What is Atypical Endometrial Hyperplasia?
By Dr. Kate Dudek
Endometrial hyperplasia occurs when the lining of the uterus becomes abnormally thick. Usually it happens when the endometrial glands undergo abnormal (hyperplastic) proliferation. Of particular concern is atypical endometrial hyperplasia (AEH), which is considered to be a precursor to endometrial cancer. In fact, another name for the condition is 'carcinoma in-situ'.
Not all atypical lesions will develop into cancer, some regress without the need for treatment; however, it is estimated that up to 40% of women who are diagnosed with AEH will go on to develop endometrial carcinoma. In contrast, women with non-atypical endometrial hyperplasia have a 10% chance of receiving a subsequent cancer diagnosis.
Facts about endometrial cancer
Endometrial cancer is the second most common gynaecological cancer worldwide, and the most common in developed countries. In developing countries, cervical cancer remains the most common cancer of the female reproductive tract. However, unlike cervical cancer, which is declining in incidence across many countries, mainly due to an increased awareness of pap screening and the development of the HPV vaccine; the incidence rates of endometrial cancer are steadily increasing.
Approximately 75% of endometrial cancers are oestrogen-dependent, arising as a result of chronic stimulation of the endometrium by oestrogen. The excess of oestrogen causes the cells of the endometrium to grow, unopposed by progesterone. Historically, endometrial cancer was considered to be a predominantly postmenopausal condition; associated with erratically fluctuating hormone levels. However, it is becoming increasingly prevalent in pre-menopausal women of childbearing age, probably due to a strong association with obesity and polycystic ovary syndrome (PCOS).
If endometrial cancer is diagnosed early (stage I), the five year survival rates are thought to be as high as 92%. However, if diagnosed at stage IV, five year survival rates fall to between 20 and 26%. This highlights the value of early diagnosis and, as AEH usually precedes endometrial cancer by several years, this gives a critical window of opportunity for preventative action and/or close monitoring.
Risk Factors for atypical endometrial hyperplasia
As with endometrial cancer, the predominant risk factor for AEH is chronic exposure of the endometrium to unopposed oestrogens. Obesity is a risk factor for AEH (and endometrial cancer) in postmenopausal women because adipose tissue becomes a major source of oestrogens once the ovaries stop functioning. Adipose tissue contains high levels of an enzyme called aromatase, which converts circulating androgens into oestrogens.
One of the reasons why the incidence of AEH is increasing in younger women is because of the rising rates of PCOS. PCOS is a hormonal condition, affecting up to 10% of females of reproductive age. It is confusingly named, as not all women with PCOS will have polycystic ovaries; a physiologically more accurate (if less user-friendly) name would be hyperandrogenic anovulation, as many women experience anovulatory menstrual cycles, with an excess of androgens. Without ovulation, the lining of the uterus will not be shed and the endometrial cells will continue to proliferate.
Alternative risk factors for AEH include immunosuppression, with one study showing that women who had undergone a kidney transplant were significantly more likely to develop AEH.
Some women with endometrial polyps find that they have AEH, although the likelihood of one causing the other is slim. It is more likely that the two coexist as they are both driven by an excess of oestrogen.
Symptoms, diagnosis and treatment
The main symptom of AEH is abnormal uterine bleeding. Approximately 15% of women who experience postmenopausal bleeding are found to have AEH. Abnormal bleeding can be due to other factors, including polyps, but should always be investigated by your doctor.
Most cases of AEH will be diagnosed by biopsy or dilation & curettage. Treatment typically depends on the age of the woman, as well as her reproductive status. Postmenopausal females will usually undergo a hysterectomy; however, those that are hoping to preserve their fertility may attempt progesterone therapy first. For those women who opt against surgery, regular monitoring is essential due to the high association between AEH and malignancy.
The challenges of AEH
Diagnosing and classifying AEH is not without its difficulties. For a start, the 'normal' endometrium is a dynamic structure that is constantly undergoing phases of proliferation, shedding and regrowth. Determining when this cellular growth is abnormal is not easy.
Furthermore, as yet, there is no way of definitively establishing which instances of AEH will progress to endometrial cancer. The current treatment of choice is preventative in nature, involving removal of the entire uterus via hysterectomy. Whilst, this irrefutably eliminates the risk of endometrial cancer, it is a drastic approach, particularly considering a significant proportion of women who have AEH will not go on to develop cancer. There is an urgent need to identify a biomarker capable of predicting, with a high degree of certainty, which lesions will become cancerous and which lesions are likely to spontaneously regress with time.
- Bobrowska, K., et al. “High Rate of Endometrial Hyperplasia in Renal Transplanted Women.” Transplantation Proceedings, vol. 38, no. 1, 2006, pp. 177–179., doi:10.1016/j.transproceed.2005.12.007.
- Ginsburg, Ophira, et al. “The Global Burden of Women’s Cancers: a Grand Challenge in Global Health.” The Lancet, vol. 389, no. 10071, 25 Feb. 2017, pp. 847–860., doi:10.1016/s0140-6736(16)31392-7.
- Kelly, P, et al. “Endometrial Hyperplasia Involving Endometrial Polyps: Report of a Series and Discussion of the Significance in an Endometrial Biopsy Specimen.” BJOG: An International Journal of Obstetrics & Gynaecology, vol. 114, no. 8, 12 June 2007, pp. 944–950., doi:10.1111/j.1471-0528.2007.01391.x.
- Lacey, J V, et al. “Endometrial Carcinoma Risk among Women Diagnosed with Endometrial Hyperplasia: the 34-Year Experience in a Large Health Plan.” British Journal of Cancer, vol. 98, no. 1, 15 Jan. 2008, pp. 45–53., doi:10.1038/sj.bjc.6604102.
- Manna, P.r., et al. “Dysregulation of Aromatase in Breast, Endometrial, and Ovarian Cancers.” Progress in Molecular Biology and Translational Science Molecular and Cellular Changes in the Cancer Cell, vol. 144, 2016, pp. 487–537., doi:10.1016/bs.pmbts.2016.10.002.
- Murali, Rajmohan, et al. “Classification of Endometrial Carcinoma: More than Two Types.” The Lancet Oncology, vol. 15, no. 7, June 2014, pp. e268–e278., doi:10.1016/s1470-2045(13)70591-6.
- Sanderson, Peter A., et al. “New Concepts for an Old Problem: the Diagnosis of Endometrial Hyperplasia.” Human Reproduction Update, vol. 23, no. 2, 1 Mar. 2017, pp. 232–254., doi:10.1093/humupd/dmw042.