Carcinoma of the Endometrium

Slide 1 · Carcinoma of the Endometrium

Pathogenesis • Molecular classification • Morphology • Clinical correlation

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish endocrine-associated endometrioid carcinoma from serous carcinoma.

Explain the four molecular classes and their biological basis.

Recognize the implications of glandular architecture, invasion and cytologic grade.

Relate abnormal uterine bleeding, histologic sampling and clinical extent to management.

Slide 3 · Endometrial carcinoma: The disease entity

A malignant epithelial neoplasm arising in the lining of the uterine corpus.

It is the leading invasive cancer of the female genital tract in the United States.

The common morphologic types are endometrioid and serous carcinoma.

Precursors and molecular alterations differ across biological subtypes.

Slide 4 · Two complementary ways to classify disease

Histologic phenotype

Architecture: Endometrioid vs serous morphology

Differentiation and cytologic atypia

Relation to precursor lesions

Molecular phenotype

POLE-ultramutated

Mismatch repair–deficient / MSI

Copy-number low / NSMP

Copy-number high / TP53-abnormal

Histologic appearance and molecular subtype are related, but not identical.

Slide 5 · Clinical importance: A changing epidemiologic pattern

Endometrial carcinoma as more common than cervical carcinoma in the United States.

Reduction in cervical precursor disease and increasing endometrial cancer in younger women contribute to the shift.

Most cases are recognized following abnormal or postmenopausal vaginal bleeding.

Slide 6 · One pathway to endometrioid malignancy

Prolonged estrogenic drive

Persistent proliferative stimulation

Endometrial hyperplasia

Gland:stroma ratio rises

Atypical hyperplasia / EIN

Clonal cytologic atypia

Endometrioid carcinoma

Malignant proliferation with invasion

Atypical hyperplasia is an important precursor—not an inevitable outcome.

Slide 7 · What “endometrial hyperplasia” means

The endometrium has more proliferating glands relative to the intervening stroma.

Abnormally crowded and irregularly shaped glands can cause abnormal bleeding.

Hyperplasia without atypia and atypical hyperplasia differ in cancer risk.

Slide 8 · Hyperplasia without atypia versus atypical hyperplasia

Without atypia

Architectural crowding and variable gland size

Cytology resembles proliferative endometrium

Usually retains some intervening stroma

Uncommon progression to carcinoma

Atypical hyperplasia / EIN

Crowded, complex glands with nuclear atypia

Clonal genetic alterations

Overlaps morphologically with low-grade carcinoma

Substantial concurrent carcinoma risk

Slide 9 · Why atypical hyperplasia is a precursor

Atypical hyperplasia and carcinoma may share mutations in PTEN, ARID1A, PIK3CA and KRAS.

Shared abnormalities support a common evolving neoplastic clone.

Coexistent invasive carcinoma can be missed in limited sampling.

Carcinoma at hysterectomy in up to 40% diagnosed with atypical hyperplasia.

Slide 10 · Sources of excess estrogenic stimulation

Metabolic

Obesity

Peripheral androgen-to-estrogen conversion

Ovarian

Anovulation

Polycystic ovarian syndrome

Estrogen-producing tumors

Exogenous

Prolonged estrogen exposure

Unopposed estrogenic substances

The pathway is especially relevant to endometrioid carcinoma.

Slide 11 · Obesity and a proliferative endometrium

Increased adipose tissue

Peripheral aromatization

Greater estrogenic exposure

Sustained endometrial signaling

Glandular proliferation

May produce hyperplasia

Clonal progression

Cancer only in a subset

Slide 12 · Metabolic associations require causal care

Obesity is a major epidemiologic association for endometrioid carcinoma.

Hypertension and type 2 diabetes commonly coexist in affected patients.

Co-occurrence does not establish that hypertension independently causes the cancer.

Distinguish associated clinical conditions from established molecular tumor drivers.

Slide 13 · Hereditary predisposition: Two distinct mechanisms

PTEN / Cowden syndrome

Germline PTEN mutation

Dysregulated PI3K/AKT signaling

Higher risk of endometrial and certain other cancers

Mismatch repair / Lynch syndrome

Heritable mismatch repair defect

Microsatellite instability can develop

Raises risk of endometrial and colorectal cancer

Slide 14 · Growth signaling through PI3K and AKT

PI3K pathway

Pro-growth cellular signaling

AKT activity

Downstream signaling amplification

Estrogen receptor output

Increased target-gene expression

Endometrial growth advantage

Supports neoplastic proliferation

This is an original simplified pathway: No claim that each component acts in isolation.

Slide 15 · PTEN: Loss of a growth-regulatory brake

PTEN encodes a lipid phosphatase that restrains PI3K/AKT signaling.

Loss of PTEN function releases this negative regulation.

PTEN mutations are found in hyperplasia and many endometrioid carcinomas.

Mutation alone does not predict which hyperplasias will progress.

Slide 16 · PIK3CA and KRAS: Cooperating oncogenic alterations

PIK3CA

Encodes a catalytic component of PI3K

Activating alterations increase growth signaling

Frequent in endometrioid carcinoma

KRAS

Oncogene with activating mutations in a subset

Can also increase PI3K/AKT pathway output

Tumors may acquire more than one pathway alteration

Slide 17 · ARID1A: Chromatin regulation intersects signaling

ARID1A participates in the regulation of chromatin structure.

Loss-of-function alterations occur in many endometrioid carcinomas.

ARID1A loss to pro-oncogenic PI3K/AKT-related gene expression, with the mechanism unresolved.

Slide 18 · From precursor clone to overt carcinoma

Early molecular alteration

E.g., PTEN pathway disruption

Clonal atypical hyperplasia

Architectural + nuclear atypia

Additional driver alterations

Growth advantage accumulates

Invasive endometrioid tumor

Destructive gland growth

Conceptual multistep progression; The exact order varies among tumors.

Slide 19 · Four principal molecular classes

POLE-mutated

DNA proofreading defect

Ultramutated genome

MMR-deficient

Mismatch repair failure

Microsatellite instability

NSMP / copy-number low

Often endometrioid

PI3K/AKT pathway

P53-abnormal

Copy-number high

Often serous or high-grade

Slide 20 · POLE-ultramutated endometrial tumors

A pathogenic DNA polymerase ε proofreading defect generates an exceptionally high somatic mutation burden.

Most of the acquired mutations are passengers rather than oncogenic drivers.

Tumors with this phenotype can contain prominent infiltrating T cells.

Slide 21 · MMR-deficient and MSI-hypermutated tumors

Mismatch repair normally corrects certain replication-associated DNA errors.

Loss of repair activity leads to microsatellite instability and accumulation of mutations.

Alterations may be sporadic, including MLH1 promoter methylation, or related to Lynch syndrome.

Slide 22 · Copy-number low / NSMP endometrial carcinomas

A common molecular phenotype among endometrioid tumors.

It lacks the defining ultramutated, MMR-deficient or copy-number-high profile.

Mutations favoring PI3K/AKT signaling are frequent in this group.

“NSMP” = no specific molecular profile; It does not mean no pathogenic mutations.

Slide 23 · Copy-number high / TP53-mutated carcinomas

Numerous genomic copy-number alterations reflect chromosomal instability.

Disruptive TP53 mutation is a defining frequent feature.

The group is enriched for serous and some high-grade endometrioid morphologies.

Slide 24 · Molecular phenotype is not a histologic synonym

Molecular class

Molecular hallmark

Common morphologic setting

POLE-mutated

Proofreading defect / ultramutation

May be endometrioid

MMR-deficient

Repair dysfunction / MSI

Often endometrioid

NSMP

No class-defining feature

Usually endometrioid

P53-abnormal

TP53 disruption / copy-number high

Often serous; May be high-grade endometrioid

Slide 25 · Genomic instability has different causes

Sequence-level instability

POLE: Replication proofreading fails

MMRd: Mismatch repair fails

High numbers of sequence mutations

Chromosomal instability

P53-abnormal: Broad copy-number changes

Many gains and losses across the genome

Often aggressive serous phenotype

Slide 26 · Why immune infiltrates may be prominent

Many somatic mutations can produce altered peptide sequences.

Novel protein epitopes may be recognized as tumor neoantigens.

Increased tumor-infiltrating T cells in POLE- and MMR-defective tumors.

Their presence does not guarantee an effective anti-tumor immune response.

Slide 27 · Endometrioid carcinoma: The dominant morphology

Approximately 80–85% of endometrial carcinomas.

Tumor glands often resemble those of proliferative endometrium.

Many cases arise in an estrogen-associated clinical setting.

Grade varies with the proportion of glandular versus solid tumor growth.

Slide 28 · Endometrioid carcinoma: Gross patterns

Localized growth

Polypoid or fungating tumor mass

May arise in the uterine fundus

Can be detected during investigation of bleeding

Diffuse growth

Broader involvement of endometrial lining

Potential progression to myometrial invasion

Extension to adjacent tissues in advanced disease

Slide 29 · Endometrioid histology: Architecture is central

Neoplastic epithelium forms glands with resemblance to proliferative endometrium.

Crowded glands may show complex or confluent growth.

Solid tumor areas increase with decreasing glandular differentiation.

Desmoplastic stroma or confluent growth may support carcinoma over hyperplasia.

Slide 30 · Grading endometrioid carcinoma: A visual model

Grade 1: Predominantly glands

Schematic

Well formed glandular architecture

Grade 2: Glands + solid growth

Schematic

Solid areas present but ≤ 50%

Grade 3: Predominantly solid

Schematic

Solid growth > 50%

Editable architectural schematics—not diagnostic histology or a substitute for microscopy.

Slide 31 · Grade 1: Well-formed glandular architecture

Grade 1: Predominantly glands

Schematic

Well formed glandular architecture

The well-differentiated pattern may resemble proliferative endometrial glands.

Slide 32 · Grade 2: Mixed glandular and solid regions

Grade 2: Glands + solid growth

Schematic

Solid areas present but ≤ 50%

’ three-tier description, solid growth occupies no more than half the tumor.

Slide 33 · Grade 3: Predominantly solid growth

Grade 3: Predominantly solid

Schematic

Solid growth > 50%

’ three-tier description, solid growth accounts for more than half the tumor.

Slide 34 · Architectural grade versus nuclear atypia

Architectural grading

How much tumor forms glands?

How much grows in solid sheets?

This is the grading foundation

Cytologic assessment

Nuclear variability and atypia

Mitotic activity and high-grade features

May raise concern about serous or other carcinoma

Grading rules depend on histotype and applicable classification criteria.

Slide 35 · Squamous differentiation: An important exception

A subset of endometrioid tumors contains squamous differentiation.

Squamous components may appear bland or markedly malignant.

Glandular differentiation—not the squamous component—determines the architectural grade.

Slide 36 · Atypical hyperplasia versus carcinoma

Atypical hyperplasia / EIN

Crowded clonal glands with cytologic atypia

May be difficult to distinguish in limited material

Concurrent carcinoma may be present elsewhere

Well-differentiated carcinoma

Confluent or complex growth

Desmoplastic stromal response may be present

Definite invasion supports carcinoma

Adequacy of tissue sampling is central to the differential diagnosis.

Slide 37 · Myometrial invasion changes anatomic extent

Endometrium

Myometrium

Beyond uterus

Tumor extension

Invasion beyond endometrium reaches uterine smooth muscle.

Increasing local extension opens routes for regional spread.

Anatomic invasion differs conceptually from architectural grade.

Slide 38 · Endometrioid carcinoma: Routes of progression

Endometrial tumor

Localized or diffuse growth

Myometrial invasion

Extension through uterine wall

Regional spread

Adjacent tissues / pelvic nodes

Distant spread

Lung, liver, bone in late disease

Slide 39 · The endocrine context is not universal

Estrogen-related risk is especially characteristic of endometrioid carcinoma.

Not all endometrial cancers arise from atypical hyperplasia.

Serous tumors typically develop in an atrophic rather than hyperestrogenic background.

Slide 40 · Serous carcinoma: Clinically aggressive histotype

A high-grade tumor with biology distinct from usual endometrioid carcinoma.

That serous tumors account for about 15% of cases.

Affected patients tend to be older than patients with endometrioid carcinoma.

Deep invasion or extrauterine spread can already be present at diagnosis.

Slide 41 · Endometrial background in two major histotypes

Endometrioid phenotype

Often follows unopposed estrogenic stimulation

May be preceded by atypical hyperplasia

Frequently associated with PI3K/AKT pathway mutation

Serous phenotype

Usually arises in atrophic endometrium

Surface epithelial precursor is described

TP53 alteration is strongly characteristic

Slide 42 · TP53 dysfunction in serous carcinoma

Disruptive TP53 alterations are found in the large majority of serous tumors.

Many are missense mutations leading to accumulation of altered p53 protein.

Aberrant p53 immunostaining can provide morphologic–molecular correlation.

Broad copy-number alterations are characteristic of the subtype.

Slide 43 · Serous intraepithelial lesion to disseminating carcinoma

Abnormal surface epithelium

Early TP53 pathway disruption

Intraepithelial carcinoma

Malignant cells remain surface-limited

Invasive serous carcinoma

Cytologically high-grade cells

Transtubal spread

Peritoneal implantation possible

Surface-limited disease can already be biologically dangerous.

Slide 44 · Serous carcinoma: Cytology can trump architecture

Tumors may show papillary or glandular architecture.

Cells are markedly atypical, hyperchromatic and often have high nuclear-to-cytoplasmic ratios.

Atypical mitoses and prominent nucleoli reinforce high-grade morphology.

A gland-forming growth pattern does not make serous carcinoma low grade.

Slide 45 · All serous carcinomas are considered high grade

The designation is based on intrinsic cytologic and biological features.

Architectural patterns can vary within the tumor.

Endometrioid three-tier glandular grading must not be applied to regrade a serous carcinoma.

Slide 46 · Why extrauterine spread can precede deep invasion

Serous tumor cells exfoliate

Detach from endometrial surface

Transit through tubes

Anatomic communication

Peritoneal implantation

Extrauterine tumor deposits

A conceptual model of transtubal dissemination.

Slide 47 · Endometrioid and serous carcinoma: Essential contrasts

Feature

Endometrioid

Serous

Typical substrate

Estrogenic drive / EIN

Atrophic endometrium

Genetic emphasis

PI3K/AKT, MMR, POLE

TP53, copy-number high

Histology

Glands ± solid areas

High-grade papillary or glandular

Grading

Architectural grades 1–3

Intrinsically high grade

Spread

Often invasion-led

Early extrauterine seeding possible

Slide 48 · Other morphologic types share molecular pathways

Robbins also names clear cell, undifferentiated/dedifferentiated and mesonephric-like carcinomas.

Molecular profiling can place many uncommon histotypes into one of the four major classes.

Morphologic recognition remains necessary; A molecular group alone is not the histotype.

Slide 49 · Abnormal vaginal bleeding is the key clinical clue

Presentation may include irregular bleeding during reproductive years.

Postmenopausal bleeding is a frequent reason for evaluation.

A tumor can initially be asymptomatic, so absence of bleeding does not exclude it.

Slide 50 · How symptoms lead to tissue diagnosis

Abnormal bleeding

Especially postmenopausal

Clinical evaluation

Determine need for endometrial sampling

Biopsy / curettage tissue

Histologic architecture and atypia

Pathologic diagnosis

Histotype, grade and additional tests

Slide 51 · There is no routine screening test

No screening test is available for endometrial cancer.

Symptom-triggered evaluation therefore has practical importance.

A negative routine cervical screening result does not establish the absence of endometrial cancer.

Slide 52 · Histologic tissue sampling is indispensable

What sampling can establish

Presence of atypical epithelial proliferation

Morphologic carcinoma type

Clues to grade and molecular assessment

What limited samples may miss

A focal coexistent carcinoma in EIN

Definite myometrial invasion

The full extent of extrauterine dissemination

Slide 53 · Morphologic diagnosis and extent answer different questions

Biopsy or curettage identifies the neoplasm and its cellular features.

Assessment of myometrial or extrauterine invasion generally requires evaluation beyond surface tumor alone.

Molecular findings refine classification but do not substitute for assessing anatomic extent.

Slide 54 · MMR testing links tumor pathology to inherited risk

Confirmed endometrial carcinoma

Tissue-based diagnosis

Evaluate MMR phenotype

Identify deficient pathway

Consider sporadic vs hereditary cause

MLH1 silencing or Lynch mechanism

Assess hereditary implications

Patient/family cancer risk context

Slide 55 · Why Lynch syndrome matters beyond the uterus

Endometrial carcinoma can be a sentinel malignancy for Lynch syndrome.

Hereditary Lynch syndrome among approximately 3–5% of patients with endometrial cancer.

Recognition matters because associated colorectal and other cancer risks extend beyond the original tumor.

Slide 56 · Grade and stage measure different disease properties

Histologic grade

Differentiation of malignant epithelium

For endometrioid tumors, mainly glandular versus solid growth

Tumor-intrinsic phenotype

Anatomic stage

How far the tumor has extended

Uterine confinement vs cervical / extrauterine extension

Requires information about tumor distribution

Slide 57 · Anatomic stage: Simplified progression of extent

I — Uterine corpus

Confined to uterine body

II — Cervical stroma

Extends into cervical stroma

III — Pelvic extension

Outside uterus, within true pelvis

IV — Beyond pelvis / mucosa

Extrapelvic or bladder/rectal mucosa

Simplified Robbins anatomic teaching scheme; Not the complete modern FIGO 2023 staging algorithm.

Slide 58 · Local extension differs from distant dissemination

Endometrium

Myometrium

Beyond uterus

Tumor extension

Confined endometrial disease is anatomically different from cervical stromal extension.

Regional extension may affect pelvic tissues and lymphatic drainage.

Peritoneal or distant disease changes clinical stage and therapy planning.

Slide 59 · Prognosis is multifactorial

Anatomic extent

Stage at detection

Myometrial / extrauterine spread

Morphologic features

Histotype

Endometrioid grade

Molecular biology

POLE, MMR, NSMP, p53 pathways

Biological heterogeneity

Stage, grade and histologic subtype; Molecular class adds biological context.

Slide 60 · Why serous carcinoma has a worse outcome

Marked cytologic atypia and TP53-associated genomic instability accompany aggressive biology.

Exfoliation and transtubal spread can cause extensive extrauterine disease despite limited primary uterine involvement.

An apparently small uterine tumor must therefore not be assumed to represent low overall disease burden.

Slide 61 · Treatment follows histotype and anatomic extent

Endometrioid carcinoma

Surgery is a major primary modality

Adjuvant treatment depends on recurrence risk and spread

Extrauterine disease may require systemic treatment

Serous carcinoma

Aggressive biological phenotype

Systemic therapy may be considered even without overt distant disease

Multimodal strategies reflect spread risk

Source-level principles only; Drug regimens and current treatment criteria require contemporary guideline review.

Slide 62 · Molecular results can inform therapy

Hypermutated MSI and POLE-ultramutated tumors with the use of checkpoint inhibition.

HER2 amplification is described in a subset, especially among TP53-mutated tumors.

Predictive utility, treatment eligibility and approvals must be evaluated using current evidence and guidance.

Slide 63 · Case discussion: Abnormal bleeding and glandular atypia

A postmenopausal patient has irregular bleeding. Endometrial sampling reveals crowded atypical glands and foci of confluent epithelial growth.

What key diagnostic distinction must be resolved?

Discuss the underlying tissue findings and molecular rationale before revealing the answer.

Slide 64 · Case reasoning: Atypical hyperplasia or carcinoma?

Consider atypical hyperplasia

Crowded clonal glands with atypical nuclei

Limited samples may not establish invasion

Concurrent malignancy is possible

Consider carcinoma

Confluent epithelial growth

Desmoplasia or destructive invasion

Extent may only be resolved with more tissue

Slide 65 · Case discussion: High-grade tumor in an atrophic uterus

An older patient has a cytologically high-grade glandular endometrial tumor, abnormal p53 expression, and a relatively atrophic background.

Which morphologic–molecular phenotype is most likely?

Discuss the underlying tissue findings and molecular rationale before revealing the answer.

Slide 66 · Case reasoning: Serous carcinoma

Supporting clues

Atrophic endometrial background

Marked nuclear pleomorphism despite gland formation

TP53-associated phenotype

Immediate implications

Treat as intrinsically high grade

Assess extrauterine dissemination

Avoid equating glandular growth with low-risk biology

Slide 67 · Integrated pattern-recognition checklist

Question

Observation

Interpretive value

Clinical substrate?

Estrogenic vs atrophic

Suggests common histotype

Tumor structure?

Glands vs high-grade papillae

Histologic classification

Molecular profile?

POLE / MMR / NSMP / p53

Biological subgroup

Has it invaded?

Myometrium / beyond uterus

Anatomic extent

Inherited risk?

MMR abnormalities

Possible Lynch work-up

Slide 68 · Synthesis: Three independent diagnostic axes

Histotype: What the tumor looks like (endometrioid, serous or another form).

Molecular class: The principal altered genomic process.

Stage: Where the tumor is anatomically distributed.

These axes provide complementary—not interchangeable—information.

Slide 69 · Core concepts to retain

Atypical hyperplasia / EIN is an important precursor to endometrioid carcinoma.

PI3K/AKT dysregulation is central to many endometrioid tumors.

Serous carcinoma is associated with TP53 abnormality and a risk of early extrauterine dissemination.

Abnormal bleeding prompts tissue diagnosis; Stage and histotype are fundamental to prognosis.

Slide 70 · References and teaching scope

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

Carcinoma overview, endometrial hyperplasia and adjacent endometrioid / serous sections were used to support this lecture.

All architectural and mechanistic illustrations are native editable PowerPoint schematics, not histologic specimens.

Contemporary FIGO staging algorithms and management recommendations should be verified independently when required.