Hereditary GI Cancer Syndromes: Hereditary GI Cancer Syndromes: Lynch Syndrome

0:00Welcome to Board Pearls. This is episode two of five of the Hereditary GI Cancer Syndromes chapter, in the Special Populations and Acute or Supportive Care module. This episode is Lynch syndrome, organ by organ and gene by gene. The patient is the son of the woman from episode one, and he has just tested positive for her MSH2 variant. His case shows why mismatch repair tumors behave the way they do, how his gene sets his risk in each organ, when his colonoscopy starts and how often it's repeated, which other organs need surveillance and why his gene matters for his urinary tract, what aspirin does for him, and how a Lynch colon cancer is treated differently. Along the way, other genes and other relatives show how the program changes.

0:41Here's the patient. A twenty-four-year-old man is the son of the woman with endometrial cancer from episode one. Through cascade testing, he's found to carry her pathogenic MSH2 variant. He's well, has never had a colonoscopy, and has no symptoms. His mother's family history, once explored, includes a maternal uncle who had colon cancer at forty-one.

1:03He has Lynch syndrome, found before any cancer, and every part of his program follows from what the syndrome breaks. Lynch syndrome is autosomal dominant, caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, or by three-prime deletions in EPCAM that silence MSH2. MLH1 and MSH2 together account for more than ninety percent of confirmed cases. Mismatch repair is the cell's spell-check after DNA replication, and it matters most at microsatellites, short repeated sequences where copying errors are common. Without it, tumors become microsatellite unstable and accumulate a high mutational burden. That burden is why high microsatellite instability, MSI-high, tumors, whether from Lynch or sporadic, respond to checkpoint inhibitors.

1:59A Lynch colorectal cancer has a typical appearance. It's right-sided and mucinous, often with tumor-infiltrating lymphocytes and Crohn-like lymphoid aggregates around it, and about half arise before fifty. A substantial minority of carriers, particularly MSH6 and PMS2 carriers, have their first cancer in their fifties or sixties, which is one reason screening by pedigree alone misses them.

2:24The pedigree criteria explain why his family was found through his mother's tumor rather than their history. The Amsterdam two criteria require three relatives with verified Lynch-spectrum cancers, colorectal, endometrial, upper urinary tract, or small bowel, across two or more generations, with at least one diagnosed before fifty and familial adenomatous polyposis, FAP, excluded. The revised Bethesda criteria select patients whose tumors should be tested. Both now sit behind universal tumor immunohistochemistry, IHC, but they still help recognize families. His family has two known affected relatives, his mother and his uncle, which falls short of the Amsterdam requirement of three. Universal testing of his mother's tumor found what the pedigree couldn't.

3:14His gene sets his risk, organ by organ, and each surveillance interval is matched to how long precancerous disease stays detectable in that organ. MLH1, MSH2, and EPCAM carry the highest colorectal risk, forty-six to sixty-one percent over a lifetime, with a mean age at diagnosis of forty-four, and an endometrial risk of thirty-four to fifty-four percent. MSH6 carries a lower colorectal risk, about ten to forty-four percent, and it's the only Lynch gene in which uterine cancer outranks colorectal cancer as the main lifetime risk, so MSH6 programs put more weight on gynecologic surveillance and raise risk-reducing hysterectomy earlier. PMS2 is the most attenuated, with substantial colorectal risk mainly in carriers with a strong family history. As an MSH2 carrier, he's in the highest-risk group for his colon.

4:12His colonoscopy schedule follows a rule. Colonoscopy runs every one to two years, starting at twenty to twenty-five or five years before the youngest affected relative was diagnosed, whichever is younger. He's twenty-four, inside the twenty to twenty-five window. His uncle was diagnosed at forty-one, and five years before that is thirty-six, which is later. So the younger age applies, and he starts now, repeating every one to two years. The average-risk interval of ten years would be far too long, because Lynch adenomas progress to cancer quickly.

4:45If he does develop colon cancer, the operation is larger than usual. A Lynch colorectal cancer, particularly with MLH1 or MSH2, is treated in most cases with an extended colectomy, a subtotal colectomy with ileorectal anastomosis, rather than a segmental resection, because the risk of a second, metachronous cancer in the remaining colon is high. His rectum is then examined every year. Had his uncle's variant been known when his cancer was found, an extended colectomy would have been the usual operation for him too.

5:17An advanced cancer would be treated with immunotherapy. For advanced MSI-high or mismatch repair-deficient cancers, pembrolizumab is first-line, based on a randomized trial in colorectal cancer. The high mutational burden produces abundant neoantigens, and when the programmed death one, PD-1, brake is released, they drive a strong T-cell response against the tumor.

5:40His gene matters most outside the colon in his urinary tract. Upper urinary tract cancer of the renal pelvis and ureter, distinct from bladder cancer, carries a lifetime risk of four to twelve percent concentrated in MSH2 carriers, because the rapidly renewing lining of the renal pelvis and ureter behaves like colonic crypts when mismatch repair fails. So he has annual urinalysis with cytology from thirty to thirty-five, and positive cytology leads to a computed tomography, CT, urogram and ureteroscopy.

6:11His stomach is the next organ at risk. Gastric cancer surveillance is most worthwhile in MLH1 and MSH2 carriers with Asian ancestry or a family history of gastric cancer, with a baseline upper endoscopy and random gastric biopsies at thirty to forty, closer to forty for MSH6 carriers, then every two to four years. Testing for and eradicating Helicobacter pylori is part of the program, because Lynch gastric cancers arise on a background of chronic atrophic gastritis with intestinal metaplasia, and H. pylori is the main driver of that inflammation. He has no Asian ancestry and no family history of gastric cancer, so his yield from endoscopy is lower, but a baseline upper endoscopy with H. pylori testing in his thirties is still considered. Small bowel cancer is raised in relative terms but rare in absolute terms, so capsule endoscopy or CT enterography is reserved for symptoms.

7:10His pancreas is watched only if his family history changes. Lynch alone carries a lifetime pancreatic cancer risk of about six percent, below the threshold at which surveillance helps more than it harms. Only carriers with at least one first- or second-degree relative with pancreatic cancer enroll in annual endoscopic ultrasound, EUS, or pancreatic-protocol magnetic resonance imaging, MRI, from fifty, or ten years before the earliest case in the family. The same absolute-risk principle keeps BRCA, ATM, and PALB2 carriers without that family history out of pancreatic surveillance, as episode five explains. No one in his family has had pancreatic cancer, so he isn't enrolled unless that changes.

7:56Two more organs complete his program. Prostate screening with a digital rectal exam and prostate-specific antigen, PSA, starts at forty. And a dermatology exam every one to two years looks for the sebaceous tumors of Muir-Torre syndrome, the form of Lynch syndrome with skin involvement. Muir-Torre is Lynch with sebaceous neoplasms: sebaceous adenoma, sebaceoma, sebaceous carcinoma, or keratoacanthoma. The sebaceous tumors are themselves microsatellite unstable, and finding one in a family suggestive of Lynch is an indication for germline testing. A sebaceous adenoma removed from his skin would be part of his syndrome, which is the reason for his skin checks.

8:35He's also offered aspirin, and the reason it's standard took years to emerge. In a randomized trial of aspirin, six hundred milligrams daily, against placebo for at least two years in Lynch carriers, the original analysis showed no colorectal benefit. Follow-up at ten years, and registry follow-up at twenty years, showed a substantial reduction in colorectal cancer, appearing only after five years. The interpretation is that aspirin acts on the early biology of adenomas, which takes years to show up as fewer cancers. The best dose is still being studied, and current practice accepts daily aspirin anywhere from eighty-one to six hundred milligrams. For him, it's a long-term decision, because the benefit takes years to appear.

9:18His mother, and any sister who carries the variant, need a gynecologic program. Endometrial cancer is the most common Lynch cancer outside the colon and often the first cancer in a female carrier, as it was for his mother. Surveillance is endometrial biopsy plus transvaginal ultrasound every one to two years from thirty to thirty-five, with cancer antigen one twenty-five, CA-125, added in postmenopausal carriers, and the same annual ultrasound, with CA-125 after menopause, serves as the ovarian screen.

9:52Risk-reducing total hysterectomy with bilateral salpingo-oophorectomy is offered once childbearing is complete, because in a study of prophylactic surgery, no carrier who had the operation developed endometrial or ovarian cancer, while a substantial share of those under surveillance did. Sampling and ultrasound are a bridge to surgery, not a permanent substitute. A twenty-eight-year-old sister who also tested positive would start colonoscopy now and endometrial sampling with ultrasound from thirty to thirty-five, with surgery discussed once she'd finished having children. Had the family variant been in MSH6, her uterus rather than her colon would carry her greatest lifetime risk, and that conversation would come earlier.

10:35Two less common forms explain other presentations in Lynch families. Turcot syndrome of the Lynch type is Lynch with high-grade glioma, glioblastoma or astrocytoma, and it's told apart from the FAP form of Turcot, which brings medulloblastoma, by the brain tumor histology. Constitutional mismatch repair deficiency is the recessive form, in which both copies of MLH1, MSH2, MSH6, or PMS2 are mutated. Affected children develop café-au-lait macules that mimic neurofibromatosis type one, and a devastating cancer burden: colorectal cancer in more than eighty percent over a lifetime, brain tumors in seventy percent by age nine, and blood cancers. Their surveillance begins in infancy, with a complete blood count every six months from age one, brain MRI every six months from two, colonoscopy every year from six, upper endoscopy and capsule endoscopy every year from eight, and pelvic and urine screening from twenty.

11:32One family pattern looks like Lynch and isn't. Familial colon cancer syndrome X is a family that meets the Amsterdam I criteria but whose tumors are microsatellite stable with intact mismatch repair proteins. Its colorectal relative risk is about two point three, with no added risk outside the colon, and colonoscopy runs every three to five years starting ten years before the youngest affected relative. If his uncle's tumor had been microsatellite stable with intact proteins and no variant had been found, his family would fit that pattern, and his program would shrink to colonoscopy alone.

12:07Here are the traps the boards set in these patients. Starting colonoscopy at forty-five, or repeating it every ten years, in a Lynch carrier. Forgetting the rule of five years before the youngest affected relative. Doing a segmental resection for an MLH1 or MSH2 cancer. Forgetting urinalysis with cytology in an MSH2 carrier. Skipping H. pylori eradication. Enrolling every Lynch carrier in pancreatic surveillance. Forgetting that MSH6 puts the uterus first. Treating endometrial sampling as a substitute for surgery. Abandoning aspirin because the early results looked negative. And confusing familial colon cancer syndrome X with Lynch syndrome.

12:50So, start to finish. Lynch surveillance is tailored by gene. Colonoscopy runs every one to two years from twenty to twenty-five, or five years before the youngest affected relative, whichever is younger, and colorectal risk appears later in MSH6 and PMS2 carriers. Women are offered hysterectomy with salpingo-oophorectomy after childbearing, with endometrial sampling and ultrasound as a bridge, and in MSH6 carriers endometrial risk exceeds colorectal risk.

13:19The rest of the program adds upper endoscopy with H. pylori eradication from thirty to forty, annual urinalysis with cytology for MSH2 carriers, prostate screening from forty, skin exams for Muir-Torre tumors, and pancreatic surveillance only when a relative has had pancreatic cancer. Aspirin is offered, because its colorectal benefit appears with long-term use. A Lynch colon cancer is treated with extended colectomy, and an advanced MSI-high cancer with pembrolizumab.

13:50Episode three is familial adenomatous polyposis and MUTYH-associated polyposis.

13:58For 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 two of five of chapter thirty-six, and I'll see you in the next one.