Familial Adenomatous Polyposis

Description

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder in which patients develop numerous colorectal adenomas as teenagers. Colorectal adenocarcinoma develops in 100% of
untreated FAP patients, often before age 30 and nearly always by age 50.

Epidemiology

FAP occurs in 1 in 10000 individuals and is the second most common inherited colorectal cancer syndrome. About 30% of individuals with FAP have no known family history and represent de novo adenomatous polyposis coli (APC) mutations.

Pathogenesis

• Autosomal dominant disorder in which there are germline loss-of-function mutations involving the APC locus on chromosome 5q21 leading to the development of thousands of adenomatous polyps
• One or more of these polyps undergoes malignant transformation, giving rise to colon cancer. As with other tumour suppressor genes, both copies of APC must be lost for an adenoma to arise.
• Several additional mutations must then occur for adenomas to progress into cancers.

Variants

Specific APC mutations have been associated with other manifestations of FAP and partly explain variants such as Gardner syndrome and Turcot syndrome.

• Gardener Syndrome: Characterised by extracolonic features (mnemonic: DOPE): Desmoid tumours, Osteomas (Mandible, skull, long bones), Papillary thyroid carcinoma, Epidermoid cysts

• Turcot Syndrome: Rarer. Characterised by Cafe-au-lait spots and CNS tumours (Glioblastoma or medulloblastoma)

Clinical Features

• Extraintestinal manifestations: Congenital hypertrophy of the retinal pigment epithelium (screened at birth)
• Fundic gland polyps and adenomas in > 50%
• Duodenum: Adenomas of 2nd part and periampullary in > 50%
• Periampullary cancer: 2nd most frequent site of cancer outside colon (12% of FAP patients)
• Jejunum and ileum Adenomas, lymphoid hyperplasia in > 20%
• Pancreatic ductal adenocarcinoma
• Associated with increased incidence of malignant CNS tumours
• Soft tissue tumours (e.g., desmoid), surgical sites
• Osteoma

Complications

One of the major complications of FAP is the development of colorectal cancer. FAP patients have a nearly 100% lifetime risk of developing colon cancer if the colon is not removed.

Pathological Features

Aetiology	Molecular Defect	Gene	Inheritance	Histology	Side
FAP	APC/WNT pathway	APC	AD	Tubular, villous; typical adenocarcinoma	None
MYH-associated polyposis	DNA mismatch repair	MYH	AR	Sessile serrated adenoma; mucinous adenocarcinoma	None
HNPCC	DNA mismatch repair	MLH1, MSH2	AD	Sessile serrated adenoma; mucinous adenocarcinoma	Right
Sporadic colon cancer	APC/WNT pathway	APC	None	Tubular, villous; typical adenocarcinoma	Left
	DNA mismatch repair	MLH1, MSH2	None	Sessile serrated adenoma; mucinous adenocarcinoma	Right
	Hypermethylation	MLH1, BRAF	None	Sessile serrated adenoma; mucinous adenocarcinoma	Right

AD autosomal dominant, AR autosomal recessive

Radiological Features

General Features

• Location: Colon > stomach > duodenum > small bowel
• Size: Varies from pinpoint to > 1 cm
• Morphology: Sessile or pedunculated, polypoid lesions

Fluoroscopy

• Innumerable variably sized, radiolucent filling defects or ring-shadows on barium enema
• Carpet entire colon, especially rectosigmoid
• May be widely scattered radiolucent filling defects
• Multiple small filling defects (polyps) in stomach, duodenum, jejunum, and ileum

CT

• Useful for diagnosing and staging colon carcinomas

Diagnosis & Classification

Classically, at least 100 polyps are required for the diagnosis of FAP.

Differential Diagnosis

• MUTYH-associated polyposis (MAP): Autosomal recessive disorder where patients do not have APC loss but have bi-allelic mutations of the base-excision repair gene MUTYH (or MYH). MAP is characterized by fewer than 100 polyps, which appear at later ages. Colon cancer development is also delayed. In addition, sessile serrated adenomas and hyperplastic
  polyps, often with KRAS mutations, are frequently present in those with MAP.
• Gardner Syndrome
• Turcot Syndrome

Management

• Prophylactic colectomy is the standard of care for the prevention of colorectal cancer; however, patients remain at risk for neoplasia at other extracolonic sites such as the ampulla of Vater and the stomach.