Types

• Epithelial ovarian tumours (derived from coelomic epithelium) include mucinous and serous cystadenocarcinoma, endometrioid carcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma and mixed mesodermal tumour.^[1]
  • Accounts for 85-95% of all ovarian cancers.
  • May be classified as serous or mucinous cystadenocarcinoma (most common), endometrioid, undifferentiated, or clear cell.
  • Occurs most commonly in women aged over 50 years.
• Cancer of low malignant potential:^[2]
  • Accounts for 15% of all epithelial ovarian cancers.
  • Are benign to intermediate and occur more frequently in the younger population; the mean age at diagnosis is 40 years.
  • 10-year survival is 95% for stage I lesions, the majority of patients (70-85%) having stage I lesions at diagnosis.
  • Even stage III with lymph node metastases has reasonable survival.
  • Recurrence may occur even 20 years after initial therapy.
• Germ cell tumours include dysgerminomas, endodermal sinus tumours, embryonal carcinoma, polyembryoma, choriocarcinoma, teratoma, gonadoblastoma and mixed forms:^[3]
  • Derived from primitive germ cells of embryonic gonad.
  • Accounts for 20% of all ovarian tumours.
  • Most lesions are found in the second and third decades.
  • Usually presents as a rapidly enlarging abdominal mass, which causes considerable pain.
  • They often rupture or undergo torsion.
  • Dysgerminoma is the most common type and has an excellent prognosis for stage I tumours.
  • Endodermal sinus tumour is the second most common and accounts for 22% of germ cell tumours. It may be associated with raised alpha-fetoprotein (AFP) and has a poor prognosis.
• Sex cord stromal tumours, including granulosa-theca cell tumours, Sertoli-Leydig tumours, gynandroblastoma and lipid cell tumours.
• Neoplasms metastatic to the ovary, including gastrointestinal tract (Krukenberg's tumours), breast, endometrium and lymphoma.
• Immature malignant teratoma:
  • Accounts for less than 1% of ovarian teratomas.
• Embryonal carcinoma:
  • Highly malignant tumour accounting for 4% of malignant ovarian germ cell tumours.
  • Mean age at presentation is 15 years with abdominal or pelvic mass.
  • More than half have hormonal abnormalities such as precocious puberty, irregular uterine bleeding, amenorrhoea, or hirsutism.
  • The tumour produces human chorionic gonadotrophin (hCG).
• Polyembryoma:
  • Highly malignant, non-radiosensitive tumour. Response to chemotherapy is unknown.
• Choriocarcinoma (non-gestational):
  • Occurs in children or young adults and secretes hCG.

Epidemiology

• Prevalence in the UK in 2008 was 16.2 per 100,000 people.^[4] The average lifetime risk for women in developed countries is about 1 in 70.^[5]
• Ovarian cancer accounts for 5% of all cancers among women. It is the fourth most common cause of cancer deaths in the UK, causing more deaths than any other female genital tract cancer. It has a lifetime risk of 2%.^[6]
• Median age at diagnosis is 61 years, peaking at 75-79 years but it can occur at any age. Elderly women are more likely than younger women to be in an advanced stage of disease at initial diagnosis.
• Stromal, germ cell and epithelial carcinomas can occur in postmenopausal women.
• Oral contraceptives appear to reduce the risk of ovarian cancer for up to 10 years following cessation of use. This protective effect appears to apply to patients with BRCA mutations as well.

Risk factors

• Hormone replacement therapy (HRT):^[7][8]
  • The use of oestrogen-only HRT for more than five years is associated with an increase in the risk of ovarian cancer.
  • The use of oestrogen-only HRT for less than five years does not appear to increase this risk.
  • Combined HRT is also associated with a small increase in the risk of ovarian cancer after five or more years of use.
  • Past users of HRT are not at an increased risk of developing or dying from ovarian cancer.
• Diet: a high-fat diet may play a role in the aetiology of ovarian cancer.
• History of infertility and use of fertility drugs, eg clomifene.
• Nulliparous women are more likely to develop an ovarian malignancy than women who have been pregnant three or more times.
• Early menarche, late menopause and increasing age are also risk factors.
• Family history of ovarian cancer.
• Women with a prior history of ovarian cancer or breast cancer have an increased risk of ovarian cancer. BRCA1 gene confers familial susceptibility for the breast-ovarian cancer syndrome.
• Studies suggest a link between ovarian endometriosis and clear-cell ovarian cancer, possible linked to mutation of the ARID1A gene.^[9] 
• Highest rates of ovarian cancer are found in industrialised countries, with the exception of Japan.

Screening

• No screening method has been shown to affect mortality significantly even if high-risk women are screened. Screening may result in unnecessary surgery.
• Women with a family history that appears to increase their risk of developing ovarian cancer should be referred to a clinical genetics service for full assessment of risk. Women with genetic mutations of BRCA1 or BRCA2 genes should be counselled regarding prophylactic oophorectomy and removal of Fallopian tubes at an appropriate time.^[10][11]
• One large study showed that screening with a combination of CA-125 and transvaginal ultrasound found that most cases detected were in an advanced stage and that further research was needed to determine the effect of screening on mortality figures.^[12]

Presentation

75% of patients present with advanced (stage III or IV) disease:^[10]

• Onset of symptoms is insidious. Early symptoms are often vague, such as abdominal discomfort, abdominal distension or bloating, urinary frequency or dyspepsia.^[13] Constitutional symptoms include fatigue, weight loss, anorexia and depression.
• It most commonly presents with a pelvic or abdominal mass that may be associated with pain. Abdominal, pelvic or back pain is usually a late sign and seen only with early disease that is complicated by torsion, rupture, or infection. It may cause abnormal uterine bleeding.
• Often associated with ascites. One third of patients with ascites also have a pleural effusion.
• Ovarian cancers metastasise to pelvic and periaortic lymph nodes as well as over the pelvic and abdominal peritoneum.

Differential diagnosis^[5]

• Functioning ovarian cyst.
• Benign ovarian tumour.
• Uterine or tubal mass.
• Endometriosis.
• Bowel mass or primary peritoneal carcinoma.
• Secondary carcinoma: breast, gastrointestinal tract, lymphomas and pelvic-organ tumours may all metastasise to ovary.

Investigations^[6]

In primary care

• Consider tests for ovarian cancer in women (especially over the age of 50) who present frequently (particularly more than twelve times a year) with the following symptoms:
  • Abdominal distension (often described as 'bloating').
  • Early feeling of fullness whilst eating (satiety) and/or loss of appetite.
  • Pelvic or abdominal pain.
  • Urinary frequency or urgency.
• Consider ovarian cancer tests for women of 50 or over who have a 12-month history of irritable bowel syndrome (this rarely presents for the first time at this age).
• Also consider testing women who present with unexplained fatigue, weight loss or change in bowel habit.
• Women who do not warrant testing at the time should be advised to return if they have any symptoms which persist or become more frequent

If the woman comes into a category that warrants investigation:

• Organise a CA-125 test.
• If this is reported as raised (35 IU/ml or greater) arrange pelvic and abdominal ultrasound scans.
• If the scan is suggestive of ovarian cancer, refer the patient urgently.
• Consider investigating women for other causes if they have a normal or raised CA-125 but a normal scan.

In the absence of any definitive diagnosis, advise the woman to return if her symptoms become more frequent or persistent.

In secondary care

• CA-125, pelvic and abdominal ultrasound, if not already done in primary care.
• Consider CT scan of the pelvis and abdomen if CA-125, ultrasound and clinical status suggest malignancy, to establish the extent of disease (may also need CT scan of the thorax if clinically appropriate).
• Do not use MRI routinely.
• Calculate a risk malignancy index score (a method of assessing risk using age, ultrasound score, menopausal status, a clinical impression score and serum CA-125 level) and refer to a specialist multidisciplinary team if greater than 250.
• In women under 40, exclude endodermal sinus tumours by arranging alpha-fetoprotein (AFP). Also check beta human chorionic gonadotrophin (beta-hCG) to identify women who may have dysgerminomas, embryonal carcinomas or choriocarcinomas.
• If cytotoxic therapy is to be offered, discuss risks and benefits of obtaining tissue confirmation first. This may be done at laparotomy, or via percutaneous image-guided biopsy
• Occasionally, chemotherapy may be offered without tissue confirmation.

Associated diseases^[5]

Three different familial syndromes of cancer have been identified:

• Site-specific: at risk of development of ovarian cancer only.
• Breast-ovarian: increased risk of either cancer alone or in combination. BRCA1 and BRCA2 susceptibility genes are responsible for at least 90% of hereditary breast-ovarian cancer and site-specific ovarian cancer cases.
• Non-polyposis colon carcinoma families: increased risk of ovarian, endometrial and breast cancer.

Staging

The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging.^[1]

• Stage I ovarian cancer is limited to the ovaries:
  • Stage IA: tumour is limited to one ovary, the capsule is intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.
  • Stage IB: tumour is limited to both ovaries, capsules intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.
  • Stage IC: tumour is limited to one or both ovaries with any of the following: capsule ruptured, tumour on ovarian surface, malignant cells in ascites or peritoneal washings.
• Stage II ovarian cancer is tumour involving one or both ovaries with pelvic extension and/or implants:
  • Stage IIA: extension and/or implants on the uterus and/or Fallopian tubes. No malignant cells in ascites or peritoneal washings.
  • Stage IIB: extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
  • Stage IIC: pelvic extension and/or implants (stage IIA or stage IIB) with malignant cells in ascites or peritoneal washings.
• Stage III ovarian cancer is tumour involving one or both ovaries with microscopically confirmed peritoneal implants outside the pelvis:
  • Superficial liver metastasis equals stage III.
  • Stage IIIA: microscopic peritoneal metastasis beyond pelvis (no macroscopic tumour).
  • Stage IIIB: macroscopic peritoneal metastasis beyond pelvis less than 2 cm in greatest dimension.
  • Stage IIIC: peritoneal metastasis beyond pelvis greater than 2 cm in greatest dimension and/or regional lymph node metastasis.
• Stage IV ovarian cancer is tumour involving one or both ovaries with distant metastasis. Parenchymal liver metastasis equals stage IV.

Management^[5][6][14]

If epithelial ovarian cancer is suspected on the basis of physical examination and imaging, an exploratory laparotomy is usually done for histological confirmation, staging and tumour debulking. The standard comprehensive surgical staging approach consists of a total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO) along with examination of all peritoneal surfaces, an infracolic omentectomy, biopsies of pelvic and para-aortic lymph nodes and clinically uninvolved areas and peritoneal washings.

Further management is then determined by the stage and histology of the tumour. Adjuvant therapy to surgery for epithelial ovarian cancer varies according to the stage of the disease but, in most cases, will consist of chemotherapy. Because of late diagnosis, much of the appropriate management is often directed towards palliative care.

Surgery

• Standard treatment is surgery (staging and optimal debulking) followed by adjuvant chemotherapy in most cases. Even if optimal surgery is not possible, removing as much tumour as possible will provide significant palliation of symptoms.
• Borderline lesions may be treated with conservative surgery.
• In early disease, assessment of peritoneal cytology, hysterectomy, removal of ovaries and Fallopian tubes and infracolic omentectomy should be performed.^[11]
• Management of early ovarian cancer in young women who desire future childbearing may be more conservative, ie a unilateral salpingo-oophorectomy and staging but the long-term safety is uncertain.
• In advanced disease, debulking is recommended. Interval debulking is recommended if there is evidence of a response to chemotherapy as determined by CA-125 and imaging.

Chemotherapy

• Germ cell tumours are treated with surgery and multi-agent chemotherapy in most cases.
• Advanced epithelial ovarian cancer is very sensitive to chemotherapy with responses in the range of 70-80% to first-line chemotherapy. The majority, however, relapse and ultimately die of chemotherapy-resistant disease. Second-line chemotherapy to date is disappointing in all forms of epithelial ovarian cancer, with virtually no chance of successful second-line treatment following failure of initial regime.
• The introduction of intraperitoneal chemotherapy has been a significant advance.
• National Institute for Health and Clinical Excellence (NICE) guidelines for the use of chemotherapy:^[15][16]
  • It is recommended that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone (cisplatin or carboplatin) be offered as alternatives for first-line chemotherapy (usually following surgery) in the treatment of ovarian cancer.
  • When relapse occurs after an initial (or subsequent) course of first-line chemotherapy, additional courses of treatment should be considered, using different treatment options.
  • Paclitaxel in combination with a platinum-based compound (carboplatin or cisplatin) is recommended as an option for the second-line (or subsequent) treatment of women with platinum-sensitive or partially platinum-sensitive advanced ovarian cancer, except in women who are allergic to platinum-based compounds.
  • Single-agent paclitaxel is recommended as an option for the second-line (or subsequent) treatment of women with platinum-refractory or platinum-resistant advanced ovarian cancer and for women who are allergic to platinum-based compounds.
  • Pegylated liposomal doxorubicin hydrochloride (PLDH) is recommended as an option for the second-line (or subsequent) treatment of women with partially platinum-sensitive, platinum-resistant or platinum-refractory advanced ovarian cancer and for women who are allergic to platinum-based compounds.
  • Topotecan is recommended as an option for second-line (or subsequent) treatment only for those women with platinum-refractory or platinum-resistant advanced ovarian cancer, or those who are allergic to platinum-based compounds, for whom PLDH and single-agent paclitaxel are considered inappropriate.
• The following definitions are used by NICE:
  • Platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses 12 months or more after completion of initial platinum-based chemotherapy.
  • Partially platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses between 6 and 12 months after completion of initial platinum-based chemotherapy.
  • Platinum-resistant ovarian cancer: disease that relapses within six months of completion of initial platinum-based chemotherapy. Platinum-refractory ovarian cancer: disease that does not respond to initial platinum-based chemotherapy.

Radiotherapy

• There is little evidence that radiotherapy is superior to chemotherapy for advanced stage III and IV disease.
• Radiotherapy can be used in earlier disease with small residual tumour bulk. There are few studies comparing radiotherapy and chemotherapy in stage I and II disease.

Complications^[5]

• Complications of the tumour: torsion, rupture, infection.
• Complications of treatment: bone marrow depression, infection, neurotoxicity, nephrotoxicity, ototoxicity.
• Complications of advanced disease: malnutrition, electrolyte imbalance, small and large bowel obstruction, infection, ascites, pleural effusion.

Prognosis

• Overall, 5-year survival in ovarian epithelial carcinoma is 35%.^[6] This low rate occurs because of the preponderance of late-stage disease at diagnosis:^[10]
  • Stages I and II: 80-100%
  • Stage III: 15-20%
  • Stage IV: 5%
• Patients under the age of 50 in all stages have considerably better 5-year survival than older patients (40% compared with 15%).
• Survival rates have doubled in a 30-year period. This is thought to have resulted in advances in surgery, better chemotherapy agents such as platinum-based drugs and the more co-ordinated care offered by specialised centres.^[6]
• Dysgerminomas treated by surgery and radiation have an excellent cure rate in both early- and late-stage disease.
• Endodermal sinus tumour has poor prognosis.