1.15 Lynch Syndrome & Polyposis Syndromes
Key Takeaways
- Lynch syndrome is autosomal dominant mismatch-repair (MMR) deficiency caused by MLH1, MSH2, MSH6, PMS2, or EPCAM deletion leading to MSH2 loss—distinct from polyposis-predominant syndromes
- Tumor testing with MMR immunohistochemistry and/or MSI informs who needs germline Lynch evaluation; MLH1-absent tumors often need BRAF/MLH1 methylation workup for sporadic epigenetics
- Amsterdam and Bethesda criteria are historical/clinical selection tools; they do not replace modern tumor testing and multi-gene germline strategies when indicated
- Lynch extracolonic risks include endometrium, ovary, stomach, urothelial tract, small bowel, and others in a gene-specific pattern
- FAP (APC, adenomatous polyposis) differs from MAP (biallelic MUTYH, recessive) and from Lynch (few polyps, MMR-driven cancers)—polyposis burden and inheritance separate these entities
1.15 Lynch Syndrome & Polyposis Syndromes
Quick Answer: Lynch = dominant MMR gene defect (MLH1, MSH2, MSH6, PMS2, EPCAM), few polyps, MSI-high/MMR-deficient tumors, extracolonic risks. FAP = APC adenomatous polyposis (dominant). MAP = biallelic MUTYH (recessive). Use IHC/MSI ± germline panels; do not confuse polyposis count with Lynch.
Colorectal hereditary cancer questions hinge on one skill: separate Lynch from polyposis syndromes using phenotype (polyp number), inheritance, and molecular pathway (MMR vs WNT/APC vs base-excision repair).
Lynch Syndrome: Features and Genes
Lynch syndrome (formerly HNPCC) is the most common inherited colorectal cancer predisposition syndrome. It is autosomal dominant and caused by pathogenic variants in DNA mismatch repair (MMR) genes, or by EPCAM deletions that epigenetically silence MSH2.
| Gene | Pairing / notes | Clinical flavor (high-level) |
|---|---|---|
| MLH1 | Heterodimerizes with PMS2 | Often higher colorectal penetrance among Lynch genes |
| MSH2 | Heterodimerizes with MSH6; EPCAM deletions → MSH2 loss | Classic Lynch; extracolonic spectrum prominent |
| MSH6 | With MSH2 | Sometimes later onset / attenuated colorectal pattern relative to MLH1/MSH2 |
| PMS2 | With MLH1 | Generally lower penetrance on average; still actionable |
| EPCAM | 3′ deletions transcriptionally silence MSH2 | Counsel as MSH2-related Lynch risk |
Natural History and Tumor Spectrum
Lynch-associated colorectal cancers tend to be right-sided, may show mucinous or medullary histology, tumor-infiltrating lymphocytes, and microsatellite instability-high (MSI-H) / MMR-deficient phenotypes. Lifetime colorectal cancer risk is substantially elevated versus the general population, with gene-specific differences emphasized in NCCN Genetic/Familial High-Risk Assessment: Colorectal guidelines.
Extracolonic cancers (gene-weighted) commonly discussed in counseling:
| Site | Counseling relevance |
|---|---|
| Endometrium | Often the sentinel cancer in women; gynecologic risk-reduction discussions |
| Ovary | Elevated in Lynch—distinct management from BRCA RRSO scripts |
| Stomach / small bowel | Upper GI surveillance considerations in selected patients |
| Urothelial (renal pelvis/ureter) | Especially with MSH2 historically emphasized |
| Other | Pancreas, brain (rare), sebaceous neoplasms (Muir-Torre spectrum), prostate discussions vary by gene/evidence |
Muir-Torre refers to Lynch with sebaceous skin tumors; Turcot historically linked brain tumors with colorectal predisposition (MMR or APC contexts)—know the association labels without over-calling rare phenotypes.
MSI, IHC, and Diagnostic Strategy
Universal or near-universal tumor screening on colorectal (and often endometrial) cancers uses:
- MMR immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2 protein presence/absence
- and/or MSI testing (PCR/NGS) classifying MSI-H vs MSS
| IHC pattern (simplified) | Interpretation pathway |
|---|---|
| Loss of MLH1 ± PMS2 | Consider sporadic MLH1 promoter methylation (± BRAF V600E in CRC) before or alongside germline testing |
| Loss of MSH2 ± MSH6 | Strongly consider germline MSH2/EPCAM (and related) evaluation |
| Isolated MSH6 or PMS2 loss | Point toward those genes; technical pitfalls exist |
| All proteins present / MSS | Lynch less likely for that tumor, but clinical judgment may still warrant germline panel if pedigree is striking |
Constitutional MMR deficiency (CMMRD) is the rare biallelic childhood-onset phenotype—different counseling from heterozygous Lynch.
Amsterdam and Bethesda Criteria (Conceptual Use)
| Tool | Role on today’s exam |
|---|---|
| Amsterdam I/II | Family-history rules of thumb (multiple CRC/Lynch cancers across generations, young ages)—sensitive for classic families, miss many real Lynch cases |
| Bethesda (revised) | Flags tumors for MSI/IHC testing historically |
| Modern practice | Tumor testing pathways + clinical criteria + multi-gene germline panels; criteria are aids, not gatekeepers that “rule out” Lynch |
Exam tip: a vignette meeting Amsterdam supports suspicion, but normal IHC does not always end evaluation if clinical concern remains, and abnormal IHC needs methylation/BRAF triage when MLH1 is lost.
Surveillance and Risk Reduction (Lynch)
NCCN-style colorectal management for Lynch typically includes earlier and more frequent colonoscopy than average-risk schedules (often beginning in the 20s–early 30s depending on gene/family history, with shortened intervals). Additional considerations:
- Endometrial symptom awareness ± screening approaches; discussion of hysterectomy ± BSO after childbearing for risk reduction in selected women
- Aspirin chemoprevention discussions appear in evidence/guideline conversations—counsel as evolving/shared decision-making with clinicians
- Immunotherapy relevance for MSI-H metastatic disease is an oncology management concept analogous to “results change treatment”
Polyposis Syndromes vs Lynch
| Syndrome | Gene / inheritance | Polyp phenotype | Key contrast with Lynch |
|---|---|---|---|
| Familial adenomatous polyposis (FAP) | APC, AD | Hundreds to thousands of colorectal adenomas (classic); attenuated FAP (AFAP) has fewer | Polyposis-driven; CHRPE, desmoids, duodenal polyps, thyroid; childhood screening for classic FAP |
| MUTYH-associated polyposis (MAP) | Biallelic MUTYH, AR | Oligopolyposis to polyposis overlapping AFAP counts | Recessive—parents usually unaffected; siblings at 25% risk; partners may need carrier testing |
| Lynch syndrome | MMR genes / EPCAM, AD | Usually few or no florid polyposis | Cancer from MMR deficiency, not carpeting adenomas |
| Other | NTHL1, polymerase proofreading (POLE/POLD1), SPS, etc. | Variable | Panel testing when phenotype unclear |
FAP Management Anchors
Classic FAP often leads to discussion of colectomy timing in adolescence/young adulthood, lifelong endoscopic surveillance of remaining GI tract, and extracolonic surveillance (duodenum, thyroid, desmoid risk). Attenuated FAP may present later with fewer polyps—easily confused with MAP or Lynch if molecular testing is skipped.
MAP Counseling Anchors
Explain autosomal recessive inheritance clearly. Unaffected parents who are heterozygous carriers do not have the MAP phenotype themselves (heterozygous MUTYH modest risk nuances exist in literature but are not MAP). After biallelic identification, offer testing to siblings and discuss partner carrier screening for reproductive risk of affected children.
Diagnostic Strategy Algorithm (Board-Level)
- Quantify polyp burden and ages of adenomas/cancers.
- If polyposis → prioritize APC / MUTYH (and related polyposis genes) on a panel.
- If Lynch-like cancers with few polyps → tumor IHC/MSI ± germline MMR panel.
- Integrate pedigree (dominant vs possibly recessive).
- Assign surveillance using current NCCN colorectal gene-specific tables.
Confusing Lynch with FAP is a classic miss: polyp count + molecular pathway prevent that error.
A colorectal tumor shows loss of MSH2 and MSH6 on immunohistochemistry, with retained MLH1 and PMS2. Which germline evaluation is most appropriate to prioritize?
Which feature best distinguishes classic FAP from Lynch syndrome?
How should Amsterdam criteria be used in contemporary Lynch syndrome evaluation?
A patient has 40–50 colorectal adenomas in mid-adulthood, no germline APC pathogenic variant, and unaffected parents. Which syndrome is highest on the differential?