eMedicine Specialties > Obstetrics and Gynecology > General Gynecology

Premalignant Lesions of the Endometrium

Author: Jing Wang Chiang, MD, Clinical Assistant Professor of Obstetrics and Gynecology, Stanford University School of Medicine; Chief of Gynecologic Oncology, Department of Obstetrics and Gynecology, Santa Clara Valley Medical Center
Coauthor(s): Nicole Wilcox, MD, MPH, Staff Physician, Department of Obstetrics and Gynecology, Santa Clara Valley Medical Center
Contributor Information and Disclosures

Updated: Sep 3, 2008

Introduction

Endometrial hyperplasia involves the proliferation of endometrial glands that results in a greater than normal gland-to-stroma ratio. This results in varying degrees of architectural complexity and cytologic atypia. The clinical significance of this diagnosis is progression to or concurrent endometrioid endometrial adenocarcinoma.

This article reviews the classification, pathophysiology, clinical features, and treatment of endometrial hyperplasia.

For other information, see Medscape's Ob/Gyn & Women's Health Specialty Center.

Background

Endometrial hyperplasia is believed to produce a continuum of lesions that may be precursor to endometrial carcinoma of endometrioid histology. The classification of endometrial hyperplasia has had numerous terminology. The classification below is currently the most commonly accepted system and is accepted by the World Health Organization (WHO) and the International Society of Gynecologic Pathologists. This system characterizes the glandular architectural pattern as simple or complex and describes the presence or absence of nuclear atypia.

• Simple hyperplasia - Increased number of glands but regular glandular architecture
• Complex hyperplasia - Crowded irregular glands
• Simple hyperplasia with atypia - Simple hyperplasia with presence of cytologic atypia (prominent nucleoli and nuclear pleomorphism)
• Complex hyperplasia with atypia - Complex hyperplasia with cytologic atypia

The original study by Kurman et al found that lesions with varying degrees of complexity and presence of atypia, when left untreated, progressed to adenocarcinoma at different rates. Simple hyperplasia was associated with a 1% rate of progression to cancer, 3% rate of progression to complex hyperplasia, and 8% rate of progression to simple atypical hyperplasia, whereas complex atypical hyperplasia had a 29% rate of progression to cancer.¹

Not only does the concern exist for atypical hyperplasia progressing to invasive cancer, but numerous studies found concurrent carcinoma at rates ranging from 17-52%.^2,3,4,5 The latest prospective Gynecologic Oncology Group study found that 306 patients with preoperative biopsies that diagnosed atypical endometrial hyperplasia had concurrent invasive adenocarcinoma in 42.6% of hysterectomy specimen.⁶ Part of the difficulty in diagnosing concurrent carcinoma is due to lack of reproducibility in diagnosing hyperplasia, especially atypical hyperplasia versus carcinoma among even expert gynecologic pathologists.^7,8,9,6

Pathophysiology

Endometrial hyperplasia results from continuous estrogen stimulation that is unopposed by progesterone. This can be due to endogenous estrogen or exogenous estrogenic sources. Endogenous estrogen may be caused by chronic anovulation associated with polycystic ovary syndrome (PCOS) or perimenopause. Obesity also contributes to unopposed estrogen exposure due to chronic high levels of estradiol that result from aromatization of androgens in adipose tissue and conversion of androstenedione to estrone. Endometrial hyperplasia and cancer can also result from estradiol-secreting ovarian tumors such as granulosa cell tumors.

Exogenous estrogen without progesterone has been associated with increased endometrial hyperplasia and adenocarcinoma.¹⁰ The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that unopposed estrogen exposure with 0.625 mg of conjugated equine estrogens increased the risk of complex hyperplasia by 22.7% and atypical hyperplasia by 11.8% over 3 years of use compared with a less than 1% increase in placebo controls.¹¹ The risk of endometrial cancer was not increased when 2.5 mg of medroxyprogesterone acetate was used in combination with 0.625 mg of conjugated equine estrogens in 8506 women in the Women's Health Initiative (WHI) study.¹²  Tamoxifen, with its estrogenic effect on the endometrium, increases the risk of endometrial hyperplasia and endometrial cancer. The risk of progression to cancer is associated with an increased duration of use.¹³

The exact mechanism of estrogen's role in the transformation of normal endometrium to hyperplasia and cancer is unknown. Genetic alterations are known to be associated with hyperplasia and type I endometrial cancers. Lesions with hyperplasia are associated with microsatellite instability and defects in DNA mismatch repair genes. PTEN tumor suppressor gene mutations have also been found in 55% of hyperplasia cases and 83% of hyperplasia cases once it has progressed to endometrial cancer.¹⁴

Mortality/Morbidity

Endometrial carcinoma is the most common gynecologic malignancy and the fourth most common cancer in women, with a projected 40,100 cases diagnosed in the United States in 2008.¹⁵ Significant morbidity or mortality can occur if endometrial hyperplasia is untreated or concurrent malignancy is present.

Endometrial hyperplasia is often associated with irregular or heavy vaginal bleeding, which can lead to disruptions with quality of life. Occasionally, uterine hemorrhaging occurs, which may necessitate medical or surgical interventions, loss of fertility, and blood transfusion therapy.

Sex

Endometrial hyperplasia only affects females.

Age

Endometrial hyperplasia is most frequently diagnosed in postmenopausal women, but women of any age can be at risk if they are exposed to a source of unopposed estrogen. Endometrial hyperplasia can frequently be seen in young women with chronic anovulation.

Clinical Features

Other risk factors for endometrial hyperplasia are the same as those for type I endometrial adenocarcinoma, including obesity, nulliparity, early menarche, and late menopause. While unopposed estrogen in oral contraceptive pills or estrogen replacement therapy increases the risk of hyperplasia and cancer, combination oral contraceptive pills and combination hormone replacement therapy does not increase and may decrease the risk of hyperplasia and cancer.

The most common clinical presentation of patients with endometrial hyperplasia is abnormal uterine bleeding, whether in the form of menorrhagia, metrorrhagia, or postmenopausal bleeding. Others present with abnormal vaginal discharge or Pap smear results showing glandular abnormalities.

When abnormal bleeding is present, a full history and physical examination is warranted with careful examination of the lower genital tract for lesions of the vulva, vagina, cervix, and palpation of uterus and ovaries. The source of vaginal discharge or bleeding, the size of the uterus and endometrial cavity, and any pelvic masses should be noted. If the patient is obese and a pelvic examination is inadequate, pelvic ultrasonography may be helpful.

Diagnosis of endometrial hyperplasia is usually made by sampling the endometrial cavity using Pipelle endometrial biopsy in the office or dilation and curettage in the operating room. Tissue sampling should be performed in women with risk factors who present with symptoms of abnormal vaginal bleeding or discharge. This includes women older than 40 years with abnormal bleeding, younger than 40 years with bleeding and risk factors, with persistent bleeding, and with unopposed estrogen replacement therapy. In addition, a biopsy should be performed in women with AGUS (atypical glandular cells of undetermined significance) Pap smear or endometrial cells in Pap smears of women older than 40 years.^16,17 While no evidence of improved survival has been documented, some also advocate routine screening by endometrial biopsy in asymptomatic women with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome or those on tamoxifen therapy.

If a patient does not tolerate an office biopsy or has cervical stenosis, endovaginal ultrasonography is an effective method to assess thickness of the endometrial echo complex and to evaluate uterine bleeding. While endovaginal ultrasonography has a sensitivity of greater than 96% for ruling out endometrial carcinoma, if the endometrial echo complex is less than 5 mm, persistent bleeding, despite a thin stripe, still warrants tissue biopsy because of the risk of missing a type 2 cancer that is not associated with hyperplasia and thickening of the endometrial echo complex.¹⁸

Treatment

Once a tissue diagnosis of endometrial hyperplasia is made, treatment depends on the patient's symptoms such as degree of bleeding, presence of cytologic atypia, patient's surgical risks, and wish for future childbearing. Progestins can effectively treat endometrial hyperplasia, and they can serve as prevention of recurrence in those with continued risk factors. Hyperplasia without atypia responds well to progestins. More than 98% of women with hyperplasia treated with cyclic progestins experienced regression of the disease in 3-6 months.¹⁹ The PEPI trial showed a 94% normalization of complex or atypical hyperplasia in 45 women treated with progestins.¹¹ Multiple regimens of progestin therapy have been found effective in reversing hyperplasia.

• Medroxyprogesterone acetate (Provera), 10-20 mg qd, or cyclic 12-14 days per month
• Micronized vaginal progesterone (Prometrium), 100-200 mg qd or cyclic 12-14 days per month
• Levonorgestrel-containing IUD (Mirena), 1-5 years
• Megestrol acetate (Megace), 40-200 mg per day, usually reserved for women with atypical hyperplasia

If hyperplasia with atypia is found on dilation and curettage (D&C) or endometrial biopsy, definitive treatment with hysterectomy is recommended due to the high rate of concurrent endometrial cancer. However, if the patient has not completed childbearing or is not a surgical candidate, then concurrent cancer must first be ruled out by D&C with hysteroscopy prior to medical management. Because D&C and Pipelle biopsy only sample 50-60% of the endometrial lining, focal lesions containing adenocarcinoma may be missed. Biopsy is recommended after 3 months to check for response to medical therapy, and continued surveillance after regression of the lesion is recommended every 6-12 months if risk factors persist.

The need for hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma presents a barrier to nonsurgical management of endometrial hyperplasia. A recent Gynecologic Oncology Group study examined the histomorphometric 4-class rule ("4C", which measures epithelial abundance, thickness, and nuclear variation) as applied to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy.²⁰ Women with endometrial biopsies or curettages with a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured.

Qualifying biopsies were stratified into high- and low-risk histomorphometric subgroups. Assignment to a high-risk category by 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease. 

At present, this use of histomorphometry is most suited to a centralized reference laboratory performing histomorphometry for a variety of diagnostic applications. However, in the future, formal histomorphometry of endometrial biopsies using the 4C rule may become a more common method to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and therefore may qualify for nonsurgical therapy.

Keywords

premalignant lesions of the endometrium, endometrial hyperplasia, EH, endometrial neoplasia, endometrial intraepithelial neoplasia, EIN, endometrial carcinoma, endometrioid endometrial adenocarcinoma, simple hyperplasia, complex hyperplasia, simple hyperplasia with atypia, complex hyperplasia with atypia, adenocarcinoma, exogenous estrogen, endogenous estrogen, estrogen stimulation unopposed by progesterone, uterine hemorrhaging, chronic anovulation, menorrhagia, metrorrhagia, postmenopausal bleeding, Pipelle endometrial biopsy, hereditary nonpolyposis colorectal cancer, HNPCC, tamoxifen therapy

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Susan B Tate, MD, and Charles N Landen, MD, to the development and writing of this article.

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