Familial Adenomatous Polyposis

Slide 1 · Familial Adenomatous

Polyposis

APC-mediated colorectal neoplasia: molecular pathogenesis, morphology and clinical implications

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how an inherited APC defect predisposes colorectal epithelium to adenoma formation.

Recognize the classic polyp burden and the microscopic features of colorectal adenomas.

Connect untreated FAP to the timing and near-certainty of colorectal carcinoma.

Identify extracolonic manifestations and distinguish FAP from MUTYH-associated polyposis.

Slide 3 · FAP is a hereditary adenomatous polyposis syndrome

Autosomal dominant predisposition to numerous colorectal adenomas.

Polyps commonly begin during the teenage years.

Underlying defect: Germline alteration of the APC tumor-suppressor gene.

Neoplastic risk reflects the cumulative burden of adenomas.

Numerous mucosal adenomas

Independent neoplastic polyps can arise across the colorectum

Schematic — not a specimen

Slide 4 · What “familial” signifies—and what it does not

About three quarters of classic FAP cases are inherited from an affected parent.

The remaining cases apparently arise from de novo germline mutations.

Absence of a recognized family history therefore does not exclude FAP.

A familial phenotype is explained by a constitutional predisposition, not transmitted polyps.

INTERPRETATION

A de novo APC mutation can still be transmitted to the next generation.

Slide 5 · Adenomas appear early in life

The classic phenotype begins with many colorectal adenomas in adolescence.

Untreated disease follows a distinctive age-related neoplastic course.

Histology and family history must be interpreted together.

Teenage years

Numerous adenomas

Before 30 years

Cancer often develops

By 50 years

Cancer nearly always present if untreated

Slide 6 · Classic FAP: The conventional polyp threshold

At least 100 colorectal adenomas

The textbook uses ≥100 polyps for classic FAP; Thousands may be present. This threshold does not describe every APC-related phenotype.

Slide 7 · Polyp multiplicity is more characteristic than appearance

Hundreds to thousands of mucosal adenomas may coexist.

An individual adenoma can look like a conventional sporadic adenoma.

The striking clue is multiplicity throughout the large bowel.

Diffuse polyposis

Schematic bowel wall, not a gross photograph

Slide 8 · Autosomal dominant inheritance

A constitutional APC mutation can segregate vertically through a family.

An inherited mutation is present before adenomas appear.

The phenotype arises after additional alterations in individual colonic crypts.

Illustrative autosomal dominant transmission

Shading denotes a hypothetical affected relative

Slide 9 · Inherited versus de novo FAP

≈75% inherited

The remaining ≈25% appear de novo in the source text; These are textbook proportions, not a patient-specific probability.

Slide 10 · APC: The initiating molecular lesion

APC is a negative regulator of the Wnt/β-catenin signaling pathway.

Its normal tumor-suppressive role restrains epithelial proliferation.

A germline pathogenic change predisposes many colonic epithelial cells to acquire a second event.

Loss of APC function is a central early event in the classic adenoma–carcinoma sequence.

Slide 11 · APC is a tumor-suppressor gene on chromosome 5q21

The inherited allele carries a loss-of-function defect.

Each adenoma arises only after remaining APC function is sufficiently lost.

This recessive cellular mechanism produces an autosomal dominant family phenotype.

APC alleles in one epithelial cell

Inherited altered allele

Remaining functional allele

Somatic inactivation (“second hit”)

Schematic — sequential hits

Slide 12 · The two-hit model explains an inherited cancer risk

Germline APC mutation

Somatic loss of remaining APC function

Dysregulated Wnt signaling

Adenoma initiation

Two genetic “hits” are required at the cell level, even though the syndrome transmits dominantly.

Slide 13 · First hit is inherited; Second hit occurs in the epithelium

At birth, colonic cells already carry one altered APC allele.

A second somatic inactivation can arise in a susceptible epithelial clone.

Independent second hits help explain multiple separate adenomas.

APC alleles in one epithelial cell

Inherited altered allele

Remaining functional allele

Somatic inactivation (“second hit”)

Schematic — sequential hits

Slide 14 · The multiplicity of polyps reflects clonal opportunity

Extensive colorectal mucosa provides many susceptible epithelial crypts.

The predisposition increases opportunities for independent adenoma initiation.

Each visible polyp represents a localized neoplastic epithelial population.

The syndrome is not a single polyp extending throughout the colon.

Slide 15 · Wnt signaling is normally regulated

Wnt ligand binding alters the fate of intracellular β-catenin.

In unstimulated cells, an APC-containing complex promotes β-catenin destruction.

Low nuclear β-catenin restricts the transcriptional growth program.

APC destruction complex

β-catenin degradation

Low nuclear β-catenin

APC intact; No Wnt stimulation

Slide 16 · Normal colon epithelium without a Wnt signal

APC-containing destruction complex

β-catenin degraded

Low nuclear β-catenin

Restrained Wnt target expression

The destruction pathway is an active growth-control mechanism, not passive absence of stimulation.

Slide 17 · Normal Wnt stimulation is a regulated proliferative signal

Wnt binds cell-surface receptors in the Frizzled family.

Wnt signaling prevents formation of the β-catenin destruction complex.

Stabilized β-catenin can enter the nucleus and cooperate with TCF.

Target-gene activation is physiologically controlled by external signaling.

Slide 18 · APC loss simulates persistent Wnt stimulation

In the absence of functional APC, β-catenin destruction is impaired.

β-catenin accumulates even without normal upstream stimulation.

This activates a persistent epithelial growth program.

APC function lost

β-catenin accumulates

Nucleus: β-catenin + TCF

MYC / CCND1 transcription

Slide 19 · APC deficiency links genotype to growth signaling

Loss of APC function

β-catenin accumulation

β-catenin–TCF transcription

Pro-proliferative gene expression

The pathway is a molecular explanation for adenomatous epithelial expansion.

Slide 20 · β-catenin enters the nucleus and partners with TCF

APC normally helps retain β-catenin below a proliferative threshold.

Without functional destruction, β-catenin translocates to the nucleus.

β-catenin interacts with TCF to activate transcription.

APC function lost

β-catenin accumulates

Nucleus: β-catenin + TCF

MYC / CCND1 transcription

Slide 21 · MYC and cyclin D1 connect signaling to cell growth

Wnt-responsive genes include MYC and CCND1.

CCND1 encodes cyclin D1, a regulator of cell-cycle progression.

Elevated expression contributes to epithelial proliferation.

APC loss thus perturbs growth control rather than merely changing polyp shape.

Slide 22 · Normal Wnt regulation versus APC loss

Process

APC function preserved

APC function lost

β-catenin handling

Targeted degradation without Wnt

Accumulation despite absent upstream signal

Nuclear β-catenin

Low without Wnt

Increased

TCF target genes

Regulated induction

Persistent stimulation

Epithelial consequence

Controlled proliferation

Increased neoplastic potential

Slide 23 · APC loss initiates adenomas but does not complete carcinogenesis

Loss of both functional APC copies promotes the transition to an adenoma.

Additional somatic alterations accumulate with neoplastic progression.

The classic adenoma–carcinoma pathway is multistep.

This distinction explains why adenoma and carcinoma are different diagnoses.

Slide 24 · The adenoma–carcinoma sequence is multistep

APC inactivation is an early initiating alteration.

Additional mutations affect growth, apoptosis and cell-cycle control.

Advanced lesions may progress to invasive colorectal adenocarcinoma.

APC inactivation

Early adenoma

Additional genetic alterations

Invasive carcinoma

Slide 25 · KRAS activation accompanies later adenoma progression

Activating KRAS mutations can promote cell growth and reduce apoptosis.

The source places KRAS changes later than APC loss.

For sporadic adenomas, KRAS mutations become more frequent as lesions enlarge.

These population-level correlations are not a molecular diagnostic rule for any individual FAP polyp.

Slide 26 · SMAD2 and SMAD4: Removal of growth inhibition

SMAD2 and SMAD4 are effectors of TGF-β growth-inhibitory signaling.

Loss of their tumor-suppressive function reduces constraints on proliferation.

These alterations can contribute to further progression.

APC-initiated adenoma

Additional molecular hits

Loss of TGF-β restraint

Progression potential

Slide 27 · TP53 changes belong mainly to advanced progression

The source describes TP53 mutation as common in colorectal carcinomas.

It is uncommon in adenomas, placing it relatively late in this pathway.

TP53 loss helps remove safeguards against malignant evolution.

Do not conflate APC-mediated initiation with TP53-associated late events.

Slide 28 · Molecular progression: A simplified teaching sequence

APC loss

Early adenoma

Additional KRAS / SMAD alterations

Late TP53 abnormalities

Carcinoma

The diagram is conceptual: Individual tumors need not follow a uniform molecular order.

Slide 29 · Why FAP informed sporadic colorectal cancer biology

Germline APC mutations identify a causal initiating mechanism in FAP.

Acquired APC defects occur in a large proportion of sporadic adenomas and colorectal cancers.

The shared APC/β-catenin pathway links inherited and sporadic tumorigenesis.

An inherited syndrome can illuminate a common molecular route to cancer.

Slide 30 · Morphologic signature: A bowel filled with adenomas

Numerous discrete adenomas populate colorectal mucosa.

FAP polyps are not individually distinguishable from sporadic adenomas.

A carpet-like distribution is strongly suggestive when combined with the clinical phenotype.

Diffuse polyposis

Schematic bowel wall, not a gross photograph

Slide 31 · Gross disease burden can exceed a thousand polyps

The threshold for classic FAP is at least 100 polyps.

Thousands of adenomas may occur within the colon.

Polyps may differ in size and shape within the same bowel.

Numerous mucosal adenomas

Independent neoplastic polyps can arise across the colorectum

Schematic — not a specimen

Slide 32 · Many adenomas may coexist in a single field

The source figure illustrates three tubular adenomas in one microscopic field.

Neoplastic multiplicity is visible at histologic as well as gross scale.

Each lesion should still be evaluated by usual adenoma morphology.

Adenomatous change can begin in very few crypts

Schematic crypt field

Slide 33 · Microscopic adenomas can involve one or two crypts

Dysplasia may be limited to one or two crypt profiles.

Overlying mucosa can appear normal to the naked eye.

This supports the concept of early crypt-level neoplastic initiation.

Adenomatous change can begin in very few crypts

Schematic crypt field

Slide 34 · Flat and depressed adenomas occur in FAP

Not every FAP adenoma protrudes as a conspicuous polyp.

Flat or depressed lesions are also prevalent in FAP.

The broad surface morphology must not be used to exclude an adenomatous lesion.

Invisible microscopic adenomas further widen the morphologic spectrum.

Slide 35 · Adenoma histology does not identify hereditary origin

Indistinguishable

Apart from their multiplicity, FAP-associated adenomas are morphologically indistinguishable from sporadic adenomas.

Slide 36 · Tubular adenoma: Gland-forming architecture

Tubular adenomas have rounded or tubular glands.

They are often relatively small and may be pedunculated.

Architectural classification is separate from the diagnosis of dysplasia.

Tubular

Villous

Rounded gland profiles

Long finger-like projections

Architectural schematic; Not histology

Slide 37 · Villous adenoma: Elongated mucosal projections

Villous adenomas feature slender villous projections.

Villous architecture is associated with more frequent carcinoma, partly through larger lesion size.

Dysplasia remains the defining neoplastic epithelial abnormality.

Tubular

Villous

Rounded gland profiles

Long finger-like projections

Architectural schematic; Not histology

Slide 38 · Tubulovillous adenomas combine two architectural patterns

Tubular glands coexist with villous projections.

Classification records architecture rather than a distinct hereditary etiology.

As with tubular and villous adenomas, cytologic epithelial dysplasia is present.

Slide 39 · Architecture: Useful language, limited prognostic isolation

Adenoma pattern

Dominant architecture

Interpretive caution

Tubular

Rounded / tubular glands

Morphology alone does not imply FAP

Villous

Slender villous projections

Often larger; size influences cancer risk

Tubulovillous

Mixed tubular and villous

Architecture alone has limited clinical significance

Slide 40 · Pedunculated adenomas develop a fibromuscular stalk

A polyp may have a slender stalk containing vessels from the submucosa.

The stalk is usually covered by non-neoplastic epithelium.

Dysplasia may also extend onto the stalk in some polyps.

Epithelial dysplasia is the defining histologic feature

Schematic surface epithelium

Slide 41 · Sessile lesions need the same dysplasia assessment

Sessile adenomas have a broad attachment to mucosa.

Gross configuration does not establish biologic grade.

Flat, depressed, sessile and pedunculated lesions can all contain neoplastic epithelium.

Slide 42 · Adenomatous dysplasia: The nuclear phenotype

Nuclei become hyperchromatic and elongated.

Nuclear stratification disrupts orderly epithelial maturation.

Changes are often most evident near the luminal surface.

Epithelial dysplasia is the defining histologic feature

Schematic surface epithelium

Slide 43 · Additional cytologic changes support dysplasia

Prominent nucleoli may accompany nuclear atypia.

Eosinophilic cytoplasm can be conspicuous.

Goblet cells are often reduced relative to normal mucosa.

Interpret these findings within an adenomatous architectural context.

Slide 44 · Polyp size correlates with invasive cancer risk

Most small conventional adenomas do not contain invasive carcinoma.

The source identifies lesion size as the strongest gross correlate of invasive cancer.

Its example: Invasive cancer is rare in adenomas below 1 cm, but nearly 40% of those over 4 cm have invasive foci.

These estimates describe adenomas generally, not a FAP-specific per-polyp prediction.

Slide 45 · High-grade dysplasia: Local lesion risk, not a field label

High-grade dysplasia increases the likelihood of cancer within that adenoma.

The source states it does not itself increase cancer risk in other separate polyps of the same patient.

In FAP, the total risk is nevertheless substantial because the number of adenomas is very high.

Slide 46 · Intramucosal carcinoma is not the same as deep invasion

Intramucosal carcinoma invades lamina propria but does not extend through muscularis mucosae.

Functional lymphatics are absent from colonic mucosa, so metastatic potential is minimal.

Submucosal invasion creates clinically meaningful risk of spread.

Mucosa

Muscularis mucosae

Submucosa

Risk of metastatic spread increases after invasion of submucosa

Layer schematic; Not micrograph

Slide 47 · Depth of invasion changes clinical interpretation

Lesion level

Anatomic extent

Clinical implication

Adenoma / dysplasia

Confined above basement membrane

Premalignant lesion

Intramucosal carcinoma

Invades lamina propria; not through muscularis mucosae

Little/no metastatic potential

Invasive adenocarcinoma

Invades through muscularis mucosae into submucosa or beyond

Potential for metastatic spread

Slide 48 · Pathology of an invasive carcinoma drives management decisions

Depth of invasion is a key feature in an adenoma containing carcinoma.

The invasive component is assessed for grade and vascular / lymphatic invasion.

Distance to the resection margin also informs further therapy.

These are lesion-level considerations distinct from management of the inherited predisposition.

Slide 49 · Untreated classic FAP has near-certain colorectal cancer

100% of untreated patients develop colorectal adenocarcinoma.

Risk arises from progressive neoplasia in a very large population of adenomas.

This statement applies to untreated classic FAP, not every attenuated phenotype.

100%

Colorectal adenocarcinoma risk without treatment

Risk estimate in the stated textbook cohort

Slide 50 · Carcinoma appears at a much younger age than sporadic CRC

Cancer develops often before age 30 years in untreated FAP.

It is described as occurring nearly always by age 50 years.

Early adolescent adenoma formation creates a prolonged interval of neoplastic risk.

Teenage years

Numerous adenomas

Before 30 years

Cancer often develops

By 50 years

Cancer nearly always present if untreated

Slide 51 · Prophylactic colectomy addresses colorectal risk

The untreated cancer risk underpins proactive surgical management.

Prophylactic colectomy as standard care.

Removing the at-risk colon prevents the colorectal cancer trajectory described for untreated FAP.

Colectomy

Prevents colorectal cancer

Does NOT remove extracolonic neoplasia risk

Slide 52 · Colectomy does not eliminate all FAP neoplasia

Colorectal cancer prevention is not synonymous with cure of a multisite predisposition.

Extracolonic gastrointestinal adenomas and cancers remain possible.

Management must therefore account for residual risk outside the removed colon.

Colectomy

Prevents colorectal cancer

Does NOT remove extracolonic neoplasia risk

Slide 53 · The ampulla of Vater is an extracolonic neoplasia site

The ampulla of Vater as a common extracolonic site of adenomas.

Malignant progression can occur without treatment.

Upper gastrointestinal risk persists after colorectal surgery.

Colorectum — many adenomas

Ampulla of Vater — adenomas / cancer

Stomach — adenomas / cancer

Sites named (not scale diagram)

Slide 54 · Gastric adenomas and carcinomas can accompany FAP

The stomach is another extracolonic site highlighted.

Adenomas may arise outside the colorectum in affected patients.

Colorectal polyp count alone does not capture the syndrome’s full neoplastic spectrum.

Colorectum — many adenomas

Ampulla of Vater — adenomas / cancer

Stomach — adenomas / cancer

Sites named (not scale diagram)

Slide 55 · Congenital retinal pigment epithelial hypertrophy

Congenital hypertrophy of retinal pigment epithelium (CHRPE) may occur in FAP.

It can be detected at birth, before colorectal polyposis emerges.

The source presents it as a potential adjunct to early screening.

It is an associated finding, not by itself a sufficient diagnosis of FAP.

Slide 56 · Gardner syndrome belongs to the APC-related spectrum

The source associates Gardner syndrome with APC variants.

It combines adenomatous polyposis with possible osteomas and desmoid tumors.

Skin cysts and thyroid tumors are also listed in the source table.

APC germline variant

Colorectal adenoma burden

Associated manifestations may vary

Genotype–phenotype relation is incomplete

Slide 57 · Turcot syndrome includes colorectal polyposis and CNS tumors

The Robbins polyposis table groups an APC-associated Turcot phenotype with FAP.

Medulloblastoma and glioblastoma are listed as associated CNS neoplasms.

The term has broader historical usage; The slide follows the supplied APC-centered table.

APC germline variant

Colorectal adenoma burden

Associated manifestations may vary

Genotype–phenotype relation is incomplete

Slide 58 · APC-associated extraintestinal findings

Phenotype

Selected manifestations

Teaching significance

Classic FAP

CHRPE

May precede intestinal polyps

Gardner phenotype

Osteomas, desmoid and thyroid tumors, skin cysts

Extracolonic phenotype

Turcot phenotype (APC-associated)

CNS tumors listed: medulloblastoma, glioblastoma

Broader syndromic spectrum

Slide 59 · Attenuated FAP is included in the APC spectrum

The source table explicitly recognizes attenuated FAP as APC-associated.

The designation distinguishes it from the classic high-burden presentation.

The supplied excerpt does not define an exact polyp-count or age cutoff for attenuated FAP.

Do not apply the classic ≥100 criterion indiscriminately across all APC-associated phenotypes.

Slide 60 · APC variants show genotype–phenotype associations

Specific APC mutations have been associated with differences in manifestations.

Gardner and Turcot phenotypes exemplify syndromic heterogeneity.

The source does not supply a comprehensive codon-level map or deterministic predictions.

APC germline variant

Colorectal adenoma burden

Associated manifestations may vary

Genotype–phenotype relation is incomplete

Slide 61 · Adenomatous polyposis may occur without an APC defect

Patients with multiple polyps but without APC loss.

Some have pathogenic alterations in the MUTYH base-excision repair gene.

This defines MUTYH-associated polyposis (MAP), a separate hereditary syndrome.

Multiple adenomas therefore do not prove APC-associated FAP.

Slide 62 · MUTYH-associated polyposis is autosomal recessive

MAP is caused by biallelic MUTYH mutations.

The relevant molecular pathway is base-excision DNA repair.

The inheritance pattern differs fundamentally from autosomal dominant classic FAP.

FAP: APC; Autosomal dominant

MAP: MUTYH; Autosomal recessive

Hereditary mechanisms are distinct

Slide 63 · MAP tends to have fewer polyps and later presentation

The source describes MAP as often involving fewer than 100 polyps.

Clinical presentation generally occurs at later ages than classic FAP.

Colorectal cancer development is correspondingly delayed.

There is phenotypic overlap; Polyp number alone is not a molecular diagnosis.

Slide 64 · Classic FAP versus MUTYH-associated polyposis

Feature

Classic FAP

MAP

Causal gene

APC

MUTYH

Inheritance

Autosomal dominant

Autosomal recessive

Repair/signaling process

Wnt / β-catenin regulation

Base-excision repair

Typical polyp burden

≥100, sometimes thousands

Often <100

Cancer chronology

Early if untreated

Later than classic FAP

Slide 65 · MAP may contain serrated and hyperplastic polyps

Sessile serrated and hyperplastic polyps frequently coexist in MAP.

KRAS mutations are often identified in these lesions.

This mixed polyp spectrum contrasts with a purely adenomatous shorthand.

The source does not claim that serrated morphology is diagnostic of MAP.

Slide 66 · Lynch syndrome differs by mismatch-repair deficiency

Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is linked to inherited mismatch-repair gene mutations.

The cited textbook highlights MSH2 and MLH1 among implicated genes.

Its presentation is not defined by hundreds of adenomatous polyps.

This mechanism is distinct from APC loss and MUTYH-associated base-excision repair deficiency.

Slide 67 · Three hereditary colorectal-neoplasia mechanisms

Syndrome

Core molecular lesion

Inheritance / typical phenotype

Familial adenomatous polyposis

APC → Wnt/β-catenin deregulation

Autosomal dominant; numerous adenomas

MUTYH-associated polyposis

MUTYH → base-excision repair defect

Autosomal recessive; fewer polyps, later

Lynch syndrome

Mismatch-repair genes (e.g., MSH2, MLH1)

Autosomal dominant; nonpolyposis phenotype

Slide 68 · Diagnostic reasoning starts with phenotype and family pattern

Characterize the number and histologic type of colorectal polyps.

Ask whether the pattern suggests an autosomal dominant or recessive disorder.

Interpret APC versus MUTYH versus mismatch-repair mechanisms in context.

The provided Robbins section does not specify a current genetic-testing panel or surveillance protocol.

Slide 69 · Conceptual diagnostic distinction

Numerous adenomas

Inheritance pattern

APC / MUTYH mechanism

Syndromic assessment

Conceptual educational flow; It is not a clinical genetic-testing guideline.

Slide 70 · Clinical implications for relatives follow from inheritance

Autosomal dominant transmission creates risk across successive generations.

De novo APC disease explains an isolated proband despite an absent family history.

Affected individuals may have extracolonic manifestations before bowel symptoms.

Disease recognition has implications beyond the patient in whom polyps were discovered.

Slide 71 · Case 1: Numerous adenomas in adolescence

HYPOTHETICAL TEACHING CASE

A teenager undergoes evaluation and is found to have hundreds of colorectal adenomas. One parent had a colectomy in early adulthood.

Which hereditary mechanism is most consistent with the phenotype?

Why do many independent adenomas arise?

What is the principal consequence of leaving the colon untreated?

Slide 72 · Case 2: FAP without a family history

HYPOTHETICAL TEACHING CASE

A patient has a classic FAP-type polyp burden, but neither parent reports colorectal polyps or cancer.

Does the negative family history rule out FAP?

What genetic explanation is specifically mentioned by Robbins?

Which extracolonic observations might provide additional clues?

Slide 73 · Case 3: Fewer adenomas with later presentation

HYPOTHETICAL TEACHING CASE

An adult presents later in life with several dozen colorectal adenomas. The family pattern does not suggest clear vertical transmission.

Which alternative inherited polyposis syndrome should be considered?

Which DNA repair pathway is affected?

How does inheritance differ from classic FAP?

Slide 74 · Integrated synthesis: Four essential pathology connections

APC loss removes a restraint on β-catenin/TCF-driven epithelial growth.

A constitutional first hit leads to numerous separate adenomas after additional local events.

The adenomas resemble sporadic adenomas but carry an overwhelming aggregate cancer risk.

Colectomy prevents colorectal carcinoma while extracolonic neoplasia risk remains.

Slide 75 · Reference and source boundaries

Primary: Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th ed. (2026), Chapter 17, pp. 738–743.

Mechanistic parent context: Chapter 7, pp. 264–265 (APC and Wnt/β-catenin).

Source tables and figure descriptions were consulted in Markdown; the original chapter PDF was not supplied.

All slide diagrams are original editable schematics, not digitized Robbins figures or genuine microscopy.