Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome.

Barrow E, Jagger E, Brierley J, Wallace A, Evans G, Hill J & McMahon R (2010) Histopathology56, 331–344 Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome Aims:  To assess semiquantitative immunohistochemistry as used in the diagnosis of Lynch syndrome. Methods and Results:  Tumour sections from 51 mutation carriers and 17 controls were stained with antibodies against MLH1, MSH2, MSH6 and PMS2. Intensity of immunoreactivity and percentage positivity were recorded on scales of 0–3 and 0–4, respectively. These scores were multiplied for a score of 0–12 per slide. Receiver–operator characteristic (ROC) curves of staining performance for the identification of mutation carriers were evaluated, and optimum cut-offs calculated. The area under the MLH1 ROC curve was 0.981 [95% confidence interval (CI) 0.952, 1.000]. The area under the MSH2 ROC curve was 0.899 (95% CI 0.796, 1.000). For MLH1 staining, a score ≤4 gives a sensitivity of 100.0% (95% CI 84.0, 100.0) and a specificity of 91.5% (95% CI 79.6, 97.6) for identifying MLH1 mutation carriers. For MSH2 staining, a score ≤4 gives a sensitivity of 87.5% (95% CI 61.7, 98.4) and specificity of 88.5% (95% CI 76.5, 95.6) for identifying MSH2 mutation carriers. Conclusions:  This study supports a semiquantitative slide assessment method. Protein expression may occur in the context of known pathogenic mutations, a potential pitfall in the screening process.