Immunohistochemical and Molecular Characteristics with Prognostic Significance in Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We analyzed 100 cases of DLBCL to evaluate the prognostic value of immunohistochemical markers derived from the gene expression profiling-defined cell origin signature, including MYC, BCL2, BCL6, and FOXP1 protein expression. We also investigated genetic alterations in BCL2, BCL6, MYC and FOXP1 using fluorescence in situ hybridization and assessed their prognostic significance. BCL6 rearrangements were detected in 29% of cases, and BCL6 gene alteration (rearrangement and/or amplification) was associated with the non-germinal center B subtype (non-GCB). BCL2 translocation was associated with the GCB phenotype, and BCL2 protein expression was associated with the translocation and/or amplification of 18q21. MYC rearrangements were detected in 15% of cases, and MYC protein expression was observed in 29% of cases. FOXP1 expression, mainly of the non-GCB subtype, was demonstrated in 37% of cases. Co-expression of the MYC and BCL2 proteins, with non-GCB subtype predominance, was observed in 21% of cases. We detected an association between high FOXP1 expression and a high proliferation rate as well as a significant positive correlation between MYC overexpression and FOXP1 overexpression. MYC, BCL2 and FOXP1 expression were significant predictors of overall survival. The co-expression of MYC and BCL2 confers a poorer clinical outcome than MYC or BCL2 expression alone, whereas cases negative for both markers had the best outcomes. Our study confirms that DLBCL, characterized by the co-expression of MYC and BCL2 proteins, has a poor prognosis and establishes a significant positive correlation with MYC and FOXP1 over-expression in this entity.

Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

“…Specifically interesting in this scenario is that MYC translocations or MYC overexpression by other means is associated with poor survival, in particular in DLBCLs that also overexpress BCL2. 55,56 For such double-hit DLBCL patients, and also in DLBCL patients with just high MYC levels, SUMOi could be an attractive approach.…”

Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate‐associated large B lymphoproliferative disorders

“…Furthermore, BCL2 expression was significantly weaker than in control DLBCL samples ( P < 0.05). Bellas et al . demonstrated that expression of BCL2 and/or cMYC proteins led to significantly poorer overall survival in 100 patients with DLBCL ( P < 0.05).…”

“…Furthermore, BCL2 expression was significantly weaker than in control DLBCL samples (P < 0.05). Bellas et al 22 demonstrated that expression of BCL2 and/or cMYC proteins led to significantly poorer overall survival in 100 patients with DLBCL (P < 0.05). In RA patients with EBV + MTX-BLPD, low BCL2 expression in tumour cells may influence tumour regression even in non-GCB cell phenotype tumours, and result in better prognosis.…”

Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy

“…13–17 Meanwhile, several other biomarkers, including CD5, p53, MYC expression, MYC/BCL2 co-expression, TP53 mutation, BCL2 , MYC rearrangement, and MYC / BCL2 double hit, have been implicated in mechanisms of disease and have been suggested as predictors of poor prognosis in DLBCL. 18–24 Thus far, no large studies have explored the relationship between these high-risk pathologic features and the various types of BM involvement in DLBCL patients.…”