Endometrial Hyperplasia

Slide 1 · Endometrial Hyperplasia

Mechanism • morphology • malignant potential • interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Interpret the gland-to-stroma relationship in endometrial tissue.

Explain persistent estrogenic stimulation and PTEN-related signaling.

Differentiate hyperplasia without atypia from atypical hyperplasia/EIN.

Connect morphology to carcinoma risk and clinical decisions.

Slide 3 · The defining lesion

Abnormal proliferation of endometrial glands relative to the stroma

The diagnostic concept is architectural: Glands occupy disproportionately more tissue.

Slide 4 · Two compartments of the endometrium

Glandular epithelium

Endometrial stroma

Hormone-responsive epithelial structures

Proliferation alters the glandular component

Cellular supporting tissue between glands

Acts as the reference compartment for gland crowding

Slide 5 · Architecture: Baseline versus hyperplasia

Reference

Hyperplasia

Original schematic — not an H&E micrograph

Original schematic — not an H&E micrograph

Compare the relative amount of stroma between gland profiles.

Slide 6 · Abnormal uterine bleeding: A diagnostic clue

Endometrial hyperplasia is a clinically important cause of abnormal bleeding.

The same symptom may arise from hormonal disorders, polyps, inflammation or neoplasia.

Histologic classification is needed because morphology predicts different clinical concerns.

Slide 7 · Normal cycle: Gland proliferation and differentiation

Menses

Shedding of functionalis

Proliferation

Glands and stroma regenerate

Ovulation

Progesterone becomes available

Differentiation

Secretory and stromal changes

Hyperplasia develops in a different hormonal context: Proliferation persists without adequate counter-regulation.

Slide 8 · Proliferative endometrium is not hyperplasia

Physiologic proliferation

Pathologic hyperplasia

Straight, tubular glands

Regular pseudostratified epithelium

Stroma also proliferates

Glands increase relative to stroma

Size and shape become irregular

Estrogenic stimulation persists

Slide 9 · Unopposed estrogen: The causal sequence

Estrogen exposure

Proliferative signal

Inadequate progesterone

Failure to differentiate

Persistent gland growth

Architectural distortion

Abnormal bleeding

Clinical presentation

A hormonal imbalance can create the setting for both nonatypical hyperplasia and endometrioid tumorigenesis.

Slide 10 · Anovulation prolongs estrogenic stimulation

Anovulation means that no corpus luteum forms.

The usual postovulatory progesterone-associated morphologic response does not develop.

Repeated cycles of estrogen-dominant proliferation may cause architectural abnormalities.

Slide 11 · Anovulatory endometrium versus hyperplasia

Anovulatory pattern

Hyperplastic lesion

Proliferative-type glands can persist

Secretory transformation is absent

Mild cystic changes may resolve

Gland-to-stroma proportion is increased

Glands may be irregular or crowded

Diagnostic focus includes atypia

Do not diagnose atypical hyperplasia from hormonal context alone.

Slide 12 · Sources of prolonged estrogenic influence

Anovulation

Repeated cycles without a progesterone-dominant secretory phase.

Endogenous estrogen

Obesity and hormonally active ovarian conditions.

Exogenous exposure

Prolonged administration of estrogenic substances.

Slide 13 · Obesity and peripheral estrogen generation

Peripheral conversion of androgens to estrogens is a recognized mechanism.

Excess estrogen availability can sustain endometrial proliferation.

Obesity therefore contributes to the endocrine setting in which hyperplasia develops.

Slide 14 · Polycystic ovarian syndrome

PCOS is among the conditions linked to endometrial hyperplasia.

Anovulation supplies the mechanistic connection in many affected individuals.

Endometrial findings must be interpreted in the context of the hormone milieu.

Slide 15 · Menopause and estrogen-associated exposure

Menopause is listed among the clinical settings associated with hyperplasia.

The relevant lesion-driving factor is persistent estrogenic stimulation, not age alone.

Abnormal bleeding in this setting requires attention because carcinoma is a differential diagnosis.

Slide 16 · Granulosa cell tumors as a hormonal source

Functioning ovarian granulosa cell tumors can produce estrogen.

Their endocrine activity can stimulate uterine glandular proliferation.

An ovarian lesion may therefore underlie an endometrial abnormality.

Slide 17 · Ovarian cortical stromal hyperplasia

Excessive ovarian cortical function is included among the associated conditions.

The pathophysiologic link is increased endogenous estrogenic activity.

Etiologic assessment should not be confined to the endometrial compartment.

Slide 18 · Exogenous estrogenic substances

Prolonged estrogenic therapy can provide sustained proliferative signaling.

The balance between estrogenic and progesterone-associated influences is clinically relevant.

Exposure history is part of understanding the histologic lesion.

Slide 19 · Etiology: Three useful mechanisms

Hormone-cycle failure

Anovulation prevents ordinary progesterone-linked differentiation.

Hormone overproduction

Adipose conversion or ovarian endocrine production raises estrogenic influence.

Hormone administration

Exogenous estrogen adds sustained stimulation.

Slide 20 · Hormonal drive and genetic alteration

Hormonal background

Molecular alteration

Provides a proliferative environment

Includes anovulation and excess estrogen

Helps explain benign glandular expansion

Can establish clonal growth advantage

May be shared with endometrioid carcinoma

Does not itself confirm future progression

Slide 21 · PTEN: Growth-suppressive function

PTEN is a tumor suppressor encoding a lipid phosphatase.

Its normal activity restrains PI3K/AKT signaling.

Loss of PTEN removes an inhibitory control on cellular growth signaling.

Slide 22 · PTEN loss and growth signaling

PTEN inactivation

Loss of pathway brake

PI3K/AKT

Enhanced signaling

Estrogen-receptor targets

Greater transcriptional activity

Epithelial proliferation

Growth advantage

Conceptual mechanism based on the signaling relationships.

Slide 23 · Estrogen-receptor and PI3K/AKT convergence

PI3K/AKT signaling can enhance estrogen-receptor-dependent transcription.

PTEN loss may amplify responses to estrogenic trophic signals.

This provides a plausible link between molecular mutation and hormone-sensitive tissues.

Slide 24 · PTEN mutations in hyperplasia

>20%

Hyperplasia lesions

PTEN mutations in more than one fifth of endometrial hyperplasias, with and without atypia. This is a frequency observation—not an individual risk estimate.

Slide 25 · PTEN alterations in carcinoma

30–80%

Endometrial carcinomas

A broad reported range across endometrial carcinoma cohorts indicates that PTEN changes are common. The range must not be used as a progression probability.

Slide 26 · An early molecular event is not a crystal ball

What PTEN supports

What PTEN does not establish

An early role in endometrial neoplasia

Mechanistic overlap between lesions

Clonal molecular pathway relevance

It does not predict which individual hyperplasia progresses

A mutation alone does not diagnose carcinoma

Mutation prevalence is not progression risk

Slide 27 · Cowden syndrome: An inherited PTEN context

Cowden syndrome is associated with germline PTEN alteration.

Affected individuals have increased occurrence of endometrial carcinoma and certain other tumors.

A germline predisposition is distinct from an acquired mutation within an endometrial lesion.

Slide 28 · Germline and acquired PTEN alterations

Germline alteration

Somatic alteration

Present in constitutional DNA

Associated with inherited susceptibility

Illustrated by Cowden syndrome

Acquired within glandular cells

Can occur in hyperplasia and carcinoma

May contribute to clonal proliferation

Slide 29 · Shared driver mutations support a precursor relationship

Molecular studies identify acquired driver mutations in hyperplasia and carcinoma.

Matching alterations in paired atypical hyperplasia and carcinoma support related clones.

The evidence strengthens the concept of atypical hyperplasia/EIN as a precursor lesion.

Slide 30 · From proliferation to neoplasia: Conceptual model

Estrogenic milieu

Promotes proliferation

Molecular alterations

Clonal growth advantage

Atypical glands

Precursor morphology

Carcinoma

Possible subsequent outcome

This conceptual progression is not inevitable; Many hyperplasias do not progress.

Slide 31 · A classification with clinical consequences

Without atypia

Crowded glands with predominantly proliferative-type cytology; Low progression risk.

Atypical hyperplasia / EIN

Complex crowded glands and cytologic atypia; Substantial carcinoma association.

Slide 32 · Morphology begins with the ratio

More glands relative to intervening stroma

Architectural interpretation comes before assessing the epithelial nuclei.

Slide 33 · Hyperplasia without atypia: Distribution of glands

Original schematic — not an H&E micrograph

Crowding is variable

A greater gland-to-stroma ratio than normal proliferation.

Gland profiles differ in size and contour.

Some intervening stroma is usually visible.

Slide 34 · Gland size and shape: Schematic contrast

Typical profiles

Variable profiles

Original schematic — not an H&E micrograph

Original schematic — not an H&E micrograph

In nonatypical hyperplasia, gland dilation and shape variability are typical features.

Slide 35 · Cystically dilated glands

Original schematic — not an H&E micrograph

Dilated gland lumina

Some glands are enlarged relative to adjacent glands.

Dilation contributes to architectural irregularity.

Gland dilation alone does not establish atypia.

Slide 36 · Focal back-to-back glands can occur without atypia

With stroma

Focally crowded

Original schematic — not an H&E micrograph

Original schematic — not an H&E micrograph

Focal crowding must be interpreted alongside the nuclear features.

Slide 37 · Nuclei in hyperplasia without atypia

Epithelial nuclei retain features resembling proliferative endometrium.

Architectural complexity varies and is not synonymous with nuclear atypia.

Nuclear morphology is therefore essential for the two-category classification.

Slide 38 · After estrogen withdrawal: Cystic atrophy

Nonatypical hyperplasia reflects persistent estrogenic stimulation.

When estrogenic stimulation is withdrawn, hyperplasia may evolve into cystic atrophy.

The tissue response illustrates the hormonal dependence of these lesions.

Slide 39 · Progression of hyperplasia without atypia

~1–3%

Reported progression

Robbins characterizes progression to adenocarcinoma as rare. This estimate refers to hyperplasia without atypia and must not be applied to atypical hyperplasia/EIN.

Slide 40 · Atypical hyperplasia: Complex gland architecture

Without atypia

With atypia

Original schematic — not an H&E micrograph

Original schematic — not an H&E micrograph

Greater crowding and branching are features of atypical hyperplasia/EIN.

Slide 41 · Architectural atypia: Branching and complexity

Atypical hyperplasia contains complex patterns of proliferating glands.

Glands are often arranged back-to-back.

Irregular branching produces complex gland outlines.

Slide 42 · Cellular orientation: The loss of polarity

Normal endometrial glandular cells maintain orientation to the basement membrane.

In atypical hyperplasia, epithelial cells become rounded and lose this orientation.

This cytologic change adds evidence beyond gland crowding alone.

Slide 43 · Atypical nuclei: Vesicular chromatin

Nuclei may appear rounded with open, vesicular chromatin.

Conspicuous nucleoli are an additional characteristic.

Nuclear differences help separate atypical from nonatypical hyperplasia.

Slide 44 · Architecture and cytology are complementary

Architectural axis

Cytologic axis

Gland-to-stroma ratio

Back-to-back glands

Branching and irregular gland shape

Cell polarity

Nuclear shape and chromatin

Visibility of nucleoli

Atypia is a nuclear diagnosis interpreted within glandular architecture.

Slide 45 · WHO two-category classification

Feature

Without atypia

Atypical hyperplasia / EIN

Architecture

Crowding; Variable dilation

Complex; Often back-to-back

Nuclear appearance

Proliferative-like

Rounded; Vesicular; Nucleoli

Clonality

Not required for diagnosis

Clonal outgrowth emphasized

Clinical implication

Rare progression

High concern for carcinoma

Slide 46 · Why EIN matters beyond morphology

Atypical hyperplasia/EIN represents clonal proliferation with multiple genetic alterations.

Its morphologic and molecular features overlap with well-differentiated endometrioid carcinoma.

This explains both its precursor designation and the challenge of excluding carcinoma.

Slide 47 · Atypical hyperplasia versus well-differentiated carcinoma

Atypical hyperplasia / EIN

Endometrioid carcinoma

Complex, crowded glandular proliferation

Nuclear atypia

May coexist with carcinoma

Morphologic and genetic overlap

Cannot always be excluded in limited tissue

Definitive distinction may require hysterectomy

Slide 48 · Concurrent carcinoma at hysterectomy

Up to 40%

After an EIN diagnosis

That up to 40% of patients diagnosed with atypical hyperplasia have carcinoma identified in the hysterectomy specimen. This is a coexistence estimate, not a prospective progression rate.

Slide 49 · Sampling can limit certainty

A small sample provides only part of the endometrial tissue architecture.

Atypical hyperplasia and well-differentiated carcinoma may be difficult to distinguish in that material.

A final hysterectomy specimen can reveal carcinoma not established on the preceding biopsy.

Slide 50 · Endometrioid carcinoma: The relevant malignant endpoint

Endometrioid carcinoma is the most common endometrial carcinoma type.

Many lesions occur in the same estrogen-associated context as endometrial hyperplasia.

Atypical hyperplasia may represent an identifiable precursor to this carcinoma.

Slide 51 · Shared mutations reinforce biologic continuity

PTEN, ARID1A, PIK3CA and KRAS alterations in paired precursor and carcinoma components.

Their shared presence supports a related clonal origin.

These observations do not convert any single biomarker into a validated progression test.

Slide 52 · Diffuse hyperplasia and a discrete polyp

Endometrial hyperplasia

Endometrial polyp

Defined by gland-stroma imbalance

Patterns of gland proliferation and atypia

Driven often by endocrine influences

Localized exophytic endometrial mass

Projects into uterine cavity

Distinct gross architecture and possible other associations

Slide 53 · Abnormal bleeding: Essential alternatives

Process

Source-based distinction

Anovulatory endometrium

Hormonal bleeding with persistent proliferative pattern

Endometrial polyp

Focal exophytic lesion in the cavity

Chronic endometritis

Inflammatory process with endometrial plasma cells

Endometrial hyperplasia

Increased gland-to-stroma ratio ± atypia

Endometrial carcinoma

Malignant neoplastic lesion

Slide 54 · Teaching approach to a hyperplastic sample

Confirm crowding

Gland–stroma assessment

Review nuclear features

Atypia present?

Assign category

Nonatypical vs EIN

Address carcinoma

Assess sampling limits

Teaching sequence only—not a complete diagnostic or management guideline.

Slide 55 · Why management differs by category

Without atypia

Atypical hyperplasia / EIN

Rare carcinoma progression

Often hormonally responsive lesion

Requires appropriate clinical interpretation

Substantial concurrent carcinoma concern

Hysterectomy often used

Fertility preservation needs close follow-up

Slide 56 · Atypical hyperplasia: Hysterectomy

Hysterectomy as a standard management option for atypical hyperplasia.

The approach also addresses uncertainty about an unsampled carcinoma.

Management is determined by clinical circumstances, not morphology alone.

Slide 57 · Fertility-preserving approach in selected patients

Young patients desiring fertility may receive a trial of progestin therapy.

Close follow-up is necessary to evaluate lesion regression.

This is a selected-patient alternative rather than equivalent exclusion of carcinoma.

Slide 58 · Persistent atypia changes the management discussion

Failure of regression after a fertility-preserving approach prompts consideration of uterine removal.

Hysterectomy after unsuccessful progestin management.

The pathologic endpoint of interest is resolution versus persistence of atypical disease.

Slide 59 · Case 1: Hormonal setting

Illustrative teaching vignette

An adult with repeated anovulatory cycles develops irregular uterine bleeding. The sample contains enlarged irregular glands, but nuclei resemble proliferative endometrium.

Which classification is best supported—and why?

Slide 60 · Case 1: Interpret both components

The hormonal context supports prolonged estrogenic stimulation.

Increased gland crowding with proliferative-type nuclear features is compatible with hyperplasia without atypia.

Nuclear atypia is not established solely by gland shape or cystic dilation.

Slide 61 · Case 2: Crowding plus atypia

Illustrative teaching vignette

An endometrial sample shows crowded branching glands, rounded nuclei, vesicular chromatin and conspicuous nucleoli.

What is the category, and what key limitation follows?

Slide 62 · Case 2: Classify and interpret limitations

The architectural and nuclear findings support atypical hyperplasia/EIN.

Its overlap with well-differentiated endometrioid carcinoma prevents certainty in some limited samples.

Carcinoma at hysterectomy in up to 40% of such cases.

Slide 63 · Case 3: The PTEN inference trap

Illustrative teaching vignette

An endometrial hyperplasia sample carries a PTEN alteration. A colleague states that carcinoma progression is now inevitable.

Is that conclusion justified by Robbins?

Slide 64 · Case 3: Mutation is not destiny

PTEN inactivation is common in hyperplasia and carcinoma.

Its occurrence supports an early molecular role in tumorigenesis.

PTEN alteration does not predict which hyperplasia progresses to carcinoma.

Slide 65 · Five diagnostic propositions

Hyperplasia is a gland-to-stroma imbalance.

Persistent estrogenic stimulation is the principal etiologic context.

PTEN–PI3K/AKT signaling provides a molecular growth mechanism.

Atypia, not crowding alone, separates the two WHO categories.

EIN requires special attention because concurrent carcinoma is common.

Slide 66 · Principal reference and image limitation

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

The uterine corpus, hormonal disorders, hyperplasia and adjacent carcinoma text informed this lecture.

All tissue architecture drawings are editable teaching schematics, not microscopic evidence.

Robbins figure 22.23 is discussed conceptually; no copyrighted textbook photomicrographs have been reproduced.