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The granulosa cell tumor of the ovary is classified as a sex-cord stromal tumor by pathologists. These tumors are the most common ovarian tumors which produce estrogen, leading to symptoms and signs of estrogen excess such as endometrial hyperplasia. Occasionally, these tumors may produce androgens leading to virilization. These tumors all have malignant potential and cases of recurrence or metastases 20-30 years after initial diagnoses have been described.


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SYNONYMS Adult granulosa cell tumor
INCIDENCE 1-2% of all ovarian tumors
AGE RANGE-MEDIAN 50-55 years peak



Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors.

Mayr D, Kaltz-Wittmer C, Arbogast S, Amann G, Aust DE, Diebold J.

Pathological Institute, University of Munich, Munich, Germany.

Mod Pathol 2002 Sep;15(9):951-7 Abstract quote

The cytogenetic abnormalities of granulosa cell tumors (GCT) of the ovary are only partially known. Up to now, mainly numerical chromosomal aberrations have been described.

Therefore we performed a comprehensive study on paraffin-embedded material of 20 GCT (17 adult, 3 juvenile; patient age between 16 and 78 y) combining comparative genomic hybridization (CGH); fluorescence in situ hybridization (FISH) using DNA-specific probes for chromosome 12, 17, 22, and X; DNA cytometry; and immunohistochemistry (inhibin, p53, Ki67). By DNA cytometry, 16 of 20 tumors (80%) were diploid. However, 6 of 16 diploid tumors (37%) showed aberrations by FISH. FISH revealed monosomy 22 in 8/18 cases (40%); trisomy 12 in 5/20 (25%); monosomy X in 2/20 (10%); and loss of chromosome 17 in one case (5%). The main findings by CGH were gains of chromosomes 12 (6 cases, 33%) and 14 (6 cases, 33%) and losses of chromosomes 22 (7 cases, 35%) and X (1 case, 5%), mostly comprising whole chromosomes or chromosome arms. Inhibin and p53 were expressed in 100% and 95% of the tumors, respectively. The Ki67 index ranged from 0% to 61%. Neither immunohistochemistry, nor DNA cytometry and molecular genetic analysis, provided statistically significant prognostic information.

In summary, our study reveals a distinctive pattern of cytogenetic alterations in GCT. Our observations confirm earlier reports that trisomy 12 and 14 are frequent aberrations; however, monosomy 22 seemingly is even more prevalent.

Multifocal intrafollicular granulosa cell tumor of the ovary associated with an unusual germline p53 mutation.

Nogales FF, Musto ML, Saez AI, Robledo M, Palacios J, Aneiros J.

Departments of Pathology, University Hospital, Granada, Spain.
Mod Pathol. 2004 Jul;17(7):868-73. Abstract quote  

A 23-year-old woman presented with a 7 cm right multicystic mass in the ovary, which corresponded microscopically to an unusual lesion consisting of a multifocal granulosa cell tumor with intrafollicular ('in situ') growth involving two-thirds of mature follicles. Stromal invasion was found in only one area where neoplastic follicles coalesced. Granulosa cells had atypical, bizarre TP53 positive nuclei with hyperchromatism, abundant mitoses and numerous hyaline globules. The contralateral ovary was normal.

From the age of 10 years, the patient had a complex medical history of multiple tumors, including telangiectatic osteosarcoma, typical and malignant phyllodes tumor, reticulohistiocytoma of skin, carcinomas of the breast and lipo- and leiomyosarcoma. The female genital tract also harbored myometrial leiomyomas and an early endometrial carcinoma. Retrospective histologic study of all mesenchymal neoplasms in this patient showed, the conspicuous presence of similar bizarre TP53 positive cells with hyaline globules in all the mesenchymal neoplasms. In the genetic study, a germline p53 gene mutation was detected in exon 10, codon 336, generating a stop codon in the oligomerization domain of the protein (E336X). A further p53 mutation was found in exon 7 in the granulosa cell tumor. Mutation occurred de novo since there was no history of tumors in any family members, all of whom had a wild-type p53.

Although this patient shows a typical tumor phenotype of Li Fraumeni syndrome, the germline mutation corresponded to a highly unusual mutated domain, which is similar to the one found in childhood malignant adrenocortical tumor; also a rare neoplasm that originates in adrenocortical cells; which are closely related, both functionally and embryologically, to granulosa cells.



Average diameter 12 cm

Usually solid or cystic
Unilateral in 95% of cases

  Gray-white to yellow, reflecting lipid content
Hemorrhage is common

Gonadal tumor with granulosa cell tumor features in an adult testis

Beverly Y. Wang, MD
David S. Rabinowitz, MD
Roberto C. Granato Sr, MD
Pamela D. Unger, MD

Ann Diagn Pathol 6: 56-60, 2002. Abstract quote

Granulosa cell tumor is almost exclusively an ovarian tumor. Rare cases of granulosa cell tumor have been reported involving the testes.

We report a testicular gonadal stromal tumor with granulosa cell differentiation in a 54-year-old white man. The tumor was discovered by an ultrasound evaluation for left hydrocele. The patient was clinically asymptomatic. On frozen section, the initial impression was a malignant lymphoma. Final histology on the orchiectomy specimen showed a gonadal stromal tumor with granulosa cell features. Immunohistochemical studies excluded malignant lymphoma and germ cell tumors, consistent with a stromal tumor.

This case report illustrates the challenges for the pathologist in making an accurate diagnosis in unusual testicular tumors.



Call-Exner bodies are characteristic, especially in the microfollicular variant

Nuclei have cahracteristic grooves with uniform pale nuclei

Mitotic rate is usually low, less than 2 MF/10 hpf

Watered silk Undulating or zig-zag rows of granulosa cells, usually in single file
Sarcomatoid Monotonous cell growth
Granulosa-theca cell tumor Theca cell component may be prominent and thought to be the source of estrogen production



Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin.

Deavers MT, Malpica A, Liu J, Broaddus R, Silva EG.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Mod Pathol. 2003 Jun;16(6):584-90. Abstract quote

Because ovarian sex cord-stromal tumors (SCST) are morphologically heterogeneous neoplasms that are relatively infrequently encountered, their diagnosis can be difficult. Immunohistochemical staining may be useful for establishing the diagnosis in problematic cases.

We studied 53 ovarian SCSTs to characterize their immunohistochemical staining pattern: 17 adult granulosa cell tumors (AGCTs), 4 juvenile granulosa cell tumors (JGCTs), 3 sex cord tumors with annular tubules (SCTATs), 9 Sertoli-Leydig cell tumors (SLCTs), 10 fibromas, 5 fibrothecomas (FTs), and 5 thecomas. In 8 of the 53 cases, the tissue studied was from a metastatic site. The immunopanel included calretinin, inhibin, WT1, cytokeratin cocktail, epithelial membrane antigen (EMA), and cytokeratin 5/6 (CK5/6). The fibromas and FTs were also tested with CD10. The extent of staining was assessed in a semiquantitative fashion and ranked on a scale of 0 through 4+. All of the tumors, except for 1 metastatic SLCT, were positive for calretinin. Forty-five of the cases (85%) stained for inhibin; 1 metastatic AGCT, 3 fibromas, and 4 FTs were negative. WT1 was present in 39 tumors (74%), with expression most prominent in the SLCTs. The cytokeratin cocktail stained 23 of the 53 tumors (43%), whereas just 1 tumor was positive for EMA (1+ in a JGCT). All tumors were negative for CK5/6, and the 15 fibromas and FTs were negative for CD10.

We conclude that because cytokeratin is frequently expressed by SCSTs, in particular by granulosa cell tumors, SLCTs, and SCTATs, the inclusion of EMA in a panel may help to exclude epithelial neoplasms. In addition, WT1, present in normal granulosa cells, is expressed by a majority of SCSTs. Finally, these results demonstrate that calretinin is at least as sensitive as inhibin for ovarian SCSTs overall and that it is more sensitive than inhibin for fibromas and FTs.


Expression of calretinin and the alpha-subunit of inhibin in granular cell tumors.

Fine SW, Li M.

Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, 111 E210th St, North 4 Silver Zone, Bronx, NY 10467, USA.

Am J Clin Pathol 2003 Feb;119(2):259-64 Abstract quote

Granular cell tumors (GCTs) typically express S-100 protein, which has been used as a marker in differential diagnosis. Calretinin, a calcium-binding protein related structurally to S-100, and inhibin, a polypeptide hormone secreted primarily by ovarian granulosa cells and testicular Sertoli cells and functioning as an inhibitor for pituitary follicle-stimulating hormone secretion, are potentially useful but not well-evaluated markers for GCTs.

We studied 43 cases of GCT with antibodies to calretinin, the inhibin alpha-subunit, and S-100 protein. All tumors were positive for inhibin alpha-subunit and S-100 protein, with 50% or more cells showing moderate to strong staining. Forty tumors (93%) were positive for calretinin, ranging from focal weak to diffuse strong staining. Enhanced staining for calretinin in the tumor cells adjacent to hyperplastic squamous epithelium was observed in 9 of 13 cases showing pseudoepitheliomatous hyperplasia. Calretinin and the inhibin alpha-subunit are useful markers for GCTs.

The expression of calretinin, a primarily neuronal protein, in GCTs further supports its neural differentiation or derivation. The elevated calretinin expression in the tumor cells adjacent to the hyperplastic squamous epithelium suggests a role for calretinin in the tumor cells-squamous epithelium interaction.

Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours.

McCluggage WG, Maxwell P.

Department of Pathology, Royal Group of Hospitals Trust, Belfast and The Queen's University of Belfast, Grosvenor Road, Belfast BT12 6BL, Northern Ireland.

Histopathology 2001 May;38(5):403-8 Abstract quote

AIMS: Ovarian sex cord-stromal tumours are a heterogeneous group of neoplasms which may be confused morphologically with a wide variety of tumours. Calretinin positivity has previously been demonstrated in a small number of ovarian sex cord-stromal tumours. The aim of this study was to investigate calretinin staining in a series of these tumours and their histological mimics in order to determine the value of calretinin staining in a diagnostic setting.

METHODS AND RESULTS: Seventy-two neoplasms, including 37 ovarian sex cord-stromal tumours and 35 miscellaneous neoplasms which may enter into the differential diagnosis, were stained with a commercially available polyclonal antibody against calretinin. All sex cord-stromal tumours exhibited positivity except for a single fibrothecoma. In this group of tumours staining was generally diffuse and strong. Small numbers of the miscellaneous group of neoplasms exhibited positivity but this tended to be focal and weak, although this was not always the case. There was consistent strong positive staining of granulosa cells in follicular cysts and corpora lutea. There was also positive staining of luteinized stromal cells in two cases of ovarian stromal hyperplasia and hyperthecosis.

CONCLUSIONS: Calretinin is a sensitive immunohistochemical marker of ovarian sex cord-stromal tumours and may be useful in a diagnostic setting. However, the value is somewhat limited since occasional neoplasms which enter into the morphological differential diagnosis may be positive. Be that as it may, calretinin positivity may be of value in the diagnosis of an ovarian sex cord-stromal tumour and its differentiation from other neoplasms. In this regard, calretinin should always be used as part of a larger panel.

INHIBIN Positive

Inhibin immunohistochemical staining: a practical approach for the surgical pathologist in the diagnoses of ovarian sex cord-stromal tumors.

Zheng W, Senturk BZ, Parkash V.


Adv Anat Pathol 2003 Jan;10(1):27-38 Abstract quote

Through a brief introduction of inhibin history, characteristics of the antibody against inhibin, and normal tissue distribution of alpha-inhibin expression, this comprehensive review focuses on a practical approach to using alpha-inhibin in the differential diagnosis of ovarian sex cord-stromal tumors (SCSTs). Alpha-inhibin has become a most useful immunohistochemical marker of gonadal SCST, regardless if the tumors are primary, recurrent, or metastatic. However, pathologic diagnosis of individual SCST is still based largely on morphologic criteria.

Alpha-inhibin immunohistochemical (IHC) staining should be used only when a difficult morphologic diagnosis is encountered. In this perspective, alpha-inhibin and other properly selected markers should be ordered at the same time. This is simply because alpha-inhibin is not specific for SCSTs.

Caution should be exercised in the interpretation of alpha-inhibin-positive cells, because a wide variety of primary and metastatic ovarian tumors may contain significant numbers of alpha-inhibin-positive stromal cells. As with other immunohistochemical stains, a panel of stains and comparison with the corresponding hematoxylin and eosin (H&E) slides is necessary, especially when staining patterns and cellular localization are in question. The antibody will not help to differentiate tumors within the category of SCST. The pattern or the intensity of staining in SCSTs does not predict tumor behavior, although there is a tendency of loss of alpha-inhibin expression in poorly differentiated Sertoli or Sertoli-Leydig cell tumors.

In cases where metastatic granulosa or Sertoli-Leydig cell tumors are a concern, positive alpha-inhibin staining is diagnostic, but a negative result does not rule out metastatic disease. Calretinin has been recently recognized as a more sensitive, but less specific marker for SCSTs and it may be used to recognize an inhibin-negative SCST.

In this review, we have listed nine of the most commonly encountered clinical scenarios where alpha-inhibin and other markers could be used in diagnostic surgical pathology of ovarian tumors.



Breast carcinoma metastasis within granulosa cell tumor of the ovary: Morphologic, immunohistologic, and molecular analyses of the two different tumor cell populations.

Arnould L, Franco N, Soubeyrand MS, Mege F, Belichard C, Lizard-Nacol S, Collin F.

Departments of Pathology, Molecular Biology, and Surgery, Centre GF Leclerc, and INSERM, U-517, Faculte de Medecine, Dijon, France.

Hum Pathol 2002 Apr;33(4):445-8 Abstract quote

Gynecologic metastasis of breast carcinoma is not an infrequent event, but metastases within another tumor is very rare.

We report a case of unilateral ovarian tumor arising in a 63-year-old woman receiving tamoxifen therapy with a past history of breast carcinoma. The microscopic appearance was principally that of a granulosa cell tumor, but the presence of atypical cells closely admixed within the classical areas was reminiscent of metastasis from breast carcinoma. The diagnosis of this first reported case of breast carcinoma metastasis within granulosa cell tumor was supported by immunohistologic analysis. The diagnosis of tumor-to-tumor metastasis was also confirmed by molecular study using microdissections of samples from the initial breast tumor and from the subsequent ovarian tumor.

When compared with normal tissue, carcinomatous cells in the breast tissue exhibited genomic abnormality at the same locus as the metastatic cells in the ovary. In contrast, granulosa cell tumor areas did not show any loss of heterozygosity or instability for the microsatellites analyzed.


Prognostic Factors

All tumors have malignant potential

90% are stage I, limited to the ovary

Size of the tumor, mitotic figures, and nuclear atypia important in overall survival

5 Year Survival With no atypia-survival 92%
With moderate atypia-survival 30%
10 Year Survival

Tumors <5 cm-survival 100%
Tumors 6-15 cm-survival 57%

<2 MF-survival 70%
>3 MF-survival 37%


Recurence can occur in the pelvis and lower abdomen

Distant metastases are rare but tumors may recure 2-3 decades after initial diagnosis


Total hysterectomy and bilateral salpingo-oophorectomy for postmenopausal woman

Salpingo-oophorectomy may be acceptable in younger woman wishing to preserve fertility

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Last Updated 7/12/2004

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