Disclosures: Robert L Giuntoli, II, MD Nothing to disclose. Howard A Zacur, MD, PhD Nothing to disclose. Barbara Goff, MD Nothing to disclose. Rochelle L Garcia, MD Nothing to disclose. Sandy J Falk, MD, FACOG Employee of UpToDate, Inc.
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INTRODUCTION — Endometrial hyperplasia is characterized by a proliferation of endometrial glands of irregular size and shape. Compared with proliferative endometrium, there is an increase in the endometrial gland to stroma ratio. Endometrial hyperplasia virtually always results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone .
The classification, clinical manifestations, diagnosis, and evaluation of endometrial hyperplasia are reviewed here. Related topics can be found separately:
●Management of endometrial hyperplasia (See "Management of endometrial hyperplasia".)
●Other etiologies of abnormal uterine bleeding (See "Approach to abnormal uterine bleeding in nonpregnant reproductive-age women" and "Postmenopausal uterine bleeding".)
●Endometrial cancer (See "Endometrial carcinoma: Epidemiology and risk factors".)
HISTOLOGY AND CLASSIFICATION — Endometrial hyperplasia is characterized by a proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium. The proliferating glands vary in size and shape, and cells may have cytologic atypia. Historically, several different terms were utilized to signify abnormal proliferation of the endometrium. These terms included: "adenomatous hyperplasia", "atypical hyperplasia", and "carcinoma in situ." Some of these lesions represented endometrial cancer precursors. Because the criteria for many of the terms were never clearly standardized, the relationship between proliferative endometrial lesions and carcinoma was not always apparent . This section will discuss the World Health Organization and the Endometrial intraepithelial neoplasia classification systems for endometrial hyperplasia.
World Health Organization classification — The World Health Organization (WHO) classification of endometrial hyperplasia is the most widely used system .
Categories — The WHO classification of endometria hyperplasia is based upon two features:
●The glandular/stromal architectural pattern of the endometrium, which is described as either simple or complex
●The presence or absence of nuclear atypia
This results in four possible categories of endometrial hyperplasia:
●Simple hyperplasia without atypia
●Complex hyperplasia without atypia
●Simple atypical hyperplasia
●Complex atypical hyperplasia
Simple atypical hyperplasia is rare, and many reports use the term atypical hyperplasia to refer to all women with either simple or complex atypical hyperplasia.
In general, the WHO system correlates well with the risk of progression to endometrial carcinoma. However, a major limitation of this system is interobserver variability across pathologists reviewing the same slides [3-6]. The finding of nuclear atypia, which is the most important indicator of malignant potential, has the lowest level of interobserver agreement. As an example, two studies of 100 or more endometrial biopsy slides found concordance across pathologists for a report of nuclear atypia was only 38 to 47 percent [3,4]. (See 'Risk of carcinoma' below and 'Nuclear atypia' below.)
Normal endometrium — During the normal menstrual cycle, proliferative endometrium is found during the follicular phase, and secretory endometrium is found during the luteal phase (figure 1). Normal proliferative endometrium exhibits no crowding of glands within the stroma (<50 percent ratio of glands to stroma). Normal secretory endometrium may have >50 percent gland to stroma ratio. Although they exhibit crowding, these glands are organized, and cells comprising the glands are spaced and are not mitotically active. Normal proliferative and secretory endometrium is shown in the picture (picture 1A-B).
Simple versus complex hyperplasia — Simple and complex endometrial hyperplasia are characterized by the following features:
●Simple hyperplasia consists of glands that are mildly crowded. They are frequently cystically dilated with only occasional outpouching. Mitoses may or may not be present in the glandular cells (picture 2).
●Complex hyperplasia consists of glands that are crowded (>50 percent gland to stromal ratio); the gland-to-stroma ratio is higher in complex compared to simple hyperplasia. The glands appear disorganized and have luminal outpouching. Mitoses are typically present (picture 3).
Nuclear atypia — Nuclear atypia is the presence of nuclear enlargement; the chromatin may be either evenly dispersed or clumped . Atypical endometrial hyperplasia is usually complex, although rarely there is a finding of simple atypical hyperplasia. The features of atypical endometrial hyperplasia are:
●Complex atypical hyperplasia consists of crowding of glands lined by atypical cells (picture 4 and picture 5). Rarely, extreme complexity without marked cytologic atypia warrants a diagnosis of complex atypical hyperplasia.
A drawback of the WHO classification scheme is that the category of complex atypical hyperplasia includes both neoplasms bordering on invasive carcinoma and those that are clearly not invasive. Complex atypical hyperplasia is distinguished from grade 1 endometrial carcinoma by the presence of residual endometrial stroma that separates all glands. Variability is often noted across pathologists in making this distinction. As an example, in one study, 289 endometrial sampling specimens with a diagnosis of complex atypical hyperplasia made at a community hospital were reviewed by pathologists using WHO criteria; 25 percent of cases were downgraded to less severe histology than complex atypical hyperplasia, and 29 percent were upgraded to endometrial carcinoma .
●Simple atypical hyperplasia is characterized by cells with nuclear atypia that line glands that are separated by significant amounts of normal stroma.
Risk of carcinoma — Using the WHO classification, the presence of nuclear atypia is the most important indicator of the risk of endometrial carcinoma in women with endometrial hyperplasia.
High quality data are lacking regarding the natural history of endometrial hyperplasia. The best available data regarding the likelihood of progression from endometrial hyperplasia to carcinoma are from a classic retrospective study of 170 women who had endometrial sampling and then had a hysterectomy after an average of 13 years (range 1 to 27 years) . This study was limited by the small overall number of events and the fact that most of these women had some intervention between initial endometrial sampling and hysterectomy. Endometrial carcinoma at hysterectomy was more than 10-fold higher in women with atypical hyperplasia than in women with no atypia (23 versus 1.6 percent). The incidence of cancer for each histologic category was:
●Simple hyperplasia without atypia – 1 of 93 patients (1 percent)
●Complex hyperplasia without atypia – 1 of 29 patients (3 percent)
●Simple atypical hyperplasia – 1 of 13 patients (8 percent)
●Complex atypical hyperplasia – 10 of 35 patients (29 percent)
Similar findings reported in a case control study found that the cumulative risk of endometrial carcinoma at 19 years after diagnosis of endometrial hyperplasia was higher for women with atypia compared with those without atypia (28 versus 5 percent) .
The time course from a diagnosis of endometrial hyperplasia to carcinoma is not well established. The case control study cited above reported that the average time to diagnosis of cancer was six years in women with all types of endometrial hyperplasia .
Many women with atypical endometrial hyperplasia have coexistent endometrial carcinoma . A literature review including 2572 patients reported that 37 percent of women with a diagnosis of atypical endometrial hyperplasia on endometrial sampling were found to have endometrial carcinoma on subsequent biopsy or hysterectomy . Thus, women with a finding of atypical endometrial hyperplasia on endometrial biopsy require further evaluation. (See 'Positive endometrial sampling' below.)
Endometrial intraepithelial neoplasia system — The endometrial intraepithelial neoplasia classification system was proposed by an international group of gynecologic pathologists in 2000 . This system has not gained widespread acceptance, but is used in some institutions. The system defines two classes of endometrial changes that are relevant to clinical management:
●Endometrial hyperplasia (EH) – Changes typically observed with anovulation or other etiology of prolonged exposure to estrogen. The morphology of EH varies from proliferative endometrium with a few cysts (persistent proliferative endometrium) to bulkier endometria with many dilated and contorted glands that in other systems have been designated as "cystic glandular hyperplasia", "mild hyperplasia", or "simple hyperplasia."
●Endometrial intraepithelial neoplasia (EIN) – Endometrial precancers. Epithelial crowding in precancers displaces stroma to a point at which stromal volume is less than approximately half of total tissue volume (stroma + epithelium + gland lumen). Stromal volume can be measured using computerized morphometric analysis and assigned a D-score [13,14]. Using this method, specimens are classified as benign (D >1), indeterminate (0<D<1), or EIN (D <0).
EIN system categories do not correspond directly to specific categories in the WHO system, but there is some consistency. Most simple and some complex hyperplasias fall into the EH category. Many complex hyperplasias without atypia and most complex hyperplasias with atypia fall into the EIN category.
The EIN classification system has demonstrated high interobserver reproducibility, and studies have confirmed that EIN correlates with progression to endometrial carcinoma . A recognized drawback of the EIN system is that it lumps findings that would receive different treatments (hormonal treatment or surgery), ostensibly because of the lack of ability to reproducibly distinguish between differing severities within the EIN category .
Comparing the WHO and EIN systems — Few studies have compared the diagnostic performance of the WHO and EIN systems. The available observational data suggest that the EIN system may be better able to predict which lesions will progress to invasive disease [15,16]. As an example, a retrospective multicenter study compared the performance of the EIN and WHO classification systems for predicting progression of endometrial hyperplasia to endometrial carcinoma . The EIN system was better able to distinguish between lesions likely to progress versus those not likely to progress. With the EIN system, progression rates for the two categories were: EH (2 of 359 patients [0.6 percent]) versus EIN (22 of 118 patients [19 percent]). By comparison, use of the WHO system had the following progression rates: hyperplasia without atypia (8 of 354 patients [2 percent]) versus atypical hyperplasia (16 of 123 patients [13 percent]).
The Society of Gynecologic Oncologists recommends using a pathologic diagnosis system that utilizes criteria and terminology that distinguish between clinicopathologic entities requiring different management. The EIN system appears to better fulfill these objectives. However, the WHO classification remains more widely used .
EPIDEMIOLOGY — The best available data regarding the epidemiology of endometrial hyperplasia are from a report from a large integrated health plan that included women aged 18 to 90 over an 18-year period (1985 to 2003) . The overall incidence of endometrial hyperplasia was 133 per 100,000 woman-years. The diagnosis is most commonly made in woman age 50 to 54 years and rarely was found in women younger than age 30. The incidence of simple and complex hyperplasia without atypia were highest in women age 50 to 54 years (142 and 213 per 100,000 woman-years, respectively), whereas the rate of atypical hyperplasia was highest in women age 60 to 64 (56 per 100,000 woman-years). Trends in incidence over the accrual period demonstrated declining incidence over time, particularly for atypical hyperplasia (1985 to 1989: 23 per 100,000 woman-years versus 2000 to 2003: 5 per 100,000 woman-years). The reason for this trend is unknown. However, at the time the investigation was performed, postmenopausal hormone therapy was common practice, and in the 1980s unopposed estrogen was used more often than in the later periods of the study.
In general, reliable estimates of the incidence of endometrial hyperplasia are difficult to obtain due to many factors, including changing diagnostic criteria over time, bias of studies evaluating symptomatic women (eg, abnormal uterine bleeding), trends in postmenopausal hormone therapy, assessment technique (endometrial sampling versus hysterectomy), and concomitant diagnoses of endometrial cancer with hyperplasia.
RISK FACTORS — The risk factors for endometrial hyperplasia are the same as those for endometrial carcinoma (table 1). Most of these risk factors involve exposure of the endometrium to continuous estrogen unopposed by a progestin. This effect may be due to endogenous or exogenous hormone. Physiologically, estrogen stimulates endometrial proliferation during the normal menstrual cycle; this effect is buffered by progesterone, which inhibits endometrial proliferation and stimulates differentiation in preparation for implantation of an embryo.
In addition, women with Lynch syndrome (hereditary nonpolyposis colorectal cancer) are at a greatly increased risk of endometrial hyperplasia. (See "Endometrial and ovarian cancer screening and prevention in women with Lynch syndrome (hereditary nonpolyposis colorectal cancer)", section on 'Endometrial cancer'.)
Risk factors for endometrial neoplasia in general are discussed in detail separately. (See "Endometrial carcinoma: Epidemiology and risk factors", section on 'Risk factors'.)
CLINICAL PRESENTATION — Endometrial hyperplasia typically presents with abnormal uterine bleeding and is most common in women who are postmenopausal, and with increasing age in premenopausal women. Occasionally, women with no abnormal uterine bleeding present with abnormal findings on cervical cytology.
The clinical presentation for endometrial hyperplasia is the same as for endometrial carcinoma. This is discussed in detail separately. (See "Endometrial carcinoma: Clinical features and diagnosis", section on 'Clinical presentation'.)
DIAGNOSTIC EVALUATION — Women with a clinical presentation suspicious for endometrial hyperplasia are evaluated initially with physical examination. Pelvic sonography may also be performed to evaluate for other etiologies of abnormal uterine bleeding or to assess endometrial thickness in postmenopausal women. This evaluation is the same as for women with suspected endometrial carcinoma and is discussed in detail separately. (See "Endometrial carcinoma: Clinical features and diagnosis", section on 'Evaluation of women with suspected endometrial neoplasia'.)
DIAGNOSIS — Endometrial hyperplasia is a histologic diagnosis made based upon the results of evaluation of an endometrial biopsy, curettage sample, or hysterectomy specimen.
Diagnostic methods are the same as for endometrial carcinoma and are discussed in detail separately. (See "Endometrial carcinoma: Clinical features and diagnosis".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of endometrial hyperplasia includes other conditions that present with abnormal uterine bleeding. Women with presumed uterine bleeding should be evaluated to confirm that the source of the blood is the uterus, and not another part of the genital tract or the anus or rectum. The etiologies of uterine bleeding and other sources of genital tract bleeding are discussed separately. (See "Differential diagnosis of genital tract bleeding in women".)
In addition, for women who present with abnormal finding on cervical cytology, the differential diagnosis includes benign endometrium and cervical neoplasia. (See "Cervical and vaginal cytology: Interpretation of results", section on 'Benign-appearing endometrial cells in a woman ≥40 years' and "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Risk of premalignant or malignant disease'.)
FURTHER EVALUATION AFTER ENDOMETRIAL SAMPLING
Negative endometrial sampling
Insufficient cells on endometrial biopsy — Women with an endometrial biopsy result that has insufficient endometrial cells should have sampling repeated with an office biopsy or dilation and curettage (D&C). If two office endometrial biopsies have been unsuccessful, a D&C should be performed. Cervical stenosis, a common cause of an unsuccessful biopsy, can be managed with preprocedure cervical preparation or dilation. (See "Endometrial sampling procedures", section on 'Cervical preparation and dilation'.)
Persistent or recurrent bleeding — If bleeding persists or recurs after endometrial sampling with benign findings, further evaluation is required. In our practice, we reevaluate such cases after three to six months.
Abnormal uterine bleeding symptoms may be due to an etiology other than endometrial neoplasia. Transvaginal ultrasound, sonohysterography, or diagnostic hysteroscopy should be performed to exclude structural lesions (leiomyomas, endometrial polyp). Any structural lesions that are found should be treated, as appropriate. (See "Evaluation of the endometrium for malignant or premalignant disease" and "Hysteroscopic myomectomy" and "Endometrial polyps", section on 'Choosing a management approach'.)
In addition to evaluation for structural lesions, it is essential to repeat endometrial sampling to exclude endometrial hyperplasia or carcinoma. Reported rates of endometrial neoplasia in women evaluated for persistent or recurrent postmenopausal bleeding vary widely, from 4 to 21 percent [19,20].
Positive endometrial sampling — Women with endometrial hyperplasia should be treated, as appropriate. (See "Management of endometrial hyperplasia".)
Follow-up of biopsy or curettage results — A diagnosis of atypical endometrial hyperplasia raises concern for a coexistent endometrial carcinoma and whether repeat sampling should be performed. As noted above, coexistent endometrial carcinoma is present in approximately 37 percent of women with a preoperative diagnosis of complex atypical hyperplasia at time of hysterectomy .
Some data suggest D&C is more effective than office endometrial biopsy at detecting coexistent carcinoma; however, neither is sufficient to exclude malignancy. As an example, in a study that included 824 women with complex atypical endometrial hyperplasia, the rate of unexpected endometrial carcinoma diagnosed at hysterectomy was high for patients who underwent a single sampling procedure with either method, but was statistically significantly lower for D&C (33 versus 47 percent) . Among women who had a repeat endometrial biopsy, the rate of diagnosis at hysterectomy remained high (22 of 89; 22 percent) as did the rate for women evaluated with endometrial biopsy, followed by D&C (28 of 171; 16 percent).
If curettage D&C is performed as a follow-up to endometrial biopsy, if the results are atypical endometrial hyperplasia or carcinoma, the patient is managed as appropriate. If the results are less severe or negative, the patient should be managed based upon the results of the initial sample.
Postmenopausal women with no known estrogen source — Development of endometrial hyperplasia with or without atypia in a woman who should be estrogen-deficient requires an explanation. In the absence of other sources of estrogen (eg, estrogen therapy, obesity), such women require evaluation for an estrogen-producing tumor. This is discussed in detail separately. (See "Endometrial carcinoma: Clinical features and diagnosis", section on 'Postmenopausal women not on hormone therapy'.)
SUMMARY AND RECOMMENDATIONS
●Endometrial hyperplasia is characterized by a proliferation of endometrial glands that may progress to or coexist with endometrial carcinoma. (See 'Introduction' above.)
●The most commonly used classification system for endometrial hyperplasia is the World Health Organization system, which has four categories: simple without nuclear atypia, complex without atypia, simple atypical hyperplasia, and complex atypical hyperplasia. (See 'Histology and classification' above.)
●The endometrial intraepithelial neoplasia system is another classification system. (See 'Endometrial intraepithelial neoplasia system' above.)
●The presence of nuclear atypia is the most important indicator of the risk of endometrial carcinoma in women with endometrial hyperplasia. The risk of progression from atypical hyperplasia to carcinoma is approximately 23 to 29 percent. In addition, 17 to 52 percent of women with atypical hyperplasia are found to have coexistent endometrial carcinoma when a hysterectomy is performed. (See 'Risk of carcinoma' above.)
●Endometrial hyperplasia almost always results from excess estrogen exposure. This may be caused by obesity, anovulation, estrogen therapy without a progestin, or estrogen-producing ovarian tumors (rare). (See 'Risk factors' above.)
●Endometrial hyperplasia typically presents with abnormal uterine bleeding and is most common in women who are postmenopausal, and with increasing age in premenopausal women. Occasionally, women with no abnormal uterine bleeding present with abnormal findings on cervical cytology. (See 'Clinical presentation' above.)
●Endometrial hyperplasia is a histologic diagnosis made with sampling of the endometrium. Either an office endometrial biopsy or dilation and curettage may be performed. (See 'Diagnosis' above.)
●Neither endometrial biopsy nor dilation and curettage is sufficiently accurate to rule out endometrial carcinoma. (See 'Follow-up of biopsy or curettage results' above.)
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