MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma

Abstract

Key Points• Outcome prediction in DLBCL.• MYC status in concert with BCL2 and BCL6.MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2-and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade NonHodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP.

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

“…[9][10][11][12][13] These studies have shown that cases of diffuse large B-cell lymphoma with concurrent overexpression of MYC and BCL2 proteins have a dismal prognosis similar to those with double-hit lymphomas. The rate of so-called double-hit lymphoma-like cases as determined by immunohistochemistry is larger than the one detected by FISH.…”

“…[9][10][11][12][13] Tissue microarrays sample only a small portion of the tumor and therefore may underrepresent the heterogeneity of staining among tumor cells encountered in daily practice. The heterogeneity of MYC protein staining is not adequately addressed in these studies.…”

“…The heterogeneity of MYC protein staining is not adequately addressed in these studies. Additionally, the concordance rate is assessed among only two 10,11,13 or three 9 pathologists that might underestimate inter-observer variability among practicing pathologists. We hypothesized that these concordance rates might not be reproducible in daily practice.…”

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

“…9,10 Several studies have reported that MYC translocations independently predicted significantly poor survival in DLBCL patients. [11][12][13][14][15][16] However, other studies found inconsistent results [17][18][19] or limitations of its prognostic significance. 20,21 The clinical significance of Myc overexpression in DLBCL has also been the source of much attention and controversy.…”

“…5,13,[22][23][24] Furthermore, the poor prognosis associated with Myc overexpression was contributed by cases with Myc/Bcl-2 coexpression-'doublepositive lymphoma' (DPL)-which account for 18-44% of DLBCLs. 13,20,[23][24][25][26] However, one study showed that the prognostic value of double-positive lymphoma was lost in younger DLBCL patients with poor prognosis. 27 Inconsistent results have been reported regarding whether the prognostic significance of Myc or Myc/Bcl2 protein expression depends on MYC or MYC/BCL2 gene rearrangement status or not.…”