Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin

In addition to angioimmunoblastic T-cell lymphoma (AITL), the 2016 revised WHO classification of haematological malignancies recognizes two provisional lymphoma entities of follicular helper T-cell (TFH) derivation, namely follicular peripheral T-cell lymphoma (F-PTCL) and nodal PTCL with a TFH phenotype. Here, we performed a comprehensive, integrative clinicopathological and molecular analysis of these three entities. We found that F-PTCL and other nodal PTCL with TFH phenotype share not only immunophenotypical features, but also similar clinical, genetic and molecular features with AITL. Our results support the view that these lymphomas belong to the spectrum of a common disease. AITL and PTCL, not otherwise specified (PTCL-NOS), account for the majority of nodal PTCLs. While PTCLNOS is by definition heterogeneous and an exclusion diagnosis, AITL is characterized by a constellation of clinical, morphological, and immunophenotypical features, and defined by its cellular derivation from TFH cells. The typical pathological features, i.e., clear cells, increased vascularization, follicular dendritic cell (FDC) proliferation, and the presence of eosinophils, inflammatory cells, and EBV-positive B-blasts, are variably developed. An overlap between AITL and PTCL-NOS was substantiated by the observation that a subset of cases diagnosed as PTCL-NOS, upon routine pathological evaluation, actually harbor imprints of the TFH signature and/or express TFH-associated markers. Furthermore, the rare “follicular” T-cell lymphoma (F-PTCL), initially classified as a PTCL-NOS variant, is characterized by a TFH immunophenotype and clinicopathological features overlapping with AITL. Recently, recurrent AITL-associated TET2, DNMT3A and RHOA mutations were also found in a subset of PTCL-NOS, and tended to correlate with TFH features. Based on these recent findings, the 2016 update of the WHO classification groups AITL and other nodal lymphomas of TFH origin under the same umbrella. However, a thorough, systematic and multiparametric comparison of these entities is lacking. Here, we performed a comprehensive integrative clinicopathological and molecular analysis comparing AITL and other nodal PTCLs of TFH origin. Twenty-one such cases, including five F-PTCL, were identified in the TENOMIC biobank of the LYSA, and compared to 94 AITL and 36 PTCL-NOS. All cases were reviewed by three hematopathologists according to the 2016 WHO classification criteria ( and Online Supplementary Information). The five F-PTCL by definition comprised FDCs associated to the follicles without extrafollicular FDC expansion, and were positive for all TFH markers tested (4 or 5) (Figure 1A-B). The 16 other nodal PTCL with TFH phenotype (referred to as “TFH-like PTCL”) (Figure 1A, 1C, 1D) lacked typical morphological AITL