Uterus
Endometrial hyperplasia
Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN)

Editorial Board Member: Jennifer Bennett, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Aarti Sharma, M.D.
Ricardo R. Lastra, M.D.

Topic Completed: 20 February 2020

Revised: 9 March 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Endometrial hyperplasia[TI] review[ptyp]

Aarti Sharma, M.D.
Ricardo R. Lastra, M.D.
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Cite this page: Sharma A, Lastra RR. Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/uterusendometrialhyperplasiageneral.html. Accessed April 3rd, 2020.
Definition / general
  • Proliferation of endometrial glands with a resulting increase in gland to stroma ratio
  • Current system of classification (Kurman: WHO Classification of Tumours of the Female Reproductive Organs, 4th Edition, 2014):
    • Hyperplasia without atypia
    • Atypical hyperplasia / endometrioid intraepithelial neoplasia (AH / EIN)
      • Prior terminologies (simple and complex) are no longer included
  • AH / EIN is considered a premalignant condition
    • Increased risk of both progression to and simultaneous endometrial endometrioid adenocarcinoma
Essential features
  • Estrogen driven precursor lesion to endometrial endometrioid adenocarcinoma
  • Increase in gland to stroma ratio (> 3:1 glandular to stromal elements)
  • Divided into 2 groups: with or without atypia
  • Definitive treatment for AH / EIN is hysterectomy; progestin therapy for fertility preservation
Terminology
  • Obsolete terms:
    • Cystic hyperplasia
    • Adenomatous hyperplasia
    • Simple and complex hyperplasia
ICD coding
  • ICD-10: N85.00 - endometrial hyperplasia, unspecified
  • ICD-O: 8380/2 - endometrioid intraepithelial neoplasia
Epidemiology
Sites
Pathophysiology
  • Increased endogenous or exogenous estrogen, unopposed by progesterone (Semin Oncol Nurs 2019;35:157):
    • Initially, estrogen has mitogenic effect on both endometrial glands and stroma
    • Chronic estrogenic stimulation without progesterone affects glands to a greater extent → glandular overgrowth (hyperplasia)
Etiology
  • Premenopausal
    • Polycystic ovarian syndrome (PCOS): increased circulating androgens peripherally converted into estrogen
    • Chronic anovulation / infertility: dysregulated estrogen without opposing progesterone secretion → simultaneous proliferation and breakdown
  • Peri and postmenopausal
    • Exogenous estrogen:
      • Estrogen supplementation: systemic therapy to alleviate symptoms of menopause → endometrial proliferation
      • Tamoxifen: hormonal treatment for breast cancer acts as estrogen receptor antagonist in breast but agonist in endometrium
  • Any age
    • Obesity: aromatase (enzyme converting circulating androgens to estrogen) is found in adipose tissue → peripheral hyperestrogenism (Mod Pathol 2000;13:295, Am J Obstet Gynecol 2016;214:689.e1)
    • Ovarian pathology:
      • Stromal hyperplasia and hyperthecosis: stromal luteinization → hyperandrogenism → hyperestrogenism (BJOG 2003;110:690)
      • Hormone secreting stromal tumors: granulosa cell tumor, thecoma
Clinical features
Diagnosis
Laboratory
  • No validated biomarker for endometrial hyperplasia
Radiology description
Prognostic factors
  • Endometrial hyperplasia
    • Presence / absence of atypia is most important feature
    • AH / EIN associated with:
    • Hyperplasia without atypia: progression to endometrial endometrioid adenocarcinoma in up to 4.6% of cases after 20 year followup (J Clin Oncol 2010;28:788)
Treatment
  • Endometrial hyperplasia without atypia:
    • Hysterectomy too aggressive; risk of progression to or simultaneous endometrial endometrioid adenocarcinoma is low (refer to Prognostic factors)
    • Treatments outlined below for AH / EIN acceptable within appropriate clinical context
    • Endometrial hyperplasia without atypia arising in endometrial polyp: polypectomy curative if completely excised under hysteroscopic guidance
    • Endometrial ablation can be used (not adequate alternate therapy for AH / EIN or refractory endometrial hyperplasia without atypia) (Am J Obstet Gynecol 1998;179:569)
  • AH / EIN:
    • Hysterectomy with or without bilateral salpingo-oophorectomy is definitive treatment
    • If patient desires fertility or is not a surgical candidate:
Gross description
  • Usually not grossly appreciable
  • Florid to pseudopolypoid endometrium (similar to that of secretory phase)
Gross images

Images hosted on other servers:

Endometrial hyperplasia

Frozen section description
  • Not appropriate for diagnosing hyperplasia or atypia
  • Intraoperative consultation may be utilized for diagnosing adenocarcinoma in a patient with preoperative diagnosis of AH / EIN but this is not considered standard of care
Microscopic (histologic) description
  • Endometrial hyperplasia without atypia
    • Architecture:
      • Closely packed glands such that gland to stroma ratio is > 3:1 but stroma is still present between glandular basement membranes (however minimal)
      • Variation in gland size with cystic dilatation or irregular luminal contours (budding, angulation, invagination, outpouching, papillary projections)
      • Associated with stromal breakdown
      • Increased volume of endometrial tissue on biopsy / curetting is typical but NOT required for diagnosis
    • Cytologic features:
      • Reminiscent of normal proliferative endometrium with pseudostratified, mitotically active, elongated columnar cells
      • Can show mild cellular enlargement but retain smooth nuclear contours without distinct nucleoli
      • Metaplastic changes common (eosinophilic, papillary syncytial, squamous morular, mucinous, ciliated)
  • AH / EIN
    • Architecture:
      • Similar to the spectrum described above for hyperplasia without atypia
    • Cytologic features:
      • Enlarged, rounded and irregular nuclear contours
      • Prominent, enlarged nucleoli with coarse and vesicular chromatin
      • Occasionally, cytoplasmic eosinophilia imparts a distinct low power appearance
      • Stratified cells demonstrating loss of polarity with respect to basement membrane
      • Metaplastic changes can be seen
Microscopic (histologic) images

Contributed by Aarti Sharma, M.D.

Hyperplasia without atypia


AH / EIN


AH / EIN bordering on FIGO grade I endometrial endometrioid adenocarcinoma

Virtual slides

Images hosted on other servers:

AH / EIN

Immunohistochemistry
  • Not typically useful in differential diagnosis between normal endometrium and benign / malignant endometrial proliferations
  • Loss of PTEN or PAX2 (Int J Gynecol Pathol 2015;34:40, Cancer Res 2010;70:6225)
    • Most frequently mutated genes in endometrioid endometrial carcinoma and its precursors (tumor suppressor and transcription factor inactivation, respectively)
    • Helpful but neither sensitive nor specific for AH / EIN
Molecular / cytogenetics description
Sample pathology report
  • Endometrium, curettage:
    • Disordered proliferative endometrium with focus of hyperplasia without atypia
  • Endometrium, biopsy:
    • AH / EIN focally bordering on endometrial endometrioid adenocarcinoma (FIGO grade I) (see comment)
    • Comment: There are rare minute foci suspicious for a FIGO grade 1 endometrioid endometrial adenocarcinoma. Recommend additional sampling with endometrial curettage for a more definitive diagnosis.
Differential diagnosis
Benign:
  • Compression artifact:
    • Telescoping and pseudocompression of glands due to procedure / processing artifact may create appearance of packed and back to back glands
    • Absence of peripheral stromal elements to lesion in question is a clue to artificial density
  • Cystic atrophy:
    • Can have similar low power appearance to hyperplastic endometrium with closely apposed and cystically dilated glands but these do not have the irregular contours of hyperplasia
    • Glandular lining is low cuboidal to flattened without mitotic activity, in contrast to proliferative endometrium
    • Stroma is dense and resembles that of endometrium basalis
  • Endometrial polyp:
    • Similar low power appearance in biopsies (by definition - altered, disorganized or irregular glands)
    • Distinct densely fibrotic stroma
    • Thick walled blood vessels
    • Endometrial polyps can contain foci of AH / EIN
  • Disordered proliferative endometrium:
    • No well delineated criteria
    • Histologically considered as degree below hyperplasia without atypia on a shared morphologic spectrum and distinction is often not reproducible
    • Both have similar treatment (exogenous progestin)
  • Metaplastic changes:
    • Squamous and morular metaplasia
      • When involving nonhyperplastic glands, can create false appearance of solid crowding
      • As in endometrial endometrioid adenocarcinoma, squamous component should be subtracted in assessment of glandular architecture
    • Surface syncytial and eosinophilic metaplasia
      • Similar low power appearance due to cytoplasmic eosinophilia and epithelial proliferation
      • Metaplasia is usually cytologically bland
  • Endometrial stromal / glandular breakdown:
    • Menstrual endometrium may demonstrate altered cytology, such as loss of polarity due to nuclear piling and coarsening of chromatin
    • Collapse of glands creates artificial crowding without stromal scaffolding
    • Presence of glandular aggregation amidst necrotic predecidua can deceptively mimic carcinoma

Malignant:
  • Endometrioid adenocarcinoma, FIGO grade 1:
    • Degree of atypia between the two is usually similar
    • AH / EIN should NOT have:
      • Cribriforming, confluent glands
      • Labyrinthine intraluminal connections
      • Areas of purely solid epithelium
      • Stromal alteration suggesting invasion - desmoplasia (myofibroblasts, edema, inflammation) or necrosis (intervening endometrial stroma replaced by pools of neutrophilic debris)
Board review style question #1



The uterine lesion in the image above is commonly associated with which of the following?

  1. Anovulatory menstrual cycles
  2. Brown-red and firm, infiltrative gross appearance
  3. Intrauterine device is considered definitive therapy
  4. No increased risk of endometrial carcinoma
  5. Weak staining for WT1 and GATA3
Board review answer #1
A. Anovulatory menstrual cycles. The photomicrograph shows an image of endometrioid intraepithelial neoplasia.

Comment Here

Reference: Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN)
Board review style question #2
Which of the following features is required for a diagnosis of endometrial hyperplasia?

  1. Crowded glands with minimal residual intervening stroma
  2. Diffuse nuclear staining for p53
  3. Documentation of a PTEN mutation or loss of PTEN by IHC
  4. Glands with cribriforming architecture and cytologic alterations distinct from surrounding glands
  5. Loss of mismatch repair proteins
Board review answer #2
A. Crowded glands with minimal residual intervening stroma

Comment Here

Reference: Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN)
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