What are the implications and treatment options for a patient under 50 with a tumor showing loss of MLH1 (MutL homolog 1) and PMS2 (postmeiotic segregation 2) expression, but presence of MSH2 (MutS homolog 2) and MSH6 (MutS homolog 6) expression, suggesting deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H)?

Deficient Mismatch Repair with MLH1/PMS2 Loss in a Patient Under 50

For a patient under 50 with tumor showing loss of MLH1 and PMS2 expression (with retained MSH2 and MSH6), you must immediately pursue MLH1 promoter hypermethylation testing and BRAF V600E mutation analysis to distinguish Lynch syndrome from sporadic cancer, as this distinction fundamentally changes management—Lynch syndrome requires germline genetic testing and lifelong multi-organ surveillance, while sporadic cases do not. 1

Immediate Diagnostic Algorithm

The loss of MLH1 and PMS2 together is the expected pattern because MLH1 and PMS2 function as an obligatory heterodimer complex—when MLH1 is lost, PMS2 protein becomes unstable and degrades, resulting in concurrent loss of both proteins 1, 2. This pattern accounts for approximately 93% of dMMR tumors 1.

Critical Next Steps to Distinguish Lynch Syndrome from Sporadic Cancer:

1. BRAF V600E mutation testing - The BRAF V600E point mutation is found in most tumors with acquired MLH1 promoter methylation and is extremely rare in Lynch syndrome colorectal cancers 1

2. MLH1 promoter hypermethylation testing - Demonstrating promoter hypermethylation supports a somatic (non-inherited) event, as hypermethylation of MLH1 is rare as a second "hit" in tumors with germline mutations 1

3. If BRAF is wild-type AND no MLH1 hypermethylation is present - Proceed directly to germline genetic testing for MLH1 mutations 1

Age-Specific Considerations

The patient's age under 50 is a major red flag for Lynch syndrome. Colorectal cancer diagnosed before age 50 meets the revised Bethesda guidelines and significantly increases the probability of hereditary disease 1. The National Comprehensive Cancer Network specifically recommends testing for MLH1 deficiency in patients with colorectal cancer diagnosed before age 50, as they are more likely to have Lynch syndrome 2.

Treatment Implications of dMMR/MSI-H Status

Immunotherapy Eligibility:

This tumor's dMMR status makes the patient eligible for immune checkpoint inhibitor therapy with pembrolizumab, which received FDA approval for unresectable or metastatic MSI-H or dMMR solid tumors. 3

• Pembrolizumab demonstrated an objective response rate of 39.6% (95% CI 31.7% to 47.9%) with median duration of response not reached in the registrational trials 1
• The VENTANA MMR IHC assay is the FDA-approved companion diagnostic for determining MMR status for treatment with pembrolizumab 1
• dMMR is generally equivalent to MSI-H status 1

Chemotherapy Considerations:

For stage II disease, the benefit of adjuvant chemotherapy in dMMR tumors is uncertain and may be limited. MSI-H is associated with a better prognosis than microsatellite-stable tumors, with improved disease-free survival and overall survival 4. The American Joint Committee on Cancer considers MSI-H a favorable prognostic factor 4.

Surveillance Requirements if Lynch Syndrome is Confirmed

If germline MLH1 mutation is identified, the patient requires intensive lifelong surveillance:

• Colonoscopy every 1-2 years starting at age 20-25 years (or 2-5 years before youngest family diagnosis) 1
• Colonoscopic surveillance has demonstrated a 72% decrease in mortality from colorectal cancer in Lynch syndrome patients 1
• Endometrial cancer surveillance - MLH1 carriers have a 30-51% lifetime risk of endometrial cancer 1
• Gastric cancer surveillance - Up to 18% lifetime risk 1
• Urinary tract surveillance - 2-20% lifetime risk 1
• Ovarian cancer surveillance - 4-15% lifetime risk 1

Family Implications

If Lynch syndrome is confirmed, first-degree relatives have a 50% chance of carrying the same mutation and require genetic counseling and testing. 1 Family members who test positive need the same intensive surveillance protocols 1.

Common Pitfalls to Avoid

Do not assume sporadic disease based solely on age. While approximately 10% of colorectal cancers display loss of MLH1 expression due to somatic hypermethylation (often with BRAF V600E mutation), this patient's young age makes Lynch syndrome more likely 1.

Do not skip BRAF and methylation testing before proceeding to germline testing. This sequential approach prevents unnecessary genetic testing and family anxiety in sporadic cases 1.

Recognize that isolated loss of PMS2 alone (without MLH1 loss) would suggest a different pattern—germline PMS2 mutation—and would require PMS2 genetic testing instead 1.