Case 2 -
Juvenile Granulosa Cell Tumor
University of Vermont
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An 18-year-old female presented with a history of an enlarging abdominal
mass. At surgery, a large adnexal pelvic mass was resected. The contralateral ovary and uterus appeared
A large intact multiloculated red-brown tumor with cystic and solid areas was received. The
tumor measures 39.0 x 34.5 x 20.0 cm and weighed 20 pounds. The surface was bosselated and comprised a
white-gray fibrous capsule. The multilocular cystic areas ranged in size from less than 1.0 cm to 12 cm
in diameter. Some cysts contained yellow-amber serous fluid, whilst others were filled with bloody
fluid. The solid areas comprised approximately 50% of the total tumor mass with a yellow-tan, lobular,
fleshy cut surface. Foci of necrosis and hemorrhage were also noted.
Case 2- Slide 1
Case 2 - Figure 1 - Tumor cells arranged in follicles, a focal feature alternating with more solid areas.
Case 2 - Figure 2 - Follicles contain pale eosinophilic secretions.
Case 2 - Figure 3 - Sheets of cellular tumor with mild to moderate nuclear atypia and mitotic activity (up to 2/hpf).
The tumor is characterized by solid nests and sheets of cellular neoplasm with focal follicle
formation. The solid nodules comprise proliferating granulosa cells and are arranged in sheets and
surround the follicles. The nodularity of the solid areas is accentuated by fibrothecomatous septa. The
neoplastic granulosa cells are rounded and large with an abundant eosinophilic cytoplasm. Nuclear
grooving and Cull-Exner bodies are not present. Focal larger vacuolated cells indicating an increase in
lipid content (luteinization) are also present. Mild to moderate nuclear atypia with an increased
mitotic activity (up to 2/hif power field) is noted. The follicles vary in size and shape with some
containing pale eosinophilic secretions. Granulosa cells of varying thickness line the follicles with a
layer of theca cells separating the surrounding stroma. These follicles are smaller than those seen in
adult macrofollicular granulosa cell tumors.
The diagnosis of granulosa cell tumor is confirmed with the following immunopositive markers:
inhibin (R1, Serotec), CD99 (HBA71, 013, Signet) and Calretinin (polyclonal, Zymed). EMA (E29, Dako),
keratin (AE1/AE3, Chemicon International) and MART-1 (Melan-A, A103, Biogenex) were negative. In
addition, PLAP (polyclonal, Dako), beta-hCG (polyclonal, Dako), alpha-fetoprotein (A-013-01, Biogenex),
synaptophysin (Snp88, Biogenex) and C-kit (polyclonal, Dako) were also negative.
Juvenile Granulosa Cell Tumor
Juvenile granulosa cell tumors (JGCT) occur in children and young adults, usually before age 30.
The majority of prepubertal girls with JGCT come to attention because of isosexual pseudoprecocity
(precocity without ovulation or progesterone production). Adolescents commonly present with menstrual
irregularities, amenorrhea, abdominal swelling/pain (as in the present case) or virilization.
Postpubertal women usually present with abdominal pain or menstrual irregularities. As with ovarian
tumors, ascites, tumor rupture, torsion and/or infarction may be seen at surgery.
The differential diagnosis in this age group includes germ cell tumors, small cell carcinoma and
stromal tumors. The germ cell tumors of this younger age group include yolk sac tumor, dysgerminoma and
embryonal carcinoma. These tumors lack the typical combination of solid cellular nests interspersed with
follicle formation seen in JGCT. Further, these germ cell tumors are variably immunopositive for AFP
(YST and some embryonal carcinomas), β-hCG (syncytiotrophoblasts of dysgerminoma and embryonal
carcinoma), PLAP (dysgerminoma and other germ cell tumors), CD117 (c-kit) (YST, mixed germ cell tumors
and some embryonal carcinomas) and OCT4 (dysgerminoma and embryonal carcinoma).
An important differential diagnosis to consider is the small cell carcinoma of the hypercalcemic
type. This uncommon aggressive tumor presents in young women in their twenties. The nuclei are
undifferentiated, uniform, small and hyperchromatic (may occasionally be large with open chromatin) with
brisk mitoses. Notably, this tumor may form follicular structures with eosinophilic material. Small
cell carcinoma, however, is cytokeratin and synaptophysin immunopositive and negative for inhibin.
However, synaptophysin may sometimes be negative due to the paucity of neurosecretory granules.
The stromal tumors in the differential diagnosis include tumors of the fibroma-thecoma continuum
and sclerosing stromal tumor. The fibrothecomas are solid, white to yellow, and present in older women.
They may develop extensive sclerosis and calcification. The sclerosing stromal tumor occurs in young
women as a large, solid and cystic edematous white tumor with cellular islands alternating with a myxoid,
edematous stroma and with a hemangiopericytomatous vascular pattern.
The vast majority of patients with stage 1 tumors are cured by salpingo-oophorectomy alone.
Tumor rupture or dissemination at the time of diagnosis is a poor prognostic indicator, with most
patients dying within a few years. Serum inhibin levels are useful in the follow-up of these patients.
Recurrences are treated with cisplatin-based chemotherapy with some success. Surgical cytoreduction with
salvage chemotherapy (including bleomycin and taxol) has met with some success.
In recent years, several immunohistochemical markers identifying ovarian sex cord stromal tumors
have become commercially available. These have been found to be of value in the distinction between sex
cord-stromal neoplasms and their histological mimics. These antibodies include α-inhibin,
Calretinin, Melan-A and CD99. Of these, α-inhibin appears to be the most useful, being the most
sensitive and specific immunohistochemical marker of ovarian sex cord-stromal tumors. α-inhibin is
a peptide hormone produced by ovarian granulosa cells, which selectively inhibits the release of follicle
stimulating hormone (FSH) from the pituitary gland, acting as a modulator of folliculogenesis. It is
produced and overexpressed by granulosa cell tumors (GCT), being therefore useful both as a marker for
early tumor growth and tumor recurrence before clinical manifestation. It is particularly useful in
identifying granulosa cell tumors (both adult and juvenile) with an unusual growth pattern, e.g.
distinguishing the sarcomatoid growth pattern of GCT from soft tissue tumors. Inhibin is a sensitive
immunohistochemical marker of a wide range of gonadal stromal tumors, including Sertoli-Leydig cell
tumors, steroid cell tumors and thecomas. A note of caution: β-inhibin is not entirely specific,
with immunoexpression being demonstrated in a small proportion of ovarian adenocarcinomas; emphasizing
the need for a panel of antibodies when investigating a differential diagnosis.
Calretinin is a calcium-binding protein that is expressed in neurons and mesothelial cells (and
their neoplastic counterparts). Many ovarian sex cord-stromal neoplasms are immunopositive with
Calretinin: Sertoli-Leydig cell tumors and granulosa cell tumors, being both nuclear and cytoplasmic
positive. However, fibrothecomas are negative. Calretinin has also been found to be immunopositive in
the majority of female adnexal tumors of probable Wolffian origin (FATWO). Whilst the sensitivity of
Calretinin has been compared to α -inhibin, positive staining of Calretinin in several tumors that
may morphologically mimic sex cord-stromal tumors highlights the need for a panel of antibodies when
investigating ovarian sex cord-stromal neoplasms.
CD99 (MIC2 antibody/HBA71/013) was first demonstrated as a marker for Ewing sarcoma/peripheral
primitive neuroectodermal tumors. Subsequently, CD99 was identified in a range of other tumors,
including hematopoietic neoplasms (lymphoblastic and myeloid), solitary fibrous tumors, mesenchymal
chondrosarcomas, small cell carcinomas, and sex cord-stromal tumors. The latter involved
immunoreactivity with granulosa and Sertoli cells. Interestingly, the degree of differentiation in
Sertoli-Leydig cell tumors correlated with the degree of CD99 immunoreactivity, with well-differentiated
tumors reacting more strongly. CD99 immunopositivity has also been demonstrated in sclerosing stromal
tumors and sex cord tumor with annular tubules (SCTAT). These findings suggest a diagnostic role for
CD99 as part of a panel in the investigation of tumors which include GCT and Sertoli-Leydig tumors,
especially poorly differentiated variants.
The Melan-A gene was cloned from a human melanoma cell line. The same gene was found by another
group using a different cell line and named MART-1. These two independent antibody clones recognize the
same antigen and have proven to be beneficial in the diagnosis of melanocytic lesions. The antibody A103
has been reported to highlight adrenocortical tumors and ovarian tumors such as Sertoli-Leydig cell
tumors, sex cord-stromal tumors (including adult and juvenile GCT), thecomas and FATWO. Although
moderately sensitive and specific, A103 immunoreactivity appears to be of some value in the assessment of
sex cord-stromal tumors, being positive in approximately 50% of tumors examined.
- Leong A S-Y, Cooper K, Leong F W-M. Manual of Diagnostic
Antibodies for Immunohistology. 2nd Ed. Greenwich Medical Media, UK; 2003.
- McCluggage WG. Immunohistochemical and Functional
Biomarkers of Value in Female Genital Tract Lesions. Int J Gynaecol Path 2006; 25:101-120.
- Mount SL, Eltabbakh GH, Cooper K. Recent
"non-gynecological" immunohistochemical markers in diagnostic ovarian pathology. Curr Diagn Pathol 2003;
- Roth LM. Recent Advances in the Pathology and
Classification of Ovarian Sex Cord-Stromal Tumors. Int J Gynaecol Path 2006; 25:199-215.
- Scully RE, Young RH, Clement PB. Atlas of Tumor
Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. AFIP Fascicle
23, Third Series; 1996.