Hereditary GI Cancer Syndromes: Hereditary GI Cancer Syndromes: 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. This episode is the adenomatous polyposis syndromes: classic familial adenomatous polyposis, FAP, attenuated FAP, and MUTYH-associated polyposis. The first patient is a young woman whose colonoscopy shows hundreds of polyps. Her case shows why one gene produces hundreds of adenomas, which findings outside the colon support the diagnosis, when the colon comes out and by which operation, and why the duodenum, desmoid tumors, and the thyroid become the work of her care afterward. The second patient is a man with forty adenomas and an affected brother, and his case shows how a recessive syndrome hides in a family.

0:48Here's the patient. A twenty-one-year-old woman has had intermittent rectal bleeding for six months. Colonoscopy shows hundreds of adenomas throughout her colon and rectum, the largest fourteen millimeters, with high-grade dysplasia in one. Neither of her parents has had polyps or colon cancer. An eye exam finds several patches of pigment in both retinas, and she had an extra tooth removed as a child.

1:11She has classic familial adenomatous polyposis. Classic FAP produces a hundred to more than a thousand colorectal adenomas by adolescence, mostly distal at first but covering the whole colon by adulthood, and hundreds of adenomas at twenty-one, with retinal pigment patches and an extra tooth, fits it. The syndrome is autosomal dominant, caused by germline mutation of the APC tumor suppressor on chromosome 5q21, with an incidence of about one in ten thousand. APC mutation removes the brake on Wnt signaling, and when the second copy is lost in colonic crypts, the adenoma-carcinoma sequence starts in hundreds to thousands of crypts at once. That's why one gene produces so many polyps.

1:53Her unaffected parents don't argue against the diagnosis, because roughly a quarter of cases are new mutations in patients without a family history. Germline testing confirms a pathogenic APC variant in her.

2:06Her diagnosis carries a deadline. Untreated, classic FAP carries a colorectal cancer risk approaching one hundred percent by forty, with diagnosis typically in the second or third decade. So her care has three parts: removing the colon before cancer develops, at the right time and by the right operation, and then managing the duodenal, desmoid, and thyroid disease that follows.

2:30Her eyes and teeth supported the diagnosis before the gene test returned. Congenital hypertrophy of the retinal pigment epithelium, CHRPE, is present from birth in about two-thirds of FAP carriers, and four or more lesions, or lesions in both eyes, support the diagnosis, as hers do. Skull and mandibular osteomas, epidermoid cysts, and supernumerary teeth like hers make up the Gardner syndrome picture, which is FAP with prominent features outside the colon rather than a separate disease. In a young patient with many adenomas, the eyes, teeth, and skin can make the diagnosis before the gene result.

3:05Her polyp count also separates her from attenuated FAP. Attenuated FAP comes from mutations at the far five-prime or three-prime ends of APC, and it produces fewer than one hundred polyps, mostly right-sided, appearing later, with a lifetime colorectal cancer risk of about seventy percent by sixty-five. Forty mostly right-sided adenomas at a first colonoscopy in her thirties, with an APC variant at one end of the gene, would have been attenuated FAP. One other APC variant behaves differently again: I1307K, found in Ashkenazi Jewish populations, roughly doubles colorectal cancer risk and is a separate genotype, not a form of classic FAP.

3:47That distinction decides when colonoscopy starts. At-risk and affected patients with classic FAP begin annual colonoscopy at puberty, typically ten to twelve. Patients with attenuated FAP or MUTYH polyposis begin at twenty to twenty-five, because their polyps and cancers arise later.

4:09Surveillance continues until the colon has to come out. Prophylactic colectomy is indicated for any of the following: a polyp larger than ten millimeters, high-grade dysplasia, a polyp count that rises from one exam to the next, a burden too high to clear endoscopically, or symptoms. For classic FAP, that usually means colectomy in the late teens or early twenties. She has a fourteen-millimeter polyp, high-grade dysplasia, a burden far too high to clear, and bleeding, four indications at once, so she needs colectomy now.

4:41Her rectum decides which operation. Total proctocolectomy with ileal pouch-anal anastomosis, a J-pouch, is the operation of choice when the rectum has a substantial polyp burden, because the rectum carries cancer risk that a lesser resection leaves behind. Total colectomy with ileorectal anastomosis is acceptable when the rectum has few polyps and can be cleared endoscopically, with the rectum examined every year afterward, and it's preferred in younger patients when it's feasible, because function is better and morbidity lower. Her rectum is carpeted with adenomas, so she has a proctocolectomy with an ileal pouch. Had her rectum held only a few small polyps, an ileorectal anastomosis with yearly rectal surveillance could have been reasonable.

5:24Medication can't take the place of her operation. Sulindac or celecoxib reduces the number of polyps in FAP, but neither prevents colorectal cancer or removes the need for colectomy, so they're adjuncts, and concerns about cardiovascular safety limit long-term celecoxib.

5:41With her colon gone, her duodenum becomes the main focus of surveillance. Duodenal adenomas develop in nearly all carriers over time, mostly in and around the ampulla. They're graded by the Spigelman classification, which scores four features, polyp number, polyp size, histology, and degree of dysplasia, on a four-point scale each, summing to a stage from zero to four.

6:06Her stage sets her interval. Stage zero is examined every four years, stage one every three, stage two every two, and stage three every year. Stage four carries a fourteen to thirty-six percent lifetime risk of ampullary or duodenal cancer and prompts consideration of prophylactic pancreaticoduodenectomy, because endoscopic treatment can't keep pace with the disease. Every surveillance exam includes a side-viewing duodenoscope to inspect the ampulla, because the ampulla is where malignant change most often begins, and a forward-viewing scope alone can miss it.

6:40Her operation also raises her risk of desmoid tumors. They arise in the abdominal wall, the mesentery, or the abdominal cavity, often after colectomy, and once the colon is gone they're the leading cause of death in FAP other than colorectal cancer. Mesenteric desmoids can encase vessels and bowel. Treatment depends on their site and how fast they grow, and includes nonsteroidal anti-inflammatory drugs, NSAIDs, such as sulindac, tamoxifen, cytotoxic chemotherapy, or surgery. Surveillance is clinical, with cross-sectional imaging when growth is suspected, and because surgery itself triggers desmoids, that risk is weighed in timing the colectomy. A firm, growing mesenteric mass a year after her operation is a desmoid until proven otherwise, not a recurrence of colon cancer, so it's imaged, and sulindac or tamoxifen are considered.

7:33Her thyroid needs watching as a young woman with FAP. Papillary thyroid cancer of the cribriform-morular variant arises mostly in young women with the syndrome, so annual thyroid ultrasound starts at diagnosis, which for her is now.

7:48Her variant also matters for her future children. Hepatoblastoma occurs in young children of FAP carriers, and medulloblastoma, from the FAP form of Turcot syndrome, in older children and adolescents. Because the syndrome is dominant, her children can inherit her variant, so her reproductive counseling includes pre-implantation genetic testing, which lets carrier couples select unaffected embryos during in vitro fertilization, with prenatal diagnosis by chorionic villus sampling or amniocentesis as the alternative once a pregnancy is established.

8:23Now the second patient. A fifty-two-year-old man has his first colonoscopy and has forty adenomas, mostly in the right colon. His brother had colon cancer at forty-eight with many polyps. His parents lived into their eighties without colon cancer. His APC testing is negative.

8:39He most likely has MUTYH-associated polyposis, and his family pattern is the clue. The syndrome is autosomal recessive, caused by mutations in both copies of MUTYH, a base-excision repair gene. MUTYH normally corrects oxidative G-to-T transversions. Without it, those errors accumulate and produce somatic APC mutations, the same mechanism as primary APC loss. The picture overlaps attenuated FAP: typically ten to one hundred adenomas, mostly right-sided, with a lifetime colorectal cancer risk of about sixty to eighty percent.

9:17MUTYH polyposis is considered in anyone with more than ten adenomas whose APC test is negative, or whose family shows affected siblings with unaffected parents. He has both. A negative APC test therefore leads to a panel that includes MUTYH, because his adenomas could come from either gene, and only one of them skips a generation. His panel shows biallelic MUTYH mutations.

9:45His care follows the attenuated FAP approach. Its features outside the colon resemble attenuated FAP, including duodenal polyposis, with a smaller rise in thyroid and other cancer risks, so his duodenum is surveyed as well, and his colonoscopy and surgery decisions follow the same indications.

10:04The two families lack an affected parent for different reasons. Her parents are unaffected because her mutation was new. His are unaffected because his syndrome is recessive, and each of them carries one copy. In both families, the absent history is a reason to test rather than a reason for reassurance, and affected siblings with unaffected parents point to a recessive syndrome.

10:26Here are the traps the boards set in these patients. Excluding FAP because the parents are unaffected. Starting colonoscopy for classic FAP later than puberty. Starting colonoscopy for attenuated FAP or MUTYH polyposis in childhood. Choosing an ileorectal anastomosis when the rectum is heavily involved. Using sulindac or celecoxib instead of colectomy. Skipping the side-viewing scope for the ampulla. Setting the duodenal interval without the Spigelman stage. Calling a mesenteric mass after colectomy a recurrence instead of a desmoid. Forgetting annual thyroid ultrasound. And stopping at a negative APC test when siblings are affected.

11:08So, start to finish. Classic FAP, from APC, is dominant and causes hundreds to thousands of adenomas, and a quarter of cases are new mutations. Colonoscopy runs yearly from puberty, and colectomy is done in the late teens or twenties, as a pouch when the rectum is heavily involved and an ileorectal anastomosis when the rectum is sparse and can be cleared. Attenuated FAP and MUTYH polyposis cause ten to one hundred adenomas and start colonoscopy at twenty to twenty-five, and MUTYH polyposis is recessive, with affected siblings and unaffected parents.

11:44After colectomy, the duodenum and desmoids drive care. The duodenum is examined with a side-viewing scope at intervals set by the Spigelman stage, and surgery is considered at stage four. The thyroid is screened yearly. And chemoprevention doesn't replace colectomy.

11:59Episode four is the hamartomatous syndromes, Peutz-Jeghers and Cowden.

12:05For 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.