Peritoneal Carcinomatosis of Rare Ovarian Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-Institutional Cohort from PSOGI and BIG-RENAPE.

PURPOSE: Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy. METHODS: A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (p = 0.383), whereas differences in DFS were (p < 0.001). CONCLUSIONS: CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.

[Metastatic Ovarian Granulosa Cell Tumor of the Diaphragm Resected by Video-assisted Thoracoscopic Surgery;Report of a Case].

A 75-years-old woman, who had undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for ovarian granulosa cell tumor( OGCT) 6 years ago, was admitted to our hospital to treat a mass on the right diaphragm detected by computed tomography. The mass was resected successfully by video-assisted thoracoscopic surgery and pathological diagnosis of the tumor was a metastatic OGCT of the diaphragm. To our knowledge, this is the 3rd case report of metastatic OGCT of the diaphragm.

Pseudopapillary Granulosa Cell Tumor: A Case of This Rare Subtype.

Background The pseudopapillary pattern of granulosa cell tumor is rare. Case We describe the case of a 35-year-old woman who presented with an initial diagnosis of papillary serous cystadenocarcinoma. Results Evaluation, including immunohistochemistry, led to the diagnosis of pseudopapillary granulosa cell tumor. Conclusion The pseudopapillary pattern of granulosa cell tumor is rare and must be suspected in order to utilize appropriate immunohistochemistry and reach the correct diagnosis. Inhibin positivity is particularly helpful.

Metástasis pulmonar de tumor de células de la granulosa como recurrencia del tumor primario después de diez años del tratamiento quirúrgico / Pulmonary metastasis of granulosa cell tumor as recurrence of primary tumor after 10 years of surgical treatment

Los tumores de células de la granulosa son neoplasias de bajo grado, que corresponden al 2-5% de los tumores malignos del ovario y presentan una baja incidencia. Las manifestaciones clínicas dependerán del tamaño tumoral y de la exposición prolongada a estrógenos producidos por las células neoplásicas. Habitualmente, son tumores unilaterales, sólido-quísticos con focos de hemorragia, constituidos por células pálidas con su característico pliegue nuclear, en un trasfondo fibrotecomatoso, con cuerpos de Call Exner sólo en el 30-60% de los casos. El diagnóstico se realiza con los niveles séricos de estradiol y con exámenes imagenológicos como ecotomografía ginecológica, tomografía axial computarizada o resonancia nuclear magnética. El tratamiento quirúrgico es la elección. Las recurrencias pueden ocurrir años posteriores al diagnóstico inicial y en general son pélvicas. El factor pronóstico más determinante en la evolución de la enfermedad es el estadio clínico al momento del diagnóstico. Se presenta el caso clínico de una paciente postmenopáusica con metástasis pulmonar de tumor de células de la granulosa después de diez años del tratamiento quirúrgico.

The granulosa cell tumors are low grade neoplasias that correspond to 2-5% of all malignant tumors of the ovary with a low incidence in the population. The clinical presentation depends on the tumor size and the long term exposition to estrogens produced by neoplastic cells. They are usually unilateral tumors exhibiting a mixture of cystic and solid areas with bleeding, constituted by pale cells with their characteristic nuclear groove in a fibrotecomatous background, with Call Exner bodies only in 30-60% of cases. The diagnosis is done with serum levels of estradiol and gynecological imaging analysis such as echotomography, Computerized axial tomography and magnetic nuclear resonance. The surgical treatment is the choice. The recurrences could happen years after the first diagnosis and usually are in pelvic area. The most important prognostic factor in the disease progression is the clinical stage at diagnosis. It is presented a case report of a postmenopausal patient with lung metastasis of granulosa cell tumor after ten years of surgical treatment.

Outcome of patients with recurrent adult-type granulosa cell tumors--a Taiwanese Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study is to evaluate the long-term outcome of ovarian recurrent granulosa cell tumors (GCTs) in a large series of patients treated in Taiwanese Gynecologic Oncology Group (TGOG) centers and to define the prognostic parameters for survival. MATERIALS AND METHODS: A retrospective multi-institutional review of patients with recurrent ovarian GCTs treated in TGOG centers was conducted. The clinical and pathological characteristics, treatment, and outcomes of patients with ovarian recurrent GCTs were analyzed using Kaplan-Meier and Cox proportional hazards analyses to determine the predictors for survival. RESULTS: A total of 44 patients from 16 medical centers were identified between January 1994 and December 2010. The median disease-free survival (DFS), postrecurrence survival, and overall survival (OS) were 61.5 months (range, 3.7-219.3 months), 55.8 months (range, 4.6-193.7 months), and 115.3 months (range, 17.2-390.6 months), respectively. In multivariate analysis, DFS (> 61.5 months versus ≤ 61.5 months, hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.03-0.78, p = 0.024) at the initial operation after diagnosis of relapse was the only predictor that correlated with OS. CONCLUSION: DFS after the initial operation was the only important predictor for overall survival in patients with recurrent GCTs, regardless of treatment, suggesting that the natural behavior of the tumor is a critical factor for patients with recurrent GCTs.

Long-term Remission in a Female With Multiple Relapsed Juvenile Granulosa Cell Tumor.

A 4 ½-year-old female was diagnosed with ovarian juvenile granulosa cell tumor stage IA. After complete tumor resection she received 4 courses of chemotherapy due to unfavorable histopathologic features (high mitotic index, high microvessel density, blood vessel invasion). One year after diagnosis, she experienced paraaortic lymph node relapse treated with surgery, local radiotherapy, and conventional and high-dose chemotherapy. A second, paratracheal lymph node relapse 7 months later necessitated surgical removal and radiotherapy. Subsequently an adjuvant antiangiogenesis-based treatment including paclitaxel, bevacizumab, thalidomide, and pegylated interferon was initiated and continued for 2 years. The female is now in third complete remission 6 years after second relapse.

[Haemoabdomen and haemothorax in a cow with metastatic granulosa cell tumor]. / Hämoabdomen und Hämothorax bei einem Rind mit metastasierendem Granulosazelltumor.

This case report describes the clinical, ultrasonographic, pathological and histological findings in a two-year-old Swiss Braunvieh cow with granulosa cell tumor and metastases in the abdomen and thorax. The cow was ill and had tachycardia, coughing, increased breath sounds, positive reticular foreign body tests and a tense abdominal wall. Ultrasonography revealed a massive accumulation of hypoechoic fluid in the thorax and abdomen, and abdomino- and thoracocentesis yielded red fluid indicative of abdominal and thoracic haemorrhage. Because of a poor prognosis, the cow was euthanized and examined postmortem. Multiple nodular lesions were seen in the omentum, liver, spleen and lungs. The left ovary was grossly enlarged and nodular in appearance. Histological examination of the lesions revealed granulosa cell tumour of the left ovary and metastases in the omentum, liver, spleen and lungs.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: a single-center experience.

AIM: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). MATERIAL AND METHODS: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0-42.2°C. RESULTS: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien-Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) - both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemo-exposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16-40 months). CONCLUSION: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed.

Adult granulosa cell tumors of the testis: a report of 32 cases.

The clinicopathologic features of 32 adult granulosa cell tumors (AGCT) of the testis are presented. The patients were from 14 to 87 years of age (mean 40.0 y) and underwent orchiectomy (n=30) or wedge excision (n=2). None had endocrine-related symptoms. The tumors measured 0.5 to 6.0 cm (mean 2.8 cm) and were predominantly well circumscribed and yellow-tan, except for 1, which had infiltrative borders. The predominant pattern was diffuse, but insular, spindled, microfollicular (Call-Exner bodies), trabecular, corded, watered-silk, palisading, and pseudopapillary patterns were also present. The cells contained round to ovoid nuclei with frequent longitudinal nuclear grooves, indistinct cell borders, and varying amounts of eosinophilic cytoplasm. Most tumors contained limited amounts of fibrocollagenous stroma. The mitotic count ranged from 0 to 18/10 high-power fields (HPF) (mean 4.9/10 HPF, ×400). Two tumors had prominent necrosis, and 1 had vessel invasion. Follow-up information was available for 19 patients, with a mean of 51.0 months (range, 1 to 169 mo). All were without evidence of disease except 1 who had lung metastasis at 24 months. Our findings indicate that the morphologic spectrum of testicular AGCT is similar to that of ovarian AGCT. The majority of testicular examples have a good prognosis (compared with a malignant behavior in 2 of 7 cases in 1 prior series). Lymphovascular invasion, infiltrative borders, and size >4 cm may help in identifying cases with aggressive behavior, as these features were present in the one case with metastasis in our series. Mitotic counts varied and do not appear to be of prognostic significance on the basis of our experience.

Renal metastasis of an ovarian granulosa cell tumour inducing growth of a cystic nephroma.

A 44-year-old woman presented with a large pelvic mass. Pathology revealed a granulosa cell tumour of the left ovary. The patient was followed after surgery with inhibin B levels and interval imaging. Six years later, she began to experience severe back pain. A vertebral biopsy was positive for metastatic granulosa cell tumour. She underwent radiation to the spine. Inhibin B levels began to rise and, several months later, a CT scan showed a large heterogeneous mass essentially replacing the left kidney. She underwent an open left radical nephrectomy. Pathology revealed a 12 cm cystic nephroma with a 5 cm nodule of metastatic granulosa cell tumour. Immunohistochemistry demonstrated that the mass was inhibin and oestrogen receptor positive. This is a novel presentation of these coexisting pathologies. This unique case sheds light on the possibility of induction of cystic nephroma by the altered hormonal environment created by a granulosa cell tumour metastasis.

Lung metastasis from an ovarian granulosa cell tumor 36 years after the initial diagnosis: report of a case.

This report presents the case of a late relapse of an ovarian granulosa cell tumor (GCT) that metastasized to the lung 36 years after the initial diagnosis. A 72-year-old female demonstrated multiple nodules with extrapleural signs on chest computed tomography. Positron emission tomography with (18)F-fluorodeoxyglucose ([(18)F]FDG-PET) showed that the nodules had no FDG avidity. The nodules, which appeared as polypoid lesions of the visceral pleura on thoracoscopy, were resected and diagnosed as pulmonary metastases from the GCT. This case report indicates that thorough thoracoscopic exploration of the pleural cavity is essential when intrathoracic nodules are seen on postoperative imaging examinations in GCT patients, even when the [(18)F]FDG-PET results are negative.

Management of peritoneal dissemination of recurrences granulosa cell tumor of the ovary.

Recurrences of granulosa cell tumor (GCT) of the ovary often occur as disseminated peritoneal metastasis or local mass in the pelvis. Although, various treatment options including surgery with/without systemic chemotherapy and/or radiotherapy have also been reported for treatment of recurrent GCT, there is no standardized management for recurrence of this disease. Here, we report our management strategies for the patients with peritoneal dissemination of GCT. Prior to admission to our unit, four patients were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy with the diagnosis of primary adult type GCT of the ovary. They were not received adjuvant therapy because of the localized disease in the ovary and followed-up by their gynecologists until they referred to us with metastases. The median disease free survival after primary treatment was 4.7 (range, 1-9) years. All patients with peritoneal metastases from recurrent GCT were treated with cytoreductive surgery (CRS) using peritonectomy procedures and intraoperative hyperthermic intraperitoneal chemotherapy(HIPEC) using 100 mg cisplatin for 40 min at 43 °C in our unit. Postoperative complications were graded according to National Cancer Institute's Common Toxicity Criteria. No complication and no in-hospitalization mortality were experienced in all patients. The median length of operation was 3.55 (range, 2.50-5.50) hours. The median length of stay in hospital was 13(range, 12-21) days. After a median follow-up of 4(range, 1-6) years, 1 patient was died and other 3 patients were alive with no disease progression. Our study identified that recurrent adult type of GCT with peritoneal metastases could be managed with definitive CRS and HIPEC. Larger series and long term outcome data of CRS and HIPEC will be mandatory to develop standard management option in these patients.

Primary ovarian teratoma and GCT with intra-abdominal metastasis in a dog.

This report describes the simultaneous occurrence of an ovarian teratoma and a granulosa cell tumor (GCT) with intra-abdominal metastasis in a 1.5 yr old female Doberman pinscher. At surgery, a 20 cm, smooth, intact mass associated with the left ovary and multiple 1-2 cm irregular masses in the broad ligament were found. The masses were surgically removed and submitted for histopathology. A histologic diagnosis of a teratoma and a GCT with broad ligament metastasis was made. Further treatment was elected by the owner and included two cycles of carboplatin therapy. The dog was euthanized 6 wk postoperatively for signs related to metastasis and dyspnea. Teratoma of the ovary, although it contains derivatives of all three embryonic germ cell layers, rarely presents together with either ovarian epithelial or sex cord-stromal tumors. To the authors' knowledge, this is the first reported case of an ovarian teratoma coexisting with a primary GCT with intra-abdominal metastasis in the same ovary in a dog.

A late recurring and easily forgotten tumor: ovarian granulosa cell tumor.

Ovarian granulosa cell tumor (GCT) is a malignant tumor with slow progression. The recurrence of granulosa cell tumor often happens after 5 years, leading to a 'forgotten tumor' by the patient. We present the case of a 64-year-old woman with a presentation of left flank pain. An initial computed tomography scan revealed a single tumor with multiple adjacent organ invasions. Surgical intervention was prescribed and the pathological results revealed a metastatic granulosa cell tumor. We also review the literature for the follow-up and further management of this tumor.

Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5-1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli (APC) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator ß-catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47-year-old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear ß-catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate ß-catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis.

A novel treatment strategy for ovarian cancer based on immunization against zona pellucida protein (ZP) 3.

We tested the principle of treating malignant ovarian tumors by vaccination against their ectopically expressed protein, zona pellucida glycoprotein (ZP) 3, using as the experimental model the granulosa cell tumors that develop in transgenic mice expressing the simian virus 40 T-antigen under the inhibin-α promoter (inhα/Tag). We found high ZP3 expression in granulosa cell tumors of the transgenic mice, in human surface ovarian cancer and granulosa cell lines, and in human granulosa cell tumors and their metastases. Early preventive immunization (between 2 and 5.5 mo of age) of transgenic mice with recombinant human (rh) ZP3 prevented ovarian tumorigenesis, and delayed therapeutic immunization (between 4.5 and 7 mo) reduced weights of existing tumors by 86 and 75%, respectively (P<0.001), compared to vehicle-treated control mice. No objective side effects of the immunizations were observed. Liver metastases were found in nontreated/vehicle-treated controls (n=7/39), but none following active rhZP3 immunizations (n=0/36; P<0.05). Immunization with rhZP3 was highly effective, as demonstrated by the induction of anti-ZP3 antibodies, as well as proliferative responses to the ZP3 antigen. These results signal rhZP3 immunization as a novel strategy to be developed for the immunotherapy of ovarian granulosa cell tumors, as well as for that of other malignancies that may express ZP3.

Pregnancy concomitant with metastatic adult granulosa cell tumor.

INTRODUCTION: Metastatic adult granulosa cell tumor of the ovary is rarely encountered with pregnancy. CASE REPORT AND RESULTS: Primigravida (26 years) presented at 20 weeks of gestation with acute abdomen and clinical evidence of supraclavicular lymphadenopathy and ascites. She was diagnosed of adult granulosa cell tumor (AGCT) of the right ovary following right salpingoophrectomy done 1 month prior to conception. Fine needle aspiration cytology of supraclavicular lymph node, revealed it to be a metastatic AGCT. Chemotherapy was given antepartum and she delivered a healthy preterm baby at 30 weeks. Subsequently, she had optimal debulking surgery following 6 cycles of cisplatin-based chemotherapy. Baby at 10 months of age was with normal milestones. CONCLUSIONS: The case is an unusual presentation of metastatic adult granulosa cell tumor at child bearing age. Although rapidly progressing, successful prolongation of pregnancy till 30 weeks of gestation was possible with the judicious use of chemotherapy. Fetal and maternal outcomes were favorable.

[Clinicopathologic study of juvenile granulosa cell tumor of ovary].

OBJECTIVE: To study the clinicopathologic features, diagnostic criteria and prognostic parameters of juvenile granulosa cell tumor of ovary. METHODS: The clinical and pathologic findings of 7 cases of juvenile granulosa cell tumor were retrospectively reviewed. Immunohistochemical study was carried out in 6 of these cases. The follow-up data were also analyzed. RESULTS: The mean age of the patients was 24 years (range=6 to 53 years). Four patients presented with hormonal disturbance, while 3 patients presented with abdominal pain or swelling. Six patients underwent unilateral salpingo-oophorectomy. Six cases were in stage IA and the remaining case in stage IC. Follow-up information was available in 6 patients and the duration of follow up ranged from 1 to 10 years (mean=4.3 years). Five patients remained healthy, with no evidence of tumor recurrence. One patient died of tumor metastasis one year after the diagnosis. Gross examination showed that the tumor masses ranged from 7 to 20 cm in the greatest dimension (average=13.4 cm). Four of the 7 tumors were mixed solid-cystic in appearance and 2 cases were unilocular cystic in nature. Microscopic examination showed diffuse atypical follicular structures formed by granulosa cells. The granulosa cells contained round hyperchromatic nuclei, without nuclear grooves or Call-Exner body formation (6/7). In one of the cases studied, minor foci resembling adult granulosa cell tumor were also demonstrated. The degree of cellular atypia varied (3 cases with severe atypia, 1 case with moderate atypia and 3 cases with mild atypia). The mitotic count ranged from 1 to more than 5 per 10 high-power fields. Immunohistochemical study showed diffuse positivity for vimentin (6/6). The staining for cytokeratin (AE1/AE3) and calretinin was negative. Four cases expressed CD99 and 1 case was positive for inhibin. CONCLUSIONS: Juvenile granulosa cell tumor is characterized by the presence of diffuse atypical follicular structures formed by small round cells, without nuclear grooves or Call-Exner bodies. Rare cases contain minor foci of adult granulosa cell tumor. They can be unilocular cystic in nature. The degree of nuclear atypia, mitotic activity and size of the tumor vary and do not correlate with the risk of recurrence and aggressive biologic behavior.