Ovarian cancer is one of those nightmare cancers: its vague, insidious onset means that it tends not to present until it is too late, and there is currently no effective screening programme in place to detect it at an earlier stage. Like endometrial cancer, it tends to affect older women and it is vital to consider it a possibility in women over 60 with vague abdominal or urinary symptoms.

Ovarian cancer tends to present with a pelvic mass, so I’ve included a differential diagnosis for this. I’ve also described efforts to develop an ovarian screening programme – the UKFOCSS trial is currently underway to investigate its effectiveness.

 


Introduction

Uterine anatomy

Normal Uterine Anatomy 1

ANATOMY OF THE OVARIES

  • the ovaries are a pair of small oval-shaped organs located in the female pelvis. They are the female equivalent of the testes. They function as gonads by producing female germ cells called ova, and also as endocrine glands which secrete the female sex hormones oestrogen and progesterone.
  • they lie on either side of the body of the uterus beneath the uterine tubes, within a double-layered sheet of peritoneum called the broad ligament.
  • they consist of an outer cortex, which contains the ovarian follicles, and an inner medulla containing blood vessels, nerves and lymphatics.
  • the ovaries are surrounded by a thin fibrous capsule called the tunica albuginea, which is covered externally by a modified layer of peritoneum called the germinal epithelium.
  • the fimbriae of the uterine tubes drape over the ovaries, and act to “catch” the ova after they are released and guide them into the uterus.
  • they are usually located on the lateral wall of the pelvis in a depression known as the ovarian fossa, with the external iliac vessels above, the obturator nerve laterally, and the internal iliac vessels and ureter running behind them. However, their position can be extremely variable and they tend to move around a lot during and after pregnancy.
  • they are held in place by ligaments connecting them to other structures – the ovarian ligament is continuous with the round ligament and connects them to the uterus, and the suspensory ligament of the ovary (or infundibulopelvic ligament) is part of the broad ligament which connects them to uterine tubes and the lateral wall of the pelvis, and transmits the ovarian vessels and nerves.
  • the ovaries are the only totally intraperitoneal organs in the body – this is important as it means that ectopic pregnancies can implant onto abdominal organs, and ovarian cancer can easily metastasise across the peritoneal cavity (this is known as transcoelomic spread).

 

PHYSIOLOGY

  • at birth, the ovaries contain 1-2 million ova, but only about 300-400 will ever undergo maturation
  • the ovaries usually take it in turns each month to mature and release an ovum (ovulate) during the menstrual cycle – the ovum enters the uterine tube, where it can undergo fertilisation by a sperm and develop into a fetus. If it is not fertilised, it is shed along with the endometrial lining of the uterus.
  • this process is triggered by the pituitary hormones FSH and LH
  • the developing ovarian Graafian follicle produces oestrogen, which stimulates the proliferation of the endometrium and changes in cervical mucus which make it more welcoming to sperm. It also causes a wide variety of systemic effects.
  • after ovulation has occurred, the corpus luteum produces progesterone which triggers changes in the endometrium to make it more receptive to implantation.
  • for more detail on the menstrual cycle, see here for the Geeky Medics guide

 

TERMINOLOGY

  • ovarian cancer is a malignant neoplasm arising from the tissues of the ovary – it is the leading cause of death from gynaecological cancer in the UK

Epidemiology

  • ovarian cancer accounts for 4% of cancers in UK women (about 7000 cases per yer)
  • it is the fifth most common cancer and causes 5.6% of cancer deaths (about 4000 per year)
  • there is a lifetime risk of 2.0%, or 1 in 51, for women in the UK
  • it has a peak incidence in women in their 60s and 70s, and is rare under the age of 40
  • incidence has decreased over the past 10 years, possibly due to increased use of the OCP
  • ovarian cancer is almost twice as common in developed countries than in the developing world

Aetiology and risk factors

  • ovarian cancer is believed to result from damage to the ovarian surface epithelium during ovulation
  • the “theory of incessant ovulation” basically states that the more a woman ovulates in her lifetime, the higher her risk of ovarian cancer, due to the increased cumulative damage to the epithelium and the increased risk of mutations during its subsequent repair and regeneration
  • factors leading to “incessant ovulation” include early menarche, late menopause, delayed childbearing, nulliparity, use of HRT for >5 years, use of fertility drugs such as clomiphene to stimulate ovulation, and increasing age
  • previous ovarian disease, such as ovarian cysts (2-9x risk) or endometriosis (1.5x risk), can increase risk, probably through similar mechanisms
  • pelvic radiotherapy for previous gynaecological cancers or lymphoma (1-2x risk)
  • previous breast cancer (2-4x risk) or ovarian cancer (obviously)
  • smoking is a proven risk factor for some types of ovarian cancer
  • obesity, diabetes and sedentary lifestyle can also increase risk, especially in younger women
  • occupational carcinogen exposure – asbestos is a known ovarian carcinogen (3-5x risk)
  • family history is important as several inherited genetic traits can significantly increase risk, for example BRCA1 (46% risk by age 70), BRCA2 (12% risk by age 70) and HNPCC (12% lifetime risk).
  • being tall is a risk factor, although no-one really knows why
  • protective factors include multiparity (>3 pregnancies), breastfeeding, OCP usehysterectomy, tubal ligation, exercise and aspirin

Histopathological types

~90% EPITHELIAL OVARIAN TUMOURS

  • derived from surface coelomic epithelium, generally affect the over 50s
  • 50-80% serous adenocarcinoma
  • 10% endometrioid adenocarcinoma (like endometrial cancer)
  • 3-8% mucinous adenocarcinoma
  • 4-5% clear cell adenocarcinoma
  • 2% other rare types: squamous cell, transitional cell, mixed mesodermal tumour, carcinosarcoma, undifferentiated sarcoma

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~10% OTHER TYPES

  • derived from other parts of the ovary, generally affect younger women and progress more quickly and aggressively
  • 1% sex cord stromal tumours granulosa-theca cell, Sertoli-Leydig, gynandroblastoma, lipid cell
  • 1.5% germ cell tumoursdysgerminoma, endodermal sinus (yolk sac) tumour, embryonal carcinoma, teratoma, choriocarcinoma, polyembronoma, gonadoblastoma
  • 7% metastases from other sites – gastric (Krukenberg tumour), colorectal, breast, endometrial, cervical, lymphoma, leukaemia

Symptoms

  • its insidious onset means that up to 75% of patients present with symptoms of advanced disease due to the mass effects of the tumour
  • non-specific GI symptoms such as bloating or indigestion (often misdiagnosed as IBS)
  • gradually increasing abdominal distension (often misdiagnosed as “middle-aged spread”)
  • increasing tumour size results in pressure effects causing chronic abdominal, pelvic or back pain, urinary frequency/urgency (pressure on bladder), constipation/altered bowel habit/bowel obstruction (pressure on bowel), leg swelling and DVT/PE (pressure on pelvic veins)
  • abnormal vaginal bleeding can also be a symptom
  • symptoms of metastatic disease include pleural effusion, ascites, weight loss and fatigue
  • less commonly, sudden torsion, rupture or infection of the tumour in early disease can present with acute abdominal or pelvic pain – this is a blessing in disguise as it can lead to early diagnosis.

Signs

  • general examination – cachexia, lymphadenopathy, signs of pleural effusion
  • abdominal examination – distension, ascites, palpable pelvic mass, “omental cake” metastasis
  • Cusco speculum examination – usually normal
  • bimanual palpation – palpable adnexal/pelvic mass which may be fixed and immobile

Differential diagnosis – pelvic mass

  • ovarian pathology – ovarian cyst/benign tumour, ovarian cancer
  • tubal pathology – tubo-ovarian abscess, tubal malignancy (treat as ovarian)
  • uterine pathology – pregnancy, fibroids/benign tumour, uterine cancer
  • urological pathology – distended bladder, pelvic kidney, transplanted kidney
  • GI pathology – the 6 Fs: fat, fluid, flatus, faeces, fetus, filthy big tumour
  • other abdominal pathology – primary peritoneal cancer, retroperitoneal sarcoma.

Investigations

Diagnostic tests for women with suspected cancer include:

  • history and clinical examination including Cusco speculum examination and bimanual palpation
  • always do a pregnancy test in women of reproductive age
  • tumour markers are very useful in the diagnosis of ovarian cancer: CA-125 (a coelomic epithelial antigen) is elevated in 90% of cases of advanced disease and 50% of cases of early disease. It is very sensitive for ovarian cancer but not particularly specific – it can also be raised in other gynaecological cancers, GI cancers, benign abdominal and pelvic disorders, breast cancer and diseases affecting the pleura, pericardium or peritoneum. However, performed in the correct clinical context it can be very informative and should be a standard test for suspected ovarian cancer.
  • other tumour markers for specific types of ovarian cancer include CA19-9 (mucinous epithelial), beta-hCG and placental ALP (dysgerminomas, embryonal cancers, choriocarcinoma), AFP (endodermal sinus/yolk sac tumours), inhibin (granulosa-thecal cell tumours) and LDH (some dysgerminomas) – these are usually arranged and interpreted by a specialist gynae-oncologist.
  • transabdominal +/- transvaginal ultrasound should be performed to assess the mass and check for any metastases

Initial investigations are usually carried out by GPs in primary care, and the risk of malignancy index (RMI) score provides guidance on which patients to refer to gynaecology. It provides a composite assessment of risk and allows gatekeeping of referrals to specialist centres. It is calculated as menopausal status score x ultrasound assessment score x CA-125 result. A score of >200 indicates a 75% risk of cancer and should prompt referral to a specialist gynae-oncology centre. A score of <200 represents a 3% risk of cancer and should be monitored using 4-monthly CA-125 and ultrasound.

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CT showing large ovarian tumour in the pelvis

CT showing large ovarian tumour in the pelvis 2

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Staging investigations for patients with a high RMI score include:

  • blood testsFBC (for anaemia), U+E (for renal function), LFTs (for metastases)
  • imaging CXR to check for pleural effusion or lung metastases, CT +/- MRI abdomen and pelvis to assess mass, pelvic nodes and any metastases; a PET scan may be required in advanced disease
  • invasive tests pleural or ascitic tap may be required if effusion/ascites present
  • laparoscopy and biopsy is indicated for large cystic lesions or adnexal masses to inform further management
  • formal surgical staging is usually carried out as part of definitive management described below

Grading – how aggressive is it?

There are multiple grading systems available depending on the type of ovarian cancer the patient has, e.g. FIGO, WHO, Silverberg… basically they are far too complicated to cover in detail here. Generally tumours are graded low- to high-grade, with high-grade carrying a much poorer prognosis.


Staging – how far has it spread?

Ovarian cancers are staged using the International Federation for Gynaecology and Obstetrics (FIGO) system. The TNM system can also be used, but generally gynae-oncologists prefer to use FIGO.

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ovarian cancer staging

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The mortality figures shown are for epithelial ovarian cancers, and the prognosis varies significantly depending on the type of cancer. For example, dysgerminomas have an excellent cure rate, whereas endodermal sinus (yolk sac) tumours have a very poor prognosis.


Management

Surgical management is generally the mainstay of treatment:

  • exploratory laparotomy for tumour debulking and formal surgical staging
  • this is a major procedure which generally comprises total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), infracolic omentectomy, pelvic and para-aortic lymph node sampling, peritoneal biopsies, multiple pelvic washings, sampling of ascites, inspection and sampling of the underside of the diaphragm, and removal of pretty much anything else that looks suspicious e.g. bowel, appendix, liver, spleen…
  • maximal cytoreduction (largest residual tumour deposit <2cm) can be achieved in up to 80% of patients and significantly improves survival
  • a second “interval” debulking can be carried out after chemotherapy in some cases

This excellent little video from TeamCirisano on YouTube shows the removal of a large cystic ovarian mass at laparotomy. Most of the cyst fluid is drained first to prevent unnecessary spillage and seeding of cancer cells into the abdominal cavity, then the ovary and tumour are removed.

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Medical therapies are generally used as adjuncts to surgery:

  • adjuvant chemotherapy is given to all patients >stage Ic, plus anyone stage Ia/Ib with a high grade malignancy. The standard first-line treatment is carboplatin + paclitaxel (response rate 70-80%). Second-line agents to consider include pegylated liposomal doxorubicin (PLDH) and topotecan. Response to treatment can be monitored using CA-125 levels, which decrease if treatment is effective and increase if there is a relapse.
  • intraperitoneal chemotherapy has been shown to improve survival in recent trials
  • radiotherapy is not really used in the management of ovarian cancer as the tumours tend to be very radioresistant. It is sometimes used in early stage low-bulk disease.
  • biological immunotherapy is emerging as a potential new treatment – specific monoclonal antibodies like bavacizumab (anti-VEGF) and olaparib (anti-PARP) are currently undergoing trials
  • advanced metastatic cancer (which is unfortunately very common) requires individualised palliative treatment with tumour debulking, chemoradiotherapy and symptom control

Follow-up and prognosis

  • the overall prognosis is fairly poor (42.9% 5-year survival), but varies significantly depending on the stage and type of cancer (see above)
  • women who undergo surgery for ovarian cancer are usually followed up and monitored by a specialist gynae-oncology centre, with regular pelvic examinations and CA-125 levels

Prevention strategies – potential for screening

There are several potential future options for screening for ovarian cancer:

  • genetic screening can be offered to high-risk women with a significant family history of cancer (e.g. ovarian, endometrial, breast, gastric, colorectal) – this generally involves testing for BRCA1, BRCA2 and/or HNPCC. Patients who test positive for a mutation can be monitored using CA-125 levels and TVUSS, or may choose to undergo prophylactic interventions such as BSO +/- hysterectomy.
  • pelvic examination is not a very useful screening tool – it would take 10,000 pelvic exams to detect 1 case of early ovarian cancer!
  • CA-125 (cancer antigen 125) is a glycoprotein shed by epithelial tumours. The normal range is <35IU/L. It is a sensitive test for ovarian cancer but not very specific, as it can also be raised in several other cancers and a range of benign abdominal and pelvic conditions. Despite the high false positive rate, it has been estimated that CA-125 screening could detect ovarian cancer up to 3 years earlier.
  • transvaginal ultrasound (TVUSS) is very useful in detecting ovarian cysts and assessing their malignant potential, but requires specialist sonographers and would be expensive to perform on a population screening basis.

It is clear that a screening programme for ovarian cancer would be greatly valued, as the disease characteristically does not present until it is at an advanced stage. CA-125 and TVUSS are both sensitive tests, but carry a 2-3% false positive rate in postmenopausal women – this is generally considered too high, as it could potentially lead to unnecessary surgical interventions and cause harm. However, the use of the two tests together would significantly improve the reliability of screening. The UKFOCSS trial is currently underway to assess the combined effectiveness of CA-125 and TVUSS in screening for ovarian cancer in high-risk patients with a significant family history.

 


References

Images:

1. By BruceBlaus [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)], from Wikimedia Commons

2. By James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], from Wikimedia Commons

 

Further reading sources:

 


 

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