B). Leydig cells are large and polygonal with abundant eosinophilic cytoplasm and aggregate as cords in a background of fibroedematous stroma (C and D).

Immunohistochemical staining showed tumor cells were diffusely positive for CD56, SF1, and inhibin and focally positive for pan-cytokeratin AE1/3 and calretinin (Figure 4). B-catenin was expressed in a normal membranous fashion. Ki-67 labeled over 90% of the tumor cells. The tumor cells were negative for RCC, PAX8, CD10, EMA, SALL4, and 14-3-3 Sigma. The above-mentioned immunoprofile confirms the sex cord stromal origin of the tumor and essentially excludes possibility of a metastatic renal cell carcinoma in the ovary. The gross, morphologic, and immunohistochemical features led to the diagnosis of Stage T1a gynandroblastoma composed of juvenile GCT and sex-cord stromal tumor of intermediate differentiation.

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Figure 4.

Immunohistochemical staining shows that tumor cells are diffusely positive for CD56 (A), SF1 (B), and inhibin (C). Tumor cells have a high Ki-67 labeling index (D).

Grossly the renal mass measured 3.8 cm and was yellow-orange, solid, and relatively well circumscribed. Histopathological examination revealed tumor cells arranged in nests with intervening delicate blood vessels. Tumor cells had clear cytoplasm, irregular nuclei, and conspicuous nucleoli at 40× high magnification, microscopic features consistent with clear cell renal cell carcinoma, nuclear grade 2 (Figure 5). Clinicopathologic stage was T1a. The patient was followed-up for 8 months after surgery by the time of drafting this article and is alive and free of disease.

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Figure 5.

Right kidney mass reveals typical clear cell carcinoma with mixed solid and cystic growth patterns and focal hemorrhage (A). Tumor cells arrange in nests with intervening blood vessels and have clear cytoplasm and irregular nuclei (B).

Discussion

Gynandroblastomas are rarely encountered in clinical practice. Since Meyer first described the tumor in 1931, there have been only 26 cases reported in the English literature.^{1 -3} Due to its rarity, gynandroblastoma is not included in the current World Health Organization Classification of Tumors of Female Reproductive Organs. Histopathologically, based on Scully and Young’s criteria in 1973, the diagnosis of gynandroblastoma requires more than 10% admixture of Sertoli or Sertoli cell (testicular) and granulosa cell (ovarian) elements in a typically easily recognized form.

Most cases reported had adult-type GCT as ovarian element. Only 4 cases were reported with juvenile GCT.^{4 -7} In our case, juvenile GCT accounted for approximately 45% of tumor mass. The areas of juvenile GCT display follicles of varying size and shape containing serous materials. Juvenile GCT consists of cells with abundant pale to eosinophilic cytoplasm and indistinct cell borders. Nuclei are round with relatively open chromatin and conspicuous nucleoli. Unlike adult-type GCT, nuclear grooves are less prominent and only seen in some of the tumor cells. Mitosis is brisky, and Ki-67 labeling index is greater than 90% of tumor cells. Immunohistochemically both neoplastic granulosa cells and Sertoli–Leydig cells are positive for inhibin, SF1, CD56, and calretinin. The expression of these “sex-cord stromal cell” related markers has been studied in some, but not all, of previously reported cases. Given such a limited number of cases reported in a span of more than 8 decades, it is difficult to compare immunostaining profiles case to case. However, it is noted that inhibin as a sex-cord/stromal cell-related marker was consistently expressed in gynandroblastoma when it was applied in previous studies. Our previous study indicated that almost all adult-type GCT cases overexpress 14-3-3 sigma, a chaperone protein with anti-apoptotic function. ⁸ However, 14-3-3 sigma is not expressed in neoplastic granulosa cells in this gynandroblastoma, which further supports its juvenile nature of the GCT component.

It is well known that GCT, especially adult type, is associated with endometrial carcinoma. ⁹ However, such an association with endometrial cancer has not been reported in patients with gynandroblastoma, probably due to younger age and early clinical detection in these patients. Given no known genetic syndrome linked to gynandroblastoma, second malignancy has not been reported in patients with gynandroblastoma in the literature. Although there is no known syndrome linking gynandroblastomas and renal cell carcinomas, the young age of the patient suggests a possible genetic basis predisposed her to these 2 separate neoplasms/malignancies. While these tumors are unlikely to recur, this patient is likely to be followed closely due to her concurrent renal cell carcinoma.

The molecular events involved in gynandroblastoma are largely unknown until recent discoveries. Using LOH approach Chivukula and his colleagues failed to identify most known loss of heterozygosity of known tumor suppressor genes except minor genetic instability in the 17q12.2 locus. ¹ Recent molecular studies demonstrate a strong association between the FOXL2 mutation at C134W (402 C>G) and adult-type GCT.^{10 -13} Recently, Oparka et al analyzed adult-type GTC-like components in 6 cases of gynandroblastoma and failed to detect FOXL2 mutations. ¹⁴ Their study suggests that, despite their similar morphological appearances, the GCT-like component of gynandroblastoma may have a different molecular basis from conventional adult-type GCT. This finding indicates that morphological similarity does not necessarily indicate molecular identity. Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors.^15,16 Germline DICER1 mutation has been described in females with ovarian sex cord-stromal tumors including (most commonly) Sertoli–Leydig cell tumor and (rarely) juvenile GCT and gynandroblastoma.^{17 -19} Although DICER1 germline mutation has also been reported in some kidney neoplasms, such as Wilm’s tumor ²⁰ and familial cystic nephroma, ²¹ it has not been linked to renal cell carcinoma. We have not done DICER1 mutation analysis in our case because the assay has not been set up yet in our laboratory.

Clinically gynandroblastoma in most cases are hormonally active and exhibit virilization such as hirsutism because of the presence of Sertoli or Sertoli–Leydig cell component. Almost all gynandroblastomas are stage I and behave in a benign fashion. Only one case was reported to recur after 10 years of original tumor resection, ¹ and another patient had advanced clinical stage and died with tumor. Therefore, most patients with stage I gynandroblastoma can be safely treated by surgical resection with follow up.