A rare case of ovarian gonadoblastoma flourishing into malignant mixed germ cell tumour with review of literature

Abstract

Gonadoblastoma is an extremely rare neoplasm of the ovary showing admixture of germ cells and sex cord cells. It may be associated with gonadal dysgenesis. Gonadoblastoma cells may give rise to individual germ cell tumours or mixed germ cell tumours with variable tumour components. Very few cases of ovarian gonadoblastoma admixed with malignant germ cell tumours have been recorded worldwide. Because of the rareness of the tumour, a component of gonadoblastoma might be overlooked on microscopic examination. Here we report a rare case of ovarian gonadoblastoma giving rise to an admixture of immature teratoma and dysgerminoma. We discuss microscopic features, immunohistochemistry findings and review of literature.

Introduction

Gonadoblastoma is an uncommon tumour of the ovary, first described by Scully in 1953 [1]. It is usually seen in patients with gonadal maldevelopment secondary to anomalies in genes of gonadal embryogenesis. Gonadoblastoma may develop in dysgenetic gonads in about 50–60% of cases. Patients harboring germline or somatic mutations in WT1 or SRY gene may develop gonadoblastoma [2]. Malignant mixed germ cell tumours (MMGCT) represent about 10–20% of all ovarian malignant germ cell tumours (GCT). Few mixed GCT cases may originate from gonadoblastoma in cases with normal or abnormal karyotype [3]. Here we represent a rare tumour of ovarian mixed GCT arising from a small hidden focus of gonadoblastoma.

Case report

A 21-year-old female presented in the oncosurgery department with complaints of abdominal distension, bloating and constipation. The patient had a history of primary amenorrhoea. The patient also complained of weight loss and tiredness. Karyotype was from a normal female showing 46, XX. She had no history of surgical procedures and a negative family history of any cancer. MRI study shows large heterogenous abdominopelvic mass located in a region of pouch of Douglas, bilateral adnexa and lower abdomen. The lesion is predominantly solid with a component of multiple cystic areas. Both ovaries are not seen separately from the lesion. Multiple T2 hypointense foci were seen in the left lateral aspect of mass suggestive of calcification or haemorrhage. The mass is compressing and displacing the uterus anteriorly. The uterus is elongated and partially encased by the mass; however, no infiltration is seen. The sigmoid colon is compressed by the mass and displaces posteriorly with loss of fat planes between the mass and sigmoid colon. Mass is anteriorly reaching up to the anterior abdominal wall and posterolaterally reaching up to the anterior aspect of iliac vessels as well as postero-lateral pelvic walls. The mass is heterogenous hyperintense on T2, heterogenous isointense on T1, with hyperintense foci showing contrast enhancement along with non-enhancing cystic and necrotic areas. Mild dilatation of left ureter due to compression effect. Minimal free fluid in bilateral paracolic gutters and pelvis. There is no evidence of pelvic lymphadenopathy (Fig. 1).

Fig. 1.

a Axial and b coronal T2 weighted images show heterogeneously T2 hyperintense mass lesion with multiple foci of necrosis in the pelvis. Bilateral ovaries are not seen separately from the mass lesion

Routine laboratory studies were within normal limits comprising of complete hemogram, coagulation studies, liver and renal function studies. Tumour markers study showed elevated levels of AFP (α-fetoprotein) reaching up to 12,000 ng/ml. Serum LDH levels are elevated reaching up to 2500 U/l. CA-125 level was 330 U/ml. Other tumour markers are within a normal range including β-HCG (beta-human chorionic gonadotropin), CEA (carcinoembryonic antigen) and CA-19.9. Preoperative Estradiol was 10 pg/ml and S. FSH levels were 45 mIU/ml.

Intraoperatively both the ovaries were replaced by mass, fused with each other and were stuck with the posterior wall of the atrophic uterus. The uterus was grossly atrophic and inseparable from the mass. As both the ovaries were diseased and the uterus was atrophic, fertility preservation was not possible.

As preoperative levels of AFP were high, preoperative working diagnosis was germ cell tumour, however as CA 125 levels were also high and few bilateral external iliac group lymph nodes were enlarged, so epithelial ovarian cancer was the second differential. The patient subsequently underwent surgery with en bloc removal of giant bilateral adnexal mass with the uterus. Infracolic omentectomy with bilateral pelvic lymphadenectomy, para-aortic lymph node sampling and one separate rectal serosal nodule (1.5 cm) was also submitted.

On gross examination, both the ovarian masses were adherent and difficult to delineate, measured 22.6 × 21.4 × 12.8 cm in total. Externally surface was irregular and encapsulated. Both fallopian tubes were not identified separately. On cutting, dirty hemorrhagic fluid came out showing a solid-cystic appearance. A solid area having soft to firm heterogenous, grey-white to yellowish to hemorrhagic zones. Total 29 lymph nodes (LN) were dissected from the pelvic and para-aortic region. Omentum was grossly unremarkable. Histopathology revealed features of MMGCT arising from gonadoblastoma. Hematoxylin and eosin (H&E) stained section shows predominantly area of MMGCT consisting of IT about 70% and dysgerminoma about 30%. Gonadoblastoma components show multinodular appearance comprising of admixture of germ cells and sex cord tumour cells arranged around eosinophilic material. Foci of calcification are also seen representing burnt-out gonadoblastoma. IT exhibited in form of multiple foci of immature neuroectodermal components. Immature glandular epithelium was seen in the background of immature stroma and foci of immature cartilage. The teratomatous component was adherent to the serosa of posterior uterus. Both fallopian tubes were free of tumour on microscopy. Eighteen pelvic LN, eleven para-aortic LN and omentum were free of any tumour cells. Submitted rectal nodule revealed metastatic teratoma component (Fig. 2). Final pathological staging (pTNM) as per AJCC 8th edition was pT3bN0 and FIGO staging was IIIB. IHC (Immunohistochemistry) study within gonadoblastoma revealed biphasic cells. Large cells are positive with c-kit and small cells (granulosa cells) are positive with Inhibin and FOXL2. Dysgerminoma component expressed positivity with SALL4 and PLAP (Figs. 3, 4).

Fig. 2.

a Gross showing en bloc resected bilateral adnexal mass showing predominantly solid areas and adherent to uterus posteriorly. Immature teratoma component: b immature neuroepithelium in the lower part and glandular component with myxoid stroma in the upper part (HE, × 10). c Endodermal glandular area embedded in the immature stroma (HE, × 10). d Ectodermal squamous component on left and nodules of gonadoblastoma on the right side (HE, × 10)

Fig. 3.

a HE, × 20 and b HE, × 40—gonadoblastoma having dual population of large germ cells with clear cytoplasm and smaller sex-cord cells. IHC showing nuclear positivity with inhibin (c) and FOXL2 (d) in sex-cord cells

Fig. 4.

a HE, × 20 and b HE, × 40—dysgerminoma component depicting nests of germ cells separated by fibrous septa containing scattered lymphocytes. Tumour cells are positive for PLAP (c) and SALL4 (d)

The patient had an uneventful postoperative recovery. She received three cycles of BEP based chemotherapy uneventfully. She is on a regular three-monthly follow-up and disease-free (after one and a half years of surgery).

Discussion

Gonadoblastoma is an extremely rare type of mixed germ cell-sex cord cell tumour. Patient age for gonadoblastoma varies from the neonatal period to 4th decade. Affected patients are mostly phenotypic females. About 25–35% of patients with Turner syndrome and 5% of patients with androgen insensitivity syndrome may develop gonadoblastoma [2]. The present case is a 21-year-old female with chief complaints of abdominal distension and primary amenorrhoea.

The significance of gonadoblastoma, in addition to its relation with gonadal dysgenesis, is its susceptibility to develop germ cell neoplasms. Hart and Burkons described six cases of gonadoblastoma giving rise to secondary germ cell tumours. In four cases gonadoblastoma was associated with germinoma, whereas the other two cases of mixed GCT showed germinoma with mature teratoma and germinoma with yolk sac tumour, respectively [4]. Rest all cases of gonadoblastoma with germ cell tumours have been published as a case report. A rare case was reported in a 19-year-old female with a 46, XX karyotype, of mixed GCT, exhibiting yolk sac tumour and choriocarcinoma, arising from gonadoblastoma ovary [5]. Another case report shows spermatocytic tumour and germinoma admixed with gonadoblastoma [6]. One case published of gonadoblastoma associated mixed GCT having components of dysgerminoma and hepatoid yolk sac tumour [7]. Zhu et al. described a rare case of Swyer's syndrome having gonadoblastoma associated with mature teratoma in the left ovary of 16 years old female [8]. Two different cases showing the association of gonadoblastoma with dysgerminoma have been reported by Kulkarni and Yuce et al. [9]10. Ulbright et al. described a case of hepatoid and endometrioid-like yolk sac tumour related to gonadoblastoma [11]. Similar to all these cases, this case is also presented with a combination of germ cell tumours arising from gonadoblastoma, however, unlike other cases, this case revealed an association of immature teratoma and dysgerminoma with gonadoblastoma. Dysgerminoma component is arranged in solid and nesting patterns.

Affected patients may present with symptoms of delayed puberty and virilization due to androgen production [12]. Zhu [8] reported a case report in a phenotypic female with XY genotype. In our case, the patient had a normal 46, XX female karyotype. Although the patient presented with complaints of amenorrhea, a history of virilizing symptoms was absent.

The testis-specific protein, Y-encoded (TSPY) gene, located within the gonadoblastoma locus on the Y chromosome, is considered to be the triggering factor for the development of GCT in gonadoblastoma [12]. Gonadoblastoma may give rise to any GCT, however, about 50% of cases show overgrowth by dysgerminoma. Overgrowth by other GCT, for example, yolk sac tumour, embryonal carcinoma and choriocarcinoma occurs in about 10% of cases [1, 5, 13]. Our case revealed an admixture of IT and dysgerminoma originating from gonadoblastoma.

On IHC, gonadoblastoma demonstrates positive staining with PLAP, OCT ¾, SALL4 and c-kit in germ cells. Sex-cord cells are positive for inhibin, calretinin, SF1 and FOXL2. Dysgerminoma is negative for CK, but non-dysgerminoma GCT show positivity for CK [2, 6]. Similarly present case shows CK stain positive in IT component and negative in dysgerminoma. OCT3/4 and TSPY markers in immature germ cells suggest a high risk for gonadoblastoma in patients presenting with disorders of sex development and a positive β-catenin marker is an indicator of the development of malignant germ cell tumour [14].

Patients with gonadoblastoma with GCT are treated by surgical resection followed by chemotherapy. A study by Hart [4] unveiled that one patient with mixed GCT (germinoma and endodermal sinus tumour) developed metastasis in the omentum and abdomen six months after operation and radiation therapy. Our patient received chemotherapy after surgery and she is disease-free after 18 months post-surgery. Pure gonadoblastoma and those associated with dysgerminoma have recorded favourable prognosis, albeit those associated with other types of GCT have reported unfavourable prognosis [5].

Pure gonadoblastoma may grow in size up to 8 cm, but when associated with GCT, it may grow up to enormous size, as in the present case. Gonadoblastoma consists of a biphasic population of two cell lineages, large germ cells resembling dysgerminoma cells and smaller sex cord cells similar to immature Sertoli cells or granulosa cells. Occasionally stroma may contain Leydig like cells. Tumour nests are well defined solid round to oval-shaped with occasional foci of inner calcification [5, 12]. This case shows a multinodular component of gonadoblastoma with foci of calcification within nodules. IT is indicated by ectoderm, mesoderm and endoderm components in form of immature neuroectoderm, glandular epithelium and immature cartilage, respectively. A study by Hart [4] shows iliac and paraaortic lymph nodes positive for metastatic germinoma, whereas the present case shows negative lymph nodes from the right pelvic (n − 7), left pelvic (n − 11) and para-aortic (n − 11) region.

The most common differential diagnosis of gonadoblastoma includes mixed germ cell-sex cord-stromal tumour, however, the latter is not associated with gonadal dysgenesis and lacks calcification or hyalinization. Another differential diagnosis is sex cord tumour with annular tubules, which is usually associated with the Peutz-Jeghers syndrome and lacks germ cell component. Sertoli cell nodule can be differentiated by strong SOX9 and absent FOXL2 reactivity in sex cord cells [2, 5, 13].

Conclusion

Gonadoblastoma is a peculiar form of in-situ neoplasia comprising of germ cells admixed with incompletely differentiated sex cord cells. Very rarely, gonadoblastoma may give rise to MMGCT which may or may not be associated with dysgenetic gonads. Adequate sampling is of prime importance to identify gonadoblastoma component and histopathology report should include the proportion of each germ cell tumour component along with final staging, which will be helpful to predict the prognosis and decide the role of post-operative chemo-radiotherapy treatment.