Update on peripheral T-cell lymphomas with T-helper phenotype:  Are there too many subtypes?

Follicular helper T (T_FH) cells are the providers of T-cell help to B-cells in the development of germinal centers and for the generation of most class-switched antibodies. The markers most commonly associated with T_FH activity are IL21, IL4, CD40L, BCL6, SAP, CXCR5/CXCL13, and ICOS. T-cell lymphoma genomic studies have shown that different T-cell lymphoma types express signatures typical for T_FH cells, this including angioimmunoblastic T-cell lymphoma (AITL), a related condition termed peripheral T-cell lymphoma with T_FH phenotype and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder. Angioimmunoblastic T-cell lymphoma is a well-established entity, a clinically aggressive disease with a survival of 30% OS after 5 years. Molecular and clinical studies have confirmed this as a well-established clinicopathological entity with relatively specific gene mutations, including mutations found in hematopoietic precursor cells and others. Peripheral T-cell lymphoma with T_FH phenotype is an associated disorder with histology of PTCL but a T_FH phenotype, as defined by the expression of 2-3 immunohistochemical markers. Molecular studies on this entity are showing a partial overlap with AITL. Primary cutaneous CD4+ small/medium lymphoproliferative disorder is an entirely different process that takes place in the skin, showing frank cytologic atypia, monoclonal TCR rearrangement and T_FH phenotype in the context of a clinically benign lesion. Here we review the main clinical, molecular and diagnostic features of these three lymphoproliferative processes.