Ovarian cancer – early detection and referral

Ovarian cancer is the second most common gynaecological cancer

Ovarian cancer is the second most common gynaecological cancer in New Zealand with an average of 371 new diagnoses (9.9 per 100,000 females; from 2015 – 2020) each year;^* more than cervical cancer but fewer than endometrial cancer.¹ In 2020, it was the seventh most common cancer in females.¹ The risk of ovarian cancer increases with age and it primarily affects females who are post-menopausal. This is reflected in New Zealand data where incidence first peaks between the ages of 45 – 64 years, and again in those aged > 75 years.²

There is no effective screening test for ovarian cancer, so diagnosis relies on the prompt recognition and investigation of suspicious symptoms (see: “Diagnosing ovarian cancer”).^{3 ,4} While ovarian cancer was historically considered to be a silent disease in its early stages, evidence suggests that 90 – 95% of people are symptomatic.^{3, 5} However, because symptoms are often non-specific, it is estimated that only one in 400 – 600 females who report symptoms has an ovarian malignancy.^{3, 6} Females with ovarian cancer in New Zealand reportedly visit their general practitioner an average of three to five times before having diagnostic tests for ovarian cancer.⁷

^*There are differences in published data. For consistency across the gynaecological cancer series, incidence and mortality data has primarily been obtained from the publication – Cancer: Historical summary 1948 – 2020.

Ovarian cancer incidence and mortality remain steady over time

The overall incidence and mortality from ovarian cancer in New Zealand have remained relatively steady over time (Figure 1).¹ As many people are diagnosed with ovarian cancer at an advanced stage, mortality rates are high (240 deaths on average each year from 2015 – 2018^*; 5.7 per 100,000 females).⁸ Ovarian cancer has the highest mortality of all gynaecological cancers in New Zealand, causing more deaths than the others combined.¹

^*Mortality data are available for 2019, but are preliminary so have not been included. Mortality data for 2020 are not yet available.

---

Figure 1. Age-standardised incidence and mortality rates (per 100,000 females) for ovarian cancer between 2015 and 2018 in New Zealand.¹N.B. Incidence data are available up to 2020 but have not been included in this graph for comparative purposes. Mortality data are available for 2019, but are preliminary so have not been included. Mortality data for 2020 are not yet available.

---

Ovarian cancer is more common in Pacific peoples compared with other ethnic groups (Figure 2). In 2019 (most recent ethnicity data available), the age-standardised incidence rate for Pacific peoples was 19.5 per 100,000 females which was 2.0 times greater than the rate in Māori (9.6 per 100,000 females) and 2.2 times greater than in European/Other ethnic groups (8.9 per 100,000 females).⁹

---

Figure 2. Age-standardised incidence rate (per 100,000 females) for ovarian cancer by ethnicity between 2015 and 2019 in New Zealand.⁹ N.B. Incidence data by ethnicity are not yet available for 2020.

---

Ovarian cancer has a high mortality rate, but five-year survival rates are improving

The five-year survival rate for people with ovarian cancer in New Zealand improved from 32% in the 1990s to 36% between 2010 and 2014.¹⁰ However, this remains lower than five-year survival in Australia (43%), Canada (40%) and the United Kingdom (37%) between 2010 and 2014.¹⁰ This variation may be partly explained by differences in the threshold for investigating suspicious symptoms, criteria for referral and access to oncology treatments.

Survival rates progressively decrease according to the stage of ovarian cancer and degree of spread (Table 1).¹¹ Reducing the time from presentation to referral should therefore be a key focus in primary care to help improve survival in line with other countries.

Table 1. Three-year survival rate for people with ovarian cancer in New Zealand by stage between 2010 – 2014.^{12, 13}

^*International Federation of Gynecology and Obstetrics

Epithelial ovarian cancer is the most common type of ovarian cancer

Ovarian cancer is classified into three main types:¹⁴

• Epithelial ovarian cancer – represents more than 90% of ovarian cancer diagnoses. This type of ovarian cancer is further classified into multiple subtypes (Figure 3); approximately 70% of epithelial ovarian cancers are classified as high-grade serous carcinoma.
• Sex cord-stromal tumours, e.g. granulosa cell tumours – median age at diagnosis is 58 years and only 12% occur in females aged under 40 years¹⁵
• Malignant germ cell tumours, e.g. teratomas – most common in females aged in their 20’s and two-thirds of diagnoses occur before age 40 years^{8, 15}

High-grade serous carcinomas, the most common type of ovarian cancer, usually originate in the fimbria portion of the fallopian tubes.¹⁶ These tumours grow quickly and spread early, therefore they are usually diagnosed at a late stage where prognosis is poor.¹⁷ Early diagnosis is more likely in females with other subtypes of epithelial ovarian cancer where growth is slower.¹⁷ Prognosis is generally better for people with non-epithelial ovarian cancer than those with epithelial ovarian cancer, however, this is dependent on the stage of cancer and age at diagnosis.¹⁵

Figure 3. Types of ovarian cancer, including subtypes of epithelial ovarian cancer, by frequency of diagnosis.¹⁴

Risk factors for ovarian cancer

Several factors influence the risk of developing ovarian cancer and certain exposures can have different effects on the various subtypes.¹⁸ Significant risk factors, and potential associations (Table 2), are listed below.

Ovulation

One of the most significant risk factors for epithelial ovarian cancer is the lifetime number of ovulatory cycles.¹⁴ Factors that increase the number of ovulatory cycles therefore increase the risk of ovarian cancer, e.g. early menarche, late menopause, nulliparity.¹⁴ Conversely, factors that interrupt ovulation can reduce ovarian cancer risk, e.g. oral contraceptive use (see below), pregnancy, breastfeeding, early onset menopause.^{14, 19} N.B. Other forms of contraception that disrupt ovulation may also reduce the risk of ovarian cancer, e.g. some studies link use of an intra-uterine device with a lower risk of ovarian cancer, however, further studies are required to provide definitive evidence.¹⁴

Repeated exposure to inflammation occurring in the distal fallopian tubules after ovulation may contribute to the increased risk of ovarian cancer over time, but the exact mechanism is unknown.²⁰ An alternative theory is that a greater number of ovulatory cycles is associated with an increased likelihood of spontaneous mutations from more cellular divisions, and therefore, an increased risk of malignancy.¹⁸

Genetics

Females with a family history of breast or epithelial ovarian cancer are at a significantly increased risk of developing ovarian cancer due to an inherited mutation.¹⁹ Mutations in BRCA1 and BRCA2 genes are the predominant genetic cause, with a small number of cases due to Lynch syndrome.¹⁹ Hereditary cancer syndromes are linked to 10 – 12% of ovarian cancer diagnoses;⁸ some sources report an even higher association.¹⁸ For further information, see: “Hereditary cancer syndromes”.

---

Table 2. Additional factors that are potentially associated with an increased risk of ovarian cancer.

Risk factors for non-epithelial ovarian cancer

Risk factors for sex cord-stromal tumours and malignant germ cell tumours are poorly understood due to the rarity of these. There is some evidence, however, that multiple pregnancies and use of the oral contraceptive pill may be protective against sex cord-stromal tumours.¹⁵

Diagnosing ovarian cancer

The diagnostic pathway for ovarian cancer involves the recognition of symptom patterns from a focused patient history, followed by investigation with a physical examination, including bimanual pelvic examination, serum CA 125 test and a pelvic ultrasound, if indicated (Figure 4).³ There is no evidence to support the use of investigations to detect ovarian cancer in people who are asymptomatic, including high-risk groups (see: “Hereditary cancer syndromes”).^{3, 4}

---

^*Avoid measuring CA 125 during menstruation if possible. Also measure human chorionic gonadotrophin and alpha fetoprotein if a patient is pre-menopausal.

^†Should include transvaginal ultrasound

Figure 4. A suggested approach to the diagnosis of ovarian cancer.^{3, 11}

---

Symptoms of ovarian cancer tend to be non-specific and are commonly related to another cause

Most people (70%) with early-stage ovarian cancer have been reported to present with one or more non-specific symptoms; abdominal or pelvic pain are usually the most common (see full list below).⁵ In isolation, symptoms have a low positive predictive value for ovarian cancer.⁶ Symptoms are more likely to be associated with ovarian cancer if they are in a post-menopausal female and/or if they are new, severe, unusual, recurrent or persistent, e.g. occurring 12 or more days per month.^{3, 4}

Symptoms of ovarian cancer may include:^3–5

• Abdominal bloating or distension
• Abdominal or pelvic pain
• Early satiety or loss of appetite
• Increased urinary frequency or urgency
• Changes in bowel habit^*
• Fatigue
• Unexplained weight loss
• Post-menopausal bleeding

^*New symptoms suggestive of irritable bowel syndrome (IBS) in females aged over 50 years are unusual; consider the possibility of ovarian cancer in these patients^{4, 11}

A daily symptom diary can help to quantify which symptoms the patient is experiencing and how often.¹⁷ A printable template for recording symptoms is available from: www.ovariancancer.net.au/page/134/signs-and-symptoms

Perform a physical examination and request laboratory tests for patients with symptoms of ovarian cancer

Palpate and percuss the abdomen to check for a mass or signs of ascites.¹¹ Also perform a bimanual examination to feel for adnexal masses, and check for lymphadenopathy.

Request a serum CA 125 test for all patients with symptoms suggestive of ovarian cancer (see: “The changing role of cancer antigen 125 in primary care”).^3, 11 N.B. Menstruation can raise CA 125 levels; avoid testing during this time.³ In pre-menopausal females, also measure human chorionic gonadotrophin and alpha fetoprotein, which may be elevated in those with a malignant germ cell tumour.¹¹

Additional laboratory tests may be requested (as indicated) to assess other aspects of the patient’s health and to identify other potential causes of the symptoms.

Tests may include:

• Full blood count
• Liver function tests
• CRP
• Calcium
• Creatinine and urea
• Electrolytes

Refer patients with abnormal examination findings for a pelvic ultrasound

If there are suspicious findings on physical examination, refer the patient for an urgent pelvic ultrasound,^* irrespective of CA 125 level.¹¹ The wait time for an ultrasound varies by region and by the degree to which cancer is suspected. In some situations it may be appropriate to discuss options for a privately funded ultrasound with the patient. If the results from the pelvic ultrasound are abnormal, refer the patient to a gynaecologist for further assessment.

^*Pelvic ultrasound for patients with suspected ovarian cancer usually includes a transvaginal ultrasound. It is recommended that this is discussed with patients prior to the referral so they know what to expect and because some patients may decline.

Manage patients with normal examination findings according to CA 125 level and menopausal status

Pre-menopausal:

• CA 125 level < 35 U/mL – consider differential diagnoses. Advise patients to return for re-evaluation if their symptoms worsen or persist for longer than three months. Recommend that they continue to keep a symptom diary which may help to quantify symptoms.¹⁷
• CA 125 level 35 – 200 U/mL – repeat serum CA 125 in six weeks:
  • If the CA 125 level has increased or remains elevated, refer the patient for a pelvic ultrasound and then discuss with or refer to a gynaecologist
  • If the CA 125 level has decreased, reassure the patient that it is unlikely that they have ovarian cancer; no further investigation is required unless symptoms worsen
• CA 125 level > 200 U/mL – refer the patient for a pelvic ultrasound. Once the ultrasound results are obtained, refer the patient to a gynaecologist.

Post-menopausal:

• CA 125 level < 35 U/mL – consider differential diagnoses. Advise patients to return for re-evaluation if their symptoms worsen or persist for longer than three months. Recommend that they continue to keep a symptom diary which may help to quantify symptoms.¹⁷
• CA 125 level > 35 U/mL – refer the patient for a pelvic ultrasound. Once the ultrasound results are obtained, refer the patient to a gynaecologist.

Risk of malignancy index may be calculated prior to secondary care referral

Some HealthPathways recommend calculating the risk of malignancy index (RMI) and including this in addition to the CA 125 result when requesting gynaecology referral; mark the referral as urgent if the RMI is high. The RMI uses menopausal status, CA 125 level and ultrasound results to estimate the likelihood that an identified mass is ovarian cancer. The RMI is recommended to be calculated by some international guidelines to guide decisions around referral to a gynaecological oncologist.¹¹ However, there is a lack of consensus on threshold levels for referrals and regardless of the RMI, patients with symptoms, an abnormal ultrasound or raised CA 125 level should be referred to secondary care.

For information on how to calculate the RMI, see Figure 4. A RMI calculator is also available from: www.mdcalc.com/calc/10103/risk-malignancy-index-rmi-ovarian-cancer

Reassess the patient if symptoms persist

For patients who were not initially referred to secondary care, but have unexplained symptoms that are persistent or worsening, reconsider differential diagnoses, including ovarian cancer as a cause.¹¹ It may be appropriate to repeat serum CA 125 testing, reconsider referral for a pelvic ultrasound and/or discuss with or refer the patient to a gynaecologist.³

Hereditary cancer syndromes

Mutations in BRCA1 and BRCA2 genes are associated with an increased risk of breast, ovarian and (less commonly) pancreatic cancer (Table 3).²⁹ It is estimated that 1 in 300 – 800 females has a BRCA mutation.⁸ Approximately 10% of people diagnosed with ovarian cancer have a BRCA mutation.⁸

Lynch syndrome is an inherited condition that results from a germline mutation in one of the four DNA mismatch repair genes.³⁰ It is associated with increased risk of colorectal, endometrial and ovarian cancers, among others (Table 3).³⁰ The estimated prevalence of Lynch syndrome is 1 in 279 people (males and females).³⁰ It is implicated in 2 – 3% of ovarian cancer diagnoses.⁸

BRCA genes and the DNA mismatch repair genes associated with Lynch syndrome are inherited in an autosomal dominant pattern, meaning that children of a carrier have a 50% chance of inheriting the mutation.³⁰

---

Table 3. Cumulative risk of cancer in females with a hereditary cancer syndrome.^29–31

Risk-reducing surgery for people with a hereditary cancer syndrome

A bilateral salpingo-oophorectomy is recommended for females with a BRCA mutation after childbearing is complete (or not desired), ideally between ages of 35 – 40 years.³ This reduces the risk of ovarian cancer by at least 90%.¹⁴ In BRCA mutation carriers, pre-menopausal bilateral salpingo-oophorectomy also reduces breast cancer risk by more than 50%.³ Removal of the fallopian tubes for people with a BRCA mutation is also important as these are the site of origin for some ovarian cancers.^{3, 16} Some studies have reported a 30 – 40% decrease in ovarian cancer risk after a tubal ligation or hysterectomy.¹⁴

Hysterectomy is not routinely recommended for people with a BRCA mutation, but some may opt to have their uterus removed if they are planning to take oestrogen-only menopausal hormone therapy or prophylactic tamoxifen, which are otherwise associated with an increased risk of endometrial cancer.³² People with Lynch syndrome may opt for a hysterectomy with bilateral salpingo-oophorectomy to reduce the risk of both endometrial and ovarian cancer.³³

For information on the follow-up and surveillance of a patient after curative-intent treatment for ovarian cancer, see: https://bpac.org.nz/2023/gynaecological-cancers.aspx.

---

There is a B-QuiCK summary available for this topic