1 article
Follicular lymphoma (FL) is a slow-growing B-cell lymphoma with a generally favorable prognosis. Nevertheless, its clinical course is heterogeneous, with a significant subset of patients experiencing early progression or histological transformation into diffuse large B-cell lymphoma (DLBCL), both considered to be high-risk events associated with treatment resistance and markedly inferior outcomes. Importantly, clinical risk factors have limited value in predicting these complications. This review outlines the key biologic features of FL, discussing how the novel molecular biology approaches can explain the clinical heterogeneity and high-risk disease evolution of FL.
A focused literature review was conducted using the PubMed/MEDLINE database to identify studies on follicular lymphoma and its histological transformation to diffuse large B-cell lymphoma. Priority was given to original research or review articles investigating genetic, epigenetic, transcriptional, or microenvironmental determinants of FL.
Evidence from early cytogenetic and DNA sequencing studies established BCL2 deregulation as an initiating lesion in FL, with further genetic alterations in epigenetic regulators like KMT2D, EZH2, CREBBP/EP300 occurring early on and persisting throughout the disease course. Studies of transformed FL samples indicate that aggressive evolution is associated with acquisition of additional genetic lesions, such as those affecting the cell cycle regulators CDKN2A/2B and TP53. More recently, integrated genomic, transcriptomic and spatial resolved techniques have demonstrated substantial transcriptional heterogeneity within individual genetic subclones, suggesting that the genotype alone does not determine the phenotype of the malignant cells and supporting a pathogenetic model in which clinical trajectories reflect the combined effects of genomic evolution, transcriptional cell state, and tumor-microenvironment crosstalk. Important findings, including greater infiltration with LAG3+CD8+ T cells in cases of histological transformation to DLBCL and upregulation of transcriptional programs that promote stromal expansion and B-cell receptor signaling in cases of early FL relapse, indicate that integrated profiling represents a promising avenue for identifying the biomarkers and treatment targets that are specific to high-risk disease.
Continued research concentrated on multiomic profiling of both malignant and non-malignant tumor compartments is essential in order to reveal the mechanisms of FL heterogeneity and translate these data into practical biomarkers and therapeutic strategies.