Comprehensive analysis of clinical, pathological, and genomic characteristics of follicular helper T-cell derived lymphomas

Abstract

Background The 2016 World Health Organization (WHO) classification introduced nodal lymphomas of T follicular helper (Tfh) cell origin, such as angioimmunoblastic T-cell lymphoma (AITL), follicular peripheral T-cell lymphoma (F-PTCL), and nodal peripheral T-cell lymphoma with T follicular helper phenotype (nodal PTCL with TFH phenotype). However, the accurate incidence rate and clinical characteristics of F-PTCL and nodal PTCL with TFH are unstudied. Methods Between February 2012 to June 2020, a total of 207 cases diagnosed with nodal lymphomas of T follicular helper (Tfh) cell origin and PTCL-NOS were reviewed for clinical and histopathologic data. PTCL-NOS was defined to not correlate to any of the specific entities of mature T cell lymphoma in the WHO 2016 classification. We attempted to classify PTCL-GATA3 and PTCL-TBX21 by IHC staining. Target gene analysis was performed on a few patients with sufficient blood and tissue samples additionally. Results Among 207 patients, 111 patients (53.6%) had AITL, 67 patients (32.4%) had PTCL-NOS, 19 patients (9.2%) had F-PTCL, and 10 patients (4.8%) had nodal PTCL with TFH phenotype. We re-defined and analyzed F-PTCL and nodal PTCL with TFH phenotype into other TFH lymphomas. AITL (N = 101/111, 91.0%) was found to have a higher frequency of stage III/IV cancers compared to other TFH lymphomas (N = 22/29, 75.0%) and PTCL-NOS (N = 53/67, 79.1%; p-value = 0.03). The OS of AITL and other TFH lymphomas was similarly superior to PTCL-NOS (p-value = 0.02). AITL and other TFH lymphomas showed the TBX21 subtype more commonly than the GATA3 subtype. Mutations related to the RAS family (RHOA) and those related to epigenetic regulators (IDH2, DNMT3A, and TET2) were shown mainly in AITL and other TFH lymphomas. Conclusions Other TFH lymphomas appear to be a rare disease entity around one-quarter in nodal lymphomas of T follicular helper (Tfh) cell origin. Their less aggressive clinical feature than we did not expect is utterly different from PTCL-NOS and AITL. On the other hand, other TFH lymphomas share some characteristics, such as the cell of origin, a more common TBX21 subtype, and genetic variation such as RAS family mutation and epigenetic regulators, with AITL.

Peripheral T-cell lymphoma: molecular profiling recognizes subclasses and identifies prognostic markers

“…There was a higher frequency of RHOA G17V mutations ( P < .0001) in AITL cases, as was also reported recently by Yoon et al. 21 …”

“…They were present approximately twice as frequently in AITL cases (34.09%) as in PTCL-TFH (16.66%) but could not be detected in cases of PTCL-NOS. 21,29,30 …”

First-in-class small molecule inhibitors of ICOS/ICOSL interaction as a novel class of immunomodulators

“…48 Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-Tfh) are a group of complex clinicopathological conditions that arise from the expansion of Tfh cells exhibiting high expression levels of ICOS. [50][51][52][53][54] Targeting ICOS expressed on the surface of Tfh cells has emerged as a promising therapeutic strategy for T-cell lymphomas. In this context, MEDI-570, an anti-ICOS antagonist mAb currently being evaluated in a phase I clinical trial for T-cell lymphomas (NCT02520791), showed promising clinical activity in poorrisk refractory and heavily pretreated AITL.…”

Human Germinal Center–associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma

“…A subset of AITL also show a range of B-cell proliferations that are typically associated with the Epstein-Barr virus (EBV) 21–23. These histologic findings, however, are notoriously heterogenous and can overlap with those of reactive paracortical hyperplasias, infectious and inflammatory conditions, and other PTCL 1–5,24–28. Extensive immunophenotypic panels together with molecular studies for the T-cell receptor (TCR) and B-cell receptor (BCR) gene rearrangements and mutation profiling may be necessary to arrive at a definitive diagnosis.…”

“…[21][22][23] These histologic findings, however, are notoriously heterogenous and can overlap with those of reactive paracortical hyperplasias, infectious and inflammatory conditions, and other PTCL. [1][2][3][4][5][24][25][26][27][28] Extensive immunophenotypic panels together with molecular studies for the T-cell receptor (TCR) and B-cell receptor (BCR) gene rearrangements and mutation profiling may be necessary to arrive at a definitive diagnosis. Given the lack of specificity among the range of histologies, establishing a TFH phenotype continues to be a cornerstone in the workup of PTCL.…”