Juvenile granulosa cell tumor with an unusual immunoprofile, presenting as precocious puberty.

Dear Editor,

Rokitansky, in 1855, was first to describe granulosa cell tumors of ovary as single entity.[1] They are benign tumors and are a subgroup of ovarian sex cord-stromal tumors (SCST). Pseudo precocious puberty is the most common presentation in young children. About 80% of these tumors presenting in children result in isosexual precocity.[2] As the histological diagnosis of ovarian SCST is difficult, calretinin has been proposed as a novel immunohistochemical (IHC) marker of ovarian SCST.

We describe a case of a 4-year-old girl who presented with vomiting, abdominal distension, and intermittent periumblical abdominal pain for 6 months. On physical examination, significant breast development was noticed along with development of pubic hairs. Per abdomen examination findings were of a distended abdomen with a palpable mass in the infraumblical region. Her hormonal profile was consistent with peripheral precocious puberty: Estradiol: 234 pmol/L; luteinizing hormone: <0.5 IU/L; follicle stimulating hormone: <0.5 IU/L; testosterone (total): 0.5 ng/mL; dehydroepiandrosterone sulfate: 46 ng/mL; 17-hydroxy-progesterone: 0.3 ng/mL; thyroid stimulating hormone: 2.4 mIU/L; total T4: 8.5 μg/dL; and alpha-fetoprotein (AFP): 1 ng/mL. Ultrasonography and computed tomography (CT) scan of pelvis showed a large cystic solid mass with multiple septae in lower abdomen [Figure 1c]. Laparotomy was performed and a left adenexal mass was resected and sent for histopathological examination. Grossly, the tumor was tan colored, multilobulated measuring 22 × 20 × 18 cm [Figure 1a and b]. Microscopic features on hematoxylin and eosin (H and E) staining revealed a cellular tumor with irregular and variable sized follicles having eosinophlic fluid. Tumor cells had moderate amount of eosinophilic cytoplasm with round hyperchromatic nuclei lacking grooves. Call-Exner bodies were not seen [Figure 2]. Based on the histomorphological features, diagnosis of SCST was considered. Further, IHC panel comprising of inhibin, calretinin, human chorionic gonadotropin (HCG), AFP, cytokeratin, and epithelial membrane antigen (EMA) was applied. The ovarian tumor gave strong positivity for calretinin [Figure 2 Inset]. It was negative for inhibin and rest of the IHC stains employed. Thus, the final diagnosis of juvenile granulosa cell tumor (JGCT) was made.

Figure 1

(a) Multilobulated, tan colored tumor measuring 22 × 20 × 18 cm. (b) Cut-section showing variegated appearance with solid as well as cystic areas. (c) Computed tomography (CT) scan of pelvis showed a large cystic solid mass with multiple septate in lower abdomen

Figure 2

Photomicrograph showing cellular tumor with irregular variable sized follicles. (hematoxylin and eosin stain (H and E), ×100). Inset: Photomicrograph showing proliferating tumor cells with strong calretinin positivity (H and E, ×400)

GCTs are rare SCST, encompassing 1-5% of all ovarian tumors.[3] Only 0.1% of all ovarian tumors and 4-5% of GCTs occur in children.[4] JGCT can be hormonally active, secreting estrogen. Isosexual precocity occurs in 70-80% of prepubertal girls with GCTs.[34] However, only 1% of all cases of precocious puberty in premenarchal females are due to granulosa and theca cell tumors.[5]

The differential diagnosis of JGCT includes adult GCT (AGCT) and variety of other neoplasm like malignant germ cell tumors and epithelial tumors.

Based on histomorphological features AGCT was ruled out, as the cells lacked Call-Exner bodies and grooved pale nuclei which are classic features of AGCT.

The JGCT is often misdiagnosed as malignant germ cell tumor. The follicular pattern of the JGCT is not a feature of germ cell tumor. The negative result with human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) ruled out germ cell tumors.

The distinction of GCT from a epithelial carcinomas can be aided by use of epithelial membrane antigen (EMA) which is positive in carcinomas and inhibin and calretinin is positive in GCT as in this case.[5]

The immunoprofile of our case was unusual and unique as it was inhibin negative and calretinin positive on IHC. Although inhibin has been shown to be a sensitive marker for ovarian sex cord-stromal and fibrous neoplasms, it may be negative in some cases. A negative inhibin on immunohistochemistry does not exclude a diagnosis of GCT.[6]

Calretinin, a mesothelial marker is particularly useful in the diagnosis of sex cord-stromal and fibrous neoplasms that are inhibin negative.[6]

Thus clinical parameters, hormone levels, histomorphological features may be helpful in evaluation to reach a final diagnosis in a case of precocious puberty. Correct and timely diagnosis of JGCT is important, as adjuvant treatment may not be necessary if the tumor is excised completely in early stage.