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Classification and diagnosis of endometrial hyperplasia
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Classification and diagnosis of endometrial hyperplasia
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Literature review current through: Sep 2017. | This topic last updated: Apr 27, 2017.

INTRODUCTION — The endometrium (lining of the uterus) may develop endometrial hyperplasia, which include precancerous (intraepithelial) neoplasms (atypical complex hyperplasia) and nonneoplastic entities (simple and many complex hyperplasias without atypia); these are 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 frequently results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone [1].

The classification, epidemiology, risk factors, 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 carcinoma (See "Endometrial carcinoma: Epidemiology and risk factors".)

HISTOPATHOLOGY AND CLASSIFICATION — Endometrial hyperplasia is characterized by a proliferation of endometrial glands resulting in a greater gland-to-stroma ratio (>50 percent) than observed in normal proliferative endometrium (picture 1A). The proliferating glands vary in size and shape, and cells may have cytologic atypia.

The terminology for abnormal proliferation of the endometrium has varied. Terms that have been used include: "adenomatous hyperplasia," "atypical hyperplasia," and "carcinoma in situ." Some, but not all, of these lesions represent endometrial carcinoma precursors. The diagnosis of these proliferative lesions is poorly reproducible because it is difficult to distinguish between non-neoplastic proliferations and neoplastic proliferations, and it is difficult to determine endometrial invasion in a nonhysterectomy specimen [1]. As a result, pathologists use "surrogate" markers of invasion, such as back-to-back glands and cribriform glands.

The two main classification systems for endometrial hyperplasia are the 2015 World Health Organization (WHO) system and the endometrial intraepithelial neoplasia system. The WHO system is more widely used.

Classification systems

World Health Organization classification — The 2015 WHO endometrial hyperplasia classification system has only two categories [2]:

Hyperplasia without atypia (non-neoplastic)

Atypical hyperplasia (endometrial intraepithelial neoplasm)

Previously, the 1994 WHO classification of endometrial hyperplasia had been the most widely used system [3]. The 1994 WHO classification of endometrial hyperplasia had four categories:

Simple hyperplasia without atypia

Complex hyperplasia without atypia

Simple atypical hyperplasia

Complex atypical hyperplasia

The 1994 WHO system correlated with the risk of progression to endometrial carcinoma. However, a significant limitation was interobserver variability across pathologists reviewing the same slides (table 1) [4-8]. The finding of nuclear atypia, the most important predictor of progression to (or concurrent) carcinoma, has relatively poor interobserver agreement. As an example, in one study, among unblinded academic pathologists the correlation coefficient of nuclear atypia was 0.28 [4]. Although numerous pathology features are used to diagnose endometrial hyperplasia [9], an independent review by five pathologists showed that only the presence of nucleoli was associated with high agreement in the distinction of atypical hyperplasia [5]. Interobserver variability improves with increasing specimen volume [4,5,8].

The 2015 WHO system is intended to reduce the confusion associated with numerous pathologic terms, and also to reflect that hyperplasia without atypia is a non-neoplastic change. By contrast, hyperplasia with atypia has been found to exhibit many cellular and genetic changes that are typically associated with invasive carcinoma [10].

Pathologic features of the 1994 and 2015 WHO classification schemes that are described include:

Normal endometrium – During the normal menstrual cycle, endometrium is proliferative during the follicular phase and is secretory 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 secretory phase glands exhibit crowding, they 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 – Historically, simple and complex endometrial hyperplasia were characterized by the following features. This distinction is no longer made in the 2015 WHO classification system:

Simple hyperplasia consists of glands that are mildly crowded. They are frequently cystically dilated with only occasional outpouching. Mitoses are typically present in the glandular cells (picture 2).

Complex hyperplasia consists of glands that are crowded (>50 percent gland to stroma ratio); the gland-to-stroma ratio is higher in complex hyperplasia 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, and/or prominent nucleoli may be present [11]. Gland crowding lined by atypical cells is the hallmark of endometrial intraepithelial neoplasia (picture 4 and picture 5). Rarely, extreme complexity without marked cytologic atypia warrants a diagnosis of atypical hyperplasia.

Endometrial intraepithelial neoplasia classification — The endometrial intraepithelial neoplasia (EIN) classification system was proposed by an international group of gynecologic pathologists in 2000 [12]. The EIN system has not gained widespread acceptance, most likely due to cost and/or lack of experience with the computerized D-scoring component.

The D-score is an integral part of the EIN classification [13,14]. It is a measure of stromal volume as a proportion of total tissue volume (stroma + epithelium + gland lumen). Using this method, specimens are classified as benign (D >1), indeterminate (0< D <1), or EIN (D <0). The D-score is assigned based on evaluation with computerized morphometry.

A potential alternative to computerized morphometry is subjective EIN classification. This approach appeared to correlate well with estimates using the computerized D-score in one small study of 97 women in which 8 women developed cancer [15]. However, more experience is needed to evaluate subjective assignment of the D-score in diverse practice environments.

The EIN system defines two classes of endometrial changes: benign and intraepithelial neoplasia.

Benign endometrial hyperplasia (EH, non-neoplastic) – 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 EIN displaces stroma to a point at which stromal volume is less than approximately half of total tissue volume in nonsecretory endometrium, and typically cells appear morphologically clonal and distinct from the surrounding endometrium.

EIN classification categories do not correspond directly to specific categories in the WHO system, but there is some consistency. Most simple and nonatypical complex hyperplasias fall into the EH category. Some complex hyperplasias without atypia and essentially all complex hyperplasias with atypia fall into the EIN category.

The EIN classification system has demonstrated moderate interobserver reproducibility (table 1), and studies have confirmed that EIN correlates with progression to endometrial carcinoma [13,16].

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 [12].

Comparing the WHO and EIN systems — Few studies have compared the diagnostic performance of the WHO and EIN systems. The largest population-based observational study with 138 women who developed endometrial carcinoma suggested that the EIN and 1994 WHO classification systems were similarly effective for predicting progression of endometrial hyperplasia to endometrial carcinoma [16,17]. A smaller multicenter study that was not population-based suggested that the EIN system was better able to distinguish between lesions likely to progress versus those not likely to progress, but caution is warranted in the interpretation of these findings as only 24 women with cancer were included.

The American College of Obstetrics and Gynecology and the Society of Gynecologic Oncologists recommend using a pathologic diagnosis system that utilizes criteria and terminology that distinguish between clinicopathologic entities requiring different management. The EIN system may better fulfill these objectives, but adequate comparative studies are lacking. The WHO classification remains more widely used [18,19].

The risk of progression to endometrial carcinoma using the WHO and EIN classification systems was found to be similar in a nested case-control study. Using 138 cases of endometrial carcinoma, the relative risk of carcinoma was 9.19 for atypical hyperplasia and 7.76 for intraepithelial neoplasia [16]. The risk of progression using the EIN system was also evaluated in a multicenter study: 24 of 477 women developed endometrial carcinoma at least one year after their index biopsy. The progression rate was 2.3 percent among women without atypia and 13 percent among women with atypia. Using the EIN scoring scheme, 19 percent with EIN showed progression [16].

Distinguishing hyperplasia from endometrial carcinoma — It is sometimes difficult to distinguish a precursor lesion (EIN) from endometrial carcinoma. Atypical hyperplasia or EIN is distinguished from grade 1 endometrial carcinoma by findings that suggest invasion, including: invasive pattern of glands infiltrating reactive stroma (the most definitive), cribriform glands, or confluent growth (lack of stroma between glands). Marked nuclear atypia, especially in the context of atrophic background endometrium, may be present in either endometrial intraepithelial serous neoplasm or "intraepithelial carcinoma," which is frequently associated with invasive serous carcinoma.

Variability is often noted across pathologists in distinguishing atypical hyperplasia/endometrial intraepithelial neoplasia from carcinoma. 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 unblinded pathologists using 1994 WHO criteria; 25 percent of cases were downgraded to less severe histology than complex atypical hyperplasia, and 29 percent were upgraded to endometrial carcinoma [20].

Potential biomarker use — Considerable progress has been made in the evaluation of immunohistochemical markers to distinguish atypical hyperplasia from endometrial carcinoma. Two small pathology reviews noted that the absence of PAX2 expression on immunohistochemistry was helpful in delineating EIN [21], especially when there was a background of secretory endometrium [22]. PAX2 alterations were noted to correlate well with EIN, but were less useful with the WHO classification.

As an example, in a blind review of 206 endometrial samples, the percentage of cases with complete PAX2 loss (no cells staining) increased with increasing severity of hyperplasia: normal proliferative and secretory (no cases), simple hyperplasia (17.4 percent), complex hyperplasia (59 percent), atypical hyperplasia (74.1 percent), and grade 1 endometrioid carcinomas (73.3 percent) [23]. Another small immunohistochemistry assessment noted that various clusters of proteins, including MMP-9 and BCL-2 overexpression and estrogen and progesterone receptor underexpression, were useful to differentiate endometrial carcinoma from atypical endometrial hyperplasia [24].

Squamous morules and atypical polyps — Squamous morules are seen in non-neoplastic and neoplastic endometrial processes, though they are more commonly observed in neoplasms. Women with isolated morules on sampling should be carefully followed to exclude an under-sampled or occult neoplastic glandular lesion [25]. Most endometrial polyps do not contain neoplasm. However, there can be polypoid neoplasms or neoplasms (endometrioid carcinoma or complex atypical hyperplasia or serous neoplasm) involving polyps. If neoplasm/cells suggestive of neoplasm are present in association with a biopsy, it may not be certain whether that neoplasm is confined to the polyp, and therefore further treatment and/or hysterectomy may be warranted.

RISK OF ENDOMETRIAL CARCINOMA — Women with neoplastic endometrial hyperplasia may have coexistent endometrial carcinoma or may progress to carcinoma. Using the World Health Organization (WHO) classification, the presence of nuclear atypia in endometrial hyperplasia is the most important indicator for the risk of coexisting carcinoma or progression. Women at the highest risk include those with: atypical endometrial hyperplasia or endometrial intraepithelial neoplasia (EIN) or and those with complex hyperplasia who have significant risk factors for endometrial carcinoma (table 2) [20].

Coexistent 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 [26]. Thus, women with a finding of atypical endometrial hyperplasia on endometrial biopsy require further evaluation and intervention. (See 'Positive endometrial sampling' below.)

Older age, obesity, diabetes mellitus, and complex endometrial hyperplasia are the strongest predictors of concurrent endometrial carcinoma among women with endometrial hyperplasia [27].

Progression to carcinoma — Regarding progression from hyperplasia to carcinoma, representative studies include:

A classic retrospective case series of 170 women who had endometrial hyperplasia on endometrial sampling from 1940 to 1970 and then had a hysterectomy after an average of 13 years (range, 1 to 27 years) [28]. This study was limited by several factors: small size, no controls, and most women had some intervention between initial endometrial sampling and hysterectomy. The rate of 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).

A retrospective cohort study from 1985 to 2005 included 1443 women with complex or atypical hyperplasia; subjects did not undergo hysterectomy within eight weeks from their diagnosis and did not subsequently receive unopposed estrogen [29]. Endometrial carcinoma was diagnosed over a follow-up period of 21 years in 2.9 percent of women with complex hyperplasia and 14.9 percent of women with atypical hyperplasia. This analysis included women treated and not treated with progestin. Rates of progression to carcinoma were higher in women not treated with a progestin (threefold for complex hyperplasia and fivefold for atypical hyperplasia).

A nested case-control study was performed with data from a cohort of 7947 women with an initial diagnosis of endometrial hyperplasia or disordered proliferative endometrium, using women who developed endometrial carcinoma after at least one year with controls [30]. It is important to note that women in this study may have taken unopposed estrogen, whereas the women in the population-based cohort study cited above were excluded if they took unopposed estrogen following the diagnosis of endometrial hyperplasia. The odds of progression to carcinoma were:

Nonatypical endometrial hyperplasia, cumulative risk of progression increased from 1.2 percent (year 4), to 1.9 percent (year 9), to 4.6 percent (year 19) following hyperplasia diagnosis.

Atypical hyperplasia, cumulative risk increased from 8.2 percent (year 4), to 12.4 percent (year 9), to 27.5 percent (year 19).

In a subanalysis of this cohort, the risk of carcinoma remained elevated for five or greater years after a diagnosis of atypical hyperplasia [31].

In terms of time to progression to carcinoma [16,21-24], in one population-based study that excluded all women who were diagnosed with carcinoma within one year of endometrial hyperplasia diagnosis (ie, those with a high probability of concomitant carcinoma at index and any women who subsequently took unopposed estrogen), median time to progression of carcinoma was 5.1 years (1.1 to 11.6 years) among women with complex hyperplasia and 2.5 years (1.01 to 7.9 years) for women with atypical hyperplasia [29].

In a second population-based study, median time to diagnosis of carcinoma was approximately six years from the index biopsy in all women with endometrial hyperplasia [20], and in a third non-population-based study of 477 women with endometrial hyperplasia, progression to carcinoma was on average four years (maximum, 10 years [16]) after diagnosis of endometrial hyperplasia with a maximum of 18 years of follow-up.

EPIDEMIOLOGY — 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 toward evaluating only symptomatic women (eg, abnormal uterine bleeding), trends in postmenopausal hormone therapy, assessment technique (endometrial sampling versus hysterectomy), and concomitant diagnoses of endometrial carcinoma with hyperplasia.

Large studies of the epidemiology of endometrial hyperplasia include:

A report from a large integrated health plan included women aged 18 to 90 over an 18-year period (1985 to 2003) and reported an overall incidence of endometrial hyperplasia of 133 per 100,000 woman-years [32]. The diagnosis was made most commonly in woman ages 50 to 54 years and rarely was found in women younger than age 30. The incidences 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 1985 at the beginning of the study, unopposed estrogen was commonly used; whereas from 1995 to 2003, the importance of adding progestin therapy to postmenopausal estrogen to minimize endometrial neoplasia was widely accepted.

An analysis from another large health plan from 1980 to 2003 found that the rate of endometrial hyperplasia only (without hysterectomy or cancer) declined by almost six-fold during the study period, from 852.8 per 100,000 in 1980 to 144.0 per 100,000 in 2002; rates of endometrial hyperplasia declined until 1999, but then the incidence increased, possibly due increasing rates of obesity, which is a risk factor for endometrial hyperplasia [33].

RISK FACTORS — The risk factors for endometrial hyperplasia are similar to those for endometrial carcinoma (table 2) [34,35]. 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 perimenopausal or early postmenopausal, and with increasing age in premenopausal women. Among premenopausal women, obesity, polycystic ovarian syndrome, and chronic anovulation are commonly associate factors. Occasionally, in women with no abnormal uterine bleeding, endometrial hyperplasia is detected via abnormal glandular or endometrial cells 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; however, ultrasound criteria have been set for detection of endometrial carcinoma, but not endometrial hyperplasia. Endometrial thickness is not a reliable test for endometrial neoplasia in premenopausal women. Endometrial sampling is the gold standard for diagnosis of endometrial hyperplasia (table 3 and algorithm 1). (See "Evaluation of the endometrium for malignant or premalignant disease" and "Approach to abnormal uterine bleeding in nonpregnant reproductive-age women" and "Postmenopausal uterine bleeding".)

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, endometrial 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 (Pap test report)", section on 'Benign-appearing endometrial cells in women ≥45 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 and for whom there is a clinical concern for neoplasm 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 within three to six months after endometrial sampling with benign findings, further evaluation is required.

Abnormal uterine bleeding symptoms may be due to a missed diagnosis of endometrial neoplasia or to other etiologies.

It is essential to repeat endometrial sampling to exclude endometrial neoplasm. Reported rates of endometrial neoplasia in women evaluated for persistent or recurrent postmenopausal bleeding vary widely, from 4 to 22 percent [36-38]. In particular, patients with risk factors for endometrial carcinoma should have repeat sampling (table 2). A nested case-control study of patients with an endometrial carcinoma diagnosis who had previous benign endometrial sampling showed a personal history of colorectal cancer, endometrial polyp, and morbid obesity were independently associated with the subsequent diagnosis of endometrial carcinoma [39].

Transvaginal ultrasound, sonohysterography, or diagnostic hysteroscopy should be performed to exclude structural lesions (leiomyomas, endometrial polyps). 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'.)

Positive endometrial sampling — Women with a diagnosis of endometrial hyperplasia on office endometrial biopsy or D&C may require further evaluation.

Follow-up of biopsy or curettage results — A diagnosis of atypical endometrial hyperplasia/intraepithelial neoplasm raises concern for a coexistent endometrial carcinoma. As noted above, coexistent endometrial carcinoma may be present in approximately 37 percent of women with a preoperative diagnosis of complex atypical hyperplasia at time of hysterectomy [26]. (See 'Coexistent carcinoma' above.)

Some data suggest D&C is more effective than office endometrial biopsy at detecting coexistent carcinoma; however, neither is sufficient to exclude malignant neoplasm. 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) [40]. 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).

For women with a diagnosis on office endometrial biopsy of atypical endometrial hyperplasia who desire medical management, in our practice, we perform a D&C to exclude endometrial carcinoma.

If D&C is performed as a follow-up to endometrial biopsy and the results are atypical endometrial hyperplasia or carcinoma, the patient is managed as appropriate. (See "Management of endometrial hyperplasia".)

If the results are less severe or negative, and no intervening treatment has occurred, the patient should be managed based upon the results of the initial endometrial hyperplasia classification.

For patients with endometrial hyperplasia planned for hysterectomy and who have not had a D&C, a pathologist should be available to evaluate if the intraoperative findings suggest endometrial carcinoma, and the ability to perform surgical staging should be considered.

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'.)

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SUMMARY AND RECOMMENDATIONS

The endometrium (lining of the uterus) may develop endometrial hyperplasia, which include precancerous (intraepithelial) neoplasms (atypical complex hyperplasia) and nonneoplastic entities (simple and many complex hyperplasias without atypia); these are characterized by a proliferation of endometrial glands of irregular size and shape. Neoplastic 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 has been the 1994 World Health Organization (WHO) system, which has four categories: simple without nuclear atypia, complex without atypia, simple atypical hyperplasia, and complex atypical hyperplasia. The new 2015 WHO classification system has two categories: hyperplasia without atypia (non-neoplastic) and atypical hyperplasia (endometrial intraepithelial neoplasm). (See 'World Health Organization classification' above.)

The endometrial intraepithelial neoplasia system is another classification system and uses a D score. It is a measure of stromal volume as a proportion of total tissue volume (stroma + epithelium + gland lumen). (See 'Endometrial intraepithelial neoplasia classification' above.)

The presence of nuclear atypia is the most important indicator of the risk of endometrial carcinoma in women with endometrial hyperplasia. It is sometimes difficult to distinguish a precursor lesion from endometrial carcinoma. Approximately 17 to 48 percent of women with atypical hyperplasia are found to have coexistent endometrial carcinoma when a hysterectomy is performed. (See 'Coexistent carcinoma' above.)

Endometrial hyperplasia/intraepithelial endometrioid neoplasm commonly results from excess estrogen and progesterone imbalance. This may be caused by obesity, anovulation, estrogen therapy without a progestin, or estrogen-producing ovarian tumors (rare). Women with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome are at high risk for endometrial neoplasia. (See 'Risk factors' above.)

Endometrial hyperplasia/intraepithelial neoplasm typically presents with abnormal uterine bleeding and is most common in women who are postmenopausal, and with increasing age in premenopausal women. Rarely, women with no abnormal uterine bleeding present only with abnormal findings on cervical cytology. (See 'Clinical presentation' above.)

Endometrial hyperplasia/intraepithelial neoplasm 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 detect all case of endometrial carcinoma; up to 10 percent are falsely negative. (See 'Follow-up of biopsy or curettage results' above.)

ACKNOWLEDGMENT — The authors and editors would like to recognize Drs. Robert Giuntoli and Howard Zacur, who contributed to previous versions of this topic review.

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