Endometrial Hyperplasia

What is Endometrial Hyperplasia?

Endometrial hyperplasia is an overgrowth or thickening of the endometrium (lining of the uterus) which may involve part or all of the endometrium. This diagnosis can only be made by the pathologist who examines a sample of tissue removed from the thickened endometrium by a procedure such as endometrial biopsy, D&C, or hysteroscopy. Examination under the microscope of the endometrial tissue shows proliferation (excessive growth) of both the endometrial glands as well as the surrounding tissue (stroma). The glands in the condition of hyperplasia are more crowded than normal and they show additional changes. However, the key determinant of biological behavior, i.e., potential for malignancy, is the presence of changes known as atypia within the hyperplastic tissue. There are a variety of types of hyperplasia (simple, adenomatous) which are all benign as long as they do not show “atypia”. Both, hyperplasia with atypia and without atypia may regress spontaneously over months or years. However, whereas hyperplasia without atypia rarely progresses to endometrial cancer, hyperplasia with atypia is a precancerous condition that may progress to overt malignancy. Complex atypical hyperplasia progresses to endometrial carcinoma in 29% of women. Hyperplasia without atypia (including adenomatous type) can be effectively treated with progestins (hormones with progesterone activity). Following continuous progestin treatment of 3-4 months duration, repeat sampling of the endometrial lining is required to demonstrate resolution of the hyperplasia and exclude the presence of atypia.

Hyperplasia usually develops in the presence of continuous estrogen stimulation unopposed by progesterone. During adolescence and in the years before menopause, women may have numerous cycles without ovulation (anovulatory) during which there is continuous unopposed estrogen activity. Polycystic ovary syndrome is another condition in which women are anovulatory and have an unopposed estrogen effect. Similarly, hormone replacement therapy consisting of estrogen without progesterone may lead to endometrial hyperplasia. In these situations, the addition of progesterone (by taking a progestin) or resumption of ovulation (spontaneously or with medications) can eliminate hyperplasia, especially hyperplasia without atypia.

A majority of hyperplastic lesions regress spontaneously.  During a mean follow-up of 11.4 years, disease regressed in 69% of women with Simple atypical hyperplasia and 57% of patients with Complex atypical hyperplasia.  Eight percent of Simple atypical hyperplasia and 23% of Complex atypical hyperplasia progressed to carcinoma.  In another study, Simple hyperplasia without atypia regressed in 79% over 3 years as did 94% of Complex hyperplasia without atypia.  Complex hyperplasia with atypia regressed in 55%.

Hyperplasia without atypia may also resolve spontaneously or following a D&C. On the other hand, hyperplasia with atypia tends to persist even after treatment with progestin. Currently, endometrial hyperplasia is the indication for 5% of all hysterectomies performed in the U.S. In 43% of women undergoing hysterectomy because of atypical hyperplasia (diagnosed by endometrial biopsy), the removed uterus contained endometrial carcinoma.  When a biopsy reveals endometrial hyperplasia, it is critical to evaluate the uterus before surgery with a D&C due to the high risk that concurrent cancer is present.  During hysterectomy the uterus should be inspected thoroughly and the surgeon should be ready to perform lymph node dissection if cancer is found. Hyperplasia, even after successful treatment, may recur. This is especially true if conditions of unopposed estrogen persist. It is, therefore, necessary to assure that unopposed estrogen condition does not continue by giving progesterone intermittently or, in younger women, birth control pills. Also, it is important to monitor such patients closely (using ultrasound, endometrial biopsies, etc.) long after the completion of a successful course of treatment.

What is the Treatment for Endometrial Hyperplasia?

The first step in the treatment of endometrial hyperplasia is a thorough evaluation of the endometrium by means of a D&C; this is essential to assess the presence of atypia. Hyperplasia without atypia often regresses spontaneously, after D&C or progestin treatment. Progestin, such as Provera, is given continuously, either by mouth or long-acting injections. A D&C is repeated after 3-4 months of treatment to demonstrate resolution of the hyperplasia. Failure of hyperplasia without atypia to resolve (even if no atypia is found) after repeat D&C is cause for concern. A second course of medical therapy may then be tried, consisting of high-dose progestins. Following this course of treatment, another D&C is performed. Hyperplasia with atypia is considered precancerous. It is best treated surgically with hysterectomy. However, if a patient desires future pregnancy, a trial of hormonal treatment may be given. Progesterone treatment may also be given with an intra-uterine system (IUD) containing progestin (levonorgestrel IUS). If a lower dose progestin regimen fails to clear hyperplasia with atypia, the patient may be given a choice between high-dose progestin given continuously over a period of three months or hysterectomy. Failure of the high-dose progestin treatment course to completely resolve the hyperplasia with atypia is a clear indication for hysterectomy. Resolution of the hyperplasia on the repeat D&C offers the patient the opportunity to try and conceive. However, she will require close medical supervision with repeat biopsies to monitor the endometrium until pregnancy. The D&C after completion of progesterone treatment should be delayed about a month following completion of the progesterone course of treatment in order not to miss a treatment failure. In pre-menopausal women, high-dose progestin treatment with close monitoring is an accepted alternative to hysterectomy in cases of hyperplasia with atypia. In the post-menopausal woman with endometrial hyperplasia with atypia, hysterectomy is recommended.

Recently, there have been several encouraging reports of resolution of hyperplasia following endometrial ablation (by hot water balloon, laser, or resectoscopic endometrial resection). In some cases, even atypical hyperplasia was successfully eliminated. However, at the present time, larger studies are needed to determine the overall success of such treatment modalities before we can accept them as routine alternatives in women who refuse progesterone treatment or hysterectomy.

In a recent large NIH-sponsored study, when women underwent hysterectomy because of complex hyperplasia with atypia, the hysterectomy specimen already contained endometrial cancer in 42.6% of cases; in a third of the cases, the cancer was found penetrating the myometrium.  This emphasizes the importance of proceeding with hysterectomy whenever atypical hyperplasia is found.  During surgery, the uterus must be carefully evaluated and frozen sections performed.  An expert capable of full-scale oncologic surgery for endometrial cancer should be available during the surgery.

When counseling a young woman with atypical hyperplasia who desires hormonal treatment to have children, the risks of missing an already present cancer should be emphasized. In addition, a very close follow-up with serial endometrial biopsies and D&C’s should be performed.  Following the completion of childbearing (or the recognition of the inability to conceive), the uterus and ovaries should be removed.