Updated February 8, 2018
This group of tumours is derived from the dividing cell population that would normally give rise to cells surrounding the oocytes. They comprise 1.2% of all malignant ovarian neoplasms. They tend to produce sex steroid hormones and cause symptoms of hormonal excess. Initial diagnosis is often at an early stage (around 60% confined to ovary initially). Please see below under “Pathologic classifications” for details.
- A somatic mutation in FOXL2 is found in 97% of granulosa cell tumours and can aid in diagnosis2. FOXL2 encodes a transcription factor that is expressed as a nuclear protein and is critically important in the development of granulosa cells. It may also be found in 21% of thecomas and 10% of juvenile type GCTs. In morphologically ambiguous cases, we recommend an immunopanel of inhibin A, calretinin and FOXL2, plus mutational analysis for FOXL2 (402C-G), to confirm granulosa cell tumour of adult type.
- Mutations in DICER1 are associated with Sertoli-Leydig cell tumours and other non-epithelial ovarian cancers3. DICER1 is an endoribonuclease in the RNase III family that is essential for processing microRNAs. Germline DICER1 mutations are associated with other clinical conditions including pleuropulmonary blastoma, lung cysts, cystic nephroma, thyroid nodular hyperplasia and differentiated carcinomas, and cervical sarcoma botryoides.
In view of the rarity and expectation of cure all patients with germ cell tumours should be referred to BC Cancer for assessment, and presentation at tumour board rounds is recommended for management considerations. Treatment should be recommended and reviewed by an experienced oncologist at a high-volume centre.
The majority of SCSTs (60–95%) are at stage I at the time of diagnosis. Patients with stage I have an excellent prognosis (long-term disease-free status is ∼90% of the cases). The selection of early stage SCSTs patients for any postoperative treatment is controversial. At present the relative benefit of adjuvant chemotherapy has yet to be demonstrated. Some may suggest adjuvant therapy for stage Ic patients with high mitotic index, in which case platinum-based chemotherapy is the treatment of choice.
Debulking surgery, whenever feasible, remains the most effective treatment for de-novo, metastatic or recurrent granulosa cell tumours. Conservative surgery seems to be the appropriate approach in young patients with SCSTs at stage I disease, and patients should be counselled about issues of fertility preservation. For postmenopausal women and in patients with advanced stage disease or with bilateral ovarian involvement, abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed with careful surgical staging. Lymph node metastasis is relatively rare compared with epithelial ovarian cancer.
Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs (II-IV, and all stages of Sertoli-Leydig cell tumours with poorly differentiated or heterologous elements) or recurrent disease, with an overall response rate of 63–80%, although it may or may not provide a survival advantage when used in an adjuvant setting. The BEP regimen for 3–6 cycles is for the historical standard for patients with recurrent SCSTs. Due to the rare nature of SCSTs, there are no data to guide the optimal care of patients in the post-operative setting. High grade tumours, with heterologous elements, and those with stage II-IV disease have a higher risk of future disease recurrence. The benefits of adjuvant/post-operative chemotherapy for those patients is not proven, but can be considered on an individualized basis. Alternative regimens include carboplatin and paclitaxel (CAT), etoposide plus cisplatin (EP), cyclophosphamide, doxorubicin and cisplatin (CAP); paclitaxel and carboplatin (CP), or other platinum-based combinations. Little evidence exists for the use of hormonal therapy or radiation therapy and these modalities should be restricted to selected cases.
For granulosa cell tumours, the natural history of this disease is often indolent, but is remarkably variable. Prognosis is decidedly worse if residual tumour remains after laparotomy. However, management often remains surgical in nature until further surgery is no longer possible or the patient is not eligible. There are no data supporting the use of adjuvant therapy and there are few agents with any demonstrable activity in this disease type. Limited data have demonstrated that for patients with recurrent disease aromatase inhibitors and VEGF-inhibitors may have some activity and could be considered as options for systemic therapy in recurrent, unresectable disease4,5,6. Standard platinum-based cytotoxic chemotherapy is minimally effective.
The indolent nature of SCSTs with a tendency to late recurrence (median time to relapse is ∼4–6 years), requires long-term surveillance. Several reports describe relapses occurring >20 years (up to 37 years) after diagnosis. Common sites of recurrence are the upper abdomen (55–70%) and the pelvis (30–45%). According to the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines, the following is thought reasonable:
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Year 1-2 | History and physical exam, tumour markers every 3 months
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Year 3-5 | History and physical exam, tumour markers every 6 months |
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Years 5+ | History and physical exam, tumour markers every 6 months
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Note: Follow-up recommendations are not evidence based, but are empirically derived. Clinical review should consist of general exam, pelvic exam and pelvic-rectal exam as well as tumour markers. Pelvic ultrasound should be performed every 6 months in those patients who underwent fertility sparing surgery, whereas CT scan of the chest, abdomen and pelvic is usually performed yearly as clinically indicated, although none of the guidelines recommend routine use of imaging due to insufficient evidence.
This group of tumours is derived from primordial germ cells of ovary, and may be benign or malignant. They comprise 20-25% of ovarian neoplasms, but account for only 5% of all malignant ovarian neoplasms. They arise in young women between 10 and 30 years of age and represent 70% of ovarian neoplasms in this age group.
Germ cell tumours of the ovary are relatively rare but are highly curable. Treatment should be undertaken with oversight from an expert oncologist. Preoperative assessment is as for epithelial ovarian cancer. Pre-operative tumour markers (beta-HCG, LDH, AFP) are extremely important and must be obtained. Please see below under “Pathologic classifications” for details.
In view of the rarity and expectation of cure all patients with germ cell tumours should be referred to BC Cancer for assessment, and presentation at tumour board rounds is recommended for management considerations. Treatment should be recommended and reviewed by an experienced oncologist at a high-volume centre.
Surgery
Unilateral salpingo-oophorectomy with preservation of the contralateral ovary and the uterus is now considered adequate surgical treatment for patients with GCTs, even in cases of advanced disease, because of the sensitivity of the tumour to chemotherapy, and no systematic ovarian biopsy need be performed where the contralateral ovary is macroscopically normal. As this tumour has a propensity to spread via the lymphatic route careful assessment of the pelvic and para-aortic nodes should be carried out. Since the individual gynecologist may see only one or two patients with this tumour in their practice career, telephone consultation with the BC Cancer Gyne Oncology Group should be used liberally. As a general rule, in the young patient the initial surgery for germ cell malignancy should be conservative. TAH/BSO should not be used as primary management of this disease.
Adjuvant therapy
The majority of GCTs (60–70%) are diagnosed at an early stage. Modified risk stratification similar to that used for testicular germ cell tumours can be used to prognosticate and guide therapy (Table 1).
Table 1: Modified International Germ Cell Cancer Collaborative Group (IGCCCG) Risk Model, adapted from Meisel et al7
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Good |
Intermediate |
Poor |
Dysgerminoma
| No metastases other than lung, lymph nodes, or peritoneum
| Metastases beyond lung, lymph nodes, and peritoneum
| n/a
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All other histologies
| No metastases other than lung, lymph nodes, or peritoneum AND - -AFP <1,000 ng/L
- -HCG <5,000 mIU/mL
- -LDH <1.5×ULN
| No metastases other than lung, lymph nodes, or peritoneum AND ≥1 of the following - -AFP 1,000 – 10,000 ng/mL
- -HCG 5,000 – 50,000 mIU/mL
- -LDH 1.5 – 10×ULN
| Metastases beyond lung, lymph nodes, and peritoneum OR - -AFP >10,000 ng/mL
- -HCG >50,000 mIU/mL
- -LDH >10×ULN
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In general, patients with stage IA grade 1 immature teratoma or stage IA pure dysgerminoma can be treated with surgery followed by surveillance as they are associated with excellent prognosis. All other pathologies and stages should be assessed for adjuvant chemotherapy.
These options require careful review and discussion with an experienced BC Cancer oncologist. Surveillance should only be offered to patients capable of following a rigorous program of clinical, laboratory and imaging studies.
Data show that the most employed combination systemic therapy is bleomycin, etoposide and cisplatin (BEP). Lung toxicities should be carefully assessed and monitored in regards to bleomycin. Delayed presentations of bleomycin pneumonitis are reported therefore physicians should have a low threshold for investigating new pulmonary complaints and initiating appropriate management including referral to a respirologist. Other long-term toxicities including but not limited to ototoxicity, neuropathy, secondary cancer risk, and menopause/infertility should be carefully discussed.
Long term survival rates with surgery followed by adjuvant BEP are 95-100% for early-stage nondysgerminomatous tumours and 75-80% with those with advanced disease at presentation. Results are even more favourable for ovarian dysgerminomas regardless of stage at presentation.
Advanced Disease Therapy
Patients with advanced stage disease dysgerminoma, and patients with immature teratomas, yolk sac tumour, endodermal sinus tumours, embryonal carcinoma and choriocarcinoma of the ovary (non-dysgerminoma), should undergo debulking surgery to remove as much gross tumour as possible followed by chemotherapy, but without major extensive procedures given the high chemosensitivity of these tumours. Bilateral salpingo-oophorectomy and hysterectomy should not be performed as these women are young, cure rates are high and fertility preservation is generally possible.
Platinum-based regimens have been the treatment of choice over the past decade for GCTs, with the BEP regimen becoming the most widely used. The optimal duration of therapy is still unclear, but generally three cycles of BEP are given for completely resected disease and four cycles for patients with macroscopic residual disease. Prognostication similar to that used for male testicular cancer may be appropriate (Table 1), such that 3 cycles of treatment would be used in good-risk disease and 4 cycles in intermediate and poor-risk diseases. Even though dysgerminomas are very sensitive to radiation therapy there is no evidence to support the use of adjuvant radiation therapy for advanced stage GCTs.
Salvage therapy
Patients with failed primary treatment are offered salvage treatment protocols (e.g. TIP, GPT) and in some cases high dose intensity multi drug treatment. Salvage treatment is with curative intent. All cases of chemotherapy refractory disease must be referred to BC Cancer for multidisciplinary review and treatment recommendations as some cases may also require surgery. The prognosis is variable, but cure is possible in up to 1/3 of cases treated with salvage therapy.
Follow-up
Approximately 75% of GCT recurrences occur within the first two years after initial treatment; the most common site is the peritoneal cavity and more rarely the retroperitoneal lymph nodes. According to the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines, the following is thought reasonable:
|
Year 1-2 | History and physical exam, tumour markers every 3 months
|
|
Year 3-5 | History and physical exam yearly
|
Note: Follow-up recommendations are not evidence based, but are empirically derived. Clinical review should consist of general exam, pelvic exam and pelvic-rectal exam as well as tumour markers. Pelvic ultrasound should be performed every 6 months in those patients who underwent fertility sparing surgery, whereas CT scan of the chest, abdomen and pelvic is usually performed yearly as clinically indicated (unless markers were normal prior to treatment, in which case routine imaging can be considered).
The relationship between estrogen and ovarian cancer is obscure. It is known that there are both estrogen and progesterone receptors present in many epithelial ovarian tumours. Unfortunately, the effects of exogenous hormones on these receptors are not well known. There is no evidence that estrogen has either the potential to promote recurrence or to decrease the time to recurrence. It is not necessary to withhold estrogen replacement therapy from any symptomatic woman with ovarian malignancy regardless of risk category.
In absence of a uterus, estrogen alone. With uterus in situ, continuous estrogen plus progesterone.
