A 42-year-old man with a personal history of colorectal cancer (diagnosed at age 38) and a family history of early-onset colorectal and endometrial cancers presents for genetic risk assessment. Which investigation is most appropriate to confirm Lynch syndrome (hereditary nonpolyposis colorectal cancer)?

Question

Accepted Answer

D. Microsatellite instability (MSI) testing and mismatch repair (MMR) gene immunohistochemistry on tumor tissue. ## Investigation of Choice for Lynch Syndrome Confirmation

### Clinical Presentation Clues
- Early-onset colorectal cancer (age 38, <50 years)
- Family history of early-onset colorectal AND endometrial cancer
- No mention of polyposis

These features are classic for Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC).

**Key Point:** MSI testing and MMR immunohistochemistry on the tumor are the first-line investigations to screen for Lynch syndrome. Abnormal results warrant germline MMR gene sequencing for definitive diagnosis.

### Diagnostic Algorithm for Lynch Syndrome

```mermaid
flowchart TD
  A[Early-onset CRC or family history of CRC/EC] --> B[MSI testing + MMR IHC on tumor]
  B --> C{MSI-High or MMR loss?}
  C -->|Yes| D[Germline MMR gene sequencing]
  C -->|No| E[Lynch syndrome unlikely]
  D --> F{Pathogenic mutation found?}
  F -->|Yes| G[Lynch syndrome confirmed]
  F -->|No| H[Consider other syndromes]
```

### Why MSI and MMR IHC?

| Investigation | Mechanism | Sensitivity | Specificity |
|---|---|---|---|
| **MSI testing** | Detects expansion of microsatellite repeats due to MMR deficiency | ~85% in Lynch syndrome | ~90% (some sporadic MSI-H tumors) |
| **MMR IHC** | Detects loss of MLH1, MSH2, MSH6, or PMS2 protein expression | ~90% in Lynch syndrome | ~95% (directly reflects gene function) |
| **Germline MMR sequencing** | Gold standard; identifies pathogenic mutation in MLH1, MSH2, MSH6, or PMS2 | ~95% in Lynch syndrome families | 100% (definitive) |
| **Colonoscopy** | Detects polyps and cancers; does not identify genetic predisposition | N/A | N/A |
| **Serum CEA** | Nonspecific tumor marker; reflects disease burden | Low sensitivity | Low specificity |

**High-Yield:** Lynch syndrome accounts for 2–4% of all colorectal cancers. Germline mutations in MLH1 (~60%), MSH2 (~25%), MSH6 (~7%), or PMS2 (~3%) cause loss of mismatch repair function, leading to microsatellite instability (MSI-H) and early-onset, right-sided CRC with increased risk of endometrial, ovarian, and gastric cancers.

**Clinical Pearl:** The revised Bethesda criteria recommend MSI/MMR testing for:
- CRC diagnosed before age 50
- CRC with MSI-H histology
- CRC in a patient with a Lynch syndrome-related cancer in the family
- CRC in a patient with two Lynch syndrome-related cancers (CRC, endometrial, gastric, ovarian, urothelial, biliary, small bowel)

**Mnemonic: MLH-MSH-PMS** — The four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are mutated in Lynch syndrome; loss of function causes Microsatellite Instability and early-onset cancer.

[cite:Robbins 10e Ch 7]

Answer

A. Serum carcinoembryonic antigen (CEA) and fecal occult blood test

Answer

B. Colonoscopy with polypectomy and histopathology

Answer

C. Whole-genome sequencing of peripheral blood leukocytes

Explanation

Investigation of Choice for Lynch Syndrome Confirmation

Clinical Presentation Clues

Diagnostic Algorithm for Lynch Syndrome

Why MSI and MMR IHC?

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Investigation	Mechanism	Sensitivity	Specificity
MSI testing	Detects expansion of microsatellite repeats due to MMR deficiency	~85% in Lynch syndrome	~90% (some sporadic MSI-H tumors)
MMR IHC	Detects loss of MLH1, MSH2, MSH6, or PMS2 protein expression	~90% in Lynch syndrome	~95% (directly reflects gene function)
Germline MMR sequencing	Gold standard; identifies pathogenic mutation in MLH1, MSH2, MSH6, or PMS2	~95% in Lynch syndrome families	100% (definitive)
Colonoscopy	Detects polyps and cancers; does not identify genetic predisposition	N/A	N/A
Serum CEA	Nonspecific tumor marker; reflects disease burden	Low sensitivity	Low specificity