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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1501-1502. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Grogg, K. L. Articles by Dogan, A. Search for Related Content PubMed PubMed Citation Articles by Grogg, K. L. Articles by Dogan, A. Related Collections Related Letter in Blood Online Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE To the editor: Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? We have read the paper by Kim et al1 recently published in Blood with great interest. The study reports the gene-expression profile of germinal-center T-helper (GC-Th) cells and identifies genes differentially expressed by G-C-Th cells compared with other T-cell subsets. The germinal center microenvironment not only is an essential niche for generation of B-cell response, but also is considered to be critical in the development of most human lymphoid neoplasms. Although most lymphomas originating from germinal-center lymphocytes are B-cell lymphomas, it has been suggested recently that some peripheral T-cell lymphomas,2 in particular angioimmunoblastic T-cell lymphoma (AITL), may arise from GC-Th cells.3,4 AITL is a relatively infrequent disease accounting for 1% to 2% of all lymphomas. Typically, the tumor cells of AITL have a T-helper-cell phenotype expressing CD3, CD4, and frequently CD10, similar to a subset of normal GC-Th cells.4 In early lymph-node involvement by AITL, the neoplastic T cells preferentially occupy the B-cell follicles and immediate perifollicular area, sometimes mimicking a follicular lymphoma of B-cell origin.2,3,5 This suggests that the follicle-center microenvironment is critical for tumor development. In the Kim et al1 study, one of the most highly up-regulated genes in the GC-Th cell subset was CXCL13, a chemokine critical for B-cell entry into germinal centers.6 Based on this observation, we investigated the expression of CXCL13 in AITL. We stained paraffin sections of 29 AITL lymph-node biopsies using a monoclonal antibody against CXCL13 (Clone 53610; R&D Systems, Minneapolis, MN) and standard immunohistochemical methods. All cases were previously characterized by immunohistochemical studies that documented expression of CD3 and CD4 by the tumor cells. CD10 was expressed in 22 cases. We observed striking cytoplasmic expression of CXCL13 by the vast majority of the tumor cells (> 80%) in 25 (86%) of 29 AITL cases studied. The tumor cells both within the follicles and in the interfollicular areas stained with similar intensity. All 22 cases expressing CD10 also expressed CXCL13 (Figure 1). In addition, a subset of the macrophages and follicular dendritic cells (FDCs) was labeled by CXCL13. View larger version (157K): [in this window] [in a new window]   Figure 1.. CXCL13 expression in AITL. (A) High-power view of AITL lymph-node biopsy. Typical clusters of tumor cells with clear/pale cytoplasm are present. There is marked microvascular proliferation in the background (hematoxylin and eosin [H&E]). (B) The tumor cells are positive for CD3 (immunoperoxidase). (C) There is variable expression of CD10 (immunoperoxidase). (D) The tumor-cell clusters show strong cytoplasmic expression of CXCL13 with marked paranuclear enhancement (inset, immunoperoxidase). Images were visualized under an Olympus BX51 microscope equipped with UPlanFL x40 (main panels) or x65 (inset) objective lenses and WH 10 x 22 eyepiece (Olympus, Tokyo, Japan). Images were captured with an Olympus DP70 camera and processed with Adobe PhotoShop 7.0 software (Adobe Systems, San Jose, CA).   The expression of CXCL13 by AITL provides another piece of evidence linking the tumor cells to GC-Th cells. Increased CXCL13 message in AITL was also detected by transcription-profiling studies using cDNA chips designed to detect chemokine-gene expression.7 Kim et al1 also reported selective up-regulation of several transcription factors in GC-Th cells. One of these was Bcl-6, which, like CXCL13, is overexpressed in AITL.8 These observations are important in several respects. One of the downstream effects of CXCL13 expression is induction and proliferation of FDCs, probably via stimulation of lymphotoxin-alpha production by B cells.6 Of interest, the proliferation of FDCs is a morphologic hallmark of AITL and is considered to be a requirement for histologic diagnosis.9 Another attribute of AITL is the presence of dysregulated B-cell growth. In early stages, this is primarily seen as follicular hyperplasia3,5; in later stages, a more immunoblastic and plasmacytic expansion with hypergammaglobulinaemia occurs.3,10 As CXCL13 is a critical factor in B-cell recruitment and activation, it may also be responsible for some of the B-cell abnormalities seen in AITL. Marked immune dysregulation, rather than aggressive tumor growth, is thought to be the main clinical problem in AITL, and there are attempts to treat this disease using immunomodulatory approaches.11,12 The information gained by studying normal follicle-center T cells may be helpful in the development of targeted immunomodulatory treatment strategies for this otherwise-fatal condition. The study by Kim et al1 elegantly demonstrates how such critical biologic information on tumors can be acquired by examining the putative cell of origin. Karen L. Grogg, Ayoma D. Attygalle, William R. Macon, Ellen D. Remstein, Paul J. Kurtin, and Ahmet Dogan Correspondence: Ahmet Dogan, Professor of Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55902; e-mail: dogan.ahmet{at}mayo.edu Supported in part by the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) P50 CA97274. K.L.G. performed research, analyzed data, and wrote the paper; A.D.A. performed research and analyzed data; W.R.M. performed research and analyzed data; E.D.R. performed research and analyzed data; P.J.K. designed research and analyzed data; and A.D. designed research, analyzed data, and wrote the paper. References Kim CH, Lim HW, Kim JR, Rott L, Hillsamer P, Butcher EC. Unique gene expression program of human germinal center T helper cells. Blood. 2004;104: 1952-1960.[Abstract/Free Full Text] de Leval L, Savilo E, Longtine J, Ferry JA, Harris NL. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol. 2001;25: 395-400.[Medline] [Order article via Infotrieve] Attygalle A, Al Jehani R, Diss TC, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood. 2002;99: 627-633.[Abstract/Free Full Text] Dogan A, Attygalle A, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol. 2003;121: 681-691.[CrossRef][Medline] [Order article via Infotrieve] Ree HJ, Kadin ME, Kikuchi M, et al. Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. Am J Surg Pathol. 1998;22: 643-655.[CrossRef][Medline] [Order article via Infotrieve] Ansel KM, Ngo VN, Hyman PL, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406: 309-314.[CrossRef][Medline] [Order article via Infotrieve] Ohshima K, Karube K, Kawano R, et al. Classification of distinct subtypes of peripheral T-cell lymphoma unspecified, identified by chemokine and chemokine receptor expression: analysis of prognosis. Int J Oncol. 2004;25: 605-613.[Medline] [Order article via Infotrieve] Ree HJ, Kadin ME, Kikuchi M, Ko YH, Suzumiya J, Go JH. Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Hum Pathol. 1999;30: 403-411.[CrossRef][Medline] [Order article via Infotrieve] Jaffe ES, Ralfkiaer E. Angioimmunoblastic T-cell lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: 225-226. Frizzera G, Moran EM, Rappaport H. Angio-immunoblastic lymphadenopathy with dysproteinaemia. Lancet. 1974;1: 1070-1073.[CrossRef][Medline] [Order article via Infotrieve] Advani R, Warnke R, Sikic BI, Horning S. Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine. Ann Oncol. 1997;8: 601-603.[Free Full Text] Dogan A, Ngu LS, Ng SH, Cervi PL. Pathology and clinical features of angioimmunoblastic T-cell lymphoma after successful treatment with thalidomide. Leukemia. Prepublished on March 3, 2005, as DOI: 10.1038/sj.leu.2403710. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells Laszlo Krenacs, Patrick Schaerli, Gyongyi Kis, and Eniko Bagdi Blood 2006 108: 1110-1111. [Full Text] [PDF] Related Article in Blood Online: Unique gene expression program of human germinal center T helper cells Chang H. Kim, Hyung W. Lim, Jong R. Kim, Lusijah Rott, Peter Hillsamer, and Eugene C. Butcher Blood 2004 104: 1952-1960. [Abstract] [Full Text] [PDF] This article has been cited by other articles: Z H Shah, S Harris, J L Smith, and E Hodges Monoclonality and oligoclonality of T cell receptor {beta} gene in angioimmunoblastic T cell lymphoma J. Clin. Pathol., February 1, 2009; 62(2): 177 - 181. [Abstract] [Full Text] [PDF] H. Yu, A. Shahsafaei, and D. M. Dorfman Germinal-Center T-Helper-Cell Markers PD-1 and CXCL13 Are Both Expressed by Neoplastic Cells in Angioimmunoblastic T-Cell Lymphoma Am J Clin Pathol, January 1, 2009; 131(1): 33 - 41. [Abstract] [Full Text] [PDF] M. C. Picchio, E. Scala, D. Pomponi, E. Caprini, M. Frontani, I. Angelucci, A. Mangoni, C. Lazzeri, M. Perez, D. Remotti, et al. CXCL13 Is Highly Produced by Sezary Cells and Enhances Their Migratory Ability via a Synergistic Mechanism Involving CCL19 and CCL21 Chemokines Cancer Res., September 1, 2008; 68(17): 7137 - 7146. [Abstract] [Full Text] [PDF] N. Mourad, N. Mounier, J. Briere, E. Raffoux, A. Delmer, A. Feller, C. J. L. M. Meijer, J.-F. Emile, R. Bouabdallah, A. Bosly, et al. Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials Blood, May 1, 2008; 111(9): 4463 - 4470. [Abstract] [Full Text] [PDF] L. de Leval and P. Gaulard Pathobiology and Molecular Profiling of Peripheral T-Cell Lymphomas Hematology, January 1, 2008; 2008(1): 272 - 279. [Abstract] [Full Text] [PDF] V. L. Bryant, C. S. Ma, D. T. Avery, Y. Li, K. L. Good, L. M. Corcoran, R. de Waal Malefyt, and S. G. Tangye Cytokine-Mediated Regulation of Human B Cell Differentiation into Ig-Secreting Cells: Predominant Role of IL-21 Produced by CXCR5+ T Follicular Helper Cells J. Immunol., December 15, 2007; 179(12): 8180 - 8190. [Abstract] [Full Text] [PDF] P. P. Piccaluga, C. Agostinelli, A. Califano, A. Carbone, L. Fantoni, S. Ferrari, A. Gazzola, A. Gloghini, S. Righi, M. Rossi, et al. Gene Expression Analysis of Angioimmunoblastic Lymphoma Indicates Derivation from T Follicular Helper Cells and Vascular Endothelial Growth Factor Deregulation Cancer Res., November 15, 2007; 67(22): 10703 - 10710. [Abstract] [Full Text] [PDF] G. Roncador, J.-F. G. Verdes-Montenegro, S. Tedoldi, J. C. Paterson, W. Klapper, E. Ballabio, L. Maestre, S. Pileri, M.-L. Hansmann, M. A. Piris, et al. Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma Haematologica, August 1, 2007; 92(8): 1059 - 1066. [Abstract] [Full Text] [PDF] L. de Leval, D. S. Rickman, C. Thielen, A. d. Reynies, Y.-L. Huang, G. Delsol, L. Lamant, K. Leroy, J. Briere, T. Molina, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells Blood, June 1, 2007; 109(11): 4952 - 4963. [Abstract] [Full Text] [PDF] L. Krenacs, P. Schaerli, G. Kis, and E. Bagdi Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells Blood, August 1, 2006; 108(3): 1110 - 1111. [Full Text] [PDF] E. S. Jaffe Pathobiology of Peripheral T-cell Lymphomas Hematology, January 1, 2006; 2006(1): 317 - 322. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Grogg, K. L. Articles by Dogan, A. Search for Related Content PubMed PubMed Citation Articles by Grogg, K. L. Articles by Dogan, A. 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