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Classification and diagnosis of endometrial hyperplasia

Authors: Susan D Reed, MD, MPH, Renata R Urban, MD

Section Editors: Barbara Goff, MD, Rochelle L Garcia, MD
Deputy Editor: Sandy J Falk, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2018. | 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 cancer diagnosis at hysterectomy remained high (20 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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endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 2008; 113:2073.
17. Baak JP, Mutter GL, Robboy S, et al. The molecular genetics and morphometry-based endometrial
intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia
more accurately than the 1994 World Health Organization classification system. Cancer 2005;
103:2304.
18. Trimble CL, Method M, Leitao M, et al. Management of endometrial precancers. Obstet Gynecol 2012;
120:1160.
19. Committee on Gynecologic Practice, Society of Gynecologic Oncology. The American College of
Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia.
Obstet Gynecol 2015; 125:1272. Reaffirmed July 2017.
20. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy
diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;
106:812.
21. Joiner AK, Quick CM, Jeffus SK. Pax2 expression in simultaneously diagnosed WHO and EIN
classification systems. Int J Gynecol Pathol 2015; 34:40.
22. Quick CM, Laury AR, Monte NM, Mutter GL. Utility of PAX2 as a marker for diagnosis of endometrial
intraepithelial neoplasia. Am J Clin Pathol 2012; 138:678.
23. Allison KH, Upson K, Reed SD, et al. PAX2 loss by immunohistochemistry occurs early and often in
endometrial hyperplasia. Int J Gynecol Pathol 2012; 31:151.
24. Laas E, Ballester M, Cortez A, et al. Supervised clustering of immunohistochemical markers to
distinguish atypical endometrial hyperplasia from grade 1 endometrial cancer. Gynecol Oncol 2014;
133:205.
25. Lin MC, Lomo L, Baak JP, et al. Squamous morules are functionally inert elements of premalignant
endometrial neoplasia. Mod Pathol 2009; 22:167.
26. Rakha E, Wong SC, Soomro I, et al. Clinical outcome of atypical endometrial hyperplasia diagnosed on
an endometrial biopsy: institutional experience and review of literature. Am J Surg Pathol 2012;
36:1683.
27. Matsuo K, Ramzan AA, Gualtieri MR, et al. Prediction of concurrent endometrial carcinoma in women
with endometrial hyperplasia. Gynecol Oncol 2015; 139:261.
 28. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of
"untreated" hyperplasia in 170 patients. Cancer 1985; 56:403.
29. Reed SD, Newton KM, Garcia RL, et al. Complex hyperplasia with and without atypia: clinical outcomes
and implications of progestin therapy. Obstet Gynecol 2010; 116:365.
30. Lacey JV Jr, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-
up among women with endometrial hyperplasia. J Clin Oncol 2010; 28:788.
31. Lacey JV Jr, Ioffe OB, Ronnett BM, et al. Endometrial carcinoma risk among women diagnosed with
endometrial hyperplasia: the 34-year experience in a large health plan. Br J Cancer 2008; 98:45.
32. Reed SD, Newton KM, Clinton WL, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol
2009; 200:678.e1.
33. Lacey JV Jr, Chia VM, Rush BB, et al. Incidence rates of endometrial hyperplasia, endometrial cancer
and hysterectomy from 1980 to 2003 within a large prepaid health plan. Int J Cancer 2012; 131:1921.
34. Epplein M, Reed SD, Voigt LF, et al. Risk of complex and atypical endometrial hyperplasia in relation to
anthropometric measures and reproductive history. Am J Epidemiol 2008; 168:563.
35. Epplein M, Reed SD, Voigt LF, et al. Endometrial hyperplasia risk in relation to recent use of oral
contraceptives and hormone therapy. Ann Epidemiol 2009; 19:1.
36. Twu NF, Chen SS. Five-year follow-up of patients with recurrent postmenopausal bleeding. Zhonghua Yi
Xue Za Zhi (Taipei) 2000; 63:628.
37. Ronghe R, Gaudoin M. Women with recurrent postmenopausal bleeding should be re-investigated but
are not more likely to have endometrial cancer. Menopause Int 2010; 16:9.
38. Gull B, Karlsson B, Milsom I, Granberg S. Can ultrasound replace dilation and curettage? A longitudinal
evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the
endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 2003; 188:401.
39. Torres ML, Weaver AL, Kumar S, et al. Risk factors for developing endometrial cancer after benign
endometrial sampling. Obstet Gynecol 2012; 120:998.
40. Suh-Burgmann E, Hung YY, Armstrong MA. Complex atypical endometrial hyperplasia: the risk of
unrecognized adenocarcinoma and value of preoperative dilation and curettage. Obstet Gynecol 2009;
114:523.

Topic 3217 Version 17.0

GRAPHICS

Proliferative endometrium

Note the straight non-convoluted glands, without glandular crowding.

Courtesy of Russell S Vang, MD.

Graphic 67488 Version 1.0

Endometrial Hyperplasia: Pathologist inter-observer variability for WHO and EIN classification
systems

Correlation coefficients (κ)

WHO Comments
Benign Simple Complex Atypia Carcinoma

Allison, 2008 [1] 0.76 0.16 0.21 0.35 0.55 Three academic gynecologic pathologists;
(n = 2147) blinded to diagnosis of mixture of all
specimen types in population-based study
of all specimens; correlation improved with
increased tissue volume.

Zaino, 2006 [2] 0.48 0.38 0.38 0.28 0.51 Three academic gynecologic pathologists;
(n = 302) not blinded to diagnosis by outside referring
center; initial diagnosis of atypical
endometrial hyperplasia.

Kendall, 1998 [3] 0.86 0.60 0.60 0.47 0.83 Five academic pathologists; cancer center;
(n = 100) (n = 25) (n = 25) (n = 25) (n = 25) (n = 25) specimens selected based on adequate
tissue and representative specimen.

Ordi, 2014 [4] 0.51 0.22 0.22 0.30 0.47 Three academic pathologists; unblinded;
(n = 196) cases initially diagnosed as low-grade
endometrioid lesions.

Skov, 1997 [5] – 0.21 to 0.07 to 0.42 to – Six general pathologists with six years'
(n = 198) 0.25 0.15 0.59 experience; case series.

Izadi-Mood, – 0.74 0.34 0.35 0.64 Five pathologists of varying experience;

2009 [6] (n = 25) (n = 25) (n = 25) (n = 25) representative specimens selected; no
(n = 100) normal proliferative specimens included;
blinded review.

Correlation coefficients (κ)

EIN system Comments
Benign EIN Carcinoma

Baak, 2001 [7] 0.64 0.47 0.64 Twenty academic pathologists; cancer
(n = 66) centers; specimens selected based on
adequate tissue and representative
specimen.

Ordi, 2014 [8] 0.35 0.27 0.52 Three academic pathologists; cases initially
(n = 196) diagnosed as low-grade endometrioid
lesions.

Hecht, 2005 [9] 0.54 to 0.62 0.54 to 0.62 0.54 to Three academic pathologists, sequential
(n = 97) 0.62 endometrial biopsies; did not distinguish
correlation coefficient for each diagnostic
type.

WHO: World Health Organization 1994 classification system; EIN: endometrial intraepithelial neoplasia classification system.

References:
1. Allison KH, Reed SD, Voigt LF, et al. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol 2008; 32:691.
2. Zaino RJ, Kauderer J, Trimble CL, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology
Group study. Cancer 2006; 106:804.
3. Kendall BS, Ronnett BM, Isacson C, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-
differentiated carcinoma. Am J Surg Pathol 1998; 22:1012.
4. Ordi J, Bergeron C, Hardisson D, et al. Reproducibility of current classifications of endometrial endometrioid glandular proliferations:
further evidence supporting a simplified classification. Histopathology 2014; 64:284.
5. Skov BG, Broholm H, Engel U, et al. Comparison of the reproducibility of the WHO classifications of 1975 and 1994 of endometrial
hyperplasia. Int J Gynecol Pathol 1997; 16:33.
6. Izadi-Mood N, Khaniki M, Irvanloo G, et al. Determining the inter- and intraobserver reproducibility of the diagnosis of endometrial
hyperplasia subgroups and well-differentiated endometrioid carcinoma in endometrial curettage specimens. Arch Iran Med 2009;
12:377.
7. Baak JP, Ørbo A, van Diest PJ, et al. Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of
endometrial hyperplasias. Am J Surg Pathol 2001; 25:930.
 8. Ordi J, Bergeron C, Hardisson D, et al. Reproducibility of current classifications of endometrial endometrioid glandular proliferations:
further evidence supporting a simplified classification. Histopathology 2014; 64:284.
9. Hecht JL, Ince TA, Baak JP, et al. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod
Pathol 2005; 18:324.

Graphic 109743 Version 1.0

Menstrual cycle

Graphic 62189 Version 4.0

Secretory endometrium

Note tortuous glands, subnuclear vacuoles, without glandular crowding.

Courtesy of Russell S Vang, MD.

Graphic 76588 Version 1.0

Simple endometrial hyperplasia

The endometrial glands in this lesion are irregularly distributed but widely separated by stroma, which
is also hyperplastic. The glands are mostly round or tubular, with only a few angularities encountered.

Reproduced with permission from: Silverberg SG, Kurman,RJ. Tumors of the Uterine Corpus and Gestational
Trophoblastic Disease. AFIP Atlas of Tumor Pathology, version 2.0, American Registry of Pathology, Washington
DC 1995.

Graphic 73789 Version 3.0

Complex endometrial hyperplasia

Reproduced with permission from: Silverberg SG, Kurman RJ. Tumors of the Uterine Corpus and Gestational
Trophoblastic Disease. AFIP Atlas of Tumor Pathology, version 2.0, American Registry of Pathology, Washington
DC 1995.

Graphic 57406 Version 3.0

Atypical endometrial hyperplasia (complex)

The glandular epithelium here is extremely atypical, but residual endometrial stroma separates all
glands in this field. Because of the severity of the atypia, a specimen such as this should be examined
thoroughly to rule out the concomitant presence of carcinoma.

Reproduced with permission from: Silverberg SG, Kurman RJ. Tumors of the Uterine Corpus and Gestational
Trophoblastic Disease. AFIP Atlas of Tumor Pathology, version 2.0, American Registry of Pathology, Washington
DC 1995.

Graphic 66592 Version 3.0

Atypical endometrial hyperplasia (complex)

The irregularly shaped glands in this case are very closely packed bu are still separated by residual
endometrial stroma.

Reproduced with permission from: Silverberg SG, Kurman RJ. Tumors of the Uterine Corpus and Gestational
Trophoblastic Disease. AFIP Atlas of Tumor Pathology, version 2.0, American Registry of Pathology, Washington
DC 1995.

Graphic 80373 Version 3.0

Risk factors for endometrial cancer

Relative risk (RR)

Risk factor
(other statistics are noted when used)

Increasing age 1.4% endometrial cancer prevalence in women 50 to 70 years old

Unopposed estrogen therapy 2 to 10

Tamoxifen therapy 2

Early menarche NA

Late menopause (after age 55) 2

Nulliparity 2

Polycystic ovary syndrome (chronic anovulation) 3

Obesity For type I endometrial cancer: OR 1.5 for overweight

(BMI 25.0 to <30 kg/m 2), 2.5 for class 1 obesity (30.0
to <35 kg/m 2), 4.5 for class 2 obesity (35.0 to 39.9
kg/m 2), and 7.1 for class 3 obesity (≥40.0 kg/m 2).
For type II: OR 1.2 for overweight (BMI 25.0 to <30
kg/m 2), 1.7 for class 1 obesity (30.0 to <35 kg/m 2),
2.2 for class 2 obesity (35.0 to 39.9 kg/m 2), and 3.1
for class 3 obesity (≥40.0 kg/m 2).

Diabetes mellitus 2

Estrogen-secreting tumor NA

Lynch syndrome (hereditary nonpolyposis colorectal cancer) 22 to 50% lifetime risk

Cowden syndrome 13 to 19% lifetime risk

Family history of endometrial, ovarian, breast, or colon cancer NA

BMI: body mass index; OR: odds ratio; NA: RR not available.

Data from:
Smith RA, von Eschenbach AC, Wender R, et al. American Cancer Society guidelines for the early detection of cancer: Update of early
detection guidelines for prostate, colorectal, and endometrial cancers. CA Cancer J Clin 2001; 51:38.
Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol 2013; 31:2607.

Graphic 62089 Version 13.0

Women who should undergo evaluation for endometrial hyperplasia or endometrial cancer

Abnormal uterine bleeding

Postmenopausal women – Any uterine bleeding, regardless of volume (including spotting or staining). Pelvic ultrasound to
evaluate endometrial thickness is an alternative to endometrial sampling in appropriately selected women. A thickened
endometrium should be further evaluated with endometrial sampling.

Age 45 years to menopause – In any woman, bleeding that is frequent (interval between the onset of bleeding episodes is <21
days), heavy, or prolonged (>5 days). In women who are ovulatory, this includes intermenstrual bleeding.

Younger than 45 years – Any abnormal uterine bleeding in obese women (BMI ≥30). In non-obese women, abnormal uterine
bleeding that is persistent and occurs in the setting of one of the following: chronic ovulatory dysfunction, other exposure to
estrogen unopposed by progesterone, failed medical management of the bleeding, or women at high risk of endometrial
cancer (eg, Lynch syndrome, Cowden syndrome).

In addition, endometrial neoplasia should be suspected in premenopausal women who are anovulatory and have prolonged
periods of amenorrhea (six or more months).

Cervical cytology results

Presence of AGC-endometrial.

Presence of AGC-all subcategories other than endometrial – If ≥35 years of age OR at risk for endometrial cancer (risk factors
or symptoms).

Presence of benign-appearing endometrial cells in women ≥40 years of age who also have abnormal uterine bleeding or risk
factors for endometrial cancer.

Other indications

Monitoring of women with endometrial pathology (eg, endometrial hyperplasia).

Screening in women at high risk of endometrial cancer (eg, Lynch syndrome).

These recommendations are based on an average age of menopause of 51 years. Evaluation of women who undergo menopause
earlier should be individualized based upon gynecologic history and risk of endometrial neoplasia.

BMI: body mass index; AGC: atypical glandular cells.

Graphic 58600 Version 11.0

Evaluation of abnormal uterine bleeding in nonpregnant reproductive-age women

Graphic 90594 Version 2.0

Contributor Disclosures
Susan D Reed, MD, MPH Grant/Research/Clinical Trial Support: Bayer Pharmaceuticals [Uterine fibroids,
endometriosis, uterine perforation (Levonorgestrel IUS), polycystic ovarian syndrome]. Renata R Urban,
MD Nothing to disclose Barbara Goff, MD Employment (Spouse): Lilly [General oncology (Gemcitabine,
pemetrexed)] - No relevant conflict on topics. Rochelle L Garcia, MD Nothing to disclose Sandy J Falk, MD,
FACOG Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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