T-cell lymphoma – one name with a dozen faces

What are T-cell lymphomas? How common are they? How many subtypes are there? Should we treat them differently? What are the roles of stem cell transplantation, both autologous and allogeneic? These and many other questions quickly filled the agenda of lymphoma researchers around the globe after the R.E. A.L. and, later, the WHO classification of hematologic malignancies clearly defined several distinct clinico-pathologic entities that shared one feature in common: T-cell origin. In the mid 1990s, several groups reported outcomes in patients with aggressive peripheral Tand NK-cell lymphomas (PT/NKCL). It became obvious that the survival of patients with PT/NKCL is significantly worse when compared with histologically equivalent B-cell lymphomas. The 5-year overall survival (OS) rates reported by GELA [1], GELC [2] and MDACC [3] were 35, 38 and 38%, respectively. More alarming was the fact that virtually all patients with high International prognostic index score died of their disease within 5 years of diagnosis. In addition, with the exception of a few nonrandomised studies, autologous stem cell transplantation did not appear to improve the outcomes [4]. The urgent need for new therapies of PT/NKCL was recognised. Despite the high demand for new treatments of PT/NKCL, development and execution of therapeutic trials has major challenges. First, numerous studies, including the international T-cell lymphoma project, clearly separated subtypes of PT/NKCL with extremely poor prognosis after modern treatments. These include patients with extra-nasal NK/T/nullcell lymphoma, hepatosplenic T-cell lymphoma, enteropathy-type T-cell lymphoma and adult T-cell leukemia/lymphoma (ATLL) with an estimated 5-year OS of 9, 7, 20 and 14%, respectively [5]. In contrast, patients with anaplastic large T-cell lymphoma (ALCL) with expression of ALK-1 protein have a 5-year OS rate of 70% that is significantly higher than other PT/NKCL types [6]. This extreme diversity in outcomes between PT/NKCL subtypes makes it difficult to both interpret data from past clinical trials where histologic subtypes are not separated and to apply their results to design future clinical protocols that would guide therapy for specific PT/NKCL entities. Second, epidemiologic studies including the non-Hodgkin lymphoma classification project [7] and the international T-cell lymphoma project [5] indicated considerable geographic and ethnic pre-dilection for different PT/ NKCL subtypes. Although PTCL-unspecified, angioimmunoblastic T-cell lymphoma and ALCL are the most common subtypes in Western Europe and North America, nasal-type NK/T/null-cell lymphoma and ATLL represent a significant fraction of all lymphomas in Southeast Asia and Japan, respectively. Third, molecular profiling studies clearly demonstrated differences in the intrinsic biology among various PT/NKCL subtypes [8]. These findings are in agreement with diverse outcomes seen in patients with PT/NKCLs and support the need for subtype-specific clinical trials. In summary, PT/NKCLs are clinically and biologically diverse, and unevenly represented between ethnic groups and geographic locales. These challenges create specific demands on clinical research in PT/NKCL: (1) national and global collaboration is required to capture a sufficient number of subjects with these uncommon neoplasms; (2) future studies