A 48-year-old man from Bangalore undergoes routine colonoscopy and is found to have a 2 cm sessile polyp in the sigmoid colon. Histopathology reveals tubular adenoma with high-grade dysplasia but no invasion through the muscularis propria. Immunohistochemistry shows loss of MLH1 and PMS2 expression. What is the most appropriate next step in management?

Question

Accepted Answer

A. Perform germline MLH1 mutation testing and refer for genetic counseling. ## Lynch Syndrome and MLH1 Loss

**Key Point:** Loss of MLH1 and PMS2 expression on immunohistochemistry in a colorectal adenoma is highly suggestive of Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC). This finding mandates germline genetic testing and genetic counseling before any surgical intervention.

## Diagnostic and Management Algorithm for MLH1/PMS2 Loss

```mermaid
flowchart TD
  A[Colorectal adenoma with MLH1/PMS2 loss] --> B[Suspect Lynch syndrome]
  B --> C[Germline MLH1 mutation testing]
  C --> D{Mutation confirmed?}
  D -->|Yes| E[Genetic counseling]
  E --> F[Family screening]
  E --> G[Surveillance protocol]
  D -->|No| H[Sporadic MSI-H tumor]
  H --> I[Standard management]
  G --> J[Colonoscopy every 1-2 years]
  G --> K[Consider prophylactic hysterectomy/oophorectomy]
```

## Why Germline Testing and Genetic Counseling is Correct

**High-Yield:** Loss of MLH1 and PMS2 expression indicates mismatch repair deficiency (MMR-d), which is the hallmark of Lynch syndrome. The immediate next step is germline MLH1 mutation testing followed by genetic counseling. This must precede surgical decision-making.

**Clinical Pearl:** Lynch syndrome accounts for 2–4% of all colorectal cancers and confers a 70–80% lifetime risk of colorectal cancer. Affected individuals also have increased risks of endometrial, ovarian, gastric, and urinary tract cancers. Family members must be identified and counseled.

**Mnemonic: Lynch Syndrome Features (HNPCC)** — Hereditary, Nonpolyposis, Colorectal, Cancer; Early onset (mean age 45), Multiple family members, Extracolonic cancers

**Warning:** Do not confuse MLH1 loss (Lynch syndrome) with sporadic MSI-H tumors (e.g., due to MLH1 promoter methylation in elderly patients). Germline testing is essential to distinguish them.

## Why Each Distractor Misses the Mark

### Immediate Total Colectomy
While Lynch syndrome carriers do have increased colorectal cancer risk and may eventually require colectomy, this decision must be made AFTER germline testing confirms the diagnosis and genetic counseling is completed. Performing colectomy before confirming Lynch syndrome is premature and may be unnecessary if the MMR loss is sporadic.

### Endoscopic Mucosal Resection Alone
EMR of the adenoma is technically feasible for a sessile polyp with high-grade dysplasia, but this approach ignores the underlying diagnosis of Lynch syndrome. The adenoma is a marker of a systemic genetic condition requiring family screening and lifelong surveillance—not just local polyp removal.

### Annual Surveillance and Aspirin
While surveillance colonoscopy is part of Lynch syndrome management, it should be every 1–2 years (not annually) and only AFTER germline testing and genetic counseling. Aspirin for chemoprevention in Lynch syndrome is not standard of care and would be premature without first confirming the diagnosis.

Answer

B. Perform endoscopic mucosal resection of the polyp and repeat colonoscopy in 3 months

Answer

C. Proceed with immediate total colectomy due to high risk of synchronous malignancy

Answer

D. Start surveillance colonoscopy every 1 year and prescribe aspirin for chemoprevention

Explanation

Lynch Syndrome and MLH1 Loss

Diagnostic and Management Algorithm for MLH1/PMS2 Loss

Why Germline Testing and Genetic Counseling is Correct

Why Each Distractor Misses the Mark

Immediate Total Colectomy

Endoscopic Mucosal Resection Alone

Annual Surveillance and Aspirin

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