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 "Approach to abnormal uterine bleeding in
nonpregnant reproductive-age women" and "Postmenopausal uterine bleeding".)
Endometrial cancer (See "Endometrial carcinoma: Epidemiology and risk factors".)
HISTOLOGY AND CLASSIFICATION Endometrial hyperplasia is 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 "Differential diagnosis of genital tract bleeding in women".)
In addition, for women who present with abnormal finding on cervical cytology, the differential
diagnosis includes benign endometrium and cervical neoplasia. (See "Cervical and vaginal cytology:
Interpretation of results", section on 'Benign-appearing endometrial cells in a woman 40
years' and "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Risk of
premalignant or malignant disease'.)
FURTHER EVALUATION AFTER ENDOMETRIAL SAMPLING
Negative endometrial sampling
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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Topic 3217 Version 11.0
Disclosures