Case 2 -

Peripheral T-cell Lymphoma, Unspecified (PTCL-U) Dr. H.K. Muller-Hermelink Wurzburg , Germany

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Clinical History: 63 year old female with a single enlarged lymph node, present for four months. Questionable infection and distinct arthritis. Case 2 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Discussion The category of peripheral T-cell lymphoma, unspecified (PTCL-U) was first used in the REAL classification [1] to denominate peripheral T-cell lymphomas (PTCL) that could not be further subclassified with confidence. Thus, it comprises all peripheral T-cell lymphomas that do not belong to one of the entities better defined by their characteristic genetic alterations (ALK1- overexpressing anaplastic large cell lymphoma), epidemiology (e.g. adult T-cell leukaemia/lymphoma), or clinical presentation (e.g. intestinal T-cell lymphoma, angioimmunoblastic T-cell lymphoma). PTCL-U comprises the largest group within nodal PTCL. In the international Non-Hodgkin lymphoma classification project, the overall agreement for PTCL-U was 72%, similar to the major entities of B-cell lymphomas [2] . PTCL-U does not appear to have a distinctive clinical presentation, which is in keeping with the concept of the REAL proposal that lumped heterogeneous categories [2]. Morphological variants Most cases of PTCL-U have no distinctive morphological features and are described according to their cell size. The WHO classification recognizes few distinctive morphological variants within PTCL-U, namely T-zone lymphoma and lymphoepithelioid (Lennert's) lymphoma. Lennert's lymphoma, that is characterized by a striking proliferation of epithelioid histiocytes, was shown to be derived from CD8+ T-cells, in contrast to most other PTCL [3, 4] . In later studies, distinctive characteristics of these subgroups were studied and other, new, morphological patterns were described. In addition to T-zone lymphoma which predominantly involves the paracortical thymus-dependent areas, patterns have been described relating to the B-cell follicles, namely with prominent involvement of the marginal zone [5] , the mantle zone [6] and to the germinal center [7] . In the latter CD4+ cases, that expressed bcl-6 and variably CD10, a relationship to follicular T-cells was suggested. Recently, Streubel et al. described a novel t(5;9)(q33;q22) translocation in 5/30 PTCL-U, but not other nodal PTCL [8] . Three of the cases harbouring this translocation shared a predominant involvement of lymphoid follicles and the same CD3+CD5+CD4+bcl-6+CD10+ immunophenotype. The breakpoints were delineated to ITK and SYK resulting in an expression of the Syk tyrosine kinase by Itk. The breakpoints were identical, fusing the N-terminal pleckstrin homology domain and proline-rich region of ITK to the tyrosine kinase domain of SYK. Genetics of PTCL-U Genetic data on PTCL-U are still sparse. In a study relying on comparative genomic hybridization (CGH) [9] , 43 of 44 cases (98%) of PTCL-U showed on average more than seven genetic alterations, among them recurrent losses of chromosomes 6q, 13q, 9p, 5q, 12q, and 10q, and gains of chromosome 7q. No statistical correlation between clinical features, immunophenotype, or histological type of lymphoma, and gains of 7q and losses of 6q and 13q were observed, giving indirect evidence for the secondary nature of these genetic alterations in PTCL-U. Losses of genetic material on chromosomes 6q and 13q are among the most frequent genetic alterations reported for T- and B-NHL. In classical cytogenetics, 20 to 35% of PTCL-U showed deletions on 6q. Similarly, 6q deletions were frequently observed in CGH studies of other peripheral T/NK cell lymphomas. Among the morphologically and immunohistochemically heterogeneous group of PTCL-U, genetic features may segregate at least one particular group of noncytotoxic nodal CD5+ T-cell lymphoma characterized by chromosomal losses of 5q, 12q, and 10q. Although there is a considerable overlap between the genetic features of ALK1− ALCL and PTCL-U, losses of chromosome 5q and 9p and gains of chromosome 1q may segregate PTCL-U from ALK-negative ALCL. Losses of 5q set PTCL-U apart from all other types of T-cell lymphoma. Normal counterparts PTCL-U are difficult to correlate to normal T-cell populations. The distinction of CD4+ and CD8+ subsets is not clinically relevant. For some time, the expression of cytotoxic molecules was used to characterize PTCL with similarly annoying results [3] . Distinct differentiated T-cell populations have been characterised by their activation requirements, effector functions and surface molecule expression [10] , but many functional subsets of T-cells have not yet been correlated to distinct antigen expression patterns. In a recent study, a correlation was attempted between developmental stages of PTCL and reactive activated T-lymphocytes (Geissinger et al., J Pathol, in press). All five CD4+ cases of PTCL-U clustered together. They differed from AILT in the expression of CD27, suggesting a different developmental stage. These tumors also expressed chemokine receptor CCR7 in 4 of the 5 cases and all were BCL-2 positive. This suggests long-lived antigen-experienced T-cells that are able to recirculate to lymph nodes, that are defined as central memory cells. This differentiation stage differs from that of the AILT and ALCL cases, which are derived from effector T-cell populations. The often-high proliferation rate in PTCL-U is unusual for memory cells and transformation may thus affect the cell cycle more than apoptosis in a similar fashion to aggressive B-cell non-Hodgkin lymphomas. The correlation of nodal PTCL to reactive T-cell subsets presented here may help to unravel the biology of PTCL. References Harris, N.L., et al., A Revised European-American Classification of Lymphoid Neoplasms: A Proposal From the International Lymphoma Study Group. Blood, 1994. 84(5): p. 1361-1392. Rüdiger, T., et al., Peripheral T-cell Lymphoma. Results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol, 2002. 13(1): p. 140-149. Geissinger, E., et al., Nodal peripheral T-cell lymphomas and, in particular, their lymphoepithelioid (Lennert's) variant are often derived from CD8(+) cytotoxic T-cells. Virchows Arch, 2004. 445(4): p. 334-43. Yamashita, Y., et al., Lennert's lymphoma: a variant of cytotoxic T-cell lymphoma? Am J Surg Pathol, 2000. 24(12): p. 1627-33. Rüdiger, T., et al., Peripheral T-cell lymphoma with distinct perifollicular growth pattern: a distinct subtype of T-cell lymphoma? Am J Surg Pathol, 2000. 24(1): p. 117-22. Ikonomou, I.M., et al., Peripheral T-cell lymphoma with involvement of the expanded mantle zone. Virchows Arch, 2006. 449(1): p. 78-87. de Leval, L., et al., Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol, 2001. 25(3): p. 395-400. Streubel, B., et al., Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia, 2006. 20(2): p. 313-8. Zettl, A., et al., Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations. Am J Pathol, 2004. 164(5): p. 1837-48. Chtanova, T., et al., Identification of T cell-restricted genes, and signatures for different T cell responses, using a comprehensive collection of microarray datasets. J Immunol, 2005. 175(12): p. 7837-47.