Endometrial hyperplasia / endometrioid intraepithelial neoplasia (EIN)

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

Authors: Aarti Sharma, M.D., Ricardo R. Lastra, M.D.

Editorial Board Member: Jennifer Bennett, M.D.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 20 February 2020

Revised: 9 March 2020

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

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

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Table of Contents

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

Similar to that of endometrial endometrioid adenocarcinoma
Age: fourth to sixth decades (peak fifth)
Increased circulating estrogen:
- Body mass index (BMI): dose response relationship of BMI ≥ 25 and risk of hyperplasia (Am J Obstet Gynecol 2016;214:689.e1)
- Nulliparous females (Cancer 1985;56:403, Am J Epidemiol 2008;168:563)
No race predilection

Sites

Uterus: endometrium, endometrial polyps or adenomyosis
Any tissue involved by endometriosis
- Ectopic endometrial glands / stroma are responsive to estrogen stimulation and can also develop an endometrial-like hyperplasia and subsequently carcinoma (Gynecol Oncol 2002;84:280, Gynecol Oncol 1996;60:238, Int J Gynecol Pathol 1996;15:1)

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

Abnormal or dysfunctional uterine bleeding (Obstet Gynecol Surv 2004;59:368)
Rare cases asymptomatic

Diagnosis

Pelvic / transvaginal ultrasound
Endometrial biopsy
Hysteroscopy with endometrial curettage (Eur J Gynaecol Oncol 2007;28:400)

Laboratory

No validated biomarker for endometrial hyperplasia

Radiology description

Thickened endometrial stripe on pelvic / transvaginal ultrasound (Obstet Gynecol Sci 2016;59:192)
Generally no discrete mass

Prognostic factors

Endometrial hyperplasia
- Presence / absence of atypia is most important feature
- AH / EIN associated with:
  - Progression to endometrial endometrioid adenocarcinoma in up to 28% of cases without hysterectomy after 20 year followup (J Clin Oncol 2010;28:788)
  - Concurrent endometrial carcinoma in up to 43% of cases (Cancer 2006;106:812)
    - Majority are low grade (FIGO grade 1) and low stage (FIGO stage IA or IB) (J Obstet Gynaecol Can 2008;30:896)
- 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:
  - AH / EIN arising in endometrial polyp
    - Polypectomy curative if completely excised under operative hysteroscopy
    - Hysterectomy occasionally warranted in appropriate clinical context
  - Progestin therapy: oral or intrauterine device (Am J Obstet Gynecol 2014;210:255.e1, Hum Reprod 2013;28:1231, Obstet Gynecol 2013;121:1165)
    - Latter considered superior for efficacy, compliance and prevention of recurrence
    - Can even be trialed for fertility preservation in cases up to nonmyoinvasive FIGO grade 1 endometrioid adenocarcinoma
  - Metformin controversial (Cochrane Database Syst Rev 2017;10:CD012214)

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
- Concurrent carcinoma may be missed intraoperatively due to endometrial undersampling for lack of gross lesion (Am J Obstet Gynecol 2007;196:e40, Asian Pac J Cancer Prev 2012;13:1953)

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

No reproducible genomic alterations
AH / EIN is variably associated with mutations in PTEN, PIK3CA, KRAS, CTNNB1 (Jpn J Cancer Res 1998;89:985, Cancer Res 1998;58:3254, Med Klin 1975;70:812)
- Similar to endometrial endometrioid adenocarcinoma
Loss of mismatch repair proteins resulting in progressive accumulation of microsatellite unstable loci (Mod Pathol 2019;32:1508)

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)

Additional references

Mod Pathol 2000;13:309, Semin Diagn Pathol 2010;27:199

Board review style question #1

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

Anovulatory menstrual cycles
Brown-red and firm, infiltrative gross appearance
Intrauterine device is considered definitive therapy
No increased risk of endometrial carcinoma
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?

Crowded glands with minimal residual intervening stroma
Diffuse nuclear staining for p53
Documentation of a PTEN mutation or loss of PTEN by IHC
Glands with cribriforming architecture and cytologic alterations distinct from surrounding glands
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)