Discordance between MSI-H Histology and DNA Mismatch Repair (MMR) Protein Immunohistochemistry (IHC) in Colorectal Carcinoma of Young Patients: Frequency and Clinical Significance
J Shia, C Sempoux, L Tang, N Katabi, E Vakiani, M Guo, M Weiser, Z Stadler, D Klimstra. Memorial Sloan-Kettering Cancer Center, NY
Background: IHC for MMR proteins is being increasingly used for screening colorectal cancer (CRC) patients for Lynch syndrome. MSI-H histology has also been incorporated into the revised Bethesda guidelines (BG) for identifying at risk CRC patients for MSI testing. This study aimed at analyzing the frequency and significance of early-onset CRCs that show discordance between MSI-H histology and MMR IHC staining results.
Design: A consecutive series of 280 CRC patients <50 years of age was studied. “Morphology negative – IHC abnormal” was defined as having no MSI-H histology with the highest tumor infiltrating lymphocyte (TIL) count of <5/HPF, but having loss of staining for at least 1 of the 4 major MMR proteins (MLH1, PMS2, MSH2, and MSH6). “Morphology positive – IHC normal” was defined as having a highly characteristic MSI-H histology (any histologic type plus a highest TIL/HPF count of >30) but no loss of staining for any of the 4 MMR proteins. The pathological findings were correlated with clinical characteristics.
Results: Of the 280 cases, 60 (21%) showed loss of staining for at least 1 MMR protein. Four of the 60 (7%) did not have any features of MSI-H histology with only focal areas showing a few TILs, the highest TIL/HPF being ≤5. Two of the 4 tumors lost staining for MSH2/MSH6 and 2 lost staining for MLH1/PMS2. A positive cancer family history was noted in all 4 patients, but none except 1 fulfilled the revised BG. Two patients presented with stage IV disease, and 2 stage III. Of the 220 tumors with normal IHC staining for all 4 MMR proteins, 7 (3%) exhibited a highly characteristic MSI-H histology with a median highest TIL/HPF count of 53 (range, 38 – 115). A positive cancer family history was noted in 6 of the 7 cases, but none fulfilled the revised BG. All 7 patients presented with low stage disease (stage I, n=4; stage II, n=3).
Conclusions: In this consecutive series of CRC patients < 50 years of age, 7% of the MMR IHC-abnormal tumors had no discriminating morphologic features, and 3% of the IHC-normal tumors had a highly characteristic MSI-H histology. The fact that all morphology negative-IHC abnormal cases presented with advanced disease whereas all IHC-normal but TIL-rich cases were low stage implies biologic significance of TILs. Further studies on such discrepant cases may also lead to discoveries of as yet unraveled molecular/genetic mechanisms that underlie certain early-onset CRCs.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 118, Tuesday Morning