Episode two takes Lynch syndrome, the syndrome the diagnostic framework most often surfaces, and anchors everything to one idea: lifetime cancer risk varies sharply by gene, and that gene-specific risk sets each surveillance interval to the dwell time of preinvasive disease in that organ. MLH1 and MSH2 carriers drive high colorectal and endometrial risk, while MSH6 flips uterine cancer above colorectal and MSH2 concentrates the upper urothelial risk. The reasoning extends to why the colonoscopy interval is short, why the cancer operation is extended, why endometrial surveillance is a bridge to hysterectomy, and why aspirin and pembrolizumab both trace back to the mutational burden the syndrome generates.

Topics covered

Mismatch-repair genetics and the MSI phenotype
Classic Lynch tumor histology and late-presenting carriers
Amsterdam and Bethesda criteria
Gene-specific lifetime cancer risk
Colorectal surveillance and extended colectomy
Endometrial surveillance as a bridge to hysterectomy
Urothelial, gastric, and pancreatic programs
Aspirin chemoprevention and checkpoint inhibition
Lynch variants and Syndrome X

Key decisions

Run colonoscopy every one to two years starting age twenty to twenty-five, or five years before the youngest affected relative, because Lynch adenomas progress faster than sporadic ones and a three-year interval is too long.
When a Lynch carrier develops colorectal cancer, particularly an MLH1 or MSH2 carrier, perform extended colectomy with ileorectal anastomosis rather than segmental resection, because metachronous risk in the residual colon is high, then surveil the rectum annually.
Treat MSH6 as the exception where uterine cancer outranks colorectal, discuss risk-reducing hysterectomy earlier, and offer total hysterectomy with bilateral salpingo-oophorectomy after childbearing as a bridge target rather than relying on surveillance permanently.
Gate pancreatic surveillance on family history, enrolling only carriers with a first-degree or second-degree relative with pancreatic cancer in annual EUS or MRI at age fifty, because absolute Lynch pancreatic risk near six percent sits below the surveillance threshold.
Offer daily aspirin for chemoprevention across a tolerable dose range, counseling that the colorectal benefit emerges only beyond five years and the per-protocol effect exceeds the intention-to-treat estimate.
Give pembrolizumab first-line for advanced MSI-high or mismatch-repair-deficient Lynch cancers before chemotherapy, because the high mutational burden generates the neoantigens checkpoint inhibition needs.

For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com.

Questions or feedback: hello@boardpearls.com.

(00:00) - Mismatch-repair genetics and the MSI phenotype
(01:20) - Classic histology and late-presenting carriers
(01:54) - Amsterdam and Bethesda criteria
(02:28) - Gene-specific lifetime cancer risk
(03:58) - Colorectal surveillance and extended colectomy
(04:43) - Endometrial surveillance as a bridge to surgery
(05:40) - Urothelial, gastric, and pancreatic programs
(08:06) - Aspirin and checkpoint inhibition
(09:38) - The Lynch variants and Syndrome X