Lynch syndrome (HNPCC)
Overview
Lynch syndrome (HNPCC) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in DNA mismatch repair (MMR) genes, accounting for 3-5% of all colorectal cancers.
Pathophysiology
•Germline mutation in MMR genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) - loss of DNA proofreading causes microsatellite instability (MSI-high)
•Two-hit hypothesis: inherited first hit + somatic second hit drives accelerated tumorigenesis, hence younger age at onset (~45 years vs 65-70 sporadic)
•MSI-high tumours have strong tumour-infiltrating lymphocyte response - paradoxically better stage-for-stage prognosis and dramatic response to immune checkpoint inhibitors
Presentation
•Colorectal cancer typically right-sided (proximal to splenic flexure) - presents with iron deficiency anaemia and fatigue rather than rectal bleeding
•Mean age at diagnosis ~45 years
•Extracolonic cancers: endometrial (most common extracolonic), ovarian, gastric, small bowel, urothelial, brain
•Muir-Torre variant: Lynch-associated visceral cancers + sebaceous skin tumours/keratoacanthomas
•Turcot syndrome (Lynch variant): Lynch syndrome + glioblastoma
Investigations
🥇 First-line
•Immunohistochemistry (IHC) on tumour - tests MLH1, MSH2, MSH6, PMS2 expression; loss identifies likely affected gene
•Microsatellite instability (MSI) testing - PCR-based; MSI-high supports MMR deficiency
•Critical step: MLH1 promoter methylation testing - if MLH1 lost on IHC, methylation = sporadic (not Lynch); no germline mutation present
🏆 Gold standard
•Germline genetic testing (blood) for MMR gene mutation - confirms Lynch syndrome and enables cascade family testing
•Full colonoscopy (not flexible sigmoidoscopy) - Lynch tumours are predominantly right-sided
Diagnostic criteria
Amsterdam II criteria vs Bethesda guidelines
| Feature | Amsterdam II | Bethesda guidelines |
|---|---|---|
| Purpose | Identify high-risk families (research) | Identify tumours for MSI/IHC testing (clinical) |
| Sensitivity | Misses ~30% of Lynch cases - too stringent | More sensitive for clinical practice |
| Key rule | 3-2-1 rule: ≥3 relatives with Lynch-associated cancer, ≥2 generations, ≥1 diagnosed <50 yrs; 1 must be first-degree relative of the other two; FAP excluded | CRC <50 yrs; synchronous/metachronous Lynch tumours; MSI-high histology; first-degree relative with Lynch cancer <50 yrs |
Management
•Genetic counselling and cascade testing of first-degree relatives
•Surgical (colorectal cancer): Subtotal colectomy with ileorectal anastomosis preferred over segmental resection - metachronous cancer risk up to 50% at 10 years after segmental resection
•Adjuvant chemotherapy: 5-fluorouracil-based regimens; note MSI-high tumours have reduced benefit from 5-fluorouracil monotherapy - use combined regimens (e.g. FOLFOX) for stage III
•Advanced/metastatic MSI-high disease: pembrolizumab, nivolumab (immune checkpoint inhibitors) - first-line for unresectable MSI-high metastatic colorectal cancer
•Chemoprevention: aspirin - CaPP2 trial: 600 mg/day for ≥2 years reduced Lynch-associated cancer incidence by ~50%; CaPP3 trial investigating lower doses (100-300 mg/day)
•Gynaecological prevention: Prophylactic hysterectomy + bilateral salpingo-oophorectomy (BSO) for women who have completed their family
Surveillance
•Colonoscopy - every 1-2 years from age 25 (or 5 years before youngest family diagnosis); annual for MLH1/MSH2 carriers (higher penetrance)
•Endometrial sampling or transvaginal ultrasound - annually from age 25-35 in female carriers
•Upper GI endoscopy (OGD) - every 3-5 years if family history of gastric cancer or East Asian carrier
•Annual urinalysis - particularly MSH2 carriers (highest urothelial risk)
•Colonoscopic surveillance reduces colorectal cancer mortality in Lynch carriers by ~65%
Key complications
•Colorectal cancer - lifetime risk 40-80% depending on gene
•Metachronous colorectal cancer - up to 50% at 10 years after segmental resection
•Endometrial cancer - second most common Lynch malignancy; may be the index cancer in women