Endometrial cancer

Who gets endometrial cancer and what causes it?

Cancer Research UK, which pools data from several UK registries (cancer statistics registrations for England, Wales, and Northern Ireland; cancer incidence, mortality and survival data for NHS Scotland) estimates that around 90% of all women diagnosed as having endometrial carcinoma are postmenopausal, with the mean age at diagnosis of about 60 years.4 A retrospective observational study of observed and modelled trends in 13 European countries showed that in recent years the incidence of endometrial cancer has been increasing in postmenopausal women, whereas it seems to be stable or decreasing in premenopausal and perimenopausal women.5

The precise cause of endometrial cancer is unknown, although various associated factors have been identified. Box 1 summarises recognised endogenous and exogenous risk factors for endometrial cancer. A prospective case-control study of 173 patients linked the action of chronic unopposed oestrogen on the endometrium to abnormal endometrial cell proliferation and carcinogenesis.6 Indeed, the best established risk factors ,such as obesity and nulliparity, relate to chronic exposure to oestrogen.

Excess unopposed oestrogen is also a risk factor for endometrial hyperplasia, a premalignant condition that can predispose to endometrial carcinoma. It can be typical (simple or complex) or atypical. Simple and complex hyperplasias have a 1% and 3% risk of progression to cancer, respectively. However, 30-40% of patients found to have atypical hyperplasia will have a concurrent adenocarcinoma, and the rest are at very high risk of developing the cancer.8

What types are there?

Endometrial cancer can been divided into two major types. Type 1 cancers, which account for 80-90%, are usually oestrogen dependent endometrioid adenocarcinomas, which generally have a good prognosis. Type 2 tumours usually present late, behave more aggressively, and carry a poor prognosis.9 They are not oestrogen driven and the risk of relapse and metastasis is high.7 Within this category, the commonest histological types are uterine papillary serous carcinoma and clear cell carcinoma (box 2).9

How does a patient with endometrial cancer present?

Patients with endometrial cancer classically present with postmenopausal bleeding, which is defined as bleeding that occurs at least a year after the last menstrual period. The reported absolute risk of endometrial cancer in non-users of hormone replacement therapy (HRT) who present with postmenopausal bleeding ranges from 5.7% to 11.5%.2 3 4 5 About 20% of patients with postmenopausal bleeding are found to have a malignancy, which is most commonly endometrial but can be cervical.10 11 12 Premenopausal and perimenopausal women may present with intermenstrual bleeding, often with a background of irregular, dysfunctional menstruation that suggests anovulation. Pain, vaginal discharge, and pyometra are rarer symptoms and tend to be secondary to advanced cancer.

How is the diagnosis made?

In the UK, recommendations for diagnosis and referral are based on three sets of guidelines (evidence level IV): National Institute for Health and Clinical Excellence (NICE),10 European Society for Medical Oncology (ESMO),11 and Uterus Commission of the German Gynecological Oncology Working Group (AGO-S2k).12 They recommend that the clinician obtains a detailed account of the presenting symptoms, a full drug history (HRT, oral contraceptive pill, tamoxifen), and a gynaecological history (early menarche/late menopause, known endometrial hyperplasia, parity). Medical and surgical history may be relevant (obesity, treatment for breast cancer, diabetes mellitus, hypothyroidism, hypertension, and Lynch-type syndrome). If the patient reports postmenopausal bleeding, general practitioners in the UK should refer them to a rapid access gynaecology clinic to be seen within two weeks.10 13 A premenopausal patient older than 40 years who presents with a recent onset abnormal bleeding pattern, or a premenopausal patient of any age with an abnormal bleeding pattern and any of the above risk factors for endometrial cancer, should be referred to a gynaecologist.10 11 12 The gynaecologist will normally carry out a pelvic examination to rule out other possible sources of vaginal bleeding such as lesions of the vulva, vagina, or cervix.

Two investigations are mandatory in women with suspected endometrial cancer: a transvaginal ultrasound scan and an endometrial biopsy. Transvaginal ultrasound scan is an accurate and precise screening method for endometrial cancer. A retrospective study of 339 patients found that calculating endometrial thickness was easier with transvaginal ultrasound than with transabdominal ultrasound.14 A meta-analysis of 35 studies using a 5 mm threshold to define abnormal endometrial thickening showed that 96% of women with cancer had endometrial thickness greater than 5 mm; the study reported a negative likelihood ratio of 0.08. Transvaginal ultrasound was also highly reliable in identifying postmenopausal women with vaginal bleeding who were unlikely to have carcinomatous disease (endometrial thickness of <5 mm), which would mean that unnecessary endometrial sampling could be avoided.15 A meta-analysis of data from 9031 patients concluded that endometrial thickness of less than 4-5 mm in the presence of endometrial pathology poses a very low but not negligible risk of malignancy, although this does not apply to patients who are on regular HRT or tamoxifen for breast carcinoma.16 A recent meta-analysis showed that the specificity of an abnormal transvaginal ultrasound result dropped from 92% to 77% when used in patients on HRT.15 The upper endometrial thickness limit for these patients is 8 mm if asymptomatic, but if vaginal bleeding is present a biopsy should be taken if the thickness is greater than 5 mm.

A definitive diagnosis of endometrial cancer is histological. A sample of endometrial tissue can be obtained either in the gynaecology outpatient setting using a Pipelle curette17 or by hysteroscopy and dilatation and curettage under general anaesthesia. A systematic review of 13 diagnostic evaluations showed that a Pipelle biopsy leads to a high overall diagnostic accuracy when an adequate specimen is obtained (post-test probability of endometrial cancer of 81.7% for a positive test and 0.9% for a negative test).17 These findings encourage further evaluation in cases of abnormal uterine bleeding where symptoms persist despite negative biopsy. Hysteroscopy tends to be reserved for patients who cannot tolerate outpatient examination and biopsy, patients with cervical stenosis, and patients in whom outpatient biopsy was inadequate. The accuracy of hysteroscopy in diagnosing endometrial cancer and hyperplasia in women with abnormal uterine bleeding was determined by a systematic review of data on 26 346 women.18 A positive hysteroscopy result (likelihood ratio 60.9) increased the probability of cancer to 71.8% from a pre-test probability of 3.9%, whereas a negative hysteroscopy result (likelihood ratio 0.15) reduced the probability of cancer to 0.6%. Interestingly, diagnostic accuracy tended to be higher for endometrial cancer among postmenopausal women and in the outpatient setting.18

Referral to a gynaecologic oncology specialist centre

As outlined by guidelines,10 11 12 patients with confirmed endometrial cancer require immediate referral to a specialised gynaecology oncological centre (fig 1⇓). Here, further imaging such as computed tomography and magnetic resonance imaging (MRI) is performed to assess the extent of disease and plan for optimal management according to staging. A specialist team will choose the type of treatment (surgical or non-surgical approach) and make a decision about the appropriateness of adjuvant therapy on the basis of results of imaging. MRI is able to assess the depth of myometrial invasion, pelvic lymph node enlargement, and presence of cervical invasion. A meta-analysis of 47 studies that compared the usefulness of computed tomography, ultrasound, and MRI in staging of endometrial cancer found that contrast enhanced dynamic MRI was the most reliable method of identifying patients at high risk of tumour metastasis and presence of local lymphadenopathy.19 Computed tomography is mainly used to detect disease outside the pelvis.

Fig 1 Diagnostic flowchart, NICE guidelines. D&C=dilatation and curettage, MDT=multidisciplinary team, CT=computed tomography

• Download figure
• Open in new tab
• Download powerpoint

FIGO stage I

About 80% of patients present with stage I disease and can be treated surgically with a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Palpation and imaging of para-aortic and pelvic lymph nodes can assess for tumour spread.26 A study by a gynaecological oncology group looked at the histopathology of 621 patients and found lymph node metastases in about 10% of women who clinically had cancer confined to the uterus.27

The subject of pelvic lymphadenectomy is disputed across the Atlantic. In the UK, pelvic lymphadenectomy is not routinely performed along with total abdominal hysterectomy and bilateral salpingo-oophorectomy in women with stage I disease. This stance is supported by a Cochrane Collaboration review,28 which pooled data from two randomised controlled trials29 30 (one of them being the often quoted ASTEC trial30) and examined in greater depth the value of lymphadenectomy in women with stage I disease. It found no evidence supporting a survival benefit or a reduction in the risk of disease recurrence compared with not performing it.

In the United States, however, the opposite applies and pelvic lymphadenectomy is routinely performed alongside total abdominal hysterectomy and bilateral salpingo-oophorectomy. A large retrospective observational study of 39 396 patients drawn from the Surveillance, Epidemiology, and End Results programme (1988 to 2001) compared patients who had a lymphadenectomy with those who did not. The results indicate that lymphadenectomy is advisable for stage I grade 3 disease and more advanced endometrioid uterine cancers.31

Both arguments have their strengths and weaknesses. The UK bases its approach on data from two randomised controlled trials but a total of only 1945 patients, whereas the United States’ argument is based on findings from a study that had a weaker design but included outcomes of a much larger number of patients. As concluded by the Cochrane Collaboration review, lymphadenectomy is associated with substantial short and long term morbidity. It prolongs intraoperative time, thereby increasing the risk of deep venous thrombosis and pulmonary embolism, and increases the risk of lymphoedema and pelvic lymphocyst formation.28 Nevertheless, it provides useful prognostic information and further randomised trials are needed to evaluate the benefits, if any, of lymph node sampling.

FIGO stages II-IV

Stage II disease is managed with an extended or modified radical hysterectomy, bilateral salpingo-oopherectomy, and lymph node dissection. Maximal surgical cytoreduction is offered to patients who are suitable candidates for surgery as this provides a survival benefit.32 33 According to ESMO, patients with stage III disease solely on the basis of positive peritoneal cytology are treated as patients with stage I or II disease, based on other clinicopathological data,10 because positive cytology has not been found to be an independent prognostic indicator.

How is endometrial cancer staged?

Staging of endometrial cancer is determined by the International Federation of Gynecology and Obstetrics (FIGO). Staging may be based on surgical, clinical, radiological, or histopathological criteria. However, according to the 6th annual FIGO report, which pooled data on 9386 patients (from 34 countries) treated between 1999 and 2001, surgical staging has shown better prognostic value than clinical staging.20 To incorporate this finding, FIGO staging of endometrial cancer was updated in 2009 to reflect more accurately prognosis at each stage (table⇓).21 Despite this, a recent prospective analysis examined the extent to which the stage specific overall survival altered in the 2009 system and concluded that the revised system for stage I disease did not improve its predictive ability over the 1988 system.22

How is treatment decided?

The guidelines we present here focus specifically on the most common type of endometrial cancer—endometrioid endometrial adenocarcinoma. The management of a patient diagnosed with endometrial cancer is usually decided within a multidisciplinary team setting (fig 2⇓).

Fig 2 Summary of current management of endometrial cancer

• Download figure
• Open in new tab
• Download powerpoint

What is the preferred surgical approach?

Surgical treatment of endometrial cancer comprises total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings.10 11 12 In some cases, pelvic and para-aortic lymphadenectomy and omentectomy may be performed. Surgery can be open, via laparotomy (entry via a transverse or midline incision), or laparoscopic (normal or robotically assisted). Two extensive meta-analyses and a quantitative review showed no significant difference in terms of recurrence and survival between these two surgical options.23 24 25

What is the role of radiotherapy and chemotherapy?

The broad consensus is that radiotherapy has no role for early stage low risk disease.34 Traditionally, external pelvic radiotherapy, commonly with vaginal brachytherapy, has been the adjuvant treatment of choice for patients with early stage high risk disease. A meta-analysis by the ASTEC/EN.5 study group,35 which analysed data from two randomised controlled trials—the GOG ^w1 (392 patients) and PORTEC ^w2 (714 patients) studies—reported no benefit in terms of overall, disease specific, and disease specific recurrence-free survival for patients with early endometrial cancer (FIGO stage IA-C, of any grade and histological subtype) receiving adjuvant external beam radiotherapy. Furthermore, any decrease in the incidence of local recurrence was small.35 These findings definitively refute previous trends based on conclusions from meta-analyses and quantitative analyses favouring the use of radiotherapy for patients with multiple high risk features, such as stage IC and grade 3 disease. ^w3,w4

The value of chemotherapy in stage I disease is not yet clear. Recent data from different studies (prospective, retrospective, and a randomised controlled trial) of patients with stage I or II disease suggest that chemotherapy may improve overall survival in those with high risk features, such as high grade disease, lymphovascular space involvement, or greater than 50% myometrial invasion. ^w5-w7 A randomised controlled trial of 345 patients reported no difference between radiotherapy and chemotherapy for early stage high risk disease, but this is a controversial finding since only a third of the study patients actually had early stage disease. ^w8

How should patients be followed up?

Survival outcomes vary with each FIGO stage (table). In general, prognosis depends mainly on the age and health of the patient and the histological grade and stage of the tumour. Screening of the general population is currently not practised because no benefit with regards to patient outcomes has been identified. As neatly explained by AGO-S2k, no screening methods are able to detect uterine hyperplasia or cancer with acceptable sensitivity and specificity.7 12

Any pelvic pain or vaginal or rectal bleeding could indicate disease recurrence and should be investigated promptly. Both patients and healthcare professionals should be alert for general symptoms of malignancy and metastasis such as anorexia, unexplained weight loss, and bowel, urinary, or respiratory symptoms. ESMO recommends follow-up consultations every four months with careful history and pelvic examination at each visit in the first two years after diagnosis. Appointments every six months are recommended for the next three years.11

Finally, the importance of facilitating a supportive environment for the patient and their family cannot be stressed enough. The general practitioner can act as the lynchpin, ensuring that the patient is aware of all support networks from the cancer nurse specialist to the local cancer centre.