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Background
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.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Adult granulosa cell tumor INCIDENCE 1-2% of all ovarian tumors AGE RANGE-MEDIAN 50-55 years peak
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General Average diameter 12 cm
Usually solid or cystic
Unilateral in 95% of casesGray-white to yellow, reflecting lipid content
Hemorrhage is commonMALE 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, MDAnn 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.
HISTOLOGICAL TYPES CHARACTERIZATION WELL-DIFFERENTIATED FORMS 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
Microfollicular Macrofollicular Insular Trabecular Solid-tubular Hollow-tubular POORLY DIFFERENTIATED Watered silk Undulating or zig-zag rows of granulosa cells, usually in single file Gyriform Sarcomatoid Monotonous cell growth ADDITIONAL VARIANTS Granulosa-theca cell tumor Theca cell component may be prominent and thought to be the source of estrogen production
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION GENERAL
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.CALRETININ
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.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES METASTATIC CARCINOMA
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.
PROGNOSIS AND TREATMENT CHARACTERIZATION 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%Metastasis Recurence can occur in the pelvis and lower abdomen
Distant metastases are rare but tumors may recure 2-3 decades after initial diagnosis
Treatment 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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