Gene expression profiling reveals a close relationship between follicular lymphoma grade 3A and 3B, but distinct profiles of follicular lymphoma grade 1 and 2

Abstract

A linear progression model of follicular lymphomas (FL) FL1, FL2 and FL3A has been favored, since FL3A often co-exist with an FL1/2 component. FL3B, in contrast, is thought to be more closely related to diffuse large B-cell lymphoma (DLBCL), and both are often simultaneously present in one tumor (DLBCL/FL3B). To obtain more detailed insights into follicular lymphoma progression, a comprehensive analysis of a well-defined set of FL1/2 (n=22), FL3A (n=16), FL3B (n=6), DLBCL/FL3B (n=9), and germinal center B-cell-type diffuse large B-cell lymphoma (n=45) was undertaken using gene expression profiling, immunohistochemical stainings and genetic analyses by fluorescence in situ hybridization. While immunohistochemical (CD10, IRF4/MUM1, Ki67, BCL2, BCL6) and genetic profiles (translocations of BCL2, BCL6 and MYC) delineate FL1-3A from FL3B and DLBCL/FL3B, significant differences were observed between FL1/2 and FL3A upon gene expression profiling. Interestingly, FL3B turned out to be closely related to FL3A, not categorizing within a separate gene expression cluster, and both FL3A and FL3B showed overlapping profiles in between FL1/2 and diffuse large B-cell lymphoma. Finally, based upon their gene expression pattern, DLBCL/FL3B represent a composite form of FL3B and DLBCL, with the majority of samples more closely resembling the latter. The fact that gene expression profiling clearly separated FL1/2 from both FL3A and FL3B suggests a closer biological relationship between the latter. This notion, however, is in contrast to immunohistochemical and genetic profiles of the different histological FL subtypes that point to a closer relationship between FL1/2 and FL3A, and separates them from FL3B.

Prognostic significance of histologic grade and Ki‐67 proliferation index in follicular lymphoma

“…6,9,20 Furthermore, a previous study noted that FL 3B differed from FL 1-3A with distinct cytogenetic and immunohistochemical features, 21 while further study suggested that FL 3B harboured similar gene expression profiles as FL 3A. 3 Despite these promising results, the prognostic value of grades is controversial and whether FL 3A is more closely associated with 3B remains to be elucidated.…”

“…2 In contrast, gene expression profiles showed that FL 3A closely resembled FL 3B rather than FL 1-2. 3 A much-debated question is the prognostic value of histological grading in FL. Some studies have revealed that higher grades correlated with inferior outcomes, 4,5 whereas other studies suggested that histological grade did not predict the outcome of FL.…”

“…Similarly, FL 3B is closely associated with DLBCL, suggesting that FL 3B is different from FL 1‐2 and FL 3A 2 . In contrast, gene expression profiles showed that FL 3A closely resembled FL 3B rather than FL 1‐2 3 . A much‐debated question is the prognostic value of histological grading in FL.…”

Differential expression of long non‐coding RNAs are related to proliferation and histological diversity in follicular lymphomas

“…A previous transcriptomic study observed a relatively homogeneous gene expression profiling in the different histological grades of FL, but also identified differences between FL1‐3A and FL3B (Piccaluga et al , ). Although some differences in coding gene expression profiles have also been described between FL1‐2 and FL3A, these FL subtypes are also closely related, as also shown at the genetic and immunohistochemical level (Horn et al , ). Non‐coding RNA expression profiling studies in FL have basically analysed expression and sequence alterations of microRNAs (Musilova & Mraz, ; Hezaveh et al , ).…”

Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation

“…Gene expression profiling has also revealed significantly different expression signatures between low-grade (I and II) and high-grade (IIIA and IIIB) FL suggesting that grade I-II and grade III FL may represent different biological entities. [ 35 ].…”