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Introduction

Ovarian cancer refers to several types of tumour arising from the ovaries. It is the leading cause of gynaecological cancer death in the UK. 

The early symptoms are often mild and subtle, and as such, presentation can often be late, with advanced disease.

Any of the tissues of the ovary have the potential to become neoplastic. Ovarian “growths” (tumours) are common – but 94% of all ovarian tumours are benign – these are usually simple cysts.

There are several types of ovarian cancer, depending on which cell type the tumour arises from:

  • Epithelial – 85-90%
  • Germ cell – 5-7%
    • Derived from primitive embryonic germ cells
  • Sex-cord stromal – 5-7%
    • Derived from other gonadal tissue

 

Epithelial Ovarian Cancer

Epidemiology

  • Lifetime risk – 1 in 55
  • Incidence – 22 per 100 000
    • 7000 new cases in the UK each year, resulting in 5400 deaths
  • The most deadly gynaecological cancer – results in more deaths than all other gynaecological cancers combined.
    • Probably because it presents so late due to lack of symptoms
    • Most cases present late
  • Average 5 year survival is 30%
  • Typical onset in women aged >50
  • Epithelial tumours can be sub classified into different types:
    • Serous – most common – about 50% of cases
    • Endometroid – 20%
    • Clear cell tumours – 6%
    • Mucinous – 10%
    • Brenner – rare
    • Undifferentiated

Aetiology

  • Hormonal factors
    • Increased risk with low parity / infertility
      • Nulliparity increased risk 1.5x
    • Early menarche
    • Late menopause
    • Use of HRT
      • About 1% of cases are thought to be HRT related
      • Risk is less if combined (oestrogen and progesterone) HRT is used
  • Lifestyle factors
    • Obesity – increased risk with high fat intake
    • Smoking
    • Lack of exercise
    • Talcum powder use pre-1975 (contained asbestos)
    • Occupation exposure to asbestos
  • Medical history factors
    • Previous pelvic inflammatory disease
    • Previous cancers of breast or bowel
    • Risk increases with age
    • History of endometriosis – significant increase in risk
  • Genetic factors can play a role
    • 5% of cases have a family history
    • 1% of cases follow an autosomal dominant inheritance pattern
      • BRCA1, BRCA2 and HPNCC often involved in familial cases
    • Presentation in FH disease is 10-15 years earlier than other cases
  • Increased risk in developed world
    • Incidence is low in Africa in comparison with Europe and USA

Protective factors

  • Use of oestrogen containing oral contraceptives is protective for ovarian cancer – but may slightly increase the risk of breast cancer.
    • Reduces the risk by 50%
  • Childbearing
  • Breast-feeding
  • Hysterectomy

Why is the pill protective but early menarche is not?

  • The risk is related to the number of ovulations
    • With the use of oral oestrogen containing contraceptives, ovulation is suppressed
    • Early menarche obviously increases the number of ovulations
  • Thus, the risk is related to the number of ovulations, and not the direct result of exposure to oestrogen

 

Pathology

The surface of the ovary is covered in cuboidal epithelial layer that is continuous with the lining of the peritoneum. It is from these cells that the tumour arises.

 

Clinical presentation

60% of patients present with advanced disease – stages III and IV.

Ovarian cancer tends to present later than other gynaecological tumours

  • In many other gynaecological tumours, there are often symptoms of vaginal discharge and blood, but in ovarian cancer, these are not present.

Symptoms are generally vague, and may be dismissed as IBS or other vague bowel symptoms:

  • Vague abdominal distension, bloating
  • Urinary frequency
  • Dysuria
  • Fever
  • Weight loss
  • Pelvic mass
    • May be painful or tender to examination
    • May cause dyspareunia (painful intercourse)
  • Epigastric discomfort / early satiety
  • Ascites – check for shifting dullness
  • Abnormal uterine bleeding is not common but occasionally occurs
  • Rupture / local peritonism can occur – particularly in the case of a large cyst
    • Rupture of a malignant cyst can result in the spread of malignant cells around the peritoneal cavity
    • Mucinous cyst adenomas – if these rupture, the cells contain within can escape around the peritoneam and continue to secrete mucous, resulting in a life-threatening ‘adhesion’ of the contents of the viscera, known as psudomyxoma peritonei.
  • Torsion – only occurs in small, free to move tumours. If the tumour twists, then the venous supply may become occluded, but the arterial supply continues – and the tumour may engorge and become grossly enlarged, causing great pain.
    • The tumour can twist and untwist itself, and thus the history of pain may be intermittent.
  • Endocrine / metastatic effects – e.g. may cause post-menopausal bleeding, or menstrual irregularities.
    • Metastasis can occur to the pelvic and paralytic lymph nodes, as well as the peritoneum

Differential diagnosis

Investigations

Any patient with an abdominal or pelvic mass requires urgent specialist referral.

  • Transvaginal USS
  • Bloods
    • Serum CA-125
    • Consider other causes of raised CA-125 if USS is normal (endometriosis, PID, pregnancy, other gynaecological cancer, liver disease)
    • If under 40, consider aFP and BhCG to exclude germ cell tumours
  • CT or MRI
    • May be used to assess spread of the disease
  • Biopsy
    • Required to confirm the presence of a tumour (as opposed to e.g. a benign cyst).
  • Usually, upon initial suspiscion, the GP will take a blood sample for CA125, and refer for transvaginal ultrasound.
    • CA125 – sensitive but highly unspecific. It can be raised in loads of benign and malignant conditions. It is useful to test the effectiveness of treatment, and to detect the relapse of disease.

Prognostic factors

  • Stage of tumour, including spread
  • Histological type

The patient decline seen in advanced disease is usually the result of extensive local spread, rather than metastatic disease.

Also, there is a relatively high cure rate (compared to other cancers) in advanced disease

Staging

  • Stage I
    • Ia – Confined to one ovary, capsule intact, no evidence of ovarian surface
    • Ib – same as above, both ovaries affected
    • Ic – one/both ovaries with ruptured capsule / tumour on ovarian surface / malignant cells present in ascetic fluid or in peritoneal washing
  • Stage II
    • IIa – Spread to the uterus / tubes
    • IIb – spread to other pelvic structures (broad ligament, pelvic wall, peritoneum, colon)
    • IIc – as IIa or IIb, plus malignant cells in ascetic fluid or peritoneal washing
  • Stage III
    • IIIa – spread to abdomen, beyond the pelvis, e.g. peritoneal surface of liver
    • IIIb – Spread beyond pelvis, with mets >2cm diameter
    • IIIc – spread beyond the pelvis, with mets >2cm, and involvement of pelvic /para-aortic lymph nodes
  • Stage IV – mets to lung, supraclavicular lymph nodes, malignant pleural effusion, mets in liver parenchyma (not surface)
  • 75% of cases are stage III or IV at presentation
  • For disease confined to the ovary (Stage Ic and below), survival after treatment is around 80%
  • For metastatic disease confined to the peritoneal cavity, 5 year survival is around 30%
  • For disease outside the peritoneal cavity, 5 year survival is 5-10%.
  • Most patients will die from a relapse of their disease, even if the initial tumour was ‘cured’.

 

Spread

Like most cancers, ovarian is likely to spread locally, and via lymph and blood. However, ovarian epithelial cancer typically spreads to the greater omentum:

  • The omentum usually plays a role in healing, by adhering to damaged tissue. Thus it expresses lots of adhesion proteins, making it an easy target for metastatic spread.

Other common sites of spread include:

  • Liver, lungs, bone and cerebrum
  • Lymph node involvement is common

 

Management

Most cases involve surgery (sometimes referred to as “debunking surgery” in advanced disease) followed by adjuvant chemotherapy.

Surgical

  • More effective than platinum agents only if disease bulk diameter <2cm
  • Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) – removal of ovaries and fallopian tubes
  • Omentectomy – removal of the greater omentum

Medical

  • Adjuvant chemotherapy (6 cycles) usually given in all cases. Carcoplatin + paclitaxel (Taxol) given. Carcoplatin is a platinum based drug, and paclitaxel improves its efficacy.
  • These agents increase survival by around 10% in stage Ic tumours (from 70% to 80%)
  • In more aggressive tumours, the median survival is 3 years with a combination of surgery and chemotherapy.
  • Good prognostic indicators for the use of platinum drugs:
    • Disease bulk <5cm
    • Number of disease sites <3

Follow-up

  • CA-125 levels can be monitored to see the effectiveness of treatment, as well as to detect a relapse

Prognosis

  • Survival has doubled in the last 40 years
  • Overall, 10 year survival is 35% and 5-year survival is 45%
  • Best survival rates are in women aged <40
  • Survival at 1-year by stage:
    • I – 97%
    • II – 94%
    • III – 71%
    • IV – 51%

Germ cell tumours

  • Derived from primitive germ cells
  • Account for 5-10% of all ovarian tumours
  • Typically present in women aged <35
  • Often curable – have high survival rates
  • Typically present as a rapidly enlarging abdominal mass
    • May rupture
    • May undergo torsion

Sex cord stromal tumours

  • Arise from connective tissue cells
  • <5% of all ovarian cancers

References

  • Ovarian Cancer - patient.info
  • Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
  • Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
  • Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

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