Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies

Abstract

Peripheral T cell lymphomas (PTCL) account for about 12% of lymphoid tumours worldwide. Almost half show such morphological and molecular variability as to hamper any further classification, and to justify their inclusion in a waste-basket category termed "not otherwise specified (NOS)". The latter term is used for neoplasms with aggressive presentation, poor response to therapy and dismal prognosis. In contrast to B cell lymphomas, PTCL have been the subject of only a limited number of studies to elucidate their pathobiology and identify novel pharmacological approaches. Herewith, the authors revise the most recent contributions on the subject based on the experience they have gained in the extensive application of microarray technologies. PTCL/NOS are characterised by erratic expression of T cell associated antigens, including CD4 and CD52, which have recently been proposed as targets for ad hoc immunotherapies. PTCL/NOS also show variable Ki-67 marking, with rates >80% heralding a worse prognosis. Gene expression profiling studies have revealed that PTCL/NOS derive from activated T lymphocytes, more often of the CD4+ type, and bear a signature composed of 155 genes and related products that play a pivotal role in cell signalling transduction, proliferation, apoptosis and matrix remodelling. This observation seems to pave the way for the use of innovative drugs such as tyrosine kinase and histone deacetylase inhibitors whose efficacy has been proven in PTCL primary cell cultures. Gene expression profiling also allows better distinction of PTCL/NOS from angioimmunoblastic T cell lymphoma, the latter being characterised by follicular T helper lymphocyte derivation and CXCL13, PD1 and vascular endothelial growth factor expression.

Figure 1. (A) Lymphomatous cells do not express CD4; however, CD4 is detected in some reactive small lymphocytes (alkaline phosphatase anti-alkaline phosphatase (APAAP) technique, Gill’s haematoxylin nuclear counterstaining, ×250). (B) Partial CD30 expression; it should be noted that the tumour has no anaplastic morphology (APAAP technique, Gill’s haematoxylin nuclear counterstaining, ×250). (C) Positivity for platelet-derived growth factor receptor α (PDGFRα) (APAAP technique, Gill’s haematoxylin nuclear counterstaining, ×400). (D) PDGFRα is phosphorylated (APAAP technique, Gill’s haematoxylin nuclear counterstaining, ×400). (E) CXCL13 expression by neoplastic elements in angioimmunoblastic T cell (EnVision+ technique, Gill’s haematoxylin nuclear counterstaining, ×100). (F) Ki-67 marking exceeds the 80% value (EnVision+ technique, Gill’s haematoxylin nuclear counterstaining, ×200). (G) CD52 positivity in a peripheral T cell lymphoma, not otherwise specified (APAAP technique, Gill’s haematoxylin nuclear counterstaining, ×100). (H) Strong expression of vascular endothelial growth factor in an angioimmunoblastic T cell lymphoma (EnVision+ technique, Gill’s haematoxylin nuclear counterstaining, ×200).

Figure 2. Peripheral T cell lymphoma, not otherwise specified (PTCL/NOS), and peripheral T cell lymphoma, angioimmunoblastic type (AILT), can be distinguished according to their gene expression profile. Eighty-three differentially expressed genes are plotted in the matrix.