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Ovary – Non-Epithelial Carcinoma

1. Diagnosis & Staging

Updated February 8, 2018

In a younger women <40 years of age with an ovarian/pelvic mass, non-epithelial ovarian neoplasm should be suspected, and appropriate tumour markers should be obtained (see below). All cases of suspected or confirmed non-epithelial ovarian cancer should be referred to BC Cancer for surgical and medical evaluation.

The staging system for non-epithelial ovarian cancers is generally the same as that used for epithelial ovarian cancer as defined by the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO). Stage is the most important prognostic factor established to date for SCSTs; in fact several articles have reported that patients with advanced disease have a significantly poorer survival rate. For GCTs stage is an important prognostic factor as well, though given their sensitivity to chemotherapy treatment even advanced stage disease can have a good prognosis.

Surgery for a careful examination of the abdominal cavity is mandatory1. The staging procedure typically includes infracolic omentectomy, biopsy of the diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum and peritoneal washings. There is no consensus on systemic lymphadenectomy. In general, it is accepted that only in cases with evidence of nodal abnormality is node dissection required. Endometrial curettage is recommended to rule out concomitant uterine cancers in patient with granulosa cell tumor. 

Other tumour staging includes CT chest/abdomen/pelvis, basic bloodwork and tumour markers. For SCSTs, examples of tumour markers that may be elevated include inhibin, anti-Mullerian hormones, estradiol, androgens and Mullerian inhibiting substance or MIS in granulosa cell tumour; androgens and alpha-fetoprotein in Sertoli-Leydig tumours; alpha-fetoprotein, HCG and LDH in GCTs. In patients with symptoms of hormonal access, appropriate hormonal testing should be performed.

2. Management & Follow-up

Updated February 8, 2018

2.1 Sex cord stromal tumour (SCST)

Epidemiology

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.

Genetic markers

  • 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 a-inhibin, calretinin and FOXL2, plus mutational analysis for FOXL2 (402C-G), to confirm granulosa cell tumor 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.

Management

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 tumors. 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), cyclophosphamde, 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.

Follow-up

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:

Year 1-2History and physical exam, tumour markers every 3 months
Year 3-5History and physical exam, tumour markers every 6 months
Years 5+History and physical exam, tumour markers every 6 months

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.

2.2 Germ cell tumour (GCT)

Epidemiology

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.

Management

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 tumor 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


GoodIntermediatePoor
Dysgerminoma
No metastases other than lung, lymph nodes, or peritoneum
Metastases beyond lung, lymph nodes, and peritoneum
n/a
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

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 tumor as possible followed by chemotherapy, but without major extensive procedures given the high chemosensitivity of these tumors. 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 1-2History and physical exam, tumour markers every 3 months
Year 3-5History 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). 

Estrogen Replacement Therapy

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.

Recommendation

In absence of a uterus, estrogen alone. With uterus in situ, continuous estrogen plus progesterone.

3. Pathologic Classification

Updated February 8, 2018

3. Pathologic classifications

Sex Cord Stromal Tumours (SCST)

Granulosa-Stromal Cell Tumours

  1. Granulosa cell tumour
    1. juvenile
    2. adult
  2. Tumours in the thecoma-fibroma group
    1. thecoma
      1. typical
      2. luteinized (a rare tumour has the features of luteinized thecoma and additionally, crystals of Reinke in the steroid cell component. This tumour has been called "stromal Leydig cell tumour".)
    2. fibroma
    3. cellular fibroma
    4. fibrosarcoma
    5. stromal tumour with minor sex cord elements
    6. sclerosing stromal tumour
    7. (stromal luteoma) see Steroid (Lipid) Cell Tumours, stromal luteoma
    8. unclassified (fibrothecoma)
    9. others (This category includes the rare signet ring cell stromal tumour and the myxoma).

Sertoli-Leydig Cell Tumours; Androblastomas

  1. Well differentiated
    1. Sertoli cell tumour (tubular androblastoma)
    2. Sertoli-Leydig cell tumour
    3. (Leydig cell tumour) - see Steroid (Lipid) Cell Tumours, Leydig cell tumour
  2. Of intermediate differentiation
    1. variant - with heterologous elements (specify type)
  3. Poorly differentiated (sarcomatoid)
    1. variant - with heterologous elements (specify type)
  4. Retiform
    1. variant - with heterologous elements (specify type)

Sex Cord Tumour with Annular Tubules

Gynandroblastoma

Unclassified

Steroid (Lipid Cell Tumours)

  1. Stromal luteoma
    1. Leydig cell tumour (hilus cell tumour). Some Leydig cell tumours do not arise from hilus cells but within the ovarian stroma. These tumours have been called "Leydig cell tumours, non-hilar type".

Germ Cell Tumours (GCT)

  1. Dysgerminoma
    1. Variant - with syncytiotrophoblast cells
  2. Yolk Sac Tumour (Endodermal Sinus Tumour)
    1. Variants
      1. Polyvesicular vitelline tumour
      2. Hepatoid
      3. Glandular (some glandular yolk sac tumours resemble endometrioid adenocarcinoma and have been called "endometrioid-like".
  3. Embryonal Carcinoma
  4. Polyembryoma
  5. Choriocarcinoma
  6. Teratomas
    1. Immature
    2. Mature
      1. solid
      2. cystic (dermoid cyst)
      3. with secondary tumour (e.g. to squamous cell carcinoma)
      4. retiform (homunculus)
    3. Monodermal and highly specialized
      1. struma ovarii – need to check thyroid function
        • variant - with secondary tumour (specify type)
      2. carcinoid
        • insular
        • trabecular
      3. struma carcinoid
      4. mucinous carcinoid
      5. neuroectodermal tumours (specify type)
      6. sebaceous tumours
      7. others
  7. Mixed (specify types)

Gonadoblastoma

  1. Variant - with dysgerminoma or other term cell tumour

Germ Cell - Sex Cord-Stromal Tumour

  1. Variant - with dysgerminoma or other term cell tumour

Tumours of Rete Ovarii

  1. Adenomatoid tumour
  2. Mesothelioma

Mesothelial Tumours

  1. Adenomatoid tumour
  2. Mesothelioma

Tumours of Uncertain Origin

  1. Small cell carcinoma (This tumour is of two types - one that is usually associated with paraendocrine hypercalcemia and has been called "small cell carcinoma, hypercalcemic type", and the other that has neuroendocrine features and has been designated "small cell carcinoma, pulmonary type". Probably most of the latter type belong in the surface epithelial-stromal category.)
  2. Tumour of probable Wolffian origin
  3. Hepatoid carcinoma
  4. Oncocytoma

Soft Tissue Tumours not Specific to Ovary

Malignant Lymphomas and Leukemias

Unclassified Tumours

Secondary (Metastatic) Tumours


References

  1. Colombo N, Peiretti M, Castiglione M, Group EGW. Non-epithelial ovarian cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 Suppl 4: 24-26.
  2. Shah SP, Kobel M, Senz J et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009; 360: 2719-2729.
  3. Heravi-Moussavi A, Anglesio MS, Cheng SW et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med 2012; 366: 234-242.
  4. Korach J, Perri T, Beiner M et al. Promising effect of aromatase inhibitors on recurrent granulosa cell tumors. Int J Gynecol Cancer 2009; 19: 830-833.
  5. Schwartz M, Huang GS. Retreatment with aromatase inhibitor therapy in the management of granulosa cell tumor. Gynecol Oncol Rep 2016; 15: 20-21.
  6. Tao X, Sood AK, Deavers MT et al. Anti-angiogenesis therapy with bevacizumab for patients with ovarian granulosa cell tumors. Gynecol Oncol 2009; 114: 431-436.
  7. Meisel JL, Woo KM, Sudarsan N et al. Development of a risk stratification system to guide treatment for female germ cell tumors. Gynecol Oncol 2015; 138: 566-572.

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