Advanced Granulosa Cell Tumor Research Articles

Advanced Granulosa Cell Tumors of the Ovary: A Review with a Focus on Current and Novel Therapeutic Approaches.

Granulosa cell tumor (GCT) is the most common nonepithelial ovarian malignancy. Still, it is considered rare, with a paucity of high-level evidence guiding management, particularly in the metastatic setting. Advancements in molecular pathology allowed the identification of several targetable mutations that play an important role in GCT pathogenesis. Although current management approaches rely on guidelines extrapolated from the more common epithelial subtype, the unique histopathologic and molecular characteristics of GCTs entail a more focused approach. Systemic therapy remains the cornerstone treatment for advanced disease, and although chemotherapy has been the standard for decades, targeted treatments have gained considerable attention lately. Due to the rarity of this disease, validation of new therapies in large trials is the rate-limiting step for developing evidence-based recommendations. This review sheds light on pathogenesis, clinical and molecular characteristics, and prognostic factors, and discusses current treatment options including the role of novel therapies and immune checkpoint inhibitors in advanced GCT.

Histone deacetylase inhibitor, panobinostat, exerts anti-proliferative effect with partial normalization from aberrant epigenetic states on granulosa cell tumor cell lines.

The prognosis of the patients with inoperable or advanced granulosa cell tumors (GCTs) is still poor, and therefore it is important to establish a novel treatment strategy. Here we investigated the in vitro effects of a histone deacetylase inhibitor, panobinostat (PS) on two GCT cell lines (KGN and COV434). GCT cell lines were found to be susceptible to PS treatment and it inhibited cell growth mainly by apoptosis. In cell cycle analysis, PS reduced only the ratio of S phase in GCT cell lines. Combined treatment of PS with a deubiquitinase inhibitor, VLX1570 enhanced the expression of p21, cleaved PARP, cleaved caspase-9, heme oxygenase-1, and the acetylation of histone H4 and α-tubulin, leading to an additive anti-proliferative effect on KGN and COV434. The gene set enrichment analysis revealed that PS treatment suppressed DNA replication- or cell cycle-related gene expression which led to chemotherapeutic cell death and in addition, this treatment induced activation of the gene set of adherens junction towards a normalized direction as well as activation of neuron-related gene sets that might imply unexpected differentiation potential due to epigenetic modification by a HDAC inhibitor in KGN cells. Exposure of KGN and COV434 cells to PS increased the expression of E-cadherin, one of the principal regulators associated with adherens junction in quantitative RT-PCR and immunoblotting analysis. In the present study, we indicate a basis of a novel therapeutic availability of a HDAC inhibitor for the treatment of GCTs and further investigations will be warranted.

Gastric Metastasis of an Ovarian Granulosa Cell Tumor Diagnosed in a Patient with Worsening Reflux

CASE REPORT A 60-year-old woman with a 2-year history of T1a NX M0 ovarian granulosa cell tumor (GCT) status post total abdominal hysterectomy with bilateral salpingo-oophorectomy presented with worsening reflux, abdominal pain, nausea, and loss of appetite. Esophagogastroduodenoscopy showed multiple gastric polyps with white tops and patches of necrotic appearing mucosa (Figure 1). Biopsy of the gastric polyps showed extensive surface ulceration and necrosis with associated atypical epithelioid and spindle cell proliferation (Figure 2). Although the immunohistochemical markers for sex cord-stromal tumors are negative, the histomorphology is similar to the patient's prior ovarian GCT (Figure 3). An extensive immunohistochemical marker panel performed to exclude the other common entities was negative. Thus, this most likely represents a metastasis from the ovarian GCT. Metastatic workup revealed bilateral metastatic pulmonary nodules, enlarged paraesophageal and paraaortic lymph nodes, and a brain metastasis. Patient was a poor surgical candidate and did not tolerate chemotherapy. Repeat imaging showed disease progression; she refused palliative chemoradiation and chose comfort measures.Figure 1.: Esophagogastroduodenoscopy shows multiple gastric polyps with white tops and patches of necrotic appearing mucosa.Figure 2.: Gastric polyp biopsy showing atypical epithelioid and spindle cell population.Figure 3.: Histomorphology of the gastric polyp showing (A) negative calretinin immunostain of prior tumor and (B) immunostain of present tumor.GCT is a rare sex cord-stromal tumor associated with low malignant potential.1 This tumor has a strong tendency for late recurrences, with an incidence of 25-30%, and is associated with a poor prognosis.1 Once the tumor recurs, it is fatal in 80% of cases. Most recurrences occur within 10 years after the initial diagnosis (median 4-5 years).1-4 Prognostic factors that affect the 5-year survival rate include tumor rupture, tumor stage, tumor mitotic rate, and residual disease. Common sites of metastasis are within the pelvis and the lower abdomen, with rare cases in the lung, liver, brain, bone, diaphragm, abdominal wall, and adrenal gland.1-3 Patients should be kept on a long-term follow-up protocol even if the primary tumor is occult.2 Patients with advanced metastatic GCTs are treated with aggressive surgical debulking and postoperative chemotherapy (platinum-based), especially in cases of widespread metastasis.4,5 DISCLOSURES Author contributions: J.S. Klair and K. Soota wrote the manuscript and reviewed the literature. A. Vidholia provided the pathology images and reviewed the literature. C.M. Berkowitz revised the manuscript. JS Klair is the article guarantor.

Gastric Metastasis of an Ovarian Granulosa Cell Tumor Diagnosed in a Patient with Worsening Reflux

CASE REPORT A 60-year-old woman with a 2-year history of T1a NX M0 ovarian granulosa cell tumor (GCT) status post total abdominal hysterectomy with bilateral salpingo-oophorectomy presented with worsening reflux, abdominal pain, nausea, and loss of appetite. Esophagogastroduodenoscopy showed multiple gastric polyps with white tops and patches of necrotic appearing mucosa (Figure 1). Biopsy of the gastric polyps showed extensive surface ulceration and necrosis with associated atypical epithelioid and spindle cell proliferation (Figure 2). Although the immunohistochemical markers for sex cord-stromal tumors are negative, the histomorphology is similar to the patient's prior ovarian GCT (Figure 3). An extensive immunohistochemical marker panel performed to exclude the other common entities was negative. Thus, this most likely represents a metastasis from the ovarian GCT. Metastatic workup revealed bilateral metastatic pulmonary nodules, enlarged paraesophageal and paraaortic lymph nodes, and a brain metastasis. Patient was a poor surgical candidate and did not tolerate chemotherapy. Repeat imaging showed disease progression; she refused palliative chemoradiation and chose comfort measures.Figure 1.: Esophagogastroduodenoscopy shows multiple gastric polyps with white tops and patches of necrotic appearing mucosa.Figure 2.: Gastric polyp biopsy showing atypical epithelioid and spindle cell population.Figure 3.: Histomorphology of the gastric polyp showing (A) negative calretinin immunostain of prior tumor and (B) immunostain of present tumor.GCT is a rare sex cord-stromal tumor associated with low malignant potential.1 This tumor has a strong tendency for late recurrences, with an incidence of 25-30%, and is associated with a poor prognosis.1 Once the tumor recurs, it is fatal in 80% of cases. Most recurrences occur within 10 years after the initial diagnosis (median 4-5 years).1-4 Prognostic factors that affect the 5-year survival rate include tumor rupture, tumor stage, tumor mitotic rate, and residual disease. Common sites of metastasis are within the pelvis and the lower abdomen, with rare cases in the lung, liver, brain, bone, diaphragm, abdominal wall, and adrenal gland.1-3 Patients should be kept on a long-term follow-up protocol even if the primary tumor is occult.2 Patients with advanced metastatic GCTs are treated with aggressive surgical debulking and postoperative chemotherapy (platinum-based), especially in cases of widespread metastasis.4,5 DISCLOSURES Author contributions: J.S. Klair and K. Soota wrote the manuscript and reviewed the literature. A. Vidholia provided the pathology images and reviewed the literature. C.M. Berkowitz revised the manuscript. JS Klair is the article guarantor.

Gastric Metastasis of an Ovarian Granulosa Cell Tumor (GCT) Diagnosed in a Patient Presenting With Worsening Reflux

GCT is a rare sex cord-stromal tumor and constitutes approximately 2-3% of all ovarian malignancies. Adult GCT accounts for 95% of all GCTs. Distant metastases from GCT are rare and to the best of our knowledge this is the first reported case of gastric metastasis from GCT presenting as multiple gastric polyps. 60-year-old female with history of reflux, hypertension, inferior vena cava thrombus on lovenox, granulosa cell tumor diagnosed 2 years ago s/p Total Abdominal Hysterectomy with Bilateral Salpingo-Oophorectomy, omental biopsy showing T1a NX M0 adult granulosa cell tumor presented to GI clinic with worsening reflux symptoms and loss of appetite for 3 weeks. Computed tomography (CT) chest was concerning for esophageal mass. EGD showed multiple gastric polyps, most of them had white colored tops with patches of necrotic appearing mucosa, no esophageal mass (Figure 1). Biopsy of gastric polyps showed ulcer with associated atypical epithelioid and spindle cell proliferation, favor metastasis from known granulosa cell tumor. CT chest, abdomen and pelvis showed bilateral metastatic pulmonary nodules, enlarged paraesophageal and periaortic lymph node. Brain metastasis was noted on MRI. Patient was deemed poor surgical candidate. She was started on systemic chemotherapy. She subsequently presented with worsening nausea, vomiting and abdominal pain. Repeat imaging showed worsening metastases. Radiation oncology was consulted for possible radiation of brain and paraesophageal mass. However patient decided to go forward with hospice. GCT have low malignant potential and late relapse. They are associated with a favorable prognosis, especially when they are detected in the early stages. The recurrence rates ranges between 9 and 35% and is associated with a poor prognosis. Although most recurrences are within 10 years after the initial diagnosis, there are reports of recurrence after 10 years. So, patients should be kept on a long-term follow-up protocol even if the primary tumor is occult. Spread is largely within the pelvis and the lower abdomen. Distant metastases are rare with few reported cases of lung, liver, brain, bone, diaphragm, abdominal wall, adrenal gland and supraclavicular lymph node metastasis from ovarian tumors. Patients with advanced metastatic GCTs, are typically treated with aggressive surgical resection followed by postoperative systemic chemotherapy. Radiation therapy may have some effect in cases with minimal residual disease.Figure: EGD showed multiple gastric polyps with patches of necrotic appearing mucosa.

Open label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: The Greko II study.

5577 Background: Granulosa-cell tumors (GCT) of the ovary are a rare entity characterized by presenting a punctual mutation at the FOXL2 gene 402C→G (C134W). Such mutation leads to a disregulation and overstimulation of the steroidogenic pathway and, ultimately, hormone overproduction. A prior trial by our group (GREKO I trial-GETHI 2011-03; NCT01584297) showed promising activity of ketoconazole, a CYP17 inhibitor used to control steroidogenesis in several conditions. Thus, we aimed to assess the activity of Orteronel (TAK700), a selective inhibitor of 17, 20-lyase, in GCT. Methods: An open-label phase II single arm clinical trial was designed for women with metastatic or locally advanced non-resectable GCT who harbored the somatic mutation FOXL2 402C→G (C134W) and who had not received prior treatment with any CYP17 inhibitor. Treatment consisted on Orteronel 300mg BID, given orally, continuously in a 28-day treatment cycle. The primary objective was clinical benefit rate; secondary objectives were response rate, progression free and overall survival, assessment of the impact of Orteronel in reducing hormonal overproduction and toxicity. Sample size calculation was based on a two stage Simon´s design. A power of 80% was set to differentiate between a 5% and a 25% clinical benefit rate. 20% of losses had been assumed thus 20 patients were scheduled to be enrolled. Results: Since 30/06/2014 to 11/01/2017 10 patients have been included in 9 participating institutions members of Spanish Group for Research in Orphan and Unfrequent Tumors (GETHI). Due to a low recrutiment rate the study was terminated early. Median PFS was 3 months 95%CI (0-12) with 3 patients achieving disease stabilization longer than 12 months. 2 patients remain on treatment after 16 and 14 months. Clinical benefit rate (CR + PR + SD) was 50%, 95%CI (19%-81%). Seven patients have progressed and 2 have died. Only 6 suspected unresected adverse reactions (SUSARs) have been communicated so far (chest pain, fever, febrile neutropenia, eosinophila, neutropenia and anemia). Conclusions: Orteronel achieved a significant clinical benefit in advanced GCT with an favorable toxicity profile. Clinical trial information: NCT02101684.

Advanced Granulosa Cell Tumor and Pregnancy: A Case Report, How to Treat and How to Preserve Fertility?

Granulosa cell tumors of the ovary are rare ovarian malignancy developed on stromal ovarian cells and characterized by estrogen secretion. Histologically, there are divided on two types: adult granulosa tumors, which are more frequent and occurring in perimenopausal and post-menopausal women and juvenile granulosa tumors, which are rarer and occurring in teenager and adolescent girls. The association between GCT and pregnancy is a rare condition with therapeutic challenge consisting on the pregnancy and the fertility outcome in a hand and the oncological results in the other. We present a case report of an adult granulosa cell tumor discovered fortuitously during caesarian section. We report the management of this tumor and the way to preserve the fertility.

Granulosa cell tumor of the ovary: time to launch a new prospective trial

Granulosa cell tumor of the ovary: time to launch a new prospective trial

Proteasome Inhibition by Bortezomib Decreases Proliferation and Increases Apoptosis in Ovarian Granulosa Cell Tumors

Granulosa cell tumors of the ovary represent approximately 5% of malignant ovarian tumors. The molecular pathogenesis of granulosa cell tumors is not known but 2 human granulosa cell tumor-derived cell lines, COV434 and KGN, exhibit constitutive activation of the nuclear factor kappa-B (NFkappaB)-signaling pathway. The proteasomal inhibitor, bortezomib, has a complex mode of action which includes inhibition of NFkappaB signaling. We examined the effect of bortezomib on the COV434 and KGN cells. The COV434 and KGN cells both showed a dose-dependent inhibition of cell proliferation and viability in response to bortezomib together with an increase in apoptosis. This was achieved at concentrations within the range seen for clinically responsive tumors. The NFkappaB constitutive activity was not however decreased. Genes were identified that were regulated in both lines in response to bortezomib. This study suggests that advanced granulosa cell tumors, as represented by the cell lines, may respond to bortezomib either alone or in combination with other agents.

GnRH Agonist Therapy in a Patient with Recurrent Ovarian Granulosa Cell Tumors

A 65-yr-old woman presented 17 yr status post-hysterectomy with bilateral ovarian salpingo-oophorectomy, attributable to ovarian cancer. She was admitted to our hospital, with multiple cystic liver masses and multiple large seeded masses in her abdomen and pelvic cavity. Histological examination of the pelvic masses demonstrated granulosa cell tumors. After two courses of systemic combination chemotherapy, with paclitaxel and carboplatin, the masses in the abdomen and pelvic cavity increased, and debulking surgery also failed because of peritoneal dissemination with severe adhesion. Finally, she underwent palliative radiotherapy for only the pelvic masses obstructing the urinary and GI tracts, and monthly hormonal therapy with a gonadotrophin-releasing hormone agonist; leuprorelin 3.75 mg IM. Subsequently, multiple masses beyond the range of the radiation as well as those within the radiotherapy field partially decreased. This partial response had been maintained for more than 8 months as of the last follow-up visit. Owing to its long and indolent course and the low metabolic rate of the tumors, advanced or recurrent granulosa cell tumor (GCT) requires treatment options beyond chemotherapy, surgery, and radiotherapy. Hormonal agents may provide another treatment option for advanced or recurrent GCT in those who are not candidates for surgery, chemotherapy, or radiotherapy.

Malignant advanced granulosa cell tumor of the adult testis: case report and review of the literature

Testicular granulosa cell tumors (GCTs) are very rare neoplasms. Although adult GCTs are thought to have a relatively indolent course, several reports have demonstrated the malignant potential of these lesions. In case of distant metastases, the overall survival is very short. To date, there is no well-established treatment for these tumors owing to poor results and very rapid progression. A 55-year-old male patient was diagnosed with a testicular GCT with distant lung metastases. He underwent surgical treatment with orchiectomy and adjuvant polychemotherapy (cisplantine, etoposide, and bleomycine) as well as metastasectomy of the right lung. We report the first case of a successfully treated testicular GCT with bipulmonary metastases at initial diagnosis. Thirty-nine months after treatment, the patient is alive with no evidence of disease. We subsequently reviewed all reported cases of an adult GCT in the published literature (25 published cases). This review will summarize all reported cases and discuss treatment options. The current case suggests that a combination of varying treatment modalities could be a promising and reasonable way to manage malignant advanced GCT of the adult testis.

Postoperative chemotherapy in advanced ovarian granulosa cell tumors

The objective of this research is to assess the use of first-line postoperative chemotherapy in patients with advanced ovarian granulosa cell tumor (GCT). A retrospective population-based case series identified 60 women with stage IC or greater ovarian GCT over a 25-year period. Five patients were excluded because of incomplete information. None of the patients had received chemotherapy or radiotherapy prior to the diagnosis of advanced GCT. All patients had, at a minimum, a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology was centrally reviewed and the diagnosis confirmed. Of the 55 eligible patients, the 21 women with stage III and IV disease were the main focus of the study. Clinical outcomes and survival were compared between 13 women who received combination chemotherapy and eight who did not. Univariate analysis was conducted to assess the impact of age at diagnosis, size of residual disease, and adjuvant use of radiation therapy on prognosis. For the 55 patients, median age at diagnosis was 54 years (range 22-79). Median length of follow-up was 4.4 years (range 0.3-23.3). Median time to progression was 2.3 years (range 0.3-5.3). Sixty percent of those with no macroscopic disease after primary surgery recurred within 4.5 years of diagnosis. All patients with gross residual disease (>2 cm) were dead within 4 years of diagnosis. Overall 5 years survival rate was 61.6% (95% CI (49.3-76.9)). Among stage III and IV patients, there were no differences with respect to age at diagnosis and use of radiation therapy between those who did and did not receive chemotherapy. The only statistically significant difference was the presence of macroscopic residual disease (82% vs. 22%). Although there was no statistical significant difference in overall survival, there was a trend toward a poorer outcome in the group that received chemotherapy. Survival of patients with macroscopic residual disease was not influenced by use of chemotherapy (P = 0.976). We conclude that the presence of macroscopic residual disease after primary surgery was the most important prognostic factor. Although these patients were more likely to receive postoperative chemotherapy, there was no evidence to document a beneficial effect of systemic therapy in this group of women.

Postoperative chemotherapy in advanced ovarian granulosa cell tumors

Abstract.Al-Badawi I, Brasher PMA, Ghatage P, Nation JG, Schepansky A, Stuart GCE. Postoperative chemotherapy in advanced ovarian granulosa cell tumors.The objective of this research is to assess the use of first-line postoperative chemotherapy in patients with advanced ovarian granulosa cell tumor (GCT). A retrospective population-based case series identified 60 women with stage IC or greater ovarian GCT over a 25-year period. Five patients were excluded because of incomplete information. None of the patients had received chemotherapy or radiotherapy prior to the diagnosis of advanced GCT. All patients had, at a minimum, a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology was centrally reviewed and the diagnosis confirmed. Of the 55 eligible patients, the 21 women with stage III and IV disease were the main focus of the study. Clinical outcomes and survival were compared between 13 women who received combination chemotherapy and eight who did not. Univariate analysis was conducted to assess the impact of age at diagnosis, size of residual disease, and adjuvant use of radiation therapy on prognosis. For the 55 patients, median age at diagnosis was 54 years (range 22–79). Median length of follow-up was 4.4 years (range 0.3–23.3). Median time to progression was 2.3 years (range 0.3–5.3). Sixty percent of those with no macroscopic disease after primary surgery recurred within 4.5 years of diagnosis. All patients with gross residual disease (>2 cm) were dead within 4 years of diagnosis. Overall 5 years survival rate was 61.6% (95% CI (49.3–76.9)). Among stage III and IV patients, there were no differences with respect to age at diagnosis and use of radiation therapy between those who did and did not receive chemotherapy. The only statistically significant difference was the presence of macroscopic residual disease (82% vs. 22%). Although there was no statistical significant difference in overall survival, there was a trend toward a poorer outcome in the group that received chemotherapy. Survival of patients with macroscopic residual disease was not influenced by use of chemotherapy (P = 0.976). We conclude that the presence of macroscopic residual disease after primary surgery was the most important prognostic factor. Although these patients were more likely to receive postoperative chemotherapy, there was no evidence to document a beneficial effect of systemic therapy in this group of women.

Successful Liver Treatment of a Juvenile Granulosa Cell Tumor in a 4-Year-Old Child by Regional Deep Hyperthermia, Systemic Chemotherapy, and Irradiation

Juvenile granulosa cell tumors (JGCT) of the ovary are rare in children and adolescents. About 90% are diagnosed in early-stage FIGO I with favorable prognosis. More advanced stages (FIGO II-IV) have a poor clinical outcome and chemotherapy alone cannot avoid tumor progression. Regional deep hyperthermia (RHT) induced by microwave technique has been established as an additional modality for treatment of different tumors. However, in cases with liver involvement there are technical problems which have not yet been solved. We report on a 4-year-old child who suffered from diffuse liver metastases 10 months after JGCT of the left ovary. After chemotherapy including ifosfamide, etoposide, and carboplatin in combination with RHT and consolidation radiotherapy, the patient has been in complete remission for 1 year of follow-up. This Case Report indicates the feasibility of combining surgery, chemotherapy, hyperthermia, and radiation therapy (which can also be an effective treatment modality for advanced granulosa cell tumor) for the treatment of liver metastases of JGCT, but does not allow comparisons of these treatments.

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An EORTC Gynecologic Cancer Coop. Group (GCCG) study

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An EORTC Gynecologic Cancer Coop. Group (GCCG) study

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An eortc gynecology cancer cooperative group study

Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa cell tumor of the ovary (GCTO): An eortc gynecology cancer cooperative group study

Cyclophosphamide, adriamycin, and cis-platinum for the treatment of advanced granulosa cell tumor, using serum estradiol as a tumor marker

Two cases of advanced granulosa cell tumor are described, in both of which chemotherapy comprising cyclophosphamide, adriamycin, and cis-platinum resulted in an objective partial response with marked symptomatic improvement. In one case the response continues at 12 months, in the other the response lasted for 5 months. In both cases elevated serum estradiol levels fell during treatment. A literature review reveals two previous cases in which this combination has been reported as being effective in advanced granulosa cell tumor, but this is the first report of the use of serum estradiol as a tumor marker.

Cyclophosphamide, adriamycin, and cis-platinum for the treatment of advanced granulosa cell tumor, using serum estradiol as a tumor marker

Two cases of advanced granulosa cell tumor are described, in both of which chemotherapy comprising cyclophosphamide, adriamycin, and cis-platinum resulted in an objective partial response with marked symptomatic improvement. In one case the response continues at 12 months, in the other the response lasted for 5 months. In both cases elevated serum estradiol levels fell during treatment. A literature review reveals two previous cases in which this combination has been reported as being effective in advanced granulosa cell tumor, but this is the first report of the use of serum estradiol as a tumor marker.