Endometrial Cancer Causes, Symptoms, Stages, and Treatment

Authored by , Reviewed by Dr Colin Tidy | Last edited | Meets Patient’s editorial guidelines

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This article is for Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Cancer of the Uterus (Endometrial Cancer) article more useful, or one of our other health articles.

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Treatment of almost all medical conditions has been affected by the COVID-19 pandemic. NICE has issued rapid update guidelines in relation to many of these. This guidance is changing frequently. Please visit https://www.nice.org.uk/covid-19 to see if there is temporary guidance issued by NICE in relation to the management of this condition, which may vary from the information given below.

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.

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].

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]

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.)

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[12].

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[13].

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[14].

NB: the incidence of endometrial cancer in postmenopausal women with thickened endometrium on TVUS without vaginal bleeding is low[15].

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[16].

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 the National Institute for Health and Care Excellence (NICE)[17]. This inherited condition increases the risk of certain types of cancer, including endometrial and colorectal cancer.

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.

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[19].

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[20].

Adjuvant chemotherapy

  • Adjuvant treatment is tailored according to histology and stage[21].
  • 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[22].

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.

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[23]. 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.

Increased BMI has been shown to be significantly associated with increased all-cause mortality in women with endometrial cancer[2, 24].

Further reading and references

  1. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2016)

  2. Parker VL, Sanderson P, Raw D, et al; Do we understand the pathophysiology of endometrial cancer? Eur J Gynaecol Oncol. 201536(5):595-8.

  3. Uterine cancer statistics; Cancer Research UK

  4. Arem H, Park Y, Pelser C, et al; Prediagnosis body mass index, physical activity, and mortality in endometrial cancer patients. J Natl Cancer Inst. 2013 Mar 6105(5):342-9. doi: 10.1093/jnci/djs530. Epub 2013 Jan 7.

  5. Chandra V, Kim JJ, Benbrook DM, et al; Therapeutic Options for Management of Endometrial Hyperplasia: An Update. J Gynecol Oncol. 2015 Oct 8.

  6. Doherty MT, Sanni OB, Coleman HG, et al; Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis. PLoS One. 2020 Apr 2815(4):e0232231. doi: 10.1371/journal.pone.0232231. eCollection 2020.

  7. Gottschau M, Kjaer SK, Jensen A, et al; Risk of cancer among women with polycystic ovary syndrome: a Danish cohort study. Gynecol Oncol. 2015 Jan136(1):99-103. doi: 10.1016/j.ygyno.2014.11.012. Epub 2014 Nov 20.

  8. Liao C, Zhang D, Mungo C, et al; Is diabetes mellitus associated with increased incidence and disease-specific mortality in endometrial cancer? A systematic review and meta-analysis of cohort studies. Gynecol Oncol. 2014 Oct135(1):163-71. doi: 10.1016/j.ygyno.2014.07.095. Epub 2014 Jul 27.

  9. Iqbal J, Ginsburg OM, Wijeratne TD, et al; Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review. Cancer Treat Rev. 2012 Jun38(4):318-28. doi: 10.1016/j.ctrv.2011.06.009. Epub 2011 Jul 19.

  10. Caserta D, Ralli E, Matteucci E, et al; Combined oral contraceptives: health benefits beyond contraception. Panminerva Med. 2014 Sep56(3):233-44.

  11. Clarke MA, Long BJ, Del Mar Morillo A, et al; Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis. JAMA Intern Med. 2018 Sep 1178(9):1210-1222. doi: 10.1001/jamainternmed.2018.2820.

  12. Braun MM, Overbeek-Wager EA, Grumbo RJ; Diagnosis and Management of Endometrial Cancer. Am Fam Physician. 2016 Mar 1593(6):468-74.

  13. Wong AW, Lao TH, Cheung CW, et al; Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study. BJOG. 2015 Mar 20. doi: 10.1111/1471-0528.13342.

  14. Dueholm M, Marinovskij E, Hansen ES, et al; Diagnostic methods for fast-track identification of endometrial cancer in women with postmenopausal bleeding and endometrial thickness greater than 5 mm. Menopause. 2015 Jun22(6):616-26. doi: 10.1097/GME.0000000000000358.

  15. Laiyemo R, Dudill W, Jones SE, et al; Do postmenopausal women with thickened endometrium on trans-vaginal ultrasound in the absence of vaginal bleeding need hysteroscopic assessment? A Pilot Study. J Obstet Gynaecol. 2015 Oct 14:1-4.

  16. Gkrozou F, Dimakopoulos G, Vrekoussis T, et al; Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies. Arch Gynecol Obstet. 2015 Jun291(6):1347-54. doi: 10.1007/s00404-014-3585-x. Epub 2014 Dec 19.

  17. Testing strategies for Lynch syndrome in people with endometrial cancer; NICE Diagnostics guidance, published date 28th October 2020

  18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26389270

  19. Laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer; NICE Interventional Procedure Guidance, September 2010

  20. Cibula D, Oonk MH, Abu-Rustum NR; Sentinel lymph node biopsy in the management of gynecologic cancer. Curr Opin Obstet Gynecol. 2015 Feb27(1):66-72. doi: 10.1097/GCO.0000000000000133.

  21. Morice P, Leary A, Creutzberg C, et al; Endometrial cancer. Lancet. 2015 Sep 4. pii: S0140-6736(15)00130-0. doi: 10.1016/S0140-6736(15)00130-0.

  22. Galaal K, Al Moundhri M, Bryant A, et al; Adjuvant chemotherapy for advanced endometrial cancer. Cochrane Database Syst Rev. 2014 May 155:CD010681. doi: 10.1002/14651858.CD010681.pub2.

  23. Kwon JS; Improving survival after endometrial cancer: the big picture. J Gynecol Oncol. 2015 Jul26(3):227-31. doi: 10.3802/jgo.2015.26.3.227.

  24. Secord AA, Hasselblad V, Von Gruenigen VE, et al; Body mass index and mortality in endometrial cancer: A systematic review and meta-analysis. Gynecol Oncol. 2015 Oct 30. pii: S0090-8258(15)30167-0. doi: 10.1016/j.ygyno.2015.10.020.

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