Hereditary GI Cancer Syndromes: Adenomatous Polyposis: FAP and MUTYH

0:00Welcome to Board Pearls. This is episode three of five of the Hereditary GI Cancer Syndromes chapter, in the Special Populations and Acute or Supportive Care module. In this episode we cover the adenomatous polyposis syndromes: FAP and attenuated FAP with APC, the Spigelman-staged duodenal surveillance and the timing of colectomy, and MUTYH-associated polyposis with its biallelic recessive pattern.

0:26The polyposis syndromes look like one problem from a distance and four problems up close. Hundreds or thousands of polyps in a young patient is the entry signal. What separates the syndromes is the gene driving the polyps, the histology under the microscope, and the operation the gene forces. If you know the gene, you know the polyp count, the polyp type, and the surgery. If you only know the polyp count, you cannot reason about anything that follows.

0:53Classic FAP starts with APC. The gene sits on chromosome five-q twenty-one and removes the brake on Wnt signaling when one allele is lost in the germline and the second goes in a crypt. The crypts do not lose one allele at a time across decades the way sporadic cancer does. They lose both alleles in parallel across hundreds of crypts simultaneously. That is why classic FAP produces a hundred to over a thousand adenomas by adolescence and why untreated colorectal cancer risk approaches one hundred percent by age forty. The diagnosis is usually made in the second or third decade, and roughly a quarter of cases arise de novo without a family history. So the absence of an affected parent does not exclude FAP in a young patient with hundreds of adenomas.

1:39Attenuated FAP is the same gene but a different part of the gene. Mutations at the extreme five-prime or three-prime ends of APC produce a softer phenotype. Fewer than a hundred polyps, predominantly right-sided, later onset, lifetime colorectal cancer risk closer to seventy percent by age sixty-five. The mechanism is the same Wnt brake failure, but the residual APC function at the ends of the gene tempers the polyp burden. The Ashkenazi I-thirteen-oh-seven-K APC variant is its own category, conferring a roughly two-fold relative risk rather than full FAP, and should not be folded into the FAP surveillance program.

2:19MUTYH-associated polyposis reaches the same destination by a different route, and the inheritance pattern is the giveaway. MUTYH encodes a base-excision-repair enzyme that corrects oxidative G-to-T transversions. When both alleles are knocked out, those transversions accumulate in the APC gene itself, producing somatic APC loss in colonic crypts that looks mechanistically identical to primary APC mutation. The phenotype overlaps attenuated FAP. Ten to a hundred polyps, right-sided predilection, lifetime colorectal cancer risk roughly sixty to eighty percent. The discriminator is that MAP is autosomal recessive. So the family pedigree shows affected siblings without affected parents, because both parents are heterozygous carriers and unaffected. A patient with multiple adenomas who is APC-mutation negative, especially when a sibling is affected and the parents are not, should be tested for biallelic MUTYH. The Y-one-seventy-nine-C and G-three-ninety-six-D alleles dominate in Northern European populations.

3:30The recognition stigmata for FAP each point to a specific tissue and earn their own questions. Congenital hypertrophy of the retinal pigment epithelium, CHRPE, is present from birth in about two thirds of carriers, and four or more lesions or bilateral lesions support the diagnosis. Skull and mandibular osteomas, epidermoid cysts, and supernumerary teeth define the Gardner phenotype, which is FAP with prominent extracolonic features rather than a separate disease. Papillary thyroid cancer, particularly the cribriform-morular variant in young women, drives annual thyroid ultrasound. Hepatoblastoma occurs in young children of FAP carriers. The FAP-type Turcot variant has medulloblastoma, which discriminates it from the Lynch-type Turcot variant, which has high-grade glioma. The brain tumor histology is the discriminator and the boards know it. Desmoid tumors deserve their own line because they become the dominant cause of FAP mortality after the colon is gone. They arise in the abdominal wall, mesentery, or intra-abdominal cavity, often triggered by the colectomy itself, and are managed with sulindac, tamoxifen, cytotoxic chemotherapy, or surgery depending on location and growth velocity. The fact that the colectomy itself is a desmoid trigger factors into when to do the operation.

4:51Now the surgical decision, because this is where the chapter pivots. Classic FAP gets annual colonoscopy from puberty, typically age ten to twelve. Attenuated FAP and MAP start later, age twenty to twenty-five, because the polyps and the cancer arise later. Indications for prophylactic colectomy are polyps larger than ten millimeters, high-grade dysplasia, increasing polyp number from one exam to the next, polyp burden too high to clear endoscopically, or symptoms. The operation choice depends on the rectum. When the rectum carries substantial polyp burden, total proctocolectomy with ileal pouch-anal anastomosis is the operation, because the rectum carries cancer risk that segmental resection cannot eliminate. When the rectum has low polyp burden and can be cleared endoscopically, total colectomy with ileorectal anastomosis is acceptable and is preferred in younger patients for the better functional outcome and lower morbidity. The trade is that the IRA patient needs annual rectal surveillance for life. So the question at the operation is not whether to take the colon. The question is whether to take the rectum, and the rectum decides itself based on its polyp burden.

6:00After the colectomy, the dominant ongoing surveillance burden shifts to the duodenum. Nearly every FAP carrier develops duodenal adenomas over time, predominantly in and around the ampulla, and the Spigelman classification is the framework that turns those adenomas into a surveillance schedule. Spigelman grades four features. Polyp number, polyp size, histology, and dysplasia. Each feature scores one to three points. The total gives a stage from zero to four. The reason the staging matters is that stage four duodenal polyposis carries a fourteen to thirty-six percent lifetime ampullary or duodenal cancer risk. That is high enough that endoscopic management cannot keep pace and prophylactic pancreaticoduodenectomy comes into the conversation. The intervals follow the stage. Stage zero gets EGD every four years. Stage one every three years. Stage two every two years. Stage three every year. Stage four triggers surgical evaluation. Every surveillance EGD includes side-viewing duodenoscopy with explicit ampulla inspection, because the ampulla is the dominant site for malignant transformation. The mechanism behind the schedule is that polyp dwell time before high-grade dysplasia shortens as the stage rises, so the interval has to shorten with it.

7:19Chemoprevention with sulindac or celecoxib reduces polyp number but does not prevent colorectal cancer and does not eliminate the need for surgery. So NSAIDs and COX-two inhibitors are adjuncts, not substitutes. They earn a role in desmoid management and in reducing duodenal polyp burden between scopes, but the colon still has to come out.

7:41So hold the adenomatous polyposis syndromes by gene and by the operation the gene forces. APC drives classic FAP with a hundred to over a thousand adenomas and near-certain colorectal cancer by forty. The operation is total proctocolectomy with ileal pouch when the rectum carries burden, and total colectomy with ileorectal anastomosis when it does not, so the rectum decides the operation. The same gene at its ends drives attenuated FAP, with fewer polyps, later onset, and the same surgical framework with later timing. After the colon comes out, the duodenum becomes the surveillance organ, and Spigelman staging zero through four sets the EGD interval and the prophylactic-pancreaticoduodenectomy conversation. And biallelic MUTYH mimics attenuated FAP by failing to correct the oxidative damage that drives APC loss, with the autosomal recessive pattern of affected siblings and unaffected parents as the pedigree clue.

8:40The next episode takes the hamartomatous polyposis syndromes and hereditary diffuse gastric cancer, where the histology shifts from adenoma to hamartoma and the dominant risk shifts from colorectal cancer to intussusception and to submucosal signet-ring disease: Peutz-Jeghers with STK11, the PTEN spectrum including Cowden, and CDH1-driven gastric cancer where prophylactic total gastrectomy is the standard.

9:05For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode three of five of chapter thirty six, and I'll see you in the next one.