Ovarian cancer is a malignancy arising from the ovary. It is the leading cause of death from gynaecological cancer in the UK. Early symptoms may be subtle and presentation is often late. The vast majority of ovarian cancers are classified as epithelial, as they arise from the epithelial surface of the ovary. Malignant ovarian tumours may be solid or cystic.
There are many different types of ovarian cancer. The age group affected, management and prognosis vary widely between them. Classification varies across the literature but can be broadly broken down as follows.
Epithelial ovarian tumours
- The most common type, accounting for around 90% of all ovarian cancers.
- Arise from the epithelial surface of the ovary.
- Occur most commonly in women aged over 50 years.
- There are a number of subtypes of epithelial tumours. These include:
- Serous. The most common subtype, accounting for more than half of epithelial tumours. Most occur in women between 40-60 years of age.
- Endometrioid. Account for around 20% of epithelial tumours. Most common between ages 50-70 years. Around 5% of these are linked to endometriosis.
- Clear cell tumours. 6% of epithelial tumours. Affect ages 40-80 years. Around half are associated with endometriosis.
- Mucinous tumours. 10% of epithelial tumours. Most commonly affect ages 30-50 years.
- Brenner (transitional cell) tumours. Rare.
- Undifferentiated tumours. Do not fit into any of the above categories. 15% of epithelial tumours.
Germ cell tumours
- Derived from primitive germ cells of embryonic gonad.
- Account for 5-10% of all ovarian tumours.
- Most common in younger women under the age of 35 years.
- Often curable with high survival rates.
- Usually present 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.
- Types of germ cell tumours are:
- Endodermal sinus tumours
- Embryonal carcinoma
Sex cord-stromal tumours
- Derive from connective tissue cells.
- Fewer than 5% of all ovarian tumours.
- Sertoli-Leydig tumours
- Granulosa cell tumours
Ovarian secondary tumours may arise from the breast, gastrointestinal tract, haemopoietic system, uterus or cervix.
Tumours may be:
- Borderline (tumours of low malignant potential) which do not fit into the category of benign or malignant and account for 10-15% of ovarian tumours. They are managed primarily by surgery and do not respond well to chemotherapy. Types are:
- Borderline serous - the most common.
- Borderline mucinous.
- Borderline endometrioid
Ovarian cancer has a lifetime risk of around 2% for women in England and Wales. It is the leading cause of death from gynaecological cancer.
Cancer Research UK statistics show that in the UK:
- In 2013 there were 7,284 new cases.
- In 2014 there were 4,128 deaths from ovarian cancer.
- It is the sixth most common cancer in women.
- 53% are diagnosed in women aged 65 years or older.
- Most cases are diagnosed at a late stage.
- It accounted for 5% of all cancer-related deaths in 2014.
In Europe as a whole, in 2012 there were 65,538 new cases with 42,704 deaths.
- Increasing age.
- Lifestyle. It has been estimated that 21% of ovarian cancer can be attributable to lifestyle. Factors which increase the risk include:
- Smoking. It is estimated that 3% of cases may be caused by smoking.
- Obesity. There is evidence of increased risk in postmenopausal women who are overweight.
- Lack of exercise. There is some evidence that regular physical exercise protects against some forms of ovarian cancer.
- Talcum powder use (pre-1975, after which regulation was introduced to prevent the contamination of talcum powder with asbestos).
- Occupational exposure to asbestos.
- Hormonal factors:
- 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 and late menopause.
- Hormone replacement therapy (HRT)[5, 6]. There does appear to be an increased risk of ovarian cancer associated with the current use of HRT for more than five years. This is present for both oestrogen-only and combined HRT, although higher for oestrogen-only HRT. Risk of serous and endometrioid tumours is increased, although risks of some other types may be reduced. Around 1% of cases of ovarian cancer in the UK are thought to be linked to HRT use.
- Genetic factors:
- Family history of ovarian cancer. Women with a first-degree relative with ovarian cancer have 2.7-3.5 times the risk of developing the disease. However, only 3% of cases arise in women with a positive family history.
- Presence of BRCA1 and 2 genes increases susceptibility. Presence of the BRCA1 gene increases risk by up to 65%, and BRCA2 by up to 35%. BRCA1 gene confers familial susceptibility for the breast-ovarian cancer syndrome.
- Medical history:
- Women with a prior history of ovarian cancer, breast cancer or bowel cancer have an increased risk of ovarian cancer.
- History of endometriosis confers a significant increased risk. Studies suggest a link between ovarian endometriosis and clear-cell ovarian cancer, possibly linked to mutation of the ARID1A gene.
Any factor which prevents or inhibits ovulation appears to protect against ovarian cancer. Protective factors therefore include:
- Early menopause.
- The oral contraceptive pill.
No screening method has been shown to affect mortality significantly. Screening may result in unnecessary surgery. A large trial in the USA in 2011 based on cancer antigen 125 (CA 125) levels and ultrasound scan confirmed there was no benefit to screening the general population. A UK-based study involving 202,000 women also came to the conclusion that there was insufficient evidence currently to recommend screening of the general population[11, 12]. However, tumours were detected at an earlier stage and there was some reduction in mortality. Follow-up is ongoing with a further report expected in 2019.
2013 Scottish Intercollegiate Guidelines Network (SIGN) guidelines advise that 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. Any of the following criteria would signify an increased risk:
- The woman is a known carrier of BRCA1, BRCA2, or any other known relevant cancer gene mutations.
- She has a first-degree or second-degree relative who carries a known relevant gene mutation.
- Two family members who are first-degree relatives of each other have ovarian cancer.
- A family member who has ovarian cancer at any age and is a first-degree relative of someone who developed breast cancer under the age of 50 years, or of two who developed it under the age of 60 years.
- Three or more family members with colon cancer; or two with colon cancer and one with stomach, ovarian, endometrial, small bowel or urinary tract cancer in two generations. (One must be diagnosed under the age of 50 years and they should be first-degree relatives of each other.)
- One family member with both breast and ovarian cancer.
These high-risk women should be offered genetic screening and counselling. They may be offered referral for prophylactic salpingo-oophorectomy.
Women diagnosed with ovarian cancer should be offered genetic screening for the relevant gene mutations.
58% of patients present with advanced (Stage III or IV) disease.
- Onset of symptoms is insidious. Early symptoms are often vague, such as abdominal discomfort, abdominal distension or bloating, urinary frequency or dyspepsia. 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 peri-aortic lymph nodes, as well as over the pelvic and abdominal peritoneum.
- Other causes for a mass:
- Benign ovarian tumour or cyst.
- Primary peritoneal carcinoma.
- Other pelvic malignancy (uterus, cervix, bladder, rectum).
- Secondary carcinoma: breast, gastrointestinal tract, lymphomas and pelvic-organ tumours may all metastasise to ovary.
- Other causes of ascites (eg, cirrhosis).
- Other causes of altered bowel habit or abdominal pain/bloating, such as:
In primary care
- Refer urgently any woman with ascites and/or a pelvic or abdominal mass not obviously fibroids.
- Consider tests for ovarian cancer in women (especially over the age of 50 years) who present frequently (particularly more than twelve times a month) 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 years 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. Other causes for a raised CA 125 include:
- Pelvic inflammatory disease.
- Torsion, rupture or haemorrhage of an ovarian cyst.
- Other cancer (eg, primary peritoneal cancer, lung cancer, pancreatic cancer).
- Other peritoneal pathology (trauma, irritation).
- Heart failure.
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).
- CT or MRI scan can be used for pre-operative staging. CT is the investigation of choice in the UK, although MRI may be useful for imaging other pelvic tumours, or if contrast-enhanced CT cannot be used.
- National Institute for Health and Care Excellence (NICE) and SIGN guidelines both advise using the Risk Malignancy Index 1 to assess the likelihood of malignancy, and if >250 (NICE) or >200 (SIGN), refer to a specialised multidisciplinary team.
This score is calculated as ultrasound score x menopausal score (where 1 = premenopausal and 3 = postmenopausal) x CA 125 level in U/mL. The ultrasound score is the number of the following findings on scan: multilocular cyst, solid areas, bilateral lesions, ascites, intra-abdominal metastases. (0 = no abnormalities, 1 = one abnormality, 3 = two or more).
- In women under 40 years, 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.
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.
- Nonpolyposis colon cancer families: increased risk of ovarian, endometrial and breast cancer.
The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging system remains the best indicator of prognosis and guides management strategy.
- 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.
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 (TAH and 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. Response to chemotherapy is usually good; however, relapse is common and occurs in around 75%. Further regimes for relapse may prolong survival. Much of the evidence relates to the most common subtype of epithelial cancer, serous carcinoma; however, it is increasingly clear that the different types need different treatment strategies based on the differing molecular biology involved. Available guidelines apply mainly to epithelial cancers.
Because of late diagnosis and high risk of relapse, much of the appropriate management may be directed towards palliative care.
A clinical nurse specialist should be present when the diagnosis of ovarian cancer is given.
- 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. Routine systematic lymphadenectomy in early-stage epithelial ovarian cancer is not recommended in the UK.
- 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. Treatment choice will depend on type of tumour and stage and be in partnership with the patient, who will need to be fully informed about prognosis.
- 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. There is evidence that complete clearance of all visible disease at the time of surgery is associated with a better prognosis.
- The value of surgery for relapse and palliation remains unclear.
- Adjuvant platinum-based chemotherapy improves survival in early (Stage I/IIa) epithelial ovarian cancers.
- Chemotherapy is advised for all women with Stage II-IV disease following surgery. The standard regime is paclitaxel and carboplatin given intravenously every three weeks for six cycles. Possible alternatives to paclitaxel are peglated liposomal doxorubicin (PLD) or gemcitabine.
- Intraperitoneal chemotherapy may be used as an alternative. Evidence suggests it is more effective but, as it is more difficult to deliver and associated with more risks, is not standard treatment, although it may be used in certain specialised centres. Optimal regimes are yet to be established.
- Biological therapies have been developed and continue to undergo trials as understanding of the molecular biology of the types of ovarian cancer has advanced. These targeted treatments include:
- Bevacizumab. This is a monoclonal antibody against vascular epithelial growth factor (VEGF). This helps to prevent angiogenesis (the formation of new blood vessels), which is an important part of cancer growth. This is not currently approved for use by NICE or the Scottish Medicines Consortium, (reviewed in 2013)[13, 19, 20]. Trials suggest it improves progression-free survival and quality of life in women with recurrent disease, although it has a significant risk of adverse effects.
- Poly (ADP-ribose) polymerase (PARP) Inhibitors - eg, olaparib. These are able to target cancer cells whilst sparing normal cells. They work by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. A Cochrane review concluded they improve progression-free survival in women with recurrent platinum-sensitive disease.
- With targeted therapy undergoing further evaluation, relapses are most often treated with platinum-based combination chemotherapy. There is no evidence as yet for any maintenance chemotherapy to prevent or delay relapse. NICE guidelines recommend paclitaxel or PLD for recurrent disease but not alternatives gemcitabine, trabectedin or topotecan. Gemcitabine is, however, recommended as an option by SIGN guidelines as part of a platinum-based combination. A Cochrane review found PLD to be more effective in combination with carboplatin than the paclitaxel combination and recommended it as first-line treatment in recurrent platinum-sensitive disease.
- There may in some cases be a role for hormonal therapies, where there is platinum-resistant recurrence, particular subtypes, or a wish to avoid chemotherapy. Options studied include tamoxifen, aromatase inhibitors and luteinising hormone-releasing hormone (LHRH) agonists. A Cochrane review found insufficient evidence to support the use of LHRH agonists in this situation.
CA 125 may be used to monitor efficacy of treatment and to monitor for recurrence. The need to test it in follow-up, however, can be guided by the presence of symptoms.
- 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.
Overall, in England and Wales, 10-year survival is currently 35%, and 5-year survival 46%. The highest survival rates are in women under the age of 40 years. Survival rates drop as stage of diagnosis advances, and also range with subtype. In England in 2014, survival at one year by stage was:
- Stage I: 97.3%
- Stage II: 93.5%
- Stage III: 71%
- Stage IV: 51.4%
Survival from ovarian cancer has almost doubled in the last 40 years in the UK.
Further reading and references
Fertility Sparing Treatments in Gynaecological Cancers: Scientific Impact Paper No. 35; Royal College of Obstetricians and Gynaecologists, February 2013
Ultra-radical (extensive) surgery for advanced ovarian cancer; NICE Interventional Procedure Guidance, (Nov 2013
Sundar S, Neal RD, Kehoe S; Diagnosis of ovarian cancer. BMJ. 2015 Sep 1351:h4443. doi: 10.1136/bmj.h4443.
Ai B, Bie Z, Zhang S, et al; Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment. Am J Cancer Res. 2016 Aug 16(8):1624-35. eCollection 2016.
Types and Stages of Ovarian Cancer; Ovarian Cancer Action January 2012
Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2013)
Ovarian cancer statistics; Cancer Research UK
Ovarian cancer - the recognition and initial management of ovarian cancer; NICE Clinical Guideline (April 2011)
Morch LS, Lokkegaard E, Andreasen AH, et al; Hormone therapy and different ovarian cancers: a national cohort study. Am J Epidemiol. 2012 Jun 15175(12):1234-42. doi: 10.1093/aje/kwr446. Epub 2012 Apr 19.
Beral V, Bull D, Green J, et al; Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007 May 19369(9574):1703-10.
Kim HS, Kim TH, Chung HH, et al; Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis. Br J Cancer. 2014 Apr 2110(7):1878-90. doi: 10.1038/bjc.2014.29. Epub 2014 Feb 11.
Samartzis EP, Noske A, Dedes KJ, et al; ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. Int J Mol Sci. 2013 Sep 1214(9):18824-49. doi: 10.3390/ijms140918824.
Overview of Ovarian Cancer in England: Incidence, Mortality and Survival; National Cancer Intelligence Network (NCIN)/Trent Cancer Registry report, November 2012
Buys SS, Partridge E, Black A, et al; Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8305(22):2295-303. doi: 10.1001/jama.2011.766.
Jacobs IJ, Menon U, Ryan A, et al; Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2015 Dec 16. pii: S0140-6736(15)01224-6. doi: 10.1016/S0140-6736(15)01224-6.
Management of epithelial ovarian cancer; Scottish Intercollegiate Guidelines Network - SIGN (Nov 2013)
Suspected cancer: recognition and referral; NICE Clinical Guideline (2015 - last updated July 2017)
Sapiezynski J, Taratula O, Rodriguez-Rodriguez L, et al; Precision targeted therapy of ovarian cancer. J Control Release. 2016 Oct 14243:250-268. doi: 10.1016/j.jconrel.2016.10.014.
Lawrie TA, Winter-Roach BA, Heus P, et al; Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev. 2015 Dec 17(12):CD004706. doi: 10.1002/14651858.CD004706.pub5.
Jaaback K, Johnson N, Lawrie TA; Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2016 Jan 12(1):CD005340. doi: 10.1002/14651858.CD005340.pub4.
Targeted Therapies for the Management of Ovarian Cancer: Scientific Impact Paper No. 12; Royal College of Obstetricians and Gynaecologists, September 2013
Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer; NICE Technology Appraisal Guidance, May 2013
Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer; NICE Technology Appraisal Guidance, May 2013
Rossi L, Verrico M, Zaccarelli E, et al; Bevacizumab in ovarian cancer: A critical review of phase III studies. Oncotarget. 2016 Nov 11. doi: 10.18632/oncotarget.13310.
Wiggans AJ, Cass GK, Bryant A, et al; Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2015 May 20(5):CD007929. doi: 10.1002/14651858.CD007929.pub3.
Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer; NICE Technology Appraisal Guidance, April 2016
Lawrie TA, Bryant A, Cameron A, et al; Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer. Cochrane Database Syst Rev. 2013 Jul 9(7):CD006910. doi: 10.1002/14651858.CD006910.pub2.
Wuntakal R, Seshadri S, Montes A, et al; Luteinising hormone releasing hormone (LHRH) agonists for the treatment of relapsed epithelial ovarian cancer. Cochrane Database Syst Rev. 2016 Jun 29(6):CD011322. doi: 10.1002/14651858.CD011322.pub2.
Cancer survival by stage at diagnosis for England (experimental statistics): Adults diagnosed 2012, 2013 and 2014 and followed up to 2015; Office for National Statistics (ONS)