Version May 2024
INTRODUCTION — Endometrial hyperplasia (EH) is a proliferation of endometrial glands which is typically categorized into two groups: EH without atypia (usually not neoplastic) and EH with atypia (neoplastic; also referred to as endometrial intraepithelial neoplasia [EIN]). EH, especially EH with atypia, is of clinical significance because it may progress to, or coexist with, endometrial carcinoma.
The clinical features, diagnosis, and differential diagnosis of EH are presented here. Management of EH, as well as other related topics, is discussed separately:
●Management of EH (see "Endometrial hyperplasia: Management and prognosis")
●Other etiologies of abnormal uterine bleeding (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal uterine bleeding")
●Endometrial carcinoma (see "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening" and "Endometrial carcinoma: Epidemiology, risk factors, and prevention")
CLASSIFICATION AND HISTOLOGY
Overview — The terminology and classification systems for EH have changed significantly over time (table 1). The two main classification systems for EH are the 2014 World Health Organization (WHO) system and the endometrial intraepithelial neoplasia (EIN) system [1,2]. The 2014 WHO system is more widely used [3,4].
This topic will utilize the 2014 WHO classification system. However, supporting studies cited in this topic may use other classification systems, which will be documented where appropriate.
Few studies have compared the diagnostic performance of the WHO and EIN systems; in addition, such studies utilized the 1994, rather than the 2014, WHO classification system [5].
World Health Organization classification — The 2014 WHO classification system includes the following categories [1]:
●Normal endometrium – During the normal menstrual cycle, the endometrium is proliferative in the follicular phase and is secretory in the luteal phase (figure 1). Normal proliferative endometrium exhibits no crowding of glands within the stroma (gland-to-stroma ratio <2:1) (picture 1). Normal secretory endometrium may have a gland-to-stroma ratio of >2:1 (picture 2). Although glands in the secretory phase exhibit crowding, they are organized, and cells comprising the glands are spaced and not mitotically active.
●Hyperplasia without atypia – This term was previously referred to as simple or complex hyperplasia without atypia [6].
In EH without atypia, the gland-to-stroma ratio is increased (gland-to-stroma ratio >2:1); the glands may be mildly crowded, dilated, and have luminal outpouching (picture 3) [7]. However, atypical nuclear features are not present.
●Atypical hyperplasia (hyperplasia with atypia; EIN) – This term was previously referred to as simple or complex hyperplasia with atypia [6].
In EH with atypia, the gland-to-stroma ratio is increased further, and there is a disorganization of glands with luminal outpouching, cellular mitoses, and nuclear atypia (picture 4) [7]. The chromatin may be either evenly dispersed or clumped, and/or prominent nucleoli may be present [8,9]. Rarely, extreme complexity without marked cytologic atypia warrants a diagnosis of EH with atypia.
The finding of nuclear atypia has relatively poor interobserver agreement [10-16]. This is discussed in more detail below. (See 'Subsequent evaluation of EH with atypia' below.)
This classification system is intended to reduce the confusion associated with numerous pathologic terms (eg, simple or complex, with or without atypia) and also to reflect that hyperplasia without atypia is typically a nonneoplastic change whereas hyperplasia with atypia is neoplastic and frequently associated with endometrial carcinoma [17].
Endometrial intraepithelial neoplasia classification — The EIN classification system was proposed by an international group of gynecologic pathologists in 2000 [2]. EIN classification categories do not correspond directly to specific categories in the 2014 WHO system, but there is some overlap (table 1).
The EIN system has been slow to gain widespread acceptance, most likely due to cost and/or lack of experience with the computerized D-scoring component, which is an integral part of the EIN classification system and described briefly below [18-20].
The EIN system defines two classes of endometrial changes:
●Benign endometrial hyperplasia (nonneoplastic) – This group represents changes typically observed with anovulation or prolonged exposure to estrogen. The morphology of benign EH varies from proliferative endometrium with scattered cysts [21] (persistent proliferative endometrium) to bulkier endometrium 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) – This group represents premalignant lesions on the endometrium. Epithelial glandular crowding displaces stroma to a point at which stromal volume is less than approximately one-half of total tissue volume in nonsecretory endometrium, and typically, cells appear morphologically clonal and distinct from the surrounding endometrium.
The computerized D-scoring component 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 (D between 0 and 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 including 84 patients of whom 10 percent (8 patients) developed cancer [22]. However, more experience is needed to evaluate subjective assignment of the D-score in diverse practice environments.
As with the WHO classification system, the EIN classification system also has demonstrated moderate interobserver reproducibility [23], but studies have confirmed that EIN correlates with progression to endometrial carcinoma [19,24].
EPIDEMIOLOGY — Reliable estimates of the incidence of EH are difficult to obtain due to many factors, including age and menopausal status of patients studied, changing diagnostic criteria over time, bias of studies toward evaluating only symptomatic patients (eg, abnormal uterine bleeding), trends in postmenopausal hormone therapy (eg, the use of unopposed estrogen versus estrogen plus progestin), assessment technique (eg, endometrial sampling versus hysterectomy), and concomitant diagnoses of endometrial carcinoma with hyperplasia. (See 'Natural history' below.)
EH is most common in perimenopausal or early postmenopausal patients. Representative studies include the following:
●In a study including females ages 18 to 90 from a large integrated health plan over an 18-year period (1985 to 2003), the overall incidence of EH was 133 per 100,000 woman-years [25]. The incidence of EH without atypia was highest in patients ages 50 to 54 years (between 142 and 213 per 100,000 woman-years) whereas the rate of EH with atypia was highest in patients ages 60 to 64 (56 per 100,000 woman-years).
●An analysis from another large health plan found that the rate of EH was 144 per 100,000 woman-years in 2002 [26].
RISK FACTORS — Risk factors for EH are similar to those for endometrial carcinoma (table 2) [27-29].
Most of these risk factors involve exposure of the endometrium to continuous estrogen unopposed by progestin. This effect may be due to an endogenous (eg, obesity, ovulatory dysfunction) or exogenous (eg, medications, including nonprescription and topical therapies) source of estrogen. By contrast, patients with menstrual irregularities caused by hypothalamic hypogonadism (and low serum concentrations of luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol) are not at increased risk of EH.
Patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer) or Cowden syndrome (also known as Cowden disease or multiple hamartoma syndrome) are at a greatly increased risk of EH and endometrial carcinoma.
These risk factors are discussed in detail separately. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer", section on 'Risk for endometrial cancer' and "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Genitourinary'.)
CLINICAL FEATURES
Presentation — EH typically presents with abnormal uterine bleeding. Less commonly, EH presents with the following (table 3):
●Abnormal cytologic findings on cervical cancer screening (eg, atypical glandular cells, benign endometrial cells in a patient ≥45 years) [30]. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Benign-appearing endometrial cells' and "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Risk of premalignant or malignant disease'.)
●A postmenopausal patient with a thickened endometrial stripe on imaging. (See 'Findings' below.)
●Incidental finding during hysterectomy for another indication.
The presentation of EH and endometrial carcinoma is similar and discussed in detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Clinical presentation'.)
Findings — The clinical findings of EH are similar to those of patients with endometrial carcinoma.
●Pelvic examination – Pelvic examination is usually normal since patients with EH do not typically have an enlarged or tender uterus.
●Laboratory results – Laboratory results are usually normal, except in patients with substantial abnormal uterine bleeding who may be anemic.
●Imaging – In postmenopausal patients, ultrasound may demonstrate an increased endometrial thickness with multiple cystic features and heterogeneity [31]; however, ultrasound criteria have not been set for the detection of EH as they have for endometrial carcinoma. Thus, endometrial thickness in a postmenopausal patient in the absence of bleeding is a nonspecific finding, but one that requires further evaluation for EH [32]. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease".)
These findings are discussed in more detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Clinical findings'.)
NATURAL HISTORY — EH may progress to, or coexist with, endometrial carcinoma.
The risk of progression of EH to endometrial cancer is almost fourfold higher for patients with EH with atypia (endometrial intraepithelial neoplasia [EIN]) compared with EH without atypia [33]; this is discussed in detail separately. (See "Endometrial hyperplasia: Management and prognosis", section on 'EH with atypia (EIN)' and "Endometrial hyperplasia: Management and prognosis", section on 'Eh without atypia'.)
Coexistent endometrial carcinoma may be present in up to 40 percent of patients with EH with atypia (EIN) and <1 percent of patients with EH without atypia [1,5,10,11,34]. Among patients with EH, the strongest predictors of concurrent endometrial carcinoma include older age, obesity, diabetes mellitus, and the finding of atypia on endometrial pathology [35]. In one meta-analysis including 15 retrospective studies and almost 1500 patients with EH, the overall pooled proportion of concurrent endometrial carcinoma (diagnosed within three months of EH diagnosis) was 32 percent (95% CI 26-40 percent) but with a high heterogeneity in the outcomes [36].
DIAGNOSIS — EH is a histologic diagnosis based on characteristic findings on endometrial biopsy, dilation and curettage (D&C), or hysterectomy specimen. (See 'Classification and histology' above.)
The procedure for endometrial sampling is discussed in detail separately. (See 'World Health Organization classification' above and "Endometrial sampling procedures" and "Overview of the evaluation of the endometrium for malignant or premalignant disease".)
Role of biomarkers — Immunohistochemical markers may help distinguish EH with atypia (EIN) from EH without atypia or endometrial carcinoma [4,37-42]; however, these biomarkers are investigational and not routinely performed.
Such biomarkers include the absence of paired box gene 2 (PAX2) staining [39-41], increased staining for matrix metalloproteinase 9 (MMP-9) and B-cell lymphoma 2 (Bcl-2) [37,42], and estrogen and progesterone overexpression [42]. Other serum biomarkers have also been described [43].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes endometrial carcinoma, which is distinguished from EH by the presence of invasion on histologic specimen; however, this distinction can be difficult to make unless the uterus is surgically removed and evaluated. (See 'Subsequent evaluation of EH with atypia' below.)
Findings that suggest invasion include an 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 EH with atypia (endometrial intraepithelial neoplasia [EIN]) or endometrial carcinoma.
The diagnosis of endometrial carcinoma is discussed separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis'.)
SUBSEQUENT EVALUATION OF EH WITH ATYPIA — In our practice, for patients with a diagnosis of EH with atypia (endometrial intraepithelial neoplasia [EIN]) made by office endometrial biopsy, we perform a dilation and curettage (D&C) to help exclude a coexisting endometrial carcinoma. (See 'Natural history' above.)
A finding of nuclear atypia has relatively poor interobserver agreement [10-16]. In one study including over 300 endometrial samples initially reported as EH with atypia, review by a panel of expert gynecologic pathologists supported the diagnosis in only 38 percent of cases (correlation coefficient of nuclear atypia 0.28) [14]. In a second study including 289 patients with a diagnosis of complex atypical hyperplasia (ie, EH with atypia), after review by unblinded pathologists (using the 1994 World Health Organization [WHO] criteria), 29 percent were diagnosed with more severe pathology (eg, endometrial carcinoma) [10]. Interobserver variability appears to improve with both increasing specimen volume and presence of prominent nucleoli [14-16].
Some data suggest that D&C is more effective than endometrial biopsy at detecting coexistent carcinoma, likely due to the volume of the sample obtained [11,12]. However, neither endometrial biopsy nor D&C is sufficient to exclude malignant neoplasm. In one retrospective study including over 820 patients with EH with atypia, the rate of unexpected endometrial carcinoma diagnosed at hysterectomy was higher for patients who underwent a single sampling with endometrial biopsy compared with D&C alone (45 versus 30 percent) [12]. Among patients who had a repeat sampling procedure for confirmation (with either endometrial biopsy or D&C), the rate of unexpected carcinoma at hysterectomy was lower (repeat endometrial biopsy: 20 of 89 patients [22 percent]; endometrial biopsy followed by D&C: 28 of 171 patients [16 percent]). (See "Endometrial hyperplasia: Management and prognosis", section on 'Hysterectomy'.)
SPECIAL CONSIDERATIONS
Approach to patients with nondiagnostic histopathology — Patients with an endometrial biopsy result that has insufficient endometrial cells and for whom there is a clinical concern for endometrial pathology (ie, EH with or without atypia, endometrial carcinoma) should have sampling repeated with an office biopsy or dilation and curettage (D&C). If two office endometrial biopsies are unsuccessful in providing an adequate sample, a D&C should be performed. Cervical stenosis, a common cause of an unsuccessful biopsy, can be managed with preprocedure cervical preparation (eg, misoprostol) or dilation. (See "Endometrial sampling procedures", section on 'Cervical preparation and dilation'.)
Approach to patients with benign histopathology — For patients in whom bleeding persists or recurs within three to six months after endometrial sampling with benign findings, symptoms may be due to a missed diagnosis of endometrial pathology (ie, EH, endometrial carcinoma), and further evaluation is needed.
Reported rates of EH or endometrial carcinoma in patients evaluated for persistent or recurrent postmenopausal bleeding vary widely, from 4 to 22 percent [44-46]. In particular, patients with risk factors for endometrial carcinoma should have repeat sampling (table 2). In a nested case-control study of patients with an endometrial carcinoma diagnosis who had previous benign endometrial sampling, a personal history of colorectal cancer, endometrial polyp, and body mass index ≥35 kg/m2 was independently associated with a subsequent diagnosis of endometrial carcinoma [47].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis, staging, and surgical treatment (Beyond the Basics)" and "Patient education: Abnormal uterine bleeding (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Classification
•Endometrial hyperplasia (EH) is typically categorized into two groups: EH without atypia and EH with atypia (also referred to as endometrial intraepithelial neoplasia [EIN]). EH, particularly EH with atypia, may progress to, or coexist with, endometrial carcinoma. (See 'Introduction' above.)
•The 2014 World Health Organization (WHO) classification system is the classification system that is most widely used. The EIN system is another classification system that has been slow to gain widespread acceptance. EIN classification categories do not correspond directly to specific categories in the 2014 WHO system, but there is some overlap (table 1). (See 'Classification and histology' above.)
●Risk factors – EH commonly results from exposure to continuous estrogen unopposed by a progestin; risk factors are similar to those for endometrial carcinoma (table 2). This may be caused by obesity, ovulatory dysfunction, unopposed estrogen therapy, or estrogen-producing ovarian tumors (rare). Patients with Lynch syndrome or Cowden syndrome are at high risk for endometrial neoplasia. (See 'Risk factors' above.)
●Clinical presentation – EH typically presents with abnormal uterine bleeding and is most common in perimenopausal or early postmenopausal patients. Rarely, patients will present with abnormal findings on cervical cytology. (See 'Presentation' above and 'Epidemiology' above.)
●Natural history – Coexistent endometrial carcinoma may be present in up to 40 percent of patients who have EH with atypia (EIN). (See 'Natural history' above.)
●Diagnosis – EH is a histologic diagnosis based on characteristic findings on endometrial biopsy, dilation and curettage (D&C), or hysterectomy specimen. (See 'Diagnosis' above.)
●Subsequent evaluation – In patients with a diagnosis of EH with atypia made by endometrial biopsy, we perform a D&C to help further evaluate the endometrium and exclude a coexisting endometrial carcinoma. (See 'Subsequent evaluation of EH with atypia' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert L Giuntoli, II, MD, and Howard A Zacur, MD, PhD, who contributed to an earlier version of this topic review.
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