Familial Adenomatous Polyposis (FAP)

See Hereditary Colorectal Cancer Syndromes for how this fits among the other hereditary CRC syndromes. Content below is from a textbook reference chapter (Sabiston Ch52 - Colorectal Neoplasia & Colon Cancer Surgery), not primary literature.

Genetics and epidemiology

Autosomal dominant, occurring in ~1:10,000 live births, affecting genders and races equally. Caused by a germline mutation in the APC tumor suppressor gene (chromosome 5q21), which normally regulates β-catenin. Disease severity depends on the location of the APC mutation.

• Classical FAP — 100–1000 colorectal adenomas.
• Severe FAP — >1000 adenomas.
• Attenuated FAP (AFAP) — <100 adenomas.

~25% of FAP patients have a de novo mutation (no family history). Lifetime CRC risk may exceed 90%, nearly 100% if untreated; average age at CRC diagnosis is 39 years (range 35–43) in classic FAP.

Clinical presentation

Early development of a wide range of colorectal adenomatous polyps after the second decade of life, plus many extracolonic manifestations. May be asymptomatic or present with bleeding, diarrhea, abdominal pain, or mucous discharge. Anemia, obstruction, or weight loss usually signal the presence of cancer.

Extracolonic manifestations

• Gastric: fundic gland polyps (nonneoplastic, ~50% of patients), gastric adenomas (~10%, usually antral, low cancer risk).
• Duodenal: adenomas in 30–70% of patients, with a predilection for the ampullary/periampullary regions; lifetime duodenal cancer risk 4–10% — the second most common cause of death in FAP patients. Severity graded by the Spigelman classification (points for polyp number, size, histology, and dysplasia grade; stage 0–IV determines surveillance interval, from repeat endoscopy in 5 years at stage 0 down to repeat in 6–12 months plus surgical evaluation at stage IV).
• Desmoid tumors: benign but locally invasive monoclonal fibroblast proliferations, affecting 10–15% of FAP patients (only occasionally seen in the general population). Associated with female gender and a family history of desmoids. About half arise intraabdominally in the bowel mesentery, 40% in the abdominal wall, the remainder in the back/neck/limbs — can cause pain, bowel/ureteral obstruction, vascular compromise, and perioperative complications. Together with duodenal polyposis/cancer, desmoids are a major cause of morbidity and mortality after proctocolectomy, contributing to death in ~10% of FAP patients. Surgery for intraabdominal desmoids is generally not recommended except for small, well-defined tumors with an obtainable clear margin. NSAIDs and antiestrogens have shown mixed outcomes; combination chemotherapy (including doxorubicin) is the best option for progressively growing intraabdominal desmoids.
• Thyroid cancer: 2% incidence in FAP patients.
• Less common extraintestinal malignancies: pancreatic adenocarcinoma, hepatoblastoma, medulloblastoma.
• CHRPE (congenital hypertrophy of the retinal pigment epithelium) — benign, well-delineated grayish-black/brown oval spots on fundoscopic exam, seen in 60–85% of FAP patients. Doesn’t require intervention but can aid diagnosis.
• Other associations: small bowel polyps/carcinoma, dental anomalies.
• Gardner syndrome (FAP + epidermal inclusion cysts, osteomas, desmoid tumors) and Turcot syndrome (FAP + malignant CNS tumors) are eponymous subtypes belonging to the general FAP disorder, not separate diseases.

Diagnosis

May be genetic or clinical. Genetic testing reveals an APC germline mutation in ~80% of cases. Indications for genetic counseling/testing referral: family history of FAP, personal history of

10 adenomas, personal history of adenomas plus an extracolonic manifestation.

Screening

• Colorectal: begins age 12 with flexible proctosigmoidoscopy. If polyps are seen, proceed to full colonoscopy. If none are seen on initial flex sig, repeat every 1–2 years until age 35, then every 3–5 years thereafter, for at-risk first-degree relatives who haven’t had predictive genetic testing or whose DNA analysis is inconclusive. At-risk AFAP patients: colonoscopy at ages 12, 15, 18, and 21, then every 2 years. About a third of AFAP patients can be managed long-term endoscopically by polypectomy alone.
• Upper GI: begins age 20–25; interval based on Spigelman staging.
• Thyroid: annual ultrasound recommended. Routine screening not recommended for the other extracolonic cancers.

Timing and choice of surgery

Decisions center on timing of surgery and choice of operation, depending on symptoms, age at diagnosis, and individual characteristics:

• Symptoms present (cancer risk > risk of surgery) → surgery as soon as possible.
• Asymptomatic, mild disease → discuss opportunity before age 20 (CRC before 20 is rare).
• Sized lesions or high-grade dysplasia not amenable to endoscopic resection → immediate surgery.
• Severe disease by colonoscopy or family history/genotype → as soon as practicable.
• Attenuated polyposis by colonoscopy or family history/genotype → personal decision (16–20 years if mild, 21–25 if attenuated).
• Preoperative diagnosis, positive family history, or genetic susceptibility for desmoids → delay surgery after evaluating CRC risk.
• Delaying surgery in women with a low polyp burden who wish to have children → reasonable, as long as the patient remains in a strict surveillance program.

Surgical options

Four options, each with tradeoffs:

• Proctocolectomy with IPAA — greatly reduces rectal cancer risk, especially with rectal mucosectomy and hand-sewn anastomosis. More technically demanding and higher morbidity than IRA, with more frequent bowel movements. Rectal dissection risks nerve injury (sexual/urologic dysfunction); pelvic dissection can cause infertility from adhesions — minimally invasive approaches significantly reduce this risk. Indicated for: rectal cancer, large polyp burden (>20 synchronous adenomas), adenoma with high-grade dysplasia, large (>30 mm) adenomas, or a severe familial phenotype (>1000 synchronous adenomas); also the treatment of choice for a large number of rectal polyps (optimal timing individualized). The choice between mucosectomy + hand-sewn anastomosis (removes the anal transitional zone, potentially worse function, but fewer future anal-transitional-zone adenomas) vs. a stapled anastomosis retaining some anal transitional zone (better function/fewer complications/easier to survey, but the retained zone can develop its own adenomas, manageable endoscopically/ transanally) is debated. Can be done with or without a temporary diverting loop ileostomy — classically used to reduce the impact of anastomotic leak and pelvic sepsis (leak rates without diversion reported 6–37%). Should be performed only in specialized centers by experienced surgical teams.
• Subtotal colectomy with ileorectal anastomosis (IRA) — good surgical/functional outcomes but requires long-term follow-up of the retained rectum; metachronous rectal cancer risk ~30%. Generally recommended for patients with few rectal polyps, AFAP, a family history of mild phenotype, or young women wishing to become pregnant (after genetic counseling). Should not be performed in patients with a severely diseased rectum (adenomas >3 cm, adenomas with severe dysplasia, cancer, sphincter dysfunction, or >20 rectal adenomas) or in the presence of colon cancer. IRA may give good results in AFAP, MAP, and mild FAP.
• Proctocolectomy with permanent end ileostomy — currently rarely performed as a primary strategy (usually unacceptable to young patients). Still has a role when sphincter preservation isn’t possible, after malignant transformation post-IPAA or ileal pouch failure, or with poor sphincter function.

Most patients remain eligible for chemoprevention after surgery (proctocolectomy+IPAA and colectomy+IRA both retain “at-risk” mucosa somewhere — rectal for IRA, duodenal in all cases). Sulindac/celecoxib can slow polyp growth but should not replace routine endoscopic surveillance. Regular follow-up (perianal digital exam + flexible endoscopy, yearly) is mandatory after any procedure.

MUTYH-associated polyposis (MAP)

Autosomal recessive (unlike FAP’s dominant inheritance) — germline mutation of both MUTYH alleles (chromosome 1) required; both parents of an affected individual must be at least monoallelic carriers, giving affected individuals’ siblings a 25% chance of biallelic mutation. Monoallelic MUTYH mutations are found in 0.7–1% of unselected individuals in population-based cohorts; biallelic mutations in 1.7% of unselected individuals with CRC. Biallelic mutation carries a 28-fold increased CRC risk; monoallelic carrier risk appears only moderately increased.

The colonic phenotype mimics AFAP. Consider MAP in patients with colorectal polyposis (>20 lifetime adenomas) — most polyps are adenomas, but serrated polyps or a mixture can occur. Bleeding/obstruction may occur, but disease is usually suspected from screening colonoscopy findings. Characterized by multiple colorectal adenomas plus increased CRC risk at a younger age (40–50 years); polyp burden is highly variable, usually moderate (<100 adenomas). ~20% of MAP patients have duodenal polyposis; gastric fundic gland polyps are rare. Osteomas, desmoids, and CHRPE are not associated with MAP (a useful distinguishing point from FAP).

Testing indications: 10–100 polyps, siblings of a patient with biallelic MUTYH mutation, early-onset CRC (<44–55 years), or children of monoallelic/biallelic MUTYH carriers.

Management: colonoscopy every 1–2 years. Subtotal colectomy with IRA recommended if endoscopic management fails or CRC develops. Rectal cancer is uncommon in MAP; if it occurs, consider proctocolectomy + IPAA. EGD with a side-viewing scope for accurate ampullary examination, starting age 30, repeated every 3–5 years if normal; duodenal adenoma management follows FAP recommendations.

Open items / gaps

• No primary trial data on chemoprevention efficacy, desmoid chemotherapy regimens, or comparative IPAA technique (mucosectomy/hand-sewn vs. stapled) outcomes.
• Genetic counseling logistics not covered.