Familial Adenomatous Polyposis (FAP) - Pathology

Definition and Genetics

FAP is an autosomal dominant disorder caused by germline mutations of the APC (adenomatous polyposis coli) gene on chromosome 5q21-q22. It has 80-100% penetrance and an estimated prevalence of 1 in 5,000-7,500. About 75% of cases are inherited; the rest arise from de novo mutations.

The APC gene is a classic tumor suppressor gene - the mutated allele is inherited from the affected parent, and adenomas develop when the second (wild-type) allele is subsequently lost or mutated (two-hit model). Nearly all APC mutations create a premature stop codon, producing a truncated, non-functional protein.

Robbins, Cotran & Kumar Pathologic Basis of Disease - Robbins & Kumar Basic Pathology, p. 584

Molecular Pathogenesis: The APC/Wnt Pathway

The APC protein is a key negative regulator of the Wnt signaling pathway:

In normal cells, APC forms a destruction complex with axin, conductin, and GSK3-beta kinase
This complex binds and phosphorylates beta-catenin, marking it for ubiquitin-mediated degradation in the cytoplasm
When APC is mutated/truncated, beta-catenin is no longer degraded and accumulates in the cytoplasm
Beta-catenin translocates to the nucleus and interacts with transcription factor TCF-4, upregulating genes that drive adenoma formation
Truncated APC also disrupts normal chromosomal segregation, generating chromosomal instability (CIN)

Germline mutations are distributed throughout the 5' half of the APC gene; somatic mutations cluster in the central mutation cluster region (MCR) near codon 1309.

Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 2578

Gross and Histologic Pathology

Classic FAP requires at least 100 adenomatous polyps for diagnosis; thousands may be present (Fig. 17.51 from Robbins Cotran below).

FAP - Hundreds of small polyps in the colon with a dominant polyp (gross) and multiple tubular adenomas in one microscopic field (histology)

Fig. 17.51 (Robbins Cotran): (A) Hundreds of small polyps throughout this colon with a dominant polyp. (B) Three tubular adenomas in a single microscopic field.

Key histologic features:

FAP-associated polyps are morphologically indistinguishable from sporadic adenomas - tubular or villous architecture, dysplastic epithelium
Flat or depressed adenomas are prevalent in FAP
Microscopic adenomas (1-2 dysplastic crypts only) occur in otherwise normal-appearing mucosa
Polyposis involves the entire colon and rectum with no predilection for a single region

The adenoma morphology below shows (A) pedunculated adenoma endoscopically, (B) velvety surface, and (C) tubular adenoma histology:

Colonic adenomas - endoscopic and histologic views

Fig. 17.48 (Robbins Cotran): Colonic adenomas. (A) Pedunculated adenoma, endoscopic view. (B) Velvety surface. (C) Low-magnification tubular adenoma histology.

Malignant Potential

Colorectal adenocarcinoma develops in 100% of untreated FAP patients, often before age 30, nearly always by age 50. This is the cornerstone of the condition's clinical significance.

The carcinoma pathway is via the classic adenoma-carcinoma sequence (APC/Wnt pathway), with:

Tubular or villous adenoma architecture
Typical (not mucinous) adenocarcinoma histology - in contrast to HNPCC/Lynch syndrome

Prophylactic colectomy is the standard of care and prevents colorectal cancer, but patients remain at risk for extracolonic neoplasia.

Upper GI and Small Bowel Pathology

Site	Findings
Stomach	Fundic gland polyps (most common); dysplastic change occasionally; rarely adenomas
Duodenum	Adenomas in 60-90% of FAP patients; ampulla of Vater involved in 50-85%
Periampullary	4-12% lifetime risk of duodenal/ampullary adenocarcinoma - leading cause of cancer death after prophylactic colectomy
Jejunum	Adenomas in ~40%
Ileum	Adenomas in ~20%

The Spigelman Classification (stages I-IV) stratifies duodenal polyposis severity by polyp number, size, histology, and degree of dysplasia. Stage III/IV carries highest progression risk.

FAP Variants

Gardner Syndrome

APC germline mutations (specific mutations in codon 1310-2843 region) cause FAP plus:

Osteomas of the mandible, skull, and long bones
Epidermoid/sebaceous cysts
Desmoid tumors (intra-abdominal fibromatosis) - a leading cause of morbidity
Thyroid tumors (papillary thyroid carcinoma)
Dental abnormalities (unerupted and supernumerary teeth)
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) - present from birth, useful as a screening marker

Turcot Syndrome

FAP + CNS tumors
Two-thirds have APC mutations - develop medulloblastomas
One-third have DNA mismatch repair mutations - develop glioblastomas

Attenuated FAP (AFAP)

Caused by mutations in the 5' and 3' regions of APC
Fewer than 100 adenomas (typically 10-99), predominantly in the proximal colon
Later age of polyp onset and cancer development
Duodenal/periampullary adenomas still occur; gastric fundic gland polyps present; mandibular osteomas rare

Summary table of adenomatous polyposis syndromes

Syndrome	Gene	Inheritance	Polyp Count	Key Extraintestinal Features
Classic FAP	APC	Autosomal dominant	Thousands	CHRPE, osteomas, desmoids, epidermoid cysts, thyroid tumors, medulloblastoma
Attenuated FAP	APC (5'/3' ends)	Autosomal dominant	<100, proximal	Rare mandibular osteomas
MUTYH-associated polyposis (MAP)	MUTYH (MYH)	Autosomal recessive	5-100s, later onset	CHRPE, osteomas; sessile serrated polyps, KRAS mutations
Turcot syndrome (APC type)	APC	Autosomal dominant	Hundreds	Medulloblastoma
Turcot syndrome (MMR type)	MSH2/MLH1	Autosomal dominant	Few	Glioblastoma
Polymerase proofreading-associated polyposis (PPAP)	POLD1, POLE	Autosomal dominant	Adenomas + duodenal	Endometrial cancer

Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Table 126.9

Desmoid Tumors in FAP

Desmoid tumors (aggressive fibromatosis) occur in ~10-20% of FAP patients. They are:

Locally invasive, non-metastasizing fibrous tumors arising from musculoaponeurotic structures
Predominantly intra-abdominal (mesenteric) or abdominal wall in FAP
A major cause of morbidity and post-colectomy mortality due to bowel obstruction and vascular encasement
Strongly associated with APC mutations downstream of codon 1310
Can be triggered by surgical trauma (post-colectomy)

Comparison with HNPCC/Lynch Syndrome (Pathology Key Points)

Feature	FAP	HNPCC (Lynch)
Polyp number	Hundreds to thousands	Few (1-3)
Molecular pathway	APC/Wnt (CIN)	DNA mismatch repair (MSI)
Polyp histology	Tubular/villous adenoma	Sessile serrated adenoma
Carcinoma histology	Typical adenocarcinoma	Mucinous adenocarcinoma (often)
Carcinoma site	No predilection	Right colon predominant
Key gene	APC	MSH2, MLH1

Key Points Summary

FAP = APC tumor suppressor gene mutation, autosomal dominant, 5q21-q22
>100 adenomas required for classic diagnosis; can number in thousands
Polyps histologically identical to sporadic adenomas (tubular/villous architecture)
100% lifetime risk of colorectal carcinoma if untreated
Mechanism: loss of APC → beta-catenin accumulation → Wnt pathway activation → adenoma formation
Prophylactic colectomy is standard care
Leading extracolonic cancer risk post-colectomy: periampullary/duodenal adenocarcinoma
Variants: Gardner syndrome (osteomas + desmoids), Turcot syndrome (medulloblastoma), AFAP (<100 polyps, proximal colon)
MUTYH-associated polyposis (MAP) is the autosomal recessive phenocopy

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528) | Robbins & Kumar Basic Pathology (9780323790185) | Sleisenger and Fordtran's Gastrointestinal and Liver Disease (9780323609623)

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