A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial.

BACKGROUND: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. METHODS: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. RESULTS: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. CONCLUSIONS: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.

Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients.

Granulosa cell tumors (GCTs) comprise 2% to 5% of ovarian neoplasms, with unpredictable patterns of recurrence. The HER family, GATA4, and SMAD3 genes are reportedly involved in GCT proliferation and apoptosis and may serve as new predictors of recurrence. The aim of the study was to evaluate novel predictors of recurrence in GCT from a large single institution cohort. Patients diagnosed with GCTs (n=125) between 1975 and 2014 were identified. Clinicopathologic parameters were obtained and immunohistochemical evaluation was performed of calretinin, inhibin, HER2, CD56, SMAD3, and GATA4. Statistical analyses were conducted using Fisher exact test and Kaplan-Meier survival curves and Cox regression analysis. The median follow-up period was 120 months (range, 1-465 mo). Recurrence was noted in 12/125 (9.6%) patients. Kaplan-Meier analysis showed a shorter mean disease-free interval in whites versus blacks (P=0.001), stage III-IV versus stage I-II (P=0.0001), patients treated with surgery+chemotherapy versus surgery (P=0.0001), mitotic rate ≥4 (P=0.005), severe nuclear pleomorphism (P=0.013), high HER2 expression (P=0.001), high CD56 expression (P=0.001), and high SMAD3 expression (P=0.001). On Cox regression analysis, SMAD3 and type of treatment received were the only 2 independent prognostic factors for disease-free interval (P=0.03 and P=0.007, respectively). On subanalysis for early-stage (stage I) GCTs, the need for adjuvant chemotherapy and high expression of SMAD3 continued to be independent predictors of recurrence (HR=10.2, P=0.01 and HR=8.9, P=0.001, respectively).

Mutational analysis of FOXL2 p.C134W and expression of bone morphogenetic protein 2 in Japanese patients with granulosa cell tumor of ovary.

AIM: To assess whether FOXL2 p.C134W mutation may play a role in the development of human ovarian tumors in the Japanese, we investigated the FOXL2 codon 134 mutation and protein expression of inhibin-α, bone morphogenetic protein 2 (BMP2) and follistatin (FST) in Japanese patients with granulosa cell tumor (GCT) of the ovary and other ovarian tumors. METHODS: We analyzed 114 tumor tissues from ovarian tumors, including 44 adult-type and two juvenile-type GCT of the ovary and 68 ovarian tumors by DNA sequencing. Immunohistochemistry was also performed in the adult and juvenile GCT tissues by immunostaining inhibin-α, BMP2 and FST. RESULTS: We found the FOXL2 p.C134W mutation in 27 out of 44 (61.4%) adult-type GCT of the ovary, but none in other ovarian tumors. Histologically, all of the adult-type GCT sections were positive for inhibin-α, and the expression of BMP2 and FST was detected in 14 of 44 (31.8%) and zero of 47 (0%), respectively. No significant differences regarding the diagnosed age, preoperative serum carbohydrate antigen 125 levels, or BMP2 immunopositivity between the FOXL2 p.C134W mutation-positive and mutation-negative were found in the adult-type GCT patients. CONCLUSION: Our findings suggest that FOXL2 p.C134W mutation-positive adult-type GCT of the ovary may not be common in the Japanese as compared to the previous data.

FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines.

A single, recurrent somatic point mutation (402C→G) in FOXL2 has been described in almost all adult-type granulosa cell tumors but not other ovarian neoplasms. Histopathological features of adult-type granulosa cell tumors can be mimicked by a variety of other tumors, making diagnosis of adult-type granulosa cell tumor challenging. It has been suggested that molecular testing for FOXL2 mutation might be a useful tool in the diagnosis of adult-type granulosa cell tumors. The aim of this study was to demonstrate how testing for the FOXL2 mutation can be used in a gynecological pathology consultation service and to establish clear procedural guidelines for FOXL2 testing. Immunohistochemistry for FOXL2 was done using an anti-FOXL2 polyclonal antiserum. If immunohistochemistry was positive, FOXL2 mutation status was subsequently analyzed using a TaqMan assay. A dilution experiment was done to assess the sensitivity and minimum tumor cellularity requirements for our TaqMan assay. Twenty problematic cases were assessed, where the differential diagnosis after the initial investigations included adult-type granulosa cell tumors. Differential diagnoses included: thecoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, endometrial stromal sarcoma and others. In all cases, FOXL2 immunohistochemistry was positive and in six samples the FOXL2 mutation was detected, thus confirming a diagnosis of adult-type granulosa cell tumor. The TaqMan assay was able to reliably detect the FOXL2 mutation with input DNA in the range of 2.5-20 ng, and with a minimum of 25% tumor cell nuclei. The analysis of the FOXL2 mutational status in clinical samples is a useful diagnostic tool in situations where the differential diagnosis is between adult-type granulosa cell tumor and other ovarian tumors. The TaqMan assay requires a minimum of 2.5 ng DNA, with optimal assay performance for 5 to 10 ng DNA input. Laser capture or needle-macrodissection should be undertaken to enrich samples with tumor cell content below 25%.

Chemerin inhibits IGF-1-induced progesterone and estradiol secretion in human granulosa cells.

BACKGROUND: Chemerin is a novel adipokine involved in the regulation of adipocyte development, inflammation and metabolic functions. To date, no role of this adipokine in reproductive functions has been described. In the present study, we identified chemerin and its receptor, CMKLR1 (chemokine-like receptor 1), in primary human granulosa cells (hGCs) and in a human ovarian granulosa-like tumour cell line (KGN). We also investigated the effects of recombinant human chemerin (rhChem) on steroid production and on various signalling pathways. METHODS AND RESULTS: By RT-PCR immunoblotting and immunohistochemistry, we showed that chemerin and CMKLR1 are expressed in hGCs and KGN cells. By ELISA, we also found chemerin in human follicular fluid and we observed that in 8 of 10 women the chemerin level was at least 2-fold higher in follicular fluid than in plasma. rhChem (10 or 100 ng/ml) significantly decreased insulin-like growth factor-1 (IGF-1) (10(-8) M)-induced secretion of progesterone and estradiol (as determined by radioimmunoassay) but did not affect basal-or FSH (10(-8) M)-induced steroid secretion in hGCs and KGN cells. In parallel, it also decreased IGF-1-induced p450 aromatase protein levels without affecting the protein levels of other factors involved in steroidogenesis (steroidogenic acute regulatory protein, 3-beta-hydroxysteroid dehydrogenase and p450 side-chain cleavage enzyme) in hGCs cells. All these changes were associated with a decrease in the IGF-1-induced tyrosine phosphorylation of IGF-1 receptor beta subunit and phosphorylation of mitogen-activated protein kinase extracellular signal-regulated kinases 1/2 (MAPK ERK1/2) and Akt. In hGCs and KGN cells, rhChem also decreased IGF-1-induced thymidine incorporation. Finally, we showed that rhChem rapidly activates MAPK ERK1/2, MAPK P38 and Akt phosphorylation and more slowly AMP-activated protein kinase phosphorylation under basal conditions (no IGF-1 or FSH) in primary hGC cells. CONCLUSIONS: Taken together, chemerin and its receptor (CMKLR1) are present and active in hGCs. Chemerin reduces IGF-1-induced steroidogenesis and cell proliferation through a decrease in the activation of IGF-1R signalling pathways in primary hGCs.

Collision tumor of the ovary: adult granulosa cell tumor and endometrioid carcinoma.

We report the first case of a combined adult granulosa cell tumor and endometrioid carcinoma collision tumor occurring in an ovary.

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary.

Recently, mutation of the FOXL2 gene has been consistently identified in adult granulosa cell tumors of the ovary. The purpose of this study is to investigate whether the FOXL2 mutation and mRNA expression have a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. Thirty-four adult granulosa cell tumors and 20 juvenile granulosa cell tumors were examined for the presence of the FOXL2 (C402G) mutation. Expression levels were studied by quantitative PCR and immunohistochemistry. We found that FOXL2 (C402G) mutation was present in 19/27 (70%) of the adult type tumors but in none of the juvenile granulosa cell tumors (0/18). No correlation was encountered between the presence of FOXL2 mutation and various clinicopathologic parameters except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 (C402G) mutation had a worse disease-free survival than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in both adult and juvenile granulosa cell tumors. We also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein, and there was a linear correlation between mRNA and immunohistochemical FOXL2 expression in both adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall survival and disease-free survival than those with negative or weakly immunoreactive tumors. Our data suggest that FOXL2 mutation and mRNA expression are of prognostic importance in both adult and juvenile granulosa cell tumors.

The role of FOXL2, SOX9, and ß-catenin expression and DICER1 mutation in differentiating sex cord tumor with annular tubules from other sex cord tumors of the ovary.

Sex cord tumor with annular tubules (SCTAT) is a highly rare type of ovarian sex cord-stromal tumor (SCST), the diagnosis of which remains to be challenging. The aim of this study was to scrutinize the utility of three immunohistochemical markers including Forkhead box protein 2 (FOXL2), SOX9, and ß-catenin and DICER1 mutation status in distinguishing SCTATs from other ovarian SCSTs. Nine cases of SCTAT, 10 Sertoli-Leydig cell tumor (SCLT), 10 adult-type granulosa cell tumor (AGCT), and 8 juvenile-type granulosa cell tumor (JGCT) were included in the study. SCTATs were characterized by diffuse and strong expression of SOX9, focal and weak expression of FOXL2, and the absence of DICER1 mutation. However, AGCTs and JGCTs displayed strong and diffuse expression of FOXL2, focal/no immunoreaction for SOX9. SLCTs generally showed moderate intensity of FOXL2 and SOX9 expression. Nuclear ß-catenin expression was observed in none of SLCT, 1/9 of SCTAT, 6/8 JGCT, and 4/10 AGCT cases, respectively. DICER1 hotspot mutation was detected in only 3 cases of SLCT and 2 cases of JGCT. We conclude that in addition to strong and diffuse SOX9 expression, weak/absent expression of FOXL2 is suggestive for the diagnosis of SCTAT. Hence, we suggest that inclusion of these two markers, SOX-9 and FOXL2, to the immunohistochemical panel helps in differentiation of SCTAT from other SCSTs in addition to morphologic findings. We also conclude that SCTATs of the ovary do not harbor DICER1 hotspot mutation.

Granulosa cell tumors of the ovary: a clinicopathologic and immunohistochemical study of 21 cases.

PURPOSE: To further study the clinicopathologic and immunohistochemical features of ovarian granulosa cell tumors (GCTs). METHODS: We retrospectively studied all cases of GCTs diagnosed in our laboratory over the last 10-year period. Immunohistochemistry for inhibin, vimentin, cytokeratin, Ki-67 and p53 was performed on archival paraffin blocks. Pathologic and immunohistochemical findings were correlated with the clinical records of the patients. RESULTS: Twenty-one cases (15 of the adult and 6 of the juvenile type) were retrieved. All patients were FIGO Stage I at the time of diagnosis. Recurrent disease was detected in four patients (19%) during a median follow-up of 36 months (range 2-26 years). Pathology revealed a concomitant theca-cell component in three cases, a Sertoli-Leydig component in one case, and a thecoma in one case. Archival tissue material was available in 12 cases. Immunohistochemistry was positive for: beta-inhibin in 12/12 cases (100%), vimentin in 11/12 cases (91.7%), cytokeratin in 3/12 cases (25%), CD34 in 0 cases (0%), and p53 in 2/12 cases (16.7%). The Ki-67 index was < 5% in 12/12 cases (100%). No significant correlations were observed between the pathologic and immunohistochemical parameters examined and the clinical outcome. CONCLUSIONS: Despite the relatively indolent nature and favorable prognosis of most GCTs, late recurrences are not a rare event even in Stage I patients, necessitating a close and long-term follow-up. The identification of novel prognostic markers, in addition to our traditional staging parameters such as clinical staging, is needed in order to more accurately predict probabilities of recurrence in these patients.

[Extraovarian granulosa cell tumor with FOXL2 mutation. Morphological and immunohistochemical differential diagnosis]. / Tumor de células de la granulosa extraovárico con mutación FOXL2. Diagnóstico diferencial morfológico e inmunohistoquímico.

Extraovarian granulosa cell tumor is a very uncommon tumor and the identification of a recurrent mutation in FOXL2 may be used as another diagnostic tool along with the classical morphological and immunohistochemical findings. Here, we report a new case of extraovarian granulosa cell tumor in a 57 years old female patient presented with a sub-hepatic mass and abdominal pain. Histopathological examination of the excised mass showed features of adult-type granulosa cell tumor with α-inhibin, calretinin, WT1, S100, CD99 and progesterone receptor immunoreactivity. A FOXL2 mutation was detected on molecular biology study. A final diagnosis was an extraovarian adult-type granulosa cell tumor. We discuss the histopathological and immunohistochemical differential diagnosis.

Aberrant expression of ovary determining gene FOXL2 in the testis and juvenile granulosa cell tumor in children.

PURPOSE: FOXL2 is the earliest known marker of ovarian differentiation in mammals. It is involved in ovarian somatic cell differentiation and further follicle maintenance. FOXL2 is not implicated in determination of the male gonad and it is absent in the testis. We investigated whether the rare JGCTT (juvenile granulose cell tumor of the testis), named for its histological similarity to ovarian tumor, could be the first illustration of aberrant expression of this ovary determining gene in the human testis. MATERIALS AND METHODS: Between 1990 and 2004, 3 boys with JGCTT were reported from the TGM95 database of the French Society for Childhood Cancer and from 8 pediatric endocrinology centers. Orchiectomy was performed in these patients. Immunohistochemistry of FOXL2, and co-immunofluorescence of FOXL2 and SOX9 were performed on tumor sections. RESULTS: Testicular tumor cells showed aberrant expression of FOXL2, which resembled normal ovarian granulosa cells. The localization of FOXL2 expression was nuclear without any cytoplasmic sequestration, suggesting that FOXL2 had biological activity. Conversely SOX9, which is present in the nucleus of normal testicular cells, was sequestered in the cytoplasm of granulosa tumor cells or markedly under expressed in the nuclei. In this case of residual SOX9 nuclear expression the expression of FOXL2 and SOX9 was mutually exclusive. CONCLUSIONS: To our knowledge we report the first human model of aberrant intratesticular expression of an ovary determining gene along with the extinction of SOX9 and the transdifferentiation of a testicular cell into a granulosa tumor cell.

Juvenile granulosa cell tumors of the testis: a clinicopathologic study of 70 cases with emphasis on its wide morphologic spectrum.

The clinical and pathologic features of 70 juvenile granulosa cell tumors (JGCTs) of the testis are presented. The patients were from 30 weeks gestational age to 10 years old; 60 of 67 (90%) whose ages are known to us were 6 months old or younger. Sixty-two underwent gonadectomy, 6 wedge excision, and 2 only biopsy. Twenty-six tumors were left sided and 22 right sided. Six occurred in an undescended testis and 2 in dysgenetic gonads. The most common presentation was a testicular mass (65%), followed by an "enlarging testis" (25%). Six of 14 patients in whom it was measured had "elevated" serum α-fetoprotein (AFP), likely physiologically, and 1 had gynecomastia. The tumors measured 0.5 to 5 cm (mean, 1.7 cm; median, 1.5 cm) and were most commonly well circumscribed and typically yellow-tan; approximately 2/3 had a cystic component, whereas 1/3 were entirely solid. Microscopic examination typically showed a lobular growth, punctuated in 67 cases by variably sized and shaped follicles containing material that was basophilic (21%), eosinophilic (44%), or of both characters (35%); 3 lacked follicles. In nonfollicular areas, the tumor cells typically grew diffusely but occasionally had a corded arrangement (26%) or reticular appearance (29%). The stroma was either fibrous or fibromyxoid; hemorrhage associated with hemosiderin-laden macrophages was focally seen in 16%. The tumor cells were mostly small to medium sized with round to oval nuclei containing inconspicuous nucleoli and moderate to abundant, but occasionally scant, pale to lightly eosinophilic, sometimes vacuolated, cytoplasm; nuclear grooves were infrequent (6%). Focal columnar morphology was seen in 27% of the tumors. Mitoses were plentiful in 37%, and apoptosis was prominent in 46%. Intratubular tumor was seen in 43% and entrapped seminiferous tubules in 70%. Lymphovascular invasion was present in 2 cases, rete testis involvement in 4, and necrosis in 1. Rare features/patterns included: regressed tumor with hyalinization and prominent blood vessels (13%), papillary growth (4%), basaloid morphology (1%), spindle cell predominance (1%), microcystic foci (1%), adult granulosa cell-like (1%) patterns, and hyaline globules (1%). Inhibin (16/18), calretinin (8/9), WT1 (6/7), FOXL2 (12/12), SF-1 (12/12), and SOX9 (6/11) were positive, whereas SALL4 and glypican-3 were consistently negative in the neoplastic granulosa cells. Only 1 of 10 tumors was focally positive for α-fetoprotein. JGCT is a rare neoplasm with a wide morphologic spectrum that also occurs rarely in undescended testes and dysgenetic gonads. The solid and reticular patterns may pose diagnostic challenges, but the lobular appearance and follicular differentiation are characteristic. Immunohistochemical stains may aid in its distinction from other tumors of young male individuals, particularly yolk sac tumor, a neoplasm that peaks at a somewhat later age. Twenty-four patients with follow-up, including 4 of 6 patients treated with wedge resection/biopsy, had no evidence of disease (2 to 348 mo; mean, 83 mo; median, 61 mo). One additional patient was alive at 260 months, but the disease status is unknown. The benign clinical course of all cases of JGCT with follow-up, despite often frequent mitotic activity, supports testis sparing surgery when technically feasible.

SMARCA4 (BRG1) loss of expression is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas.

Ovarian small cell carcinoma of the hypercalcemic type (SCCOHT)/ovarian rhabdoid tumor is a rare and highly malignant tumor that typically occurs in young women. Up until now the diagnosis has been made on the basis of morphology without any specific immunohistochemical (IHC) markers. However, several authors have shown recently that SCCOHTs are characterized by inactivation of the SMARCA4 gene (encoding the BRG1 protein) resulting in a loss of BRG1 protein expression in IHC. We evaluated BRG1 and INI1 expression in 12 SCCOHTs and in a series of 122 tumors that could mimic SCCOHT morphologically: 9 juvenile granulosa cell tumors, 47 adult granulosa cell tumors, 33 high-grade ovarian serous carcinomas, 9 desmoplastic round cell tumors, 13 Ewing sarcomas (5 from the pelvis and 8 from soft tissues), 1 round cell sarcoma associated with CIC-DUX4 translocation from soft tissue (thigh), 1 case of high-grade endometrial stromal sarcoma of the ovary, and 9 melanomas. Forty-four adult granulosa cell tumors were interpretable by IHC. All 12 SCCOHTs were devoid of BRG1 expression and expressed INI1. All other interpretable 119 tumors showed BRG1 nuclear positivity, with variable staining proportions, ranging from 10% to 100% of positive cells (mean: 77%, median: 80%), variable intensities (weak: 5%, moderate: 37%, strong: 58%), and distributions: diffuse in 82 cases (70%) and heterogenous in 36 cases (30%). BRG1 positivity was heterogenous in desmoplastic round cell tumors and adult granulosa cell tumors. Overall, BRG1 is a useful diagnostic marker in SCCOHT, showing the absence of expression in SCCOHT. Nevertheless, the possible heterogeneity and the variable intensity of this staining warrant caution in the interpretation of BRG1 staining in biopsy specimens.

Intermediate filamentous proteins in adult granulosa cell tumors. An immunohistochemical study of 25 cases.

Adult granulosa cell tumors (AGCTs) are classified as sex cord-stromal tumors of the ovary. However, they may be confused with other primary ovarian neoplasms. Intermediate filaments, specifically vimentin and cytokeratins, have been identified in AGCTs by immunohistochemistry performed on frozen and formalin-fixed, paraffin-embedded tissue and two-dimensional electrophoresis. Recently, however, immunohistochemical demonstration of cytokeratin has been used as supporting evidence of epithelial rather than sex cord-stromal differentiation in ovarian neoplasia. To investigate further intermediate filamentous proteins in AGCTs, 25 such tumors were studied by immunohistochemistry in formalin-fixed, paraffin-embedded sections. Cytoplasmic staining was observed, frequently in a distinct punctate, paranuclear pattern, in 14 of 25, 14 of 25, and seven of 17 tumors using monoclonal antibodies AE1/AE3, CAM 5.2, and 35BH11, respectively, which share the ability to detect low molecular weight cytokeratins. Staining for cytokeratin was not seen in any of the 17 tumors studied using the antibody 34BE12. Twenty-three of 25 tumors showed strong positivity for vimentin, characteristically seen as globoid paranuclear staining. Nine of 25 tumors contained desmin, which was restricted to the intermixed spindle cell, cortical type stromal component of the tumors. These patterns of immunoreactivity for intermediate filaments, particularly cytokeratins, are different than in common epithelial tumors of the ovary and may be useful in the differential diagnosis of ovarian neoplasia. Moreover, the immunohistochemical detection of cytokeratins should not be used as a criterion for excluding AGCT from the differential diagnosis of an ovarian neoplasm.

The inhibins and ovarian cancer.

Interest in inhibin as a marker of ovarian malignancy was stimulated by the description of elevated immunoreactive inhibin levels in the sera of patients with granulosa cell tumours. Several groups have confirmed the value of serum inhibin in the diagnosis and follow-up of patients with this uncommon malignancy. Immunoreactive inhibin levels are also frequently elevated in patients with mucinous cystadenocarcinoma and less frequently in other forms of ovarian tumour. Assay of sera using the specific dimeric inhibin assays has shown that ovarian tumours are able to secrete dimeric inhibin particularly inhibin B. The less specific alpha-subunit directed assays, however, most frequently show elevated concentrations. Used in combination with CA125 as a dual tumour marker, it appears in principle that inhibin can be a useful diagnostic agent. Immunohistochemistry for the inhibin subunits has been reported with increasing frequency as a helpful method to assess suspected ovarian stromal cell tumours. Its diagnostic accuracy for other types of ovarian adenocarcinoma appears less reliable. Expression of the inhibin subunit mRNAs has been demonstrated in a variety of ovarian malignancies. The observation that inhibin levels are elevated in ovarian cancer has stimulated studies of their relevance to the molecular pathogenesis of these malignancies. Findings to date have been largely negative with no evidence for activating mutations of the FSH receptor or of the post-receptor signalling pathway proteins.

Immunohistochemical staining of ovarian granulosa cell tumors with monoclonal antibody against inhibin.

Inhibin is a peptide hormone produced by ovarian granulosa cells and by granulosa cell tumors. Serum inhibin measurements have been used as a biochemical marker of the presence or progression of ovarian granulosa cell tumors and their metastases. In the current study, an antibody against the alpha-subunit of human inhibin was used to stain 16 cases of ovarian adult granulosa cell tumors, 15 cases of other ovarian sex cord-stromal tumors, and 51 cases of a range of ovarian and extraovarian neoplasms, many of which may mimic granulosa cell tumor. There was diffuse strong cytoplasmic staining of all cases of adult granulosa cell tumor. Diffuse positive staining also was observed in all Leydig cell tumors, and there was focal staining in a proportion of fibrothecomas. There was focal weak staining of one case of ovarian clear cell carcinoma but no staining of other ovarian and extraovarian neoplasms. Immunohistochemical staining with antibodies against inhibin is of value in the diagnosis of granulosa cell tumor and in the distinction of this neoplasm from others that may mimic it. The antibody also may be useful for the confirmation of late metastasis of granulosa cell tumor, especially when the previous history is not known.

Granulosa cell tumor of the adult testis: a clinicopathologic study of seven cases and a review of the literature.

We report a study of seven men, aged 16 to 76 years (average age, 47.4 years) with granulosa cell tumor (GCT) of the testis. Three patients presented with testicular enlargement of several years' duration and a fourth presented with a testicular enlargement of unknown duration. The tumors in three patients were detected during routine physical examination. None of the patients had endocrine-related symptoms. All tumors were well circumscribed and showed the solid, cystic, microfollicular, gyriform, insular, and trabecular patterns typical of GCT of the ovary. Call-Exner bodies were present in three tumors and two tumors had a focal spindle-cell component. In one case the surrounding testicular parenchyma showed Leydig's cell hyperplasia and a Sertoli cell nodule. The tumor cells revealed strong immunoreactivity for vimentin but showed no expression for keratin or epithelial membrane antigen. One patient developed liver and retroperitoneal lymph node metastases 121 months after initial diagnosis and died 13 months later. Another patient initially presented with retroperitoneal lymph node metastasis and developed metastasis to the inguinal lymph nodes 12 months later. Three patients are alive at 1, 4, and 37 months with no evidence of disease. Another patient died of an unrelated condition. Follow-up information was not available for the seventh patient. Twelve cases of GCT of the adult testis have been reported in the literature, with metastases occurring in two: one of these two patients had a tumor for 8 years and died of disease 5 months after diagnosis with multiple metastases and the other had metastasis at the time of diagnosis, but was free of disease for 14 years. Our findings and a review of the literature indicate that GCT of the adult testis is a rare and slow-growing neoplasm with the potential to form distant metastases. Because recurrence or distant metastasis may occur late in the clinical course, long-term follow-up of these patients is recommended.