Endometrial cancer – early detection and referral

Endometrial cancer is the most common gynaecological cancer

Endometrial cancer^* is the most common gynaecological cancer with an average of 627 new diagnoses (17.1 per 100,000 females; from 2015 – 2020) and 136 related deaths (3.3 per 100,000 females; from 2015 – 2018)^† each year in New Zealand;^** in 2020 it was the fifth most common cancer in females.⁷ The risk of endometrial cancer increases with age and it primarily affects females who are post-menopausal with an average age at diagnosis of 60 – 65 years.⁸ This is reflected in New Zealand data where the highest incidence of endometrial cancer is among females aged 45 – 64 years.⁹

^*Data in New Zealand are only available for uterine cancer overall; endometrial cancers represent approximately 95% of all uterine cancer diagnoses³

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

^**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.

Compared with other gynaecological cancers, people with endometrial cancer are usually symptomatic, and therefore more commonly diagnosed when their cancer is at an early stage and still confined to the uterus.^2, 10 The early detection and treatment of endometrial cancer is associated with a good prognosis and a five-year survival rate of up to 90%.^2, 11

The overall incidence of endometrial cancer is increasing over time

The overall incidence of endometrial cancer is increasing both in New Zealand (Figure 1) and worldwide, which is thought to reflect a rise in the prevalence of risk factors, particularly obesity and an ageing population (see: “Risk factors for endometrial cancer”).^{10, 12} The incidence of endometrial cancer in New Zealand is similar to other comparable countries, e.g. Australia, United Kingdom.¹³

Although the risk of endometrial cancer increases with age, there has been an increase in the number of people diagnosed with endometrial cancer at a younger age, i.e. aged under 40 – 50 years.^{10, 14} In particular, the incidence is increasing in younger females who are obese and Pacific peoples.^{14, 15} Mortality rates in New Zealand have remained relatively consistent over time (Figure 1).

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Figure 1. Age-standardised incidence and mortality rates (per 100,000 females) for uterine cancer between 2015 and 2018 in New Zealand.⁷ N.B. Data in New Zealand are only available for uterine cancer overall; endometrial cancers represent approximately 95% of all uterine cancer diagnoses.³ 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.

There are significant ethnic disparities associated with endometrial cancer

• Māori and Pacific peoples have a higher incidence of endometrial cancer each year, compared to European/Other (Figure 2).¹⁶ They are also more likely to be diagnosed with endometrial cancer at a higher grade and have poorer survival.^{12, 17}
• Pacific peoples have the highest incidence of endometrial cancer amongst any ethnic group and this is increasing more rapidly than in Māori and European populations.¹⁵ In 2019 (most recent ethnicity data available), the age-standardised incidence rate for Pacific peoples was 78.7 per 100,000 females, which was 2.8 times greater than the rate in Māori (27.8 per 100,000 females) and 6.0 times greater than in European/Other ethnic groups (13.1 per 100,000 females).¹⁶
• In a study published in 2009 it was estimated that 37% of endometrial cancers diagnosed in Māori and 48% in Pacific peoples were attributable to increased body mass index.¹⁸ As obesity rates continue to rise, it is likely that these numbers have increased further.
• There is a higher incidence of endometrial cancer among people living in low socioeconomic areas.¹²

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Figure 2. Age-standardised incidence rate (per 100,000 females; 95% confidence intervals)* for uterine cancer by ethnicity between 2015 and 2019 in New Zealand.¹⁶ N.B. Data in New Zealand are only available for uterine cancer overall; endometrial cancers represent approximately 95% of all uterine cancer diagnoses.³ Incidence data by ethnicity are not yet available for 2020.

^* Confidence intervals have been included as Pacific peoples have a smaller sample size than other groups, so rate estimates are less stable (i.e. rates are more likely to vary from year-to-year due to chance)

Risk factors for endometrial cancer

Most endometrial cancers are aetiologically linked to excessive exposure to endogenous or exogenous oestrogen unopposed by progesterone, with the most significant risk factors being increasing age (≥ 55 years) and obesity.^{11, 10} Some people may also have a genetic predisposition; familial cancer syndromes are estimated to cause up to 5% of all endometrial cancers.¹² Table 1 details additional risk factors.

• Obesity. The lifetime risk of endometrial cancer in females is 3% but with every five unit increase in a person’s body mass index, the relative risk increases by more than 50%.¹⁰ Excess body weight is associated with high levels of endogenous oestrogen due to the conversion of androgens to oestrogen in adipose tissue.¹¹ Higher oestrogen levels then lead to greater stimulation of the endometrium to proliferate and therefore, an increased risk of endometrial cancer.¹¹

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Table 1. Risk factors for endometrial cancer.^{3, 8, 10, 11}

Some people may be able to modify their risk of endometrial cancer

Many cases of endometrial cancer cannot be prevented, however, there is evidence that even slight changes to certain predisposing factors, e.g. obesity, can significantly reduce the risk of endometrial cancer.⁸ While an estimated six out of every ten diagnoses of endometrial cancer are attributed to obesity, more than half of all people diagnosed are not aware of this risk.¹⁷ Given the general gap in awareness regarding the modifiable risk factors for endometrial cancer, consider whether patients might benefit from a discussion on risk-reducing measures (below), if appropriate.⁸

Protective factors include:^{2, 3, 8, 10}

• A healthy diet and physical activity to maintain a healthy body weight. Studies have shown a significant reduction in endometrial cancer risk (up to 81%) in females who were obese who had bariatric surgery and maintained a normal body weight.²⁰
• High lifetime exposure to endogenous or exogenous progesterone. Progesterone opposes the risk of excessive oestrogen. The following factors have been shown to reduce the risk of endometrial cancer:
  • Regular menstrual cycles
  • Pregnancy
  • Breastfeeding
  • Prolonged combined oral contraceptive use. Risk reduces with longer duration of use and persists for several decades after cessation.
  • Combined oestrogen and progestogen menopausal hormone therapy
  • Use of a progestin-releasing intrauterine system, e.g. Mirena^*. This may be an effective risk reduction strategy for people at high risk of endometrial cancer, e.g. those with obesity.²¹

^*There is no evidence of an association between copper intrauterine devices and endometrial cancer⁸

Most people with endometrial cancer are symptomatic

There are no screening programmes for the early detection of endometrial cancer in the general population or for high-risk groups.^{4 ,10} However, symptoms of endometrial cancer usually appear early, and approximately 95% of people diagnosed with endometrial cancer are symptomatic.¹ Therefore, prompt recognition and investigation of suspicious symptoms is important to achieve optimal survival outcomes.

Abnormal bleeding (usually post-menopausal bleeding) is one of the most commonly reported symptoms in people with endometrial cancer.^{1, 2} The presence of multiple relevant symptoms and signs (see below), particularly in conjunction with risk factors should increase suspicion of endometrial cancer.³

Symptoms or signs of endometrial cancer may include:^{3, 10, 11}

• Abnormal bleeding including post-menopausal, inter-menstrual and post-coital bleeding
• Abnormal vaginal discharge
• Unexplained weight loss
• Pelvic pain
• Abdominal pain or distension
• Urinary or bowel dysfunction

Although the cause of post-menopausal bleeding is usually benign, e.g. vaginal atrophy, polyps, it is important not to miss the 5 – 10% of cases where endometrial cancer is the underlying cause.^{10, 23} Some clinicians practise by the rule that “post-menopausal bleeding is endometrial cancer until proven otherwise”.

For further information on post-menopausal bleeding, see: bpac.org.nz/2019/bleeding.aspx

Diagnosing endometrial cancer in pre-menopausal females

The diagnosis of endometrial cancer in females who are pre-menopausal is often difficult as symptoms tend to be non-specific and commonly related to another cause, e.g. heavy, prolonged or inter-menstrual bleeding.¹⁰ Given the low risk of endometrial cancer in this population, the decision of whether to investigate for this further should be guided by relevant risk factors in the patient history, e.g. family history of cancer syndromes, obesity, ethnicity (e.g. Pasifika), and clinical suspicion from examination findings.^{2, 10}

Begin initial workup with a focused history and physical examination

When assessing a patient with symptoms suggestive of endometrial cancer, begin by taking a history to identify any relevant risk factors such as family history, ethnicity (e.g. Pasifika), or factors that would result in excess exposure to unopposed oestrogen, e.g. tamoxifen use, oestrogen-only menopausal hormone therapy, obesity.^{3, 4}

If abnormal uterine bleeding is reported, determine the nature of the bleeding, including frequency, duration, quantity and precipitating factors, and ask about any associated symptoms such as pain or discomfort, fever and changes in bladder or bowel function. Consider potential causes, e.g. polycystic ovary syndrome, hypothyroidism, medicines such as anticoagulants, antidepressants or hormonal contraceptives. N.B. People newly initiated on menopausal hormone therapy may experience bleeding within the first three to six months of use and do not usually require further investigation. If bleeding occurs or persists after six months of continuous use, refer the patient for further assessment, e.g. for an ultrasound; manage according to the results.

Perform an abdominal and pelvic examination, including bimanual and speculum examination to identify any abnormalities and to exclude potential local causes of the patients symptoms.^{4, 23} Physical examination findings are often normal in patients with early stage endometrial cancer but the presence of an enlarged uterus on bimanual examination or palpable inguinal or supraclavicular nodes should increase suspicion of more advanced cancer.¹

Cervical screening should be offered to patients who are due. Further investigation is required if endometrial cells are detected by cervical cytology in people who are post-menopausal due to an increased risk (3 – 5%) of endometrial cancer.⁴ Also swab for sexually transmitted infections, e.g. chlamydia, gonorrhoea, if indicated.

There are no specific laboratory tests (other than analysis of biopsy if performed) for the diagnosis of endometrial cancer, but they may be requested (as indicated) to assess other aspects of the patient’s health and to identify any other potential underlying cause of the symptoms, e.g. hypothyroidism. Most laboratory test results will be normal except in patients with significant bleeding, who may be anaemic. Tests may include:^{19, 23, 24}

• Full blood count
• Ferritin
• Liver function tests
• Coagulation tests (prothrombin time, international normalised ratio, activated partial thromboplastin time and fibrinogen)
• Thyroid stimulating hormone
• HbA_1c
• Urine pregnancy test or serum hCG (if appropriate)

Refer patients with suspicion of endometrial cancer for a pelvic ultrasound and endometrial biopsy (pipelle)

A pelvic ultrasound^* and endometrial biopsy (pipelle) are generally recommended for patients with suspected endometrial cancer.²³ The optimal order of investigations varies depending on access and service capacity, clinical judgement and patient preference.⁴

^*Pelvic ultrasound for patients with suspected endometrial 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.

Referral for a pelvic ultrasound is most commonly requested first to exclude structural causes of the patient’s symptoms, e.g. polyps, and usually includes a transvaginal ultrasound to measure endometrial thickness.^{4, 23} Patients with endometrial pathology or a thickened endometrium (e.g. ≥ 5 mm; check local HealthPathways for regional guidance) on ultrasound require follow-up with a pipelle biopsy.^{10, 23} However, wait times for a pelvic ultrasound can be long in some regions; if wait times are likely to exceed two weeks or if there is difficulty for the patient to access care, the pipelle biopsy should be performed first.

A pipelle biopsy is used to take a sample of the endometrial tissue and has high diagnostic accuracy for detecting endometrial cancer.²³ Ideally, the pipelle biopsy should be performed in primary care, but resource limitations may mean that patients require timely referral to another general practice colleague or other provider. Prior to the biopsy procedure, provide patients with an information leaflet: www.healthinfo.org.nz/patientinfo/27989.pdf

N.B. Pipelle biopsies are contraindicated during pregnancy. Cautions include the presence of cervicitis or endometritis, pelvic inflammatory disease or other infection, coagulation disorders, anticoagulant use; check HealthPathways for a complete list of cautions. It is difficult to perform a pipelle biopsy on a patient with cervical stenosis, referral to a gynaecologist is usually required.

• Request an urgent pelvic ultrasound for patients with post-menopausal bleeding.¹⁰ If post-menopausal bleeding is persistent or recurrent (i.e. a new episode of bleeding after several months of no bleeding) also arrange referral to gynaecology irrespective of the ultrasound results.

• If a patient is taking tamoxifen and reports post-menopausal bleeding, organise a pipelle biopsy and request gynaecology referral for consideration of a hysteroscopy^* (or request hysteroscopy directly, if available)⁴ – annotate referral with “high suspicion of cancer”

  ^*Both endometrial biopsy and hysteroscopy are required in these patients as pelvic ultrasound is not sensitive nor specific for hyperplasia due to the tamoxifen-induced changes to the endometrium

Results from pelvic ultrasound and pipelle biopsy inform management decisions

If endometrial thickness from transvaginal ultrasound is < 8 mm and the results from the pipelle biopsy are normal, initiate treatment for atrophic vaginitis. Place a recall to review the patient within two months; if bleeding persists, refer the patient to a gynaecologist for further assessment.

For information on the treatment of a patient with atrophic vaginitis, see: bpac.org.nz/bpj/2014/september/vulvovaginal.aspx

Referral to gynaecology is generally indicated if:

• Pelvic/transvaginal ultrasound shows fibroids causing significant uterine enlargement or cavity distortion, endometrial polyp(s), high-risk features or other abnormalities such as cystic spaces
• The endometrial thickness is:
  • < 5 mm and there is persistent bleeding despite treatment for atrophia
  • 5 – 8 mm and the pipelle biopsy sample is inadequate
  • > 8 mm, irrespective of the results from pipelle biopsy
• The pipelle biopsy:
  • Is indicated but cannot be performed in primary care
  • Is inadequate, insufficient or limited
  • Shows hyperplasia without atypia

• Urgently refer patients to a gynaecologist if the results show hyperplasia with atypia or endometrial carcinoma. Annotate referral with “high suspicion of cancer”.

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

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