N46: The Role Of Immunohistochemistry (IHC) Testing In The Tumor Spectrum Of The Lynch Syndrome (LS)

M. Marabelli1, P. R. Rafaniello2, M. Calvello1, I. Feroce1, M. Lazzeroni1, C. Ferrari3, A. Chiappa3, M. Barberis2, L. Bertario1, B. Bonanni1

1 – Division of Cancer Prevention & Genetics, European Institute of Oncology, Milan, Italy. 2 – Division of Pathology, European Institute of Oncology, Milan, Italy. 3 – Unit of Innovative Surgical Techniques, European Institute of Oncology, Milan, Italy; University of Milan, Italy.


Aim: To validate the performance of IHC testing of Mismatch Repair (MMR) proteins in patients with LS spectrum cancers.

Method: We analyzed MicroSatellite Instability (MSI) on 461 cancers (378 colorectal, 64 gynecologycal, 19 other sites). IHC analysis of MMR proteins was performed in all samples, irrespective of the MSI status. IHC results were classified as proficient-IHC (normal expression), deficient-IHC (loss of expression), borderline-IHC (“patchy” expression); borderline-IHC cases with MSI were classified as deficient-IHC.

Excluding samples with BRAF mutation or MLH1 promoter hypermetilation (MLH1-Hy), deficient-IHC cases were addressed to germline MMR gene testing.

Results: Fifty-three patients (11.5%) had deficient-IHC: 1 for all proteins, 1 for three proteins, 41 for two proteins (32 MLH1-PMS2, 9 MSH2-MSH6), 10 for 1 protein. IHC deficiency rate was significantly different among sites: 10% colorectal, 23% endometrial/ovarian cancer, 0% in other sites (p<0.001).

Twenty-five samples had BRAF mutation or MLH1-Hy. Twenty-eight patients, including 6 borderline-IHC, were addressed to genetic testing (16 ongoing) and mutations were found in 9 patients (4 in MLH1, 4 in MSH2 and 1 in MSH6), including one borderline-IHC with MSI.

Conclusion: We support the systematic evaluation of MMR proteins in colorectal and gynecological cancers to select patients with LS. MSI could be useful to manage borderline-IHC cases.