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Cell-of-origin of transformed follicular lymphoma

Robert Kridel, Anja Mottok, Pedro Farinha, Susana Ben-Neriah, Daisuke Ennishi, Yvonne Zheng, Elizabeth A. Chavez, Hennady P. Shulha, King Tan, Fong Chun Chan, Merrill Boyle, Barbara Meissner, Adele Telenius, Laurie H. Sehn, Marco A. Marra, Sohrab P. Shah, Christian Steidl, Joseph M. Connors, David W. Scott and Randy D. Gascoyne

Key points

  • Transformed follicular lymphoma is most commonly of the GCB phenotype, but a significant minority of cases are of the ABC phenotype (16%).

  • The absence of BCL2 translocation in follicular lymphoma at diagnosis is associated with transformation into ABC-like large cell lymphoma.

Abstract

Follicular lymphoma (FL) is an indolent disease but transforms in 2-3% of patients per year into aggressive, large cell lymphoma - a critical event in the course of the disease associated with increased lymphoma-related mortality. To date, early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed follicular lymphoma is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (< 5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 transformed FL (TFL) patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (hazard ratio 13.3, P < .001). We also show that composite histology at the time of transformation predicts favourable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-centre B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.

  • Submitted June 10, 2015.
  • Accepted August 20, 2015.