The clinical and molecular taxonomy of t(14;18)-negative follicular lymphomas

Abstract

Follicular lymphoma (FL) is a neoplasm derived from germinal center B cells, composed of centrocytes and centroblasts with at least a focal follicular growth pattern. The t(14;18) translocation together with epigenetic deregulation through recurrent genetic alterations are now recognized as the hallmark of FL. Nevertheless, FL is a heterogeneous disease clinically, morphologically, and biologically. The existence of FL lacking the t(14;18) chromosomal alteration highlights the complex pathogenesis of FL, and indicates that there are alternative pathogenetic mechanisms that can induce a neoplasm with follicular center B-cell phenotype. According to their clinical presentation t(14;18)-negative FL can be divided in three broad groups; nodal presentation, extranodal presentation, and those affecting predominantly children and young adults. Recent studies have shed some light into the genetic alterations of t(14;18)-negative FL. Within the group of t(14;18)-negative FL with nodal presentation, cases with STAT6 mutations are increasingly recognized as a distinctive molecular subgroup, often co-occurring with CREBBP and/or TNFRSF14 mutations. FL with BCL6 rearrangement shows clinicopathological similarities with the t(14;18)-positive counterpart. In contrast, t(14;18)-negative FL in extranodal sites are characterized mainly by TNFRSF14 mutations in the absence of chromatin modifying gene mutations. FL in children have unique molecular landscape when compared to adults. Pediatric-type follicular lymphoma (PTFL) is characterized by MAP2K1, TNFRSF14 and/or IRF8 mutations, whereas large B-cell lymphoma with IRF4 rearrangement is now recognized as a distinct entity different from PTFL. Ultimately, the better understanding of FL biology and heterogeneity should help to understand the clinical differences and help guiding patient management and treatment decisions.

Celebrating a year of cancer research in Blood Advances

“…The review highlights comparisons with t(14;18)-positive FL because t(14;18)-negative variants have distinctive clinical and genetic features. 1 …”