Definition

Endometrial hyperplasia is an abnormal proliferation of the endometrium (i.e. greater than the normal proliferation that occurs during the menstrual cycle). It is a risk factor for the development of endometrial carcinoma.

Pathogenesis

There are four types of endometrial hyperplasia:

• Simple
• Complex
• Simple atypical
• Complex atypical

90% of cases of simple and complex hyperplasia regress spontaneously. In one study progression to carcinoma occurred in:¹

• 1% of patients with simple hyperplasia
• 3% of patients with complex hyperplasia
• 8% of patients with simple atypical hyperplasia
• 29% of patients with complex atypical hyperplasia

There is a high prevalence of underlying endometrial adenocarcinoma among women undergoing hysterectomy for any type of atypical endometrial proliferation.²

Risk factors

• Exogenous oestrogen use (without cyclical progesterone)
• Oestrogen-secreting ovarian tumour
• Tamoxifen use; it has an anti-oestrogen effect on the breast, but a pro-oestrogen effect on the uterus and bones
• Polycystic ovarian syndrome
• Hereditary non-polyposis colorectal carcinoma
• Obesity combined with diabetes

Presentation

• Endometrial hyperplasia usually presents clinically as abnormal vaginal bleeding - intermenstrual, polymenorrhoea or postmenopausal. The risk of endometrial hyperplasia in a polyp that also involves non-polypoid endometrium is significant.³
• Vaginal discharge
• Glandular abnormalities on a cervical smear

Investigations

Transvaginal ultrasound (TVUS)

Where sufficient local skills and resources exist, TVUS is an appropriate first-line procedure to identify which women with postmenopausal bleeding are at higher risk of endometrial cancer.

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, i.e. endometrial cancer being present. The threshold in the UK is 5 mm; a thickness of >5 mm gives 7.3% likelihood of endometrial cancer.⁴ A thickness of <5 mm has a negative predictive value of 98%.⁵

A recent meta-analysis found that a TVUS result of 5 mm or less reduced the risk of disease by 84%.⁶ Some pathology may be missed and it is recommended that hysteroscopy and biopsy should be performed if clinical suspicion is high.^7,8 The accuracy of assessing endometrial thickness in women with diabetes and obesity has been questioned,⁹ but models have been developed to take personal characteristics into account when predicting the risk of cancer.¹⁰

Endometrial biopsy

A definitive diagnosis in postmenopausal 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 general anaesthetic (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 GA.

A significant development has been direct referral to 'one-stop' specialist clinics.^11,12 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.

MRI scan

This can also demonstrate endometrial hyperplasia and, though not often used, may be helpful in cases where TVUS is not possible, or when superimposed invasive endometrial carcinoma is suspected.

Management

Medical

Simple endometrial hyperplasia without atypia responds to high-dose progestogens, with repeat histology after three months.
This can be effectively delivered by the levonorgestrel intrauterine system.^13,14,15 It is also given orally, if desired.

Surgical

• Endometrial ablation or transcervical resection of the endometrium (TCRE)¹⁶
• Hysterectomy - usually advised for atypical endometrial hyperplasia

Complications

Endometrial hyperplasia may develop into endometrial carcinoma. Women who don't have atypical changes have a very small risk of developing a cancer. But women with atypical changes have an increased risk. Between 10 to 20% with endometrial hyperplasia go on to develop endometrial carcinoma. This risk is higher for women with hyperplasia who have been through the menopause.

Document references

1. Kurman RJ, Kaminski PF, Norris HJ; The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985 Jul 15;56(2):403-12. [abstract]
2. Shutter J, Wright TC Jr; Prevalence of underlying adenocarcinoma in women with atypical endometrial hyperplasia. Int J Gynecol Pathol. 2005 Oct;24(4):313-8. [abstract]
3. Kelly P, Dobbs SP, McCluggage WG; Endometrial hyperplasia involving endometrial polyps: report of a series and discussion of the significance in an endometrial biopsy specimen. BJOG. 2007 Aug;114(8):944-50. Epub 2007 Jun 12. [abstract]
4. Smith-Bindman R, Weiss E, Feldstein V; How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol. 2004 Oct;24(5):558-65. [abstract]
5. Sahdev A; Imaging the endometrium in postmenopausal bleeding. BMJ. 2007 Mar 24;334(7594):635-6.
6. Gupta JK, Chien PF, Voit D, et al; Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand. 2002 Sep;81(9):799-816. [abstract]
7. Litta P, Merlin F, Saccardi C, et al; Role of hysteroscopy with endometrial biopsy to rule out endometrial cancer in postmenopausal women with abnormal uterine bleeding. Maturitas. 2005 Feb 14;50(2):117-23. [abstract]
8. Garuti G, Sambruni I, Cellani F, et al; Hysteroscopy and transvaginal ultrasonography in postmenopausal women with uterine bleeding. Int J Gynaecol Obstet. 1999 Apr;65(1):25-33. [abstract]
9. van Doorn LC, Dijkhuizen FP, Kruitwagen RF, et al; Accuracy of transvaginal ultrasonography in diabetic or obese women with postmenopausal bleeding. Obstet Gynecol. 2004 Sep;104(3):571-8. [abstract]
10. Opmeer BC, van Doorn HC, Heintz AP, et al; Improving the existing diagnostic strategy by accounting for characteristics of the women in the diagnostic work up for postmenopausal bleeding. BJOG. 2007 Jan;114(1):51-8. [abstract]
11. Panda JK; One-stop clinic for postmenopausal bleeding. J Reprod Med. 2002 Sep;47(9):761-6. [abstract]
12. Lotfallah H, Farag K, Hassan I, et al; One-stop hysteroscopy clinic for postmenopausal bleeding. J Reprod Med. 2005 Feb;50(2):101-7. [abstract]
13. Lethaby AE, Cooke I, Rees M; Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002126. [abstract]
14. Kriplani A, Singh BM, Lal S, et al; Efficacy, acceptability and side effects of the levonorgestrel intrauterine system for menorrhagia. Int J Gynaecol Obstet. 2007 Jun;97(3):190-4. Epub 2007 Mar 26. [abstract]
15. Wildemeersch D, Janssens D, Pylyser K, et al; Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas. 2007 Jun 20;57(2):210-3. Epub 2007 Jan 31. [abstract]
16. Sui L, Xie F, Cao B; Management of abnormal uterine hemorrhage with atypical endometrial hyperplasia by transcervical resection of endometrium. Int J Gynecol Cancer. 2006 May-Jun;16(3):1482-6. [abstract]

Acknowledgements