Nodal T-follicular helper cell lymphomas

WHO 2022: Nodal T-follicular helper cell lymphomas


This family includes three entities of nodal T-cell lymphomas that bear the phenotype and gene expression signatures of T-follicular helper (TFH) cells. 


Accordingly, diseases previously referred to as “angioimmunoblastic T-cell lymphoma” (AITL), “follicular T-cell lymphoma” and “peripheral T cell lymphoma with TFH phenotype” are renamed nTFHL angioimmunoblastic-type (nTFHL-AI), nTFHL follicular-type (nTFHL-F) and nTFHL not otherwise specified (nTFHL-NOS), respectively. This is to recognize their significant clinical and immunophenotypic overlap and plasticity as well as similar TFH gene expression signature and mutation

profiles. 

Nodal T-follicular helper cell lymphoma, angioimmunoblastictype (nTFHL-AI)


nTFHL-AI is the prototype with well-defined clinical, morphologic, immunophenotypic and characteristic mutational profiles. Genetically, nTFHL-AI is characterized by a stepwise acquisition of somatic changes with TET2 and DNMT3A mutations occurring early in haematopoietic stem cells, while RHOA and IDH2 mutations are also present in the neoplastic TFH cell population. 


nTFHL-F and nTFHL-NOS


nTFHL-F and nTFHL-NOS represent less wellstudied nodal lymphomas, which also express TFH markers such as PD1, ICOS, CXCL13, CD10, and BCL6 and show mutation

profiles similar to those of nTFHL-AI. Although the individual entities are defined predominantly by histopathological features, there is considerable morphologic

overlap and inter-observer variability. nTFHL-NOS is the recommended term for CD4+ lymphomas with TFH phenotype but that do not meet criteria for nTFHL-AI or nTFHL-F. The generic term nTFHL rather than nTFHL-NOS is recommended when interpreting core biopsies to prevent misclassification due to inadequate sampling. The TFH phenotype is defined as the presence of at least two TFH markers in addition to CD4. Further studies are required to determine if this definition is sufficiently robust in differentiating nTFHL-NOS from PTCL, NOS, as most cases of the former often express the less specific TFH markers such as PD1 and ICOS. In essence, the diagnosis may be challenging with many pitfalls. An integrated approach is recommended, at the very minimum requiring correlation of clinical, morphologic and immunophenotypic features, with input from genomics for clonality and mutational profiles in difficult cases.