Emerging biomarkers in ovarian granulosa cell tumors.

OBJECTIVE: Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches. METHODS: Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence. RESULTS: 59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation. CONCLUSIONS: Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

Immunohistochemical study of angiogenesis and angiogenic factors in equine granulosa cell tumours.

The first part of our study (Müller et al., 2009) characterized angiogenesis in the equine cycling ovary through histomorphological and immunohistochemical examinations (vascular endothelial growth factors A and B [VEGF A, VEGF B], vascular endothelial growth factor receptors 1 and 2 [VEGF-R1, VEGF-R2], vascular angiopoietins 1 and 2 [Ang1, Ang2], angiopoietin receptor [Tie2], and von Willebrand Factor). Since angiogenesis plays an important role in development and growth of numerous tumours, the second part of our study involved a similar examination of 70 equine granulosa cell tumours (GCTt). The results of the second study were compared with those of the normal equine ovary. Certain similarities in the expression pattern could be detected between normal, cyclical ovaries (Müller et al., 2009) and GCTt. The immunoreactivity of granulosa cells and Leydig-like cells in GCTt resembles granulosa cells and luteinized thecal cells in periovulatory cycling ovaries. The neoplastic cells support circulation, supply and growth of GCTt by contributing to angiogenesis.

Response to antiangiogenesis therapy in a patient with advanced adult-type testicular granulosa cell tumor.

As granulosa cell tumors of the adult type are extremely uncommon testicular neoplasms, relatively few case reports and case series have been published. Treatment for localized, small-volume, or oligometastatic disease is generally surgical resection alone. Visceral or widely metastatic disease is relatively rare, so there is no consensus approach to treatment. We report the case of an advanced granulosa cell tumor of the testis with a confirmed partial response to an angiogenesis inhibitor after initial resistance to cytotoxic chemotherapy.

Anti-angiogenesis therapy with bevacizumab for patients with ovarian granulosa cell tumors.

OBJECTIVE: Ovarian granulosa cell tumors tend to respond poorly to chemotherapy. We examined the clinical efficacy of bevacizumab with or without concurrent chemotherapy and evaluated the angiogenic characteristics of these patients' tumors. METHODS: We conducted a retrospective review of all patients seen at our institution from February 2004 to October 2008 who received bevacizumab for ovarian sex cord-stromal tumors. We performed immunohistochemical staining for vascular endothelial growth factor (VEGF) and CD31 when tissue was available; microvessel density was measured based on CD31 staining. Clinical data were abstracted from a chart review. RESULTS: We identified 8 patients who were treated with bevacizumab; 7 had adult granulosa cell tumors and one had a juvenile granulosa cell tumor. All patients had recurrent disease and had been previously treated with cytotoxic chemotherapy (median 3.5 regimens; range, 1-6). One patient had a complete clinical response to bevacizumab therapy, 2 patients had a partial response, 2 patients had stable disease, and 3 patients' disease progressed, yielding a response rate of 38% and a clinical benefit rate of 63%. The median progression-free survival was 7.2 months and overall survival was not reached at a median follow-up of 23.6 months after initiating bevacizumab. VEGF overexpression and microvessel density were associated with poor outcome but sample size was too small to calculate statistical significance. CONCLUSIONS: Anti-VEGF therapy is highly effective in patients with granulosa cell tumors. Based on our observations, a prospective trial has been initiated using single-agent bevacizumab in patients with recurrent ovarian sex cord-stromal tumors.

The value of cell proliferation and angiogenesis in the prognostic assessment of ovarian granulosa cell tumors.

OBJECTIVES: Most cases of granulosa cell tumors (GCT) of the ovary are characterized by a relatively good outcome. However, some tumors behave aggressively and some tend to recur many years after the initial diagnosis. Tumor growth depends on cell proliferation and angiogenesis. Thus, proliferative indices and microvessel density were studied to determine possible valuable methods to assess the GCT patient's outcome. METHODS AND STUDY DESIGN: Paraffin-embedded tissue blocks were available for 60 patients with primary GCT and were investigated by immunostaining with monoclonal antibodies against PCNA, Ki-67 and factor VIII-related antigen. The follow-up was available for 51 patients and ranged from 25 to 206 months. A clinical follow-up distribution of patients was made: 8 patients with recurrence (group I); 6 patients who lived with no evidence of recurrence for 100 months or more (group II), and 37 patients alive with no evidence of recurrence in the follow-up period of less than 100 months (group III). RESULTS: There was a statistical correlation between PCNA and Ki-67 proliferative indices. A significant increase (P <0.05) of mean PCNA and Ki-67 proliferative indices and mean tumor size was seen in patients of Group I compared to those of Group II. The mean PCNA proliferative index positively correlated with the mean Ki-67 proliferative index for Groups I and II. Mean microvessel density showed a positive correlation with mean PCNA and Ki-67 proliferative indices and with mean tumor size for Group I, whereas it was negatively correlated with PCNA proliferative index and tumor size for Group II. A positive correlation was found between mean mitotic count and both proliferative indices only for Group II. The following features were indicative of a relatively poor prognosis: GCT measuring >9 cm in diameter, PCNA >4.0%, Ki-67 >1.2%, and diffuse, insular and sarcomatoid histologic patterns. CONCLUSIONS: The findings support the importance of proliferative factors, tumor size and histologic patterns as possible prognostic indicators for estimating the biologic behavior of patients with GCT. Unfortunately, angiogenesis did not seem to be a useful determinant parameter of a possible aggressive behavior. However, a longer follow-up period with larger series may be required to assess the value of the parameters in prediction of patient survival.