Altered Subcellular Localization of c-Myc Protein Identifies Aggressive B-cell Lymphomas Harboring a c-MYC Translocation

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Abstract
Nearly 100% of Burkitt lymphomas (BLs) and 5% to 8% of diffuse large B-cell lymphomas (DLBCLs) harbor a balanced translocation involving c-MYC. Although characteristic morphologic and immunophenotypic features can identify BL in most cases, tumors with atypical features are often encountered in clinical practice. Furthermore, no morphologic or immunophenotypic finding can predict an underlying c-MYC translocation in DLBCL with certainty. Here we report on a novel monoclonal antibody recognizing the c-myc protein in formalin-fixed, paraffin-embedded tissue which we used to evaluate a spectrum of aggressive B-cell lymphomas by standard immunohistochemistry. Cases consisted of 17 BLs (15 cases with confirmed c-MYC translocation), 19 DLBCLs without a c-MYC translocation, 5 DLBCLs with a c-MYC translocation, and 2 B-cell lymphomas, unclassifiable, with features intermediate between DLBCL and BL (intermediate DBLCL/BL, one case with c-MYC translocation and one case without a c-MYC translocation). The intensity and subcellular localization of tumor-specific staining for c-myc protein was determined independently by 2 pathologists and in a blinded fashion for each case. We observed c-myc expression in the tumor cells of all cases regardless of c-MYC status. Among BLs, c-myc protein primarily localized to the nucleus of tumor cells in 15 of 17 cases (88%) and equally localized to the nucleus and cytoplasm of tumor cells in 2 of 17 cases (12%). In no case did c-myc protein primarily localize to the cytoplasm. In contrast, among DLBCLs lacking a c-MYC translocation the c-myc protein primarily localized to the cytoplasm of the tumor cells in 18 of 19 cases (95%) and equally localized to the nucleus and cytoplasm in the tumor cells in 1 of 19 cases (5%). In no case did c-myc protein primarily localize to the nucleus. Among DLBCLs with a c-MYC translocation and intermediate DBLCL/BLs, the c-myc protein primarily localized to the nucleus, or equally localized to the nucleus and cytoplasm of the tumor cells in 4 of 5 cases (80%) and 2 of 2 cases (100%), respectively. Taken together, we find that a primarily nuclear or mixed nuclear and cytoplasmic staining pattern for c-myc in an aggressive B-cell lymphoma is highly predictive of a c-MYC translocation (positive-predictive value=0.92, negative-predictive value=0.95, P<0.0001). We further show that the subcellular localization of c-myc can be determined with good interobserver agreement among pathologists (kappa statistic=0.90). Thus this novel immunohistochemsitry test is a useful tool for identifying aggressive B-cell lymphomas likely to harbor a c-MYC rearrangement and thus warrant genetic testing.