How I Diagnose Angioimmunoblastic T-Cell Lymphoma

Yi Xie, MD, PhD; Elaine S. Jaffe, MD


Am J Clin Pathol. 2021;156(1):1-14. 

In This Article

Molecular and Genetic Features

Most AITLs show clonal or oligoclonal rearrangement of the T-cell receptor genes. In addition, clonal and oligoclonal rearrangements of the B-cell receptor genes are found in up to 50% of cases, in part due to the expansion of EBV+ B cells.[60] By conventional cytogenetic analysis, clonal abnormalities, most commonly trisomy 3, trisomy 5, trisomy 21, additional X chromosome, and loss of 6q, are detected in approximately 70% of AITL cases.[61,62] The t(5;9)(q33;q22);ITK-SYK, which is reported in around 20% of follicular T-cell lymphomas, has been identified infrequently in AITL.[12,63,64]

In the past two decades, significant progress has been made in understanding the pathobiology and pathogenesis of AITL. The tumor cells in AITL are recognized to originate from TFH cells based on gene expression profiling.[9,10] Whole-exome sequencing and targeted sequencing studies have identified a group of recurrent mutations, including genes encoding the epigenetic regulators, TET2 (50%-80%), DNMT3A (20%-30%) and IDH2 (20%-45%), the small GTPase, RHOA (50%-70%), and the components of the TCR signaling pathways such as PLCG1 (14%), CD28 (9%-11%), FYN (3%-4%), and VAV1 (5%).[65–71] Among these mutations, the RHOAG17V mutation, present in up to 70% of AITLs, is also commonly observed in other T-cell lymphomas with the TFH phenotype but is seldom detected in other cancers.[48,69,71,72] Therefore, it is considered a hallmark and genetic indicator for TFH lymphoma. In contrast, the IDH2R172 mutation, occurring at a frequency of 20% to 30%, is found in AITL and is rare in other PTCLs with the TFH phenotype.[70,72]

Importantly, studies have shown that TET2 and DNMT3A mutations are not restricted to T cells but can also be identified in the admixed mature B cells in the lymph nodes and the hematopoietic stem cells of patients with AITL, whereas RHOA and IDH2 mutations appear confined to the neoplastic T cells.[66,73,74] In light of these and some other findings, a multistep and multilineal tumorigenesis has been suggested, in which initial epigenetic deregulation (TET2, DNMT3A) occurring in hematopoietic stem cells in cooperation with subsequent mutations in genes important for T-cell function (RHOA, VAV1, PLCG1, CD28, and others) leads to AITL.[72] Interestingly, previous studies have shown that clonal hematopoiesis (CH) and myeloid neoplasms such as chronic myelomonocytic leukemia and acute myeloid leukemia are more frequent in patients with AITL than in the general population.[75] In some patients, the myeloid neoplasms and AITL share common ancestral mutations in TET2 and/or DNMT3A, suggesting that they arise from divergent evolution of a common CH clone.[76,77] Moreover, Nguyen et al[74] recently reported that in addition to TET2 and DNMT3A mutations, the B cells in AITL lymph nodes can acquire additional B-cell–specific mutations in NOTCH1 and other genes, which may account for the frequent occurrence of clonal B-cell expansion in AITL.