Endometrial cancer: clinical review

Risk factors for endometrial cancer, management options, conducting a physical examination, prognosis and follow-up.

Light micrograph showing the spread of endometrial cancer cells (Picture: Garry DeLong/Science Photo Library)
Light micrograph showing the spread of endometrial cancer cells (Picture: Garry DeLong/Science Photo Library)

Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Further resources


Section 1: Epidemiology and aetiology

Endometrial cancer is considered to be less aggressive than other gynaecological malignancies. Patients with endometrial cancer tend to do better because it is possible to detect the disease at an early stage (women often present with postmenopausal bleeding). However, stage-for-stage survival is comparable to other gynaecological malignancies so healthcare professionals must remain vigilant in identifying endometrial cancer.

Most established risk factors for endometrial cancer arise from exposure of the endometrium to unopposed oestrogen. Around 37% of endometrial cancer cases are secondary to lifestyle and other external risk factors.1

Age
The peak incidence of endometrial cancer is between 65 and 75 years of age.

Menopause
Late menopause is a risk factor for endometrial cancer. This is thought to be secondary to prolonged exposure of the endometrium to unopposed oestrogens with the increased number of menstrual cycles.

Parity
Pregnancy and parity reduce the risk of endometrial cancer.

Obesity
Endometrial cancer is strongly associated with obesity. There is also an association with hypertension and type 2 diabetes.

Cigarette smoking
Cigarette smoking decreases the risk of endometrial cancer. This is thought to be because nicotine has anti-oestrogenic effects.

Unopposed oestrogen therapy

  • HRT: A Finnish study showed a 76% reduction in endometrial cancer risk in women taking continuous combined HRT. Women taking sequential HRT had a 70% increase in risk, depending on whether the progestogen was added monthly or three-monthly (180%). 2
  • Contraceptive pill: Use of the combined oral contraceptive with high oestrogen is a risk factor in premenopausal women.
  • Liver cirrhosis and polycystic ovary syndrome: These increase the risk of endometrial cancer.

Family history
Patients with hereditary non-polyposis colorectal cancer (HNPCC), otherwise known as Lynch syndrome (type 2), have a 70% lifetime risk of developing colon cancer and a 40–60% lifetime risk of endometrial cancer.3

Tamoxifen
Tamoxifen (an oestrogen modulator used in the treatment of breast cancer) increases the risk of endometrial cancer.

Epidemiology
Endometrial cancer is the most common pelvic gynaecological malignancy in developed countries,4 but it is only the fourth most common female cancer in the UK. Just over 9000 cases are diagnosed per year.5

Section 2: Making the diagnosis

Screening
There is no accepted method for endometrial cancer screening. Identification of the patients at high risk may help to detect endometrial cancer early.

A National Cancer Institute statement said that there was no role for endometrial screening in patients on tamoxifen for breast cancer. Endometrial cancers in this group were no worse than endometrial cancers in the general population for stage, histology and grade, and the prognosis was not altered by early detection through screening.6

Classification
Endometrial cancer is classified according to the FIGO (International Federation of Gynecology and Obstetrics) classification, updated in 2014. See box below:

Endometrial cancer classification
Stage I: Tumour confined to the corpus uteri
IA: Tumour confined to the uterus. No or less than half myometrial invasion
IB: Tumour confined to the uterus. More than half myometrial invasion
Stage II: Cervical stromal invasion but not beyond the uterus
Stage III: Local and/or regional spread of the tumour
IIIA: Tumour invades serosa or adnexa
IIIB: Vaginal and/or parametrial involvement
IIIC1: Pelvic node involvement
IIIC2: Para-aortic involvement
Stage IV: Tumour invades the bladder and/or bowel mucosa and/or distant metastases
IVA: Tumour invasion of the bladder and/or bowel mucosa
IVB: Distant metastases including abdominal metastases and/or inguinal lymph nodes.

Diagnostic assessment

Physical examination
Physical examination in patients with suspected endometrial cancer is often normal. It should include an inspection and palpation of the vulva and vagina to exclude other causes for vaginal bleeding. A bimanual rectal and vaginal examination should be performed to assess the pouch of Douglas, parametria and adnexae. An ovarian mass (oestrogen secreting granulosa cell or early ovarian cancer) may be noted.

Preoperative workup
Preoperative workup should include a full blood count, glucose and liver and renal function tests. A cystoscopy with or without sigmoidoscopy may also be performed if bladder or rectal involvement is suspected.

When endometrial cancer is suspected, the following may be used to aid the diagnosis:

  • Transvaginal ultrasound: performed by measuring the thickness of both endometrial surfaces. Usually endometrial thickness cut-off is 5mm but this is not reliable for perimenopausal women taking HRT. Furthermore, in women taking cyclical HRT, the thickness could change depending on when in the cycle the measurement is taken.
  • Outpatient endometrial biopsy
  • Outpatient hysteroscopy
  • Dilatation and curettage: performed under general anaesthesia.

Staging assessment

Imaging
A chest X-ray is essential in non-endometroid type cancers, for example serous carcinoma and carcinosarcomas of the endometrium. MRI is the optimum method for assessing the degree of myometrial invasion in endometroid tumours, the stage of disease, pelvic and para-aortic lymph node involvement, and the presence of occult cervical involvement.

Section 3: Managing the condition

All patients should be discussed in a multidisciplinary team meeting to assess risk and best place of treatment. Management of endometrial cancer depends on the stage of the disease.

Stage I
The recommended primary treatment for stage I endometrial cancer is complete surgical staging:

  • laparotomy or laparoscopy with peritoneal lavage for cytology
  • careful inspection and or palpation of the abdomen and pelvis (diaphragm, liver, omentum, pelvic and para-aortic lymph nodes, pelvic and bowel peritoneal surfaces).

This should be followed by total (abdominal or laparoscopic) hysterectomy and bilateral salphingo-ophorectomy. It is oncologically safe to offer a laparoscopic approach for managing endometrial cancer.

Stage II
Radical hysterectomy for cervical involvement has been recommended for stage II cancer. In the UK these patients may receive radiotherapy, usually postoperatively.

Stage III
In stage III surgery should include total abdominal hysterectomy and bilateral salpingo-ophorectomy, and aim to debulk disease. Adjuvant pelvic irradiation should be employed.

Stage IV
Treatment for stage IV cancer should be individualised to achieve local control. Pulmonary metastases are the most common site of distant disease.

A combination of surgery, radiotherapy for palliative local control, and chemotherapy for distant control can be used.

Progestogens have been demonstrated to be useful for pulmonary metastases.

Section 4: Prognosis

Prognostic factors include grade, myometrial depth of involvement, endocervical involvement and cell type.

Distant metastatic spread is primarily via the lymphatic system. Patients with stage I grade 1 have a 0–5% risk of pelvic and para-aortic lymphatic involvement. Higher grade and stage have a 10–40% risk of involvement. Lymphovascular space invasion is present in 15% of stage I cancers and this is associated with higher recurrence rates. Positive peritoneal cytology is associated with a poorer prognosis.

Recurrent disease
Most recurrences occur within the first 36 months of treatment. Some 75% of local recurrences present with vaginal bleeding or pelvic pain. Patients should be investigated to determine if the recurrence is isolated and that there is no systemic spread.

Women with recurrences have a:

  • 33% mortality within five years
  • 50% risk of local recurrence
  • 29% risk of distant recurrence

Managing recurrent disease
If the patient has had no previous radiotherapy treatment, then pelvic radiotherapy is appropriate. Patients who have had prior radiation with isolated central pelvic recurrences and no evidence of lymph node involvement should be considered for exenterative surgery. Progestogens and tamoxifen have been demonstrated to produce clinical response in 20% of patients with recurrent disease.

Section 5: Case study

A 70-year-old nulliparous woman attends the local rapid access clinic with heavy vaginal bleeding that has persisted for a week.

transvaginal ultrasound

She has insulin-dependent diabetes and was diagnosed with breast cancer two years ago, for which she is taking tamoxifen. She has no surgical history of note. She has never taken HRT and does not smoke. Her cervical smears are up-to-date and normal. Her BMI is 55.

The patient has a transvaginal ultrasound (image right).

The endometrial thickness is 19mm. The endometrial thickness cut-off point for postmenopausal women should be 4-5mm, so endometrial sampling is required.

The patient has endometrial sampling performed at the outpatient clinic. The histology report reads ‘insufficient sample’.

An inpatient hysteroscopy and biopsy is now needed. This confirms endometrial cancer. MRI demonstrates that the cancer is confined to the uterus with less than 50% myometrial invasion. So the FIGO classification is 1A.

Following discussion at MDT the recommended management is total hysterectomy and bilateral salpingo-opherectomy.

Section 6: Further resources

Guidelines

National Cancer Institute. Endometrial Cancer Screening (PDQ®): health professional version. Updated 2015.

  • Dr Abdelmageed Abdelrahman is a trainee in obstetrics and gynaecology, Northern Ireland Deanery

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References

  1. Parkin DM, Boyd L, Walker LC. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Summary and conclusions. Br J Cancer 2011;105:S77–S81.
  2. Jaakkola S, Lyytinen H, Pukkala E et al. Endometrial cancer in postmenopausal women using estradiol-progestin therapy. Obstet Gynecol 2009;114:1197–204.
  3. Gruber SB. New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 2006;130:577–87.
  4. Ferlay J, Shin HR, Bray F et al. ?GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. ?Lyon: International Agency for Research on Cancer; 2010.
  5. Cancer Research UK. Uterine cancer incidence statistics. Accessed 22 August 2016
  6. National Cancer Institute. Endometrial Cancer Screening (PDQ®): health professional version. Updated 2015.

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