Pathogenesis

Although carcinoma of the endometrium is basically adenocarcinoma, the histology is not so simple:

• Endometrioid represents 75-80% and includes ciliated adenocarcinoma, secretory adenocarcinoma, papillary or villoglandular and adenocarcinoma with squamous differentiation.
• Uterine papillary serous is less than 10%.
• Mucinous 1%.
• Clear cell 4%.
• Squamous cell is less than 1%.
• Mixed is 10%.

It may be undifferentiated.

Epidemiology

90% of women with endometrial cancer are over 50 years of age. It affects about 1 woman in 100, usually in the mid to late 50s but it can be into later life.

It is most common in Western societies but is becoming more common in Asia. In the UK there are about 7,400 new cases per year.^[1]

Risk factors

Prolonged periods of unopposed oestrogen are the main risk factor. Unopposed oestrogen means when oestrogen is not modified by the effects of progesterone.

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 carcinoma include:^[2]

• Being nulliparous - this increases the risk 2- or 3-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:
  • Diabetes mellitus and hypertension also increase the risk but this may simply be linked to obesity.
  • Polycystic ovarian syndrome and (insulin resistance) metabolic syndrome are also associated with obesity.
  • The greater the obesity, the greater the risk.
• Women who have hereditary nonpolyposis colon cancer (HNPCC)^[3] - have a 22-50% chance of developing endometrial carcinoma and are likely to get it about 15 years earlier than other women. There is a lack of evidence to suggest benefit but annual endometrial biopsy after the age of 35 is suggested.
• Exogenous hormones - can have markedly different effects. The anti-oestrogenic or pro-oestrogenic effect of a synthetic hormone varies between tissues. For example, tamoxifen is used to treat breast cancer because it has an anti-oestrogenic effect on breast tissue but it has a pro-oestrogenic effect on bone, reducing the risk of osteoporosis, and a pro-oestrogenic effect on the endometrium, increasing the risk of endometrial carcinoma. Tamoxifen is associated with an increased risk of endometrial cancer that tends to extend after five years.^[4] In the treatment of breast cancer, benefits outweigh risks but its use in prevention of the disease has been questioned.
• Tibolone - this doubles the risk of endometrial carcinoma compared with those not on hormone replacement therapy (HRT).
• Taking combined oral contraceptives - this reduces the risk of developing endometrial cancer in later life.^[5] Prolonged use increases the benefit that lasts for at least 15 years after stopping.

HRT

The Million Women Study found that HRT containing oestrogen alone increased the risk of endometrial cancer (compared to women who had never taken HRT).^[6] Progestogens, however, counteracted the adverse effect of oestrogens.The effect of continuous combined preparations was a reduction in risk, while there was no significant risk (or protection) from use of cyclical preparations. The risk of endometrial cancer was also increased by tibolone.^[5]

Since the million women were recruited in the late 1990s, around 1,300 have developed endometrial cancer.

Presentation

History

Classically, endometrial carcinoma presents as postmenopausal bleeding (PMB) and, although this is not the only cause, it must be excluded. 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.)

Investigation

Transvaginal ultrasound (TVUS) scan

Where sufficient local skills and resources exist, TVUS scan is an appropriate first-line procedure to identify which women with PMB are at higher risk of endometrial cancer.

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. The threshold in the UK is 5 mm, which provides adequate sensitivity without excessive false-positive rates in most women and a false-negative rate of 0.25-.50%.^[7] European guidelines have a lower threshold (3-4 mm) but will lead to greater numbers of biopsies.^[1][8] Some pathology may be missed and it is recommended that hysteroscopy and biopsy should be performed if clinical suspicion is high.

Models have been developed to take personal characteristics into account when predicting the risk of cancer.^[9]

Endometrial biopsy

A definitive diagnosis in PMB is made by histology. Historically, endometrial samples have been obtained by dilatation and curettage. Nowadays it is more usual to obtain a sample by endometrial biopsy, which can be undertaken using samplers. Endometrial biopsy can be performed as either an outpatient procedure or under general anaesthetic. 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.

A significant development has been direct referral to 'one stop' specialist clinics.^[10] At such clinics several investigations are available to complement clinical evaluation, including ultrasound, endometrial sampling techniques and hysteroscopy. Following such assessment, reassurance can be given, or further investigations or treatment can be discussed and arranged.

Staging

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:^[1]
Stage I endometrial cancer 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 involves the corpus and there is invasion into the cervical stroma, but has not extended outside the uterus.
Stage III has local or regional spread beyond 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 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.

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.

Management

Treatment depends upon the stage:^[1]

• Stage I requires total abdominal hysterectomy with bilateral salpingo-oophorectomy. The role of lymphadenectomy is debated.
• 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 are best treated with maximal de-bulking surgery. Although there is no conclusive evidence, a combination of surgery, radiation and chemotherapy is usual.
• Open surgery is traditionally used, but evidence supports laparoscopic methods, with equivalent survival rates and better postoperative recovery.^[11]
• When surgery is not possible because of medical contra-indications, external beam radiotherapy and intracavity radiotherapy may be used.
• Progestins are currently not recommended.
• Recurrence may respond to radiotherapy. Radical radiotherapy for local recurrence is effective in over half the cases.
• Doxorubicin gives a good but often temporary response.
• Paclitaxel and carboplatin are also used.
• Tamoxifen may have a useful adjuvant effect.

Prognosis

The overall 20-year survival rate for all forms of endometrial carcinoma is about 80%.^[1] This in comparison to 62% for clear cell and 53% for papillary carcinomas.

Prognosis depends on the type and stage of tumour. Recent changes in the FIGO staging system have created debate as to the relative efficacy of old and new systems in predicting survival.^[12] When advising patients, survival figures are approximately:

• Stage 1 has 92% five-year survival.
• Stage 2 has 75% five-year survival.
• Stage 3 has 50% five-year survival.
• Stage 4 has 20% five-year survival.