Uterus
Endometrial hyperplasia
Endometrial hyperplasia


Topic Completed: 20 February 2020

Minor changes: 29 September 2020

Copyright: 2002-2021, 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. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusendometrialhyperplasiageneral.html. Accessed April 16th, 2021.
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 style 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 style answer #2
A. Crowded glands with minimal residual intervening stroma

Comment Here

Reference: Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN)
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