A 62-year-old woman from urban India presents with iron-deficiency anaemia (Hb 7.2 g/dL, MCV 68 fL) and occult faecal blood loss. She denies abdominal pain or change in bowel habits. Colonoscopy reveals a polypoid, friable lesion in the caecum. Biopsy confirms adenocarcinoma. CT staging shows no lymph node enlargement or distant metastases. Immunohistochemistry is performed: MLH1 is lost, MSH2 is retained, MSH6 is retained, PMS2 is lost. Which molecular pathway is most likely responsible for this tumour's development?

Explanation

## Molecular Pathology Analysis ### Immunohistochemical Pattern Interpretation The loss of **MLH1 and PMS2** with retention of MSH2 and MSH6 is pathognomonic for **MLH1 deficiency**. This indicates a defect in the mismatch repair (MMR) system. **Key Point:** MLH1 and PMS2 form a heterodimer in the MMR complex. Loss of MLH1 causes secondary loss of PMS2 because PMS2 becomes unstable without its binding partner. ### Microsatellite Instability (MSI) Pathway MMR deficiency leads to: 1. Inability to correct base-pair mismatches during DNA replication 2. Accumulation of mutations in microsatellite repeats (short tandem DNA sequences) 3. High microsatellite instability (MSI-H phenotype) 4. Increased mutation burden and neoantigens ### Clinical Correlations - **Right-sided location (caecum):** MSI-associated cancers preferentially arise in the right colon - **Occult bleeding without obstruction:** Polypoid, friable morphology typical of MSI tumours - **Iron-deficiency anaemia:** Chronic blood loss from a right-sided lesion - **Absence of lymph node involvement:** Better prognosis than CIN-pathway cancers despite advanced stage **High-Yield:** MSI-H colorectal cancers have: - Better prognosis (5-year survival ~65%) despite higher stage at presentation - Improved response to immunotherapy (checkpoint inhibitors) - Association with Lynch syndrome (germline MLH1/MSH2/MSH6/PMS2 mutations) in ~40% of cases **Clinical Pearl:** The loss of MLH1 in a sporadic cancer (not Lynch syndrome) is usually due to **MLH1 promoter methylation** (epigenetic silencing), whereas germline MLH1 mutations cause Lynch syndrome. **Mnemonic: MMR Deficiency → MSI** — **M**ismatch **R**epair loss → **M**icro**S**atellite **I**nstability. ### Why Other Pathways Are Excluded | Pathway | Key Feature | Why Not This Case | |---------|-------------|-------------------| | **CIN (APC/KRAS)** | Aneuploidy, chromosomal loss | No MMR deficiency; normal MLH1/MSH2/MSH6/PMS2 | | **CIMP (BRAF/MLH1 methylation)** | Methylated MLH1 but intact protein | Would show MLH1 *retained* on IHC, not lost | | **Serrated (BRAF/MLH1 methylation)** | Methylated MLH1, BRAF mutation | Same issue: MLH1 protein would be present | [cite:Robbins and Cotran 10e Ch 17; WHO Classification of Tumours of the Digestive System 5e]