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Classification and diagnosis of endometrial hyperplasia

Authors Section Editors Deputy Editor

Robert L Giuntoli, II, MD Barbara Goff, MD Sandy J Falk, MD
Howard A Zacur, MD, PhD Rochelle L Garcia, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2013. | This topic last updated: Nov 19, 2012.

INTRODUCTION Endometrial hyperplasia is characterized by a proliferation of endometrial glands that may progress to or
coexist with endometrial carcinoma [1]. 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 "Initial approach to the premenopausal woman with abnormal uterine
bleeding" and "Postmenopausal uterine bleeding".)

Endometrial cancer (See "Endometrial carcinoma: Epidemiology and risk factors".)

HISTOLOGY AND CLASSIFICATION Endometrial hyperplasia is a characterized by a proliferation of endometrial glands

resulting in a greater gland-to-stroma ratio than observed in normal endometrium [1]. The proliferating glands vary in size and
shape and cells may have cytologic atypia. Endometrial hyperplasia may be non-neoplastic (most simple and some complex
hyperplasias) or neoplastic (some complex and all complex atypical hyperplasias). Neoplastic hyperplasia is a non-obligate
precursor to the most common form of endometrial carcinoma, endometrioid histology. This pattern of precursor and carcinoma
is similar to intraepithelial neoplasms in other body sites (eg, cervical intraepithelial neoplasia, adenoma in the colon, or ductal
carcinoma in situ of the breast). Unfortunately, the terminology for endometrial hyperplasia does not make the relationship to
malignant potential clear.

World Health Organization classification The World Health Organization (WHO) classification of endometrial hyperplasia
is the most widely used system [2].

In general, the WHO system correlates well with the risk of progression to endometrial carcinoma (see 'Risk of carcinoma'
below). 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 (see 'Nuclear atypia' below). 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].

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.

Women with simple hyperplasia without atypia are least likely to develop endometrial carcinoma, whereas women with complex
hyperplasia with atypia are most likely to develop carcinoma. The presence of nuclear atypia is the most worrisome finding.
(See 'Risk of carcinoma' 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 [7]. 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 [8].

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) [9]. 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)
[10].

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
[10].

Many women with atypical endometrial hyperplasia have coexistent endometrial carcinoma. A literature review noted the
frequency of concurrent carcinoma among patients with atypical endometrial hyperplasia ranged from 17 to 52 percent across
studies [8]. 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 [11]. 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 [12,13].
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 hyperplasia without atypia and most
complex hyperplasia 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 [12]. 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 [11].

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 [14,15]. 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 [14]. 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 [16].

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) [17]. 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 less 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, but may be the decreasing use of
unopposed estrogen therapy.

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'.)

EVALUATION OF WOMEN WITH SUSPECTED ENDOMETRIAL NEOPLASIA Women with a clinical presentation
suspicious for endometrial hyperplasia are evaluated initially with physical examination. Pelvic sonography may also be
performed to exclude another etiology 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 "Overview of causes 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 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

Office endometrial biopsy with insufficient endometrial cells 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 [18,19].

Positive endometrial sampling Women with endometrial hyperplasia should be treated, as appropriate. (See
"Management of endometrial hyperplasia".)

Office endometrial biopsy For women with atypical endometrial hyperplasia on an office endometrial biopsy, if a
hysterectomy is not planned, we suggest further evaluation with dilation and curettage to exclude a coexistent endometrial
carcinoma [20,21]. Coexistent endometrial carcinoma is present in 17 to 52 percent of women with complex hyperplasia at time
of hysterectomy, as noted above [8]. Women with endometrial carcinoma should be treated, as appropriate. (See "Overview of
endometrial carcinoma".)

If the uterine curettage results are less severe or negative, the patient should be managed based upon the results of the office
endometrial biopsy.

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.)

For women with atypical endometrial hyperplasia on an office endometrial biopsy, if a hysterectomy is not planned, we
suggest further evaluation with dilation and curettage to exclude a coexistent endometrial carcinoma. (See 'Office
 endometrial biopsy' above.)

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REFERENCES

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