Pier Paolo Piccaluga
Molecular Pathology Laboratory, Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Via Massarenti, 9 - 40138 Bologna, Italy
Peripheral T-cell lymphomas (PTCLs) are quite heterogeneous neoplasms representing about 12% of all lymphoid malignancies. They are often regarded as "orphan diseases", a designation that does not reflect their real incidence, but else the difficulties encountered in their classification, diagnosis and treatment. In this regard, unfortunately, current conventional therapies are rather ineffective, and novel approaches are indeed warranted.
In the last decade, however, high-throughput technologies, including DNA-microarrays and massive parallel sequencing allowed a better definition of at least some of the entities belonging to PTCL family as well as the identification of potential targets proposed by translational studies. First, PTCL not otherwise specified (PTCL/NOS) , the commonest PTCL subtype, was shown to be constituted by different molecular entities corresponding to different normal T-cell subsets. Of note, on the clinical ground, those corresponding to cytotoxic T-cells appeared to be provided with more unfavorable prognosis, while those corresponding to Th1-Th2 could be, at least experimentally, effectivelly targeted by MTOR inhibitors. More in general, PTCL/NOS were also found to express PDGFRs, their inhibition being effective ex vivo and in vivo. Moreover, CD30 expression was documented in about 50% of cases, this representing a solid rational for the use of anti-CD30 monoclonal antibodies in a significant fraction of cases.
As far as angioimmunoblastic T-cell lymphoma (AITL) is concerned, several somatic mutations often affecting genes involved in epigenetic regulation of gene expression, including TET2, IDH2, RHOA and DNMT3A/B, were found. Further, selective sensitivity to some agents such as plitidepsin, has been documented. Based on that, the first round of clinical trials specifically designed for AITL has been designed.
Finally, anaplastic large cell lymphoma (ALCL) was confirmed at genetic level to be constituted by two distinct disease, the ALK- and the ALK+ form. Interestingly, deep sequencing analyses demonstrated that ALK- ALCL present genetic lesions that recapitulate mechanisms analogue to those deriving from ALK activation, finally leading to STAT3 phosphorilation.