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Introduction

Endometrial cancer is a common oestrogen-dependent gynaecological cancer which mainly affects post-menopausal individuals (91% of cases in 50-year-olds).1,3

In resource-abundant countries, it is the most common gynaecological malignancy, and in resource-limited countries, it is the second most common following cervical cancer.3

Endometrial hyperplasia precedes endometrial cancer and has an incidence of at least three times that of endometrial cancer. If left untreated, endometrial hyperplasia can progress to cancer.1,4

Endometrial hyperplasia and cancer commonly present with post-menopausal bleeding (PMB), and it is estimated that 1 in 10 individuals with PMB will have endometrial hyperplasia or carcinoma. In younger individuals, it may present with changes to the menstrual cycle and heavy or irregular periods.

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Aetiology

Anatomy5

The uterus is a muscular organ responsible for the maintenance and transportation of gametes. It has three parts including the fundus, which is the uppermost part of the uterus, the body which is the usual site for implantation of the blastocyst and the cervix which is the lower part of the uterus that connects it to the vagina.

The fundus and the uterus are composed of three tissue layers: the peritoneum, myometrium, and endometrium.

  • The peritoneum is a double-layered membrane which is continuous with the abdominal peritoneum
  • The myometrium is a thick smooth muscle layer that undergoes hypertrophy and hyperplasia during pregnancy in preparation for the expulsion of the fetus.
  • The endometrium lines the uterus with a mucous membrane, this layer is subdivided into two parts including the deep stratum basalis and the superficial functionalis.

The superficial functionalis proliferates in response to oestrogens and becomes secretory in response to progesterone, this layer is shed during menstruation and regenerates from cells in the stratum basalis layer.

Progesterone causes the endometrium to become receptive to the implantation of a fertilised ovum. If fertilisation does not take place, a fall in progesterone levels triggers menstruation and shedding of the thickened endometrial layer. Both oestrogen and progesterone are implicated in the development of endometrial cancer.

Diagram of the anatomy of the uterus
Figure 1. The anatomy of the uterus.

Pathophysiology

Endometrial cancer develops due to the presence of unopposed oestrogen, this results from a lack of progesterone which can either be caused endogenously or exogenously.

Endogenous causes include polycystic ovarian syndrome, anovulatory menstrual cycles during menarche, perimenopause peripheral conversion of androstenedione to oestrone in adipose tissue, and granulosa cell tumours (which produce oestrogen).

Exogenous causes include hormone replacement therapy (HRT) containing only oestrogen and tamoxifen, an antioestrogen, which is often used for the treatment of breast cancer.

Grading and staging

Endometrial cancer develops from the endometrial lining, and the major prognostic indicators are the grade of differentiation and the FIGO stage of the disease (Table 1). These factors guide the management plan and any use of adjuvant therapies.1

Endometrial cancer is graded using the following classification: well-differentiated (G1), moderately differentiated (G2), and poorly differentiated or high-risk cell type (G3). 

Table 1. The FIGO staging of endometrial cancer.

Stage Extent of disease Estimated 5-year survival
I Limited to the body of the uterus 85%
Ia

No myometrial invasion or < 50% myometrial invasion

 
Ib > 50% myometrial invasion  
II Limited to the body of the uterus and the cervix 75%
III Extension to the uterine serosa, peritoneal cavity and/or lymph nodes 45%
IIIa Extension to the uterine serosa, adnexae, or peritoneal cavity  
IIIb Extension to the vagina or parametrium  
IIIc1 Involvement of the pelvic lymph node  
IIIc2 Involvement of the para-aortic lymph node  
IV Extension to the vagina or parametrium 25%
IVa Extension to the adjacent organs e.g., bladder or bowel  
IVb Positive inguinal lymph nodes or distant metastases  

 


Risk factors

Risk factors for endometrial cancer include:

  • Obesity
  • Conditions associated with obesity including type 2 diabetes mellitus, hypothyroidism, and hypertension
  • Early menarche
  • Late menopause
  • Nulliparity
  • Polycystic ovarian syndrome
  • Lynch syndrome (hereditary nonpolyposis colorectal cancer (HNPCC) increases the risk of colorectal, endometrial, and ovarian tumours)
  • Breast cancer (has similar risk factors as outlined above and is often treated with tamoxifen)

Protective factors against endometrial cancer include:


Clinical features

History

Typical symptoms of endometrial cancer include:1,3

  • Abnormal uterine bleeding including post-menopausal bleeding, heavy menstrual bleeding, intermenstrual bleeding, irregular bleeding, or unscheduled bleeding while on HRT
  • Increased vaginal discharge
  • Pyometra which is a collection of pus in the uterine cavity
  • Advanced disease may present as pelvic pain, oedema, rectal bleeding, weight loss, and fatigue
  • Metastatic disease may present as cough, dyspnoea, haemoptysis, abdominal pain, jaundice, bone pain, hypercalcaemia, and pathological fractures

Other important areas to cover in the history include:

  • Obstetric history: including parity and complications
  • Gynaecological history: including age at menarche, last menstrual period, menstrual cycle duration and pattern
  • Cervical smear history
  • Past medical or surgical history: including bleeding disorders, previous malignancy, polycystic kidney disease, type 2 diabetes mellitus, hypothyroidism, hypertension
  • Drug history: including use of COCP, HRT, tamoxifen, antihypertensives, or oral hypoglycaemics
  • Social history: smoking, alcohol, and recreational drug use
  • Family history: gynaecological or colorectal malignancies

Clinical examination

A full gynaecological examination, including vulval, vaginal and speculum examination, should be performed in suspected cases of endometrial cancer.

Typical clinical findings in endometrial cancer include:

  • Uterine bleeding
  • Increased vaginal discharge
  • Pyometra
  • Oedema
  • In locally advanced disease the uterus may be enlarged or immobile on palpation
  • In advanced cases, there may be a palpable pelvic mass on examination of the abdomen

Investigations

Laboratory investigations

Relevant laboratory investigations include:1,3

  • Full blood count: may show low haemoglobin and low platelets
  • CA-125: may be elevated but not usually performed for cases of suspected endometrial cancer

Imaging investigations

Relevant imaging investigations include:1,3

  • Pelvic ultrasound: to visualise the uterus, ovaries, and fallopian tubes
  • Transvaginal ultrasound: an endometrial thickness (ET) of 4mm would be an indication for further investigations such as endometrial biopsy
  • CT scan of chest, abdomen, and pelvis: may be used for preoperative staging
  • MRI pelvis: can be used to determine the local extent of the tumour and the presence of involved pelvic lymph nodes

Other investigations

Other relevant investigations include:1,3

  • Endometrial biopsy would be performed if the transvaginal ultrasound showed ET 4mm or persistent bleeding in an individual with ET ≤ 4mm. This can be done in an outpatient setting using devices including a pipelle or vabra aspirator.
  • Hysteroscopy can be performed as an outpatient under local anaesthetic or as an inpatient under general anaesthetic to visualise the endometrium.

Differential diagnoses

It is important to consider other differential diagnoses in patients with abnormal uterine bleeding. Common alternative diagnoses can be remembered using the mnemonic PALM COEIN:

  • Polyp
  • Adenomyosis
  • Leiomyoma (fibroid)
  • Malignancy/hyperplasia
  • Coagulation disorder
  • Ovulatory dysfunction
  • Endometrial (primary disorder of mechanisms regulating haemostasis)
  • Infection/Iatrogenic (medications including HRT)
  • Not yet known

Management

Surgical management

Surgery is the mainstay of treatment and allows surgical staging as well as the removal of the tumour.

The type of surgery offered is dependent on the stage of endometrial cancer:3,4

  • Stage I: total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO)
  • Stage II: exploratory laparotomy and surgical staging with radical hysterectomy, bilateral pelvic lymph node dissection (BPND) para-aortic lymph node clearance, pelvic and peritoneal washings for cytology and omental sampling
  • Stage III/IV: exploratory laparotomy with maximal tumour debulking and full surgical staging

Laparoscopic hysterectomy has gained popularity in recent years, and studies have shown better postoperative recovery in early disease.

Medical management

Medical therapies are used alongside surgery in more advanced disease:3,4

  • Radiotherapy: post-operative external beam irradiation and/or intracavity brachytherapy are given to those diagnosed with stage Ib grade 3 and stage II-IV of any grade. Radical radiotherapy can also be used for local recurrences and in patients unsuitable for major surgery.
  • Chemotherapy: doxorubicin, paclitaxel and carboplatin/cisplatin can be used in stage III and IV disease though the response rates tend to be poor.
  • Hormonal therapies: tamoxifen and progestogen can be used in recurrent or advanced disease.

Advanced metastatic cancer (stage IVb) requires palliative treatment including tumour debulking, chemoradiotherapy and the control of symptoms.


Complications

If endometrial cancer is not diagnosed and treated promptly, complications due to advanced disease can occur:6

  • Anaemia due to excessive blood loss from the uterus can present with symptoms including fatigue, weakness, and palpitations
  • Symptoms of weight loss, shortness of breath, and bone pain if there is metastasis to the bladder, rectum, vagina, or distant organs

Complications related to treatment modalities can include:

  • Bleeding
  • Infection
  • Damage to local structures (bladder, bowel, and/or vasculature)
  • Lymphoedema
  • Vaginal stenosis
  • Vaginal atrophy
  • Bowel or bladder fistula post-irradiation
  • Bladder instability
  • Sexual dysfunction

Key points

  • Endometrial cancer is the most common gynaecological malignancy in resource-abundant countries and is the second most common in resource-limited countries.
  • Major prognostic indicators are the grade of differentiation and the FIGO stage of the disease.
  • Endometrial cancer develops due to the presence of unopposed oestrogen, this results from a lack of progesterone which can either be caused endogenously or exogenously.
  • Risk factors include obesity, nulliparity, diabetes mellitus, hypertension, tamoxifen therapy, and genetic factors, including Lynch syndrome.
  • A thorough history and examination should be performed. Endometrial carcinoma is a histological diagnosis based on an endometrial biopsy or hysterectomy specimen.
  • In patients who are at low risk of disease persistence or recurrence, surgery alone is usually curative. Patients with intermediate – or high-risk disease may be treated using adjuvant therapy including radiotherapy or chemotherapy.

Reviewer

Professor Michael Geary

Consultant in Obstetrics & Gynaecology


Editor

Dr Chris Jefferies


References

  1. Collins S, Arulkumaran S, Hayes K, Jackson S, Impey L. Oxford Handbook of Obstetrics and Gynaecology. United Kingdom.: Oxford University Press.; 2013.
  2. Plaxe S, Mundt A. Overview of endometrial carcinoma. UpToDate2022.
  3. Gallos I, Alazzam M, Clark T, et al. Management of Endometrial Hyperplasia  Green-top Guideline No. 67.   RCOG/BSGE Joint Guideline. 2016.
  4. Thompson L. The Uterus. TeachMeAnatomy.2019.
  5. Faizan U, Muppidi V. Uterine Cancer. Treasure Island (FL): StatPearls Publishing; 2022.

Image references

  • Figure 1. PD-USGov. Female reproductive system. License: [CC BY-SA]

 

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