Abstract
Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category.
Highlights
The pathogenesis of peripheral T-Cell lymphoma is a complex process that largely involves the dysregulation of signaling pathways crucial for normal T-Cell development, differentiation, and virus-mediated oncogenesis
FOXP3 expression is associated with differentiation into T regulatory cells, GATA3 expression is with differentiation into the Th2 subset, TBX21 (Tbet) expression is with differentiation into the Th1 subset, and BCL6 expression is with differentiation into the T follicular helper subset [3]
Gene expression profiling and next-generation sequencing of peripheral T-Cell lymphomas have shown that disruption of normal development and differentiation can occur in any of the different signaling pathways related to T-Cell receptor (TCR) signaling, co-stimulatory signaling, and cytokine signaling
Summary
The pathogenesis of peripheral T-Cell lymphoma is a complex process that largely involves the dysregulation of signaling pathways crucial for normal T-Cell development, differentiation, and virus-mediated oncogenesis. Gene expression profiling and next-generation sequencing of peripheral T-Cell lymphomas have shown that disruption of normal development and differentiation can occur in any of the different signaling pathways related to TCR signaling, co-stimulatory signaling, and cytokine signaling It occurs mostly through point mutations and copy number changes, leading to the constitutive activation of pathways downstream of the TCR, costimulatory molecules, and/or cytokine receptors [6]. Of the mature T-Cell lymphomas with a leukemic presentation, T-Cell prolymphocytic leukemia (T-PLL) shows the most consistent recurrent genetic alterations These consist of inv(14)(q11q32) or t(14;14)(q11;q32) juxtaposing the TCR alpha/beta locus at 14q11 to the oncogenes TCL1A or TCL1B at 14q32.1, or to the oncogene MTCP1 at Xq28 in t(X;14)(q28;q11). JAK3 mutations are the only genetic alteration with prognostic significance in T-PLL associated with adverse outcomes [11]
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