Endometrial Hyperplasia
Endometrial hyperplasia is a pre-cancerous condition caused by abnormal proliferation of the endometrial glands. It commonly presents with abnormal vaginal bleeding and is clinically important because atypical hyperplasia carries a significant risk of progression to endometrial cancer.
Updated UKMLA guide to endometrial hyperplasia based on the RCOG guideline: classification, risk factors, diagnosis, and management.
Definition
Endometrial hyperplasia is defined as an irregular proliferation of the endometrial glands, which features an increase in the gland-to-stroma ratio when compared with normal proliferative endometrium.
It is known to be a precursor to endometrial cancer.
Classification
Endometrial hyperplasia is categorised into 2 distinct groups:
| Type | Definition | Implications |
|---|---|---|
| Hyperplasia without atypia | Absence of cytological atypia | Low cancer risk (progressing to endometrial cancer) (<5% over 20 years)
Majority of cases will regress spontaneously |
| Atypical hyperplasia | Presence of cytological atypia | High cancer risk (cumulative cancer risk of 8% at 4 years, 12.4% at 9 years, and 27.5% at 19 years) |
Cytological atypia refers to specific nuclear abnormalities in the glandular epithelial cells of the endometrium, including: [Ref]
- Prominent nucleoli – strongest feature
- Nuclear enlargement (disproportionately large relative to the cytoplasm)
- Nuclear pleomorphism (variation in nuclear size and shape)
- Irregularly dispersed chromatin
- Loss of polarity
Causes and Risk Factors
Primary underlying cause: oestrogen stimulates growth of endometrium without being opposed by progesterone
Risk factors that contribute to unopposed oestrogen exposure:
- Obesity
- Metabolic conditions (diabetes, hyperlipidaemia, hypertension)
- PCOSPolycystic ovary syndrome
- Reproductive history that increases lifetime oestrogen exposure
- Early menarche
- Late menopause
- Nulliparity
- Long-term use of tamoxifen
Clinical Features
Primary symptom: abnormal vaginal bleeding
- Heavy menstrual bleeding
- Intermenstrual bleeding
- Irregular bleeding
- Post-menopausal bleeding
- Unscheduled vaginal bleeding for those who are taking HRTHormone replacement therapy
- Abdominal vaginal bleeding / discharge
Based on clinical features alone, endometrial hyperplasia is indistinguishable from endometrial cancer.
Complications
The key complication is progression to endometrial cancer
- Risk is much higher in atypical hyperplasia (cumulative cancer risk of 8% at 4 years, 12.4% at 9 years, and 27.5% at 19 years)
Other:
- Up to 4% risk of co-existing ovarian cancer
- Infertility (from the hyperplastic endometrium itself or from treatment)
Red Flags and When to Refer
Since clinical features alone do not distinguish endometrial hyperplasia from endometrial cancer, the same red flags and referral indications apply for both endometrial hyperplasia and cancer.
The only way to definitively distinguish between endometrial hyperplasia and cancer is via histological examination (biopsy).
For ≥55 y/o individuals with female reproductive organs (including women, trans-men and non-binary people):
| Action | Indications |
|---|---|
| Suspected cancer pathway referral (to receive a diagnosis or exclusion of cancer within 28 days) | >55 y/o with unexplained post-menopausal bleeding that cannot be attributed to HRT* |
| Consider an urgent (within 2 weeks) TVUS | Unexplained vaginal discharge PLUS any of the following
|
Visible haematuria PLUS any of the following
|
*if <55 y/o with unexplained post-menopausal bleeding → consider a suspected cancer pathway referral
Red flags and referral for women who are taking HRT:
- Bleeding >3-6 months after starting HRT (the 6-month cut-off applies to those without risk factors for endometrial cancer)
- Bleeding >3 months after changing HRT regimen
See the Hormone Replacement Therapy (HRT) article for details on the management of unscheduled bleeding on HRT.
Investigation and Diagnosis
1st line: TVUSTrans-vaginal ultrasound
- An endometrial thickness of ≥4 mm requires further investigation (for post-menopausal women who are NOT on HRTHormone replacement therapy)
- Any abnormal bleeding in tamoxifen users should prompt urgent investigation, as ultrasound is unreliable in these patients
While TVUSTrans-vaginal ultrasound is a useful imaging tool, its primary role is to measure the thickness and structure of the endometrial lining to determine if further testing is needed. It is useful in ruling out disease; if the endometrial thickness is below the cut-off, the probability of cancer is reduced to <1%
TVUSTrans-vaginal ultrasound alone cannot reliably distinguish between endometrial hyperplasia and endometrial cancer. Histological examination (biopsy) is the only reliable way.
Further investigation (definitive): outpatient endometrial biopsy (e.g. Pipelle biopsy)
Management
Management is distinctly divided into 2 pathways
Endometrial Hyperplasia Without Atypia
| Management approach | Indications | Description |
|---|---|---|
| Active observation | Appropriate for women who have identifiable and reversible risk factors, such as:
|
Follow-up endometrial biopsies to ensure the disease is regressing |
| Medical management | Recommend for:
|
1st line: LNG-IUSLevonorgestrel intrauterine system
2nd line: continuous oral progestogens (medroxyprogesterone or norethisterone) |
Hysterectomy is NOT routinely necessary in endometrial hyperplasia without atypia, as progestogen therapy is highly effective and avoids the morbidity of major surgery.
Hysterectomy is only indicated for women who do NOT wish to preserve their fertility, PLUS:
- The disease progresses to atypical hyperplasia
- There is no regression after 12 months of medical treatment
- The disease relapses after treatment is completed
- Bleeding symptoms persist
- The woman declines medical treatment or surveillance
Atypical Endometrial Hyperplasia
1st line: total hysterectomy
- Post-menopausal women: together with bilateral salpingo-oophorectomy
- Pre-menopausal women: decision to remove the ovaries is individualised, but a bilateral salpingectomy should be considered to reduce future ovarian cancer risk
Fertility-sparing management is possible
- Indications: woman wishes to preserve her fertility or is medically unfit for surgery
- Pre-treatment assessment to exclude invasive endometrial cancer and co-existing ovarian cancer is necessary
- Choice of therapy:
- 1st line: LNG-IUSLevonorgestrel intrauterine system
- 2nd line: oral progestogens
- Once fertility is no longer required, a hysterectomy should be offered because of the high risk of disease relapse
References
RCOG Management of Endometrial Hyperplasia (Green-top Guideline No. 67)