The impact of molecular alterations and the immune microenvironment on the natural history of Follicular Lymphoma including transformation to Diffuse Large B cell Lymphoma

Abstract

The natural history of follicular lymphoma is heterogeneous with numerous relapses and remissions over many years. A substantial number of patients suffer an aggressive disease course with death due to disease within 5 years of diagnosis. The prognosis is significantly worse in patients (10-68%) who transform to an aggressive histology. The clinical parameters used to stratify patients with this disease have limited discriminative power and new prognostic biomarkers are required. Insights into the biology of the disease, with identification of potential therapeutic targets are also required. Analysis of paraffin embedded diagnostic FL biopsies from populations of patients at the extremes of overall survival (<5 years and >15 years) demonstrated that expression of CD4 T lymphocytes and a perifollicular location of forkhead box protein P3 were significantly more common in diagnostic biopsies from patients who lived >15 years. Patients with high numbers of intrafollicular CD4 T lymphocytes and higher numbers of CD68 positive macrophages were more likely to undergo rapid transformation to diffuse large B cell lymphoma (DLBCL). Analysis of sequential biopsies pre-and post-transformation from patients with FL who subsequently transformed to DLBCL demonstrated high numbers of CD68 positive macrophages in the majority of cases. The overall survival from transformation was reduced in patients in whom the number of FOXP3 positive T cells decreased/remained low compared to patients in whom the number of FOXP3 positive T cells increased/remained high. Analysis of biopsies pre-and post-transformation from patients with FL who subsequently transformed, identified mutation of TP53 in 28% of cases suggesting a limited role in the process of transformation. The immunocytochemical expression of MDM2, the TP53 regulator, was significantly higher on transformation. The phenotype of transformed FL was confirmed immunocytochemically as Germinal Centre type and two potential drug targets, Aurora Kinase B and nm23, were confirmed as being up-regulated on transformation.