Molecular Characterization of Diffuse Large B-Cell Lymphoma and Its Prognostic Significance

INTRODUCTION: Lymphomas are a diverse group of malignant neoplasms that arise from clonal expansion of neoplastic B and T lymphocytes derived from normal counterparts in the immune system. Lymphomas are broadly classified into Hodgkin’s lymphoma and non Hodgkin’s Lymphoma. The current World Health Organization (WHO) classification of lymphomas provides an up-to-date and biologically relevant approach to lymphomas by incorporating a variety of parameters (morphology, immunophenotypic findings, mole cular genetic studies and cytogenetic features) and has become the gold standard. CONCLUSION: The molecular characterization of DLBCL and the study of various cell cycle regulatory and apoptotic proteins showed statistically significant influence on prognosis only in IPI status based stratification, immunophenotypic classification (GCB/ABC), p21 expression based classification and NFkB expression based classification. The other cell cycle regulatory proteins were associated with trends consistent with conventional published studies but failed to demonstrate any statistically significant conclusions. An increase in sample size may yield statistically significant results. This could also be due to the confounding effects of various other cell cycle regulatory proteins as DLBCL is a complex multihit disease with alteration of multiple survival pathways resulting in multiple drivers of tumour cells proliferation and survival. RECOMMENDATIONS: 1. Immunohistochemistry based molecular profiling of DLBCL along with immunophenotypic classification of the GCB and ABC subtypes of DLBCL must be done routinely in all cases as part of pretreatment workup in order to identify the poor prognostic groups as candidates for early aggressive multimodal therapy. 2. P53 gene mutational studies is preferable over IHC based p53 status as this study has shown IHC based profiling of mutant phenotype (p21-/p53+++) as an unreliable surrogate marker for P53 missense mutations resulting in it’s functional loss. Further molecular studies in NFkB pathways and p21 related pathways might provide more information and possibly identify targets for therapy. 3. This study identified p21 and NFkB as the only two statistically significant variables which can be used to predict prognosis in DLBCL. Expression of NFkB in ABC phenotype identified patient group with the worst 5 years OS of 39.6%. Similarly loss of p21 expression in ABC phenotype identified the patient group with worst 5 years OS of 37.2%. Based on the differential strength of association of various molecular profile groups with prognosis, a differential point based prognostic score system should be developed to better stratify high risk groups. 4. Further molecular studies in NFkB pathways and p21 related pathways might provide more information and possibly identify targets for therapy. 5. Bcl6 is being extensively studied for molecularly targeted therapy. Hence further studies on molecular characterization of Bcl6 and its sub classification to identify a subgroup that is exquisitely bcl6 dependent DLBCL could help in identifying candidates for clinical trials involving Bcl6 inhibitors. 6. To conduct a study with larger sample size to determine if the trends seen in the present study would be amplified to reach clinical significance