Angioimmunoblastic T-cell Lymphomas With the RHOA p.Gly17Val Mutation Have Classic Clinical and Pathologic Features

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a nodal-based mature T-cell lymphoma with distinctive clinical symptomatology and histology. Research into its pathogenesis supports a cellular derivation from follicular helper T cells and overexpression of genes related to B cells, follicular dendritic cells, and vascular growth. Recently, a novel recurring somatic mutation in RHOA, encoding p.Gly17Val, was discovered in nearly 70% of AITLs and in a smaller proportion of peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS). We investigated a series of AITLs to compare RHOA mutated with wild-type case for clinicopathologic differences. Targeted exome and Sanger sequencing was performed on 27 AITLs and 10 PTCL-NOS. The RHOA G17V mutation was identified in 63% of the AITL cases and in none of the PTCL-NOS cases. The median variant allelic frequency was 14%, with a range of 0.4 to 50% in positive cases. RHOA G17V-mutated cases had a significantly higher incidence of splenomegaly and B symptoms at diagnosis, but there was no difference in overall survival between mutated and wild-type subgroups. Cases with the RHOA G17V mutation had a significantly higher mean microvessel density (P<0.01) and expressed a greater number of follicular helper T-cell markers (P<0.05) than wild-type cases. RHOA G17V is present in a significant proportion of angioimmunoblastic lymphomas and is associated with classic pathologic features of AITL. Additional studies are needed to provide a biological or functional link between altered RHOA function and these pathologic features.

Angioimmunoblastic T‐cell lymphoma contains multiple clonal T‐cell populations derived from a common TET2 mutant progenitor cell

“…In the 2016 WHO lymphoma classification, a broad category of nodal lymphoma of follicular helper cell origin, including AITL, PTCL-TFH, and follicular T-cell lymphoma, was introduced due to their overlapping morphological, immunophenotypic, genetic, and clinical presentations, while also bearing certain distinct features. Several studies show that RHOA and IDH2 mutations are strongly associated with the TFH immunophenotype and more extensive characteristics typical of AITL such as proliferation of follicular dendritic cells, high endothelial vessels, and presence of clear cells, with IDH2 mutation defining a unique subgroup of AITL [12,[45][46][47]. In support of these observations, we found RHOA mutation only in AITL and PTCL-TFH but not in PTCL-NOS, and IDH2 mutation exclusively in AITL in the present study.…”

Approach to nodal-based T-cell lymphomas

“…[33][34][35] Cases of AITL with the RHOA G17V mutation have classical clinicopathological features and tend to have higher microvessel density, more FDC proliferation and a more pronounced TFH immunophenotype compared to wild-type cases, but no prognostic significance has been observed. 36,37 Various IDH2 point mutations at the R172 residue are present in about one-third of AITL cases. [38][39][40] IDH2 mutations modify IDH2 enzymatic activity resulting in the production of an oncometabolite (2 hydroxyglutarate) ultimately altering DNA and histone methylation.…”

2016 WHO Classification update—What's new in lymphoid neoplasms

“…The latter lymphoma does not have all the features of AITL such as expanded abnormal follicular dendritic cells and may have a follicular or nodular architecture (even histologically resembling a B‐cell low grade follicular lymphoma). In particular, RHOA and IDH2 mutations seem to be associated with AITL and the Tfh phenotype . These lymphomas are known to contain large B‐immunoblasts that are often (but not always) EBV+, which can morphologically resemble Hodgkin cells.…”

“…Advances in our understanding of the biology, immunophenotype, and In particular, RHOA and IDH2 mutations seem to be associated with AITL and the Tfh phenotype. 80,85 These lymphomas are known to contain large B-immunoblasts that are often (but not always) EBV+, which can morphologically resemble Hodgkin cells. Occasionally, a large B-cell lymphoma can occur with and even obscure the T-cell lymphoma.…”