Endometrial cancer

What is endometrial cancer?

Cancer of the endometrium, or uterine cancer, is mainly adenocarcinoma arising from the lining of the uterus and is an oestrogen-dependent tumour. This is distinct from carcinoma of the cervix which is squamous cell carcinoma. Cancer of the body of the uterus could include myometrial sarcoma.

Types of endometrial cancer

The vast majority of cancers of the endometrium (80%) are adenocarcinomas. They may be undifferentiated.

There are two main types of endometrial cancer, corresponding to oestrogen-dependent endometrioid (type 1) and oestrogen-independent non-endometrioid carcinomas (type 2).¹

Who gets endometrial cancer? (Epidemiology)

90% of women with endometrial cancer are over 50 years of age. More than 90% of cases occur in women older than 50 years of age, with a median age of 63 years.¹ Endometrial cancer is the fourth most common cancer in women in the UK.²

It is most common in Western societies but is becoming more common in Asia. In the UK there are about 8,600 new cases per year.³

Endometrial cancer risk factors

Prolonged periods of unopposed oestrogen are the main risk factor. When oestrogen is not modified by the effects of progesterone, this is termed 'unopposed oestrogen'.

This may occur as a result of medication or in anovulatory cycles where the corpus luteum does not mature and secrete progesterone. The histological diagnosis can be difficult in that gross endometrial hyperplasia can look like a well-differentiated carcinoma.

Risk factors for endometrial cancer include:

• Being nulliparous - this increases the risk two- or three-fold. This may be by choice or as a result of infertility with anovulatory cycles.

• Menopause past the age of 52.

• Obesity - raises oestrogen levels:⁴

  • The greater the obesity, the greater the risk.

  • In the UK, approximately 50% of endometrial cancers are attributable to obesity.

• Endometrial hyperplasia is comprised of a spectrum of changes in the endometrium, ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma.⁵

• In a 2020 meta-analysis of studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6%. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%).⁶

• Women who have hereditary nonpolyposis colon cancer (HNPCC) have a lifetime risk of 30-60% of developing endometrial cancer.¹

• Polycystic ovary syndrome.⁷

• Diabetes mellitus - there is slight but significant and consistent increase in the risk of incidental endometrial cancer among women with type 2 diabetes mellitus.⁸

• Tamoxifen is associated with an increased risk of endometrial cancer. However, the risk of endometrial cancer is low in those women aged under 50 years who take tamoxifen for breast cancer prevention.⁹

• Unopposed oestrogen increases the risk of endometrial cancer. Progesterone, however, counteracts the adverse effect of oestrogens.

• Taking combined oral contraceptives (birth control pills) actually reduces the risk of developing endometrial cancer in later life.¹⁰

Endometrial cancer symptoms

History

Classically, endometrial cancer presents as postmenopausal bleeding (PMB) and, although this is not the only cause, it must be excluded. In a 2018 study the pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumour stage.¹¹ The pooled risk of endometrial cancer among women with PMB was only 9% (95% CI, 8%-11%), varying by use of hormone therapy and geographical region.

It may also present around or before the menopause in about 20-25% of cases with irregularities of the menstrual cycle.

Examination

Unless the disease is well advanced there is unlikely to be any physical abnormality.

If a recent cervical smear has not been taken this should be done. (Occasionally, a smear may show clumps of adenocarcinoma but this is unreliable and is not a substitute for further investigation.)

Investigating endometrial cancer

Transvaginal ultrasound (TVUS) scan

TVUS scan is the usual first-line procedure to identify which women with PMB are at higher risk of endometrial cancer.¹³

The mean endometrial thickness in postmenopausal women is much thinner than in premenopausal women. Thickening of the endometrium may indicate the presence of pathology. In general, the thicker the endometrium, the higher the likelihood of important pathology - ie endometrial cancer being present.

TVUS using a 3-mm cut-off has high sensitivity for detecting endometrial cancer and can identify women with PMB who are highly unlikely to have endometrial cancer, thereby avoiding more invasive endometrial biopsy.¹⁴

Some centres use 4 mm or even 5 mm as a cut-off for endometrial biopsy.

In addition, malignant and benign endometrial patterns can often be determined by TVUS which can help diagnosis.¹⁵

NB: the incidence of endometrial cancer in postmenopausal women with thickened endometrium on TVUS without vaginal bleeding is low.¹⁶

Endometrial biopsy

A definitive diagnosis in PMB is made by histology. In the past, endometrial samples were obtained by dilatation and curettage. A sample is now usually obtained by endometrial biopsy taken during an outpatient hysteroscopy. All methods of sampling the endometrium will miss some cancers.

Hysteroscopy

Hysteroscopy and biopsy (curettage) are the preferred diagnostic technique to detect polyps and other benign lesions. Hysteroscopy may be performed as an outpatient procedure, although some women will require general anaesthetic.

Diagnostic accuracy for hysteroscopy is high for endometrial cancer, polyps and submucous myomas but only moderate for endometrial hyperplasia.¹⁷

NB: many women also have a CXR, blood tests (FBC and LFTs). All women diagnosed with endometrial cancer should also be offered testing for Lynch syndrome, according to new guidance from NICE.¹⁸ This inherited condition increases the risk of certain types of cancer, including endometrial and colorectal cancer.

Endometrial cancer staging¹⁹

Total abdominal hysterectomy with bilateral salpingo-oophorectomy is required both as a primary treatment and for the purpose of staging.

The International Federation of Obstetrics and Gynaecology (FIGO) gives the following staging:

Stage I endometrial cancer
This is carcinoma confined to the corpus uteri:

• IA confined to endometrium with no, or less than half, myometrium invaded.

• IB invasion equal to, or more than half of, myometrium.

Stage II endometrial cancer
This involves the corpus and there is invasion into the cervical stroma but it has not extended outside the uterus.

Stage III endometrial cancer
This has local or regional spread outside the uterus:

• Stage IIIA is invasion of serosa or adnexa or positive peritoneal cytology and possibly more than one of these.

• Stage IIIB is vaginal or para-metrial metastases.

• Stage IIIC is metastases to pelvic (IIIC1) or para-aortic (IIIC2) lymph nodes, or both.

Stage IV endometrial cancer
This is involvement of the bladder or bowel mucosa, or distant metastasis:

• Stage IVA is involvement of bowel or bladder mucosa.

• Stage IVB is distant metastases including nodes in the abdomen or inguinal region.

Endometrial cancer further grouping
A further grouping with prognostic significance is possible with FIGO approval, based on degree of tumour differentiation as follows:

• G1 is 5% or less of a non-squamous or non-morular solid growth pattern.

• G2 is 6-50% of a non-squamous or non-morular solid growth pattern.

• G3 is over 50% of a non-squamous or non-morular solid growth pattern.

Endometrial cancer treatment and management¹⁹

Treatment options depend upon the endometrial cancer stage. Increasingly, laparoscopic surgical methods are undertaken, with equivalent survival rates and better postoperative recovery compared to open surgery.²⁰

When surgery is not possible because of medical contra-indications, external beam radiotherapy and intracavity radiotherapy may be used.

Stage I

• Stage I requires total abdominal hysterectomy with bilateral salpingo-oophorectomy. The role of lymphadenectomy is debated.

• The use of progestogen in the treatment of stage IA endometrioid endometrial cancer without myometrial invasion is an option for those women who want to preserve their fertility.

Stage II

• In stage II there should be radical hysterectomy with systematic pelvic node clearance. Para-aortic lymphadenectomy may also be considered. Lymphadenectomy is important for staging and as a guide for adjuvant therapy.

Stage III and IV

• Stage III and IV are best treated with maximal de-bulking surgery in those women with good performance status and resectable tumour. Although there is no conclusive evidence, a combination of surgery, radiation and chemotherapy is usual.

• Sentinel lymph node biopsy may be undertaken in some cases.²¹

Adjuvant chemotherapy

• Adjuvant treatment is tailored according to histology and stage.²²

• Postoperative platinum-based chemotherapy is associated with a small benefit in progression-free survival and overall survival irrespective of radiotherapy treatment.

• There is moderate-quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer.²³

Recurrence

• Recurrence may respond to radiotherapy. Radical radiotherapy for local recurrence is effective in over half the cases.

• The standard treatment of vaginal recurrence is radiation therapy.

• Systemic treatment of metastatic and relapsed disease may involve endocrine therapy or cytotoxic chemotherapy.

Endometrial cancer prognosis

Those women who are diagnosed early have a far better prognosis. Most recurrences will occur within the first three years after treatment. The majority of women (80% in stage I) will be diagnosed with early-stage disease and are cured with surgery.²⁷ For this group of women five-year survival rates are over 95%; however, five-year survival rates are much lower if there is regional spread or distant disease (68% and 17%, respectively).¹

The overall 20-year survival rate for all forms of endometrial cancer is about 80%. This in comparison to 62% for clear cell and 53% for papillary carcinomas.