Endometrial Carcinoma

Carcinoma of the endometrium is mainly adenocarcinoma arising from the lining of the uterus and is an oestrogen dependent tumour. This is distinct from carcinoma of cervix that is squamous cell carcinoma. Cancer of the body of the uterus could include myometrial sarcoma.

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

• Endometrioid represents 75 to 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.

This malignancy is rare below the age of 40 and affects about 1 woman in 100, usually in the mid to late 50s but it can be into later life. It is commonest in western societies but is becoming more common in Asia. In the UK there are about 5,100 new cases per year.

Risk Factors

• Being nulliparous 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) syndrome X are also associated with obesity
• The greater the obesity, the greater the risk
• Women who have hereditary nonpolyposis colon cancer (HNPCC)² have a 22 to 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-oestrogen effect on breast tissue but it has a pro-oestrogen effect on bone, reducing the risk of osteoporosis and a pro-oestrogen effect on the endometrium, increasing the risk of endometrial carcinoma. Tamoxifen is associated with an increased risk of endometrial cancer that tends to be at a more advanced stage and with a less favourable histology.³ In the treatment of breast cancer benefits outweigh risks but its use in prevention of the disease has been questioned.
• Tibolone doubles the risk of endometrial carcinoma compared with those not on HRT.
• Taking combined oral contraceptives reduces the risk of developing endometrial cancer in later life.⁴ Prolonged use increases the benefit that lasts for at least 15 years after stopping.

The Million Women Study

This study⁵ showed that women taking unopposed oestrogen are at increased risk of endometrial carcinoma compared to those who have never taken HRT but if progestogen is added this increased risk disappears.
The risk of breast cancer is greater in those on HRT with progestogen, than unopposed HRT or tibolone. Breast cancer is about 8 times more frequent than endometrial cancer. The study showed that for every 100 women on combined HRT for 5 years, 3 will develop either breast or endometrial carcinoma, compared with 2.5 for those on unopposed HRT or tibolone and 1.5 for those not on HRT.
Since the million women were recruited in the late 1990s, around 1,300 have developed endometrial cancer and over 10,000 have developed breast cancer.

History

Classically, endometrial carcinoma presents as postmenopausal bleeding and although this is not the only cause it must be excluded. It may also present around or before the menopause in about 20 to 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.]

Transvaginal Ultrasound Scan (TVUS)

Where sufficient local skills and resources exist, transvaginal ultrasound is an appropriate first-line procedure to identify which women with post-menopausal bleeding are at higher risk of endometrial cancer.
The mean endometrial thickness in post-menopausal women is much thinner than in pre-menopausal women. Thickening of the endometrium may indicate the presence of pathology. In general, the thicker the endometrium, the higher the likelihood of important pathology i.e. endometrial cancer being present. The threshold in the UK is 5mm; a thickness of >5mm gives 7.3% likelihood of endometrial cancer.⁶ A thickness of <5mm has a negative predictive value of 98%.¹A recent meta-analysis found that a TVUS result of 5 mm or less reduced the risk of disease by 84%.⁷ Some pathology may be missed and it is recommended that hysteroscopy and biopsy should be performed if clinical suspicion is high.^8,9 The accuracy of assessing endometrial thickness in women with diabetes and obesity has been questioned,¹⁰ but models have been developed to take personal characteristics into account when predicting the risk of cancer.¹¹

Endometrial Biopsy

A definitive diagnosis in post-menopausal bleeding 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 GA. All methods of sampling the endometrium will miss some cancers.

Hysteroscopy

Hysteroscopy and biopsy (curettage) is 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 anesthetic.

A significant development has been direct referral to 'one stop' specialist clinics.^12,13 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.

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 @¹⁴

• Stage I endometrial cancer is carcinoma confined to the corpus uteri:
  • IA confined to endometrium
  • IB invasion to less than half of myometrium
  • IC invasion beyond half of myometrium
• Stage II involves the corpus and the cervix, but has not extended outside the uterus:
  • Stage IIA is endocervical glandular involvement only
  • Stage IIB is cervical stromal invasion
• Stage III extends outside of the uterus but is confined to the true pelvis:
  • Stage IIIA is invasion of serosa or adnexa or positive peritoneal cytology and possibly more than one of these
  • Stage IIIB is vaginal metastases
  • Stage IIIC is metastases to pelvic or para-aortic 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 to 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

Treatment depends upon stage:

• Stage IA and IB require total abdominal hysterectomy with bilateral salpingo-oophorectomy.
• In stage IC and stage II, in addition there should be pelvic radiotherapy. Bowel complications occur in about 4%. If the patient is unfit for surgery then radiotherapy alone may be used.
• Stage III is best treated with surgery, external beam radiotherapy and intracavity radiotherapy but if the tumour is adherent to the pelvic wall it may be inoperable.
• For stage IV, if metastases are in the pelvis then combination radiotherapy is used as in stage III but for distant, such as pulmonary metastases, progestational agents are best.
• Progestational agents may be used in any advanced disease and there is a response in 15 to 30%. Stage IV tends to occur in the elderly. Treatment can produce a useful response but outlook is poor.¹⁵
• Recurrence may respond to radiotherapy. Radical radiotherapy for local recurrence is effective in over half the cases.¹⁶ It may be possible to detect progestogen receptor sites on the tumour. If they are positive there is a 75% chance of response but if negative only 7%. Negative receptor disease may respond better to chemotherapy.
• Doxyrubicin gives a good but often temporary response.
• Paclitaxel and carboplatin are also used.¹⁷
• Progestogen therapy is usually given with either medroxyprogesterone or megestrol. Tamoxifen may have a useful adjuvant effect.¹⁸

The overall 20 years survival rate for all forms of endometrial carcinoma is about 80%.¹⁹ Staging is not the only variable and aggressiveness of the tumour is very variable. Most women present at stage I.
The overall mortality for endometrial carcinoma according to stage is roughly:²⁰

The majority of endometrial cancers are relatively benign and curable but about 20% have a bleak outlook.²¹ More virulent tumours include papillary adenocarcinoma, papillary serous adenocarcinoma, adenosquamous carcinoma, and clear cell carcinoma.