Familial Adenomatous Polyposis

Familial Adenomatous Polyposis Background Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome.

Familial Adenomatous Polyposis • Background • It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon.

Familial Adenomatous Polyposis • Background • If left untreated, all patients with this syndrome develop colon cancer by age 35-40 years.

• In addition, an increased risk exists for the development of other malignancies.

Familial Adenomatous Polyposis • Pathophysiology • The APC gene is a tumor suppressor gene that is located on band 5q21.

• Normal APC protein promotes apoptosis in colonic cells.

Familial Adenomatous Polyposis • Pathophysiology • Its most important function may be to sequester the growth stimulatory effects of b-catenin, a protein that transcriptionally activates growthassociated genes in conjunction with tissuecoding factors.

Familial Adenomatous Polyposis • Pathophysiology

• ► Mutations of the APC gene result in a truncated/nonfunctional protein. • The resultant loss of APC function prevents apoptosis and allows b-catenin to accumulate intracellularly and to stimulate cell growth with the consequent development of adenomas.

• Pathophysiology • Remember

• ► This process is similar to that which occurs in sporadic adenomas. • As a result, APC is considered the gatekeeper of colonic neoplasia. Its mutation/inactivation is the initial step in the development of colorectal cancer in patients with FAP.

Familial Adenomatous Polyposis • Pathophysiology • Germline (i.e. inherited) mutations of the APC gene, as is the case with FAP, result in cells containing 1 mutated and 1 normal copy of the gene.

• Patients inherit one mutated APC allele from an affected parent, and adenomas develop as the second allele from the unaffected parent becomes mutated or lost.

Familial Adenomatous Polyposis • Pathophysiology • Remember • Consequently, every colonic epithelial cell in patients with FAP has 1 mutated APC allele. • Inactivation of the remaining normal copy of the APC gene, by deletion or mutation, ►completely removes the tumor suppressive function of APC, ► thus initiating the growth of adenomatous polyps.

Familial Adenomatous Polyposis

• Pathophysiology • Remember • Inactivation of the second APC allele occurs frequently in the colon, resulting in the development of numerous adenomas.

Familial Adenomatous Polyposis • Frequency • The frequency is constant worldwide.

Familial Adenomatous Polyposis • Mortality/Morbidity • The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. • The mean age at which colorectal cancer develops in patients with classic FAP is 39 years.

• Patients with adenomatous polyposis itself often are asymptomatic.

Familial Adenomatous Polyposis • Race • FAP has been described in all races.

• Sex • The male-to-female ratio is 1:1.

• Age • The average age of onset of polyposis in FAP is 16 years.

Familial Adenomatous Polyposis • Clinical Findings • History • Most patients with FAP are asymptomatic until they develop cancer. • As a result, diagnosing presymptomatic patients is essential.

Familial Adenomatous Polyposis • Clinical Findings • History • Of patients with FAP, 75-80% have a family history of polyps and/or colorectal cancer at age 40 years or younger.

Familial Adenomatous Polyposis • Clinical Findings • Nonspecific symptoms, such as:

• ► unexplained: • rectal bleeding (hematochezia) • diarrhea. • Or abdominal pain • in young patients may be suggestive of FAP.

Familial Adenomatous Polyposis • Clinical Findings • Physical • Congenital hypertrophy of the retinal pigment epithelium is highly specific for FAP and is best seen by slit-lamp examination. • They are discrete flat pigmented lesions of the retina. They are often multiple (63%) and bilateral (87%). They do not cause any clinical problems.

Familial Adenomatous Polyposis • Illustration

Familial Adenomatous Polyposis • Clinical Findings • Physical • They indicate that a family member has inherited the gene that causes FAP and is at risk.

Familial Adenomatous Polyposis • Clinical Findings • Physical

• ►Extracolonic Symptoms • 1) Some lesions are indicative of a Gardner variant of FAP. • Osteomas (painless bony overgrowth) of the skull and the mandible may be present. • They usually precede the clinical or radiologic diagnosis of intestinal polyposis.

• Clinical Findings • Physical • Extracolonic Symptoms

• ► Some lesions are indicative of a Gardner variant of FAP.

• Dental abnormalities, often diagnosed by using x-ray films, may include: • • • •

supernumerary teeth impacted teeth dentigerous cysts and odontomas.

• Clinical Findings • Physical • Extracolonic Symptoms

• ► Some lesions are indicative of a Gardner variant of FAP. • In prepubescent patients, epidermoid cysts on the: legs • face • scalp • •

and arms may be present.

Familial Adenomatous Polyposis • Clinical Findings • Extracolonic Symptoms • Physical • Fibromas may be present, located on the: scalp • shoulders • arms • and back. •

• Clinical Findings • Physical • Extracolonic Symptoms • 2) Desmoid tumors. • (They develop in 10% to 12% in patients with FAP)

• ☼ A palpable abdominal mass in a young patient is suggestive of FAP.

• A palpable mass upon rectal examination in a young patient is suggestive of FAP.

Familial Adenomatous Polyposis

• Clinical Findings • Physical • Extracolonic Symptoms • 3) Turcot syndrome • Is characterized by colonic polyposis typical of FAP associated with central nervous system tumors (medulloblastoma)

Familial Adenomatous Polyposis

• Clinical Findings • Physical • Extracolonic Symptoms • 4) Gastrointestinal polyps. • The prevalence of gastric polyps ranges from 34% to 100%. In the fundus of the stomach. • Most of gastric polyps associated with FAP are hyperplasic type.

Familial Adenomatous Polyposis

• Clinical Findings • Physical • Extracolonic Symptoms • Duodenal polyps, most of which are adenomatous, have been found in 24% to 90% of patients with FAP.

Familial Adenomatous Polyposis

• Clinical Findings • Physical • Extracolonic Symptoms • 5) Periampullary carcinoma • It is estimated that this nonintestinal carcinoma occurs in 12% of the patients with FAP. • • It is one of leading causes of death in patients with FAP.

Familial Adenomatous Polyposis • Causes FAP is caused by a germline mutation of the APC tumor suppressor gene, located on band 5q21. Most mutations of the APC gene are: • nonsense • or frameshift mutations

• ► leading to truncation of the APC protein (nonfunctional protein).

Familial Adenomatous Polyposis • Differential diagnosis Juvenile polyposis syndrome Hereditary nonpolyposis colon cancer Hyperplastic polyposis Nodular lymphoid hyperplasia Lymphomatous polyposis Neurofibromatosis Inflammatory polyposis

Familial Adenomatous Polyposis • Workup • Lab studies • 1)CBC • 2) Alpha-fetoprotein (AFP) blood test - For children with FAP until age 5 years as part of a screening program for hepatoblastoma.

Familial Adenomatous Polyposis

• Workup • Imaging Studies • 3) Flexible sigmoidoscopy: Visualization of more than 100 polyps usually establishes the diagnosis because of the diffuse nature of the polyposis.

Familial Adenomatous Polyposis

• Workup • Imaging Studies • 4) Colonoscopy is usually reserved for patients thought to have AAPC because of the higher incidence of right-sided polyps (proximal colonic involvement).

Familial Adenomatous Polyposis

• Workup • Imaging Studies 5) esophagogastroduodenoscopy is recommended if the sigmoidoscopy or the colonoscopy establishes the diagnosis of FAP.

Familial Adenomatous Polyposis

• Workup • Imaging Studies • 6) Dental and skull x-ray films • Are recommended in patients thought to have a Gardner variant of FAP. ( to detect osteomas and dental abnormalities).

Familial Adenomatous Polyposis • Workup • Imaging Studies • 6) Barium studies may be performed to visualize intestinal polyposis.

• 7) Periodic ultrasounds or abdominal computed tomography scans are used to check for intraabdominal desmoid tumors and pancreatic cancer.

Familial Adenomatous Polyposis • Workup • Imaging Studies • 8) Periodic ultrasound of the thyroid: This imaging study is considered because of the increased risk of thyroid cancer. • It can supplement the recommended annual physical examination of the thyroid.

Familial Adenomatous Polyposis • Other Tests • 9) genetic tests are available. • (reserved for research purposes)

Familial Adenomatous Polyposis

• Treatment • Medical • Medical care is mainly based on endoscopic surveillance to detect the onset of polyposis.

• Surgery • Consequently, surgery would prevent the development of colon cancer

• Thanks