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Mantle Cell Lymphoma Stefano A Editorials and Perspectives ers in myeloproliferative diseases: relationships with JAK2 Pascutto C, et al. Relation between JAK2 (V617F) mutation V617 F status, clonality, and antiphospholipid antibodies. J status, granulocyte activation, and constitutive mobilization Thromb Haemost 2007;5:1679-85. of CD34+ cells into peripheral blood in myeloproliferative 17. Falanga A, Marchetti M, Vignoli A, Balducci D, Russo L, disorders. Blood 2006;107:3676-82. Guerini V, et al. V617F JAK-2 mutation in patients with 23. Alvarez-Larrán A, Arellano-Rodrigo E, Reverter JC, essential thrombocythemia: relation to platelet, granulo- Domingo A, Villamor N, Colomer D, et al. Increased cyte, and plasma hemostatic and inflammatory molecules. platelet, leukocyte, and coagulation activation in primary Exp Hematol 2007;35:702-11. myelofibrosis. Ann Hematol 2008;87:269-76. 18. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, 24. Leibundgut EO, Horn MP, Brunold C, Pfanner-Meyer B, Colomer D, Villamor N, Bellosillo B, et al. Platelet turnover, Marti D, Hirsiger H, et al. Hematopoietic and endothelial coagulation factors, and soluble markers of platelet and progenitor cell trafficking in patients with myeloprolifera- endothelial activation in essential thrombocythemia: rela- tive diseases. Haematologica 2006;91:1465-72. tionship with thrombosis occurrence and JAK2 V617F allele 25. Sozer S, Fiel MI, Schiano T, Xu M, Mascarenhas J, Hoffman burden. Am J Hematol 2009;84:102-8. R. The presence of JAK2V617F mutation in the liver 19. Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk endothelial cells of patients with Budd-Chiari syndrome. HM, ten Cate H, Leyte A, et al. Elevated procoagulant Blood 2009;113:5246-9. microparticles expressing endothelial and platelet markers 26. Pieri L, Bogani C, Guglielmelli P, Zingariello M, Rana RA, in essential thrombocythemia. Haematologica 2009; Bartalucci N, et al. The JAK2V617F mutation induces consti- 94:911-8. tutive activation and agonist hypersensitivity in basophils of 20. Marchetti M, Castoldi E, Spronk HM, van OR, Balducci D, polycythemia vera. Haematologica 2009;94:1537-475. Barbui T, et al. Thrombin generation and activated protein 27. Wang J, Ishii T, Zhang W, Sozer S, Dai Y, Mascarenhas J, et C resistance in patients with essential thrombocythemia al. Involvement of mast cells by the malignant process in and polycythemia vera. Blood 2008;112:4061-8. patients with Philadelphia chromosome negative myelopro- 21. Kornberg A, Rahimi-Levene N, Yona R, Mor A, liferative neoplasms. Leukemia 23:1577-86. Rachmilewitz EA. Enhanced generation of monocyte tissue 28. Ishii T, Wang J, Zhang W, Mascarenhas J, Hoffman R, Dai Y, factor and increased plasma prothrombin fragment 1+2 lev- et al. Pivotal role of mast cells in pruritogenesis in patients els in patients with polycythemia vera: mechanism of acti- with myeloproliferative disorders. Blood 2009;113:5942-50. vation of blood coagulation. Am J Hematol 1997;56:5-11. 29. Kovanen PT. Mast cells: multipotent local effector cells in 22. Passamonti F, Rumi E, Pietra D, la Porta MG, Boveri E, atherothrombosis. Immunol Rev 2007;217:105-22. Mantle cell lymphoma Stefano A. Pileri1 and Brunangelo Falini2 1Department of Haematology and Oncological Sciences “L. and A. Seràgnoli”, Chair of Pathology and Haemolymphopathology Unit, Bologna University School of Medicine; 2Department of Haematology, Laboratory of Hematopathology, Perugia University School of Medicine. E-mail: stefano.pileri@unibo.it doi:10.3324/haematol.2009.013359 n 1982, Weisenburger et al. first introduced the con- its first experiment to overcome the discrepancies in cept of mantle-zone lymphoma.1 According to the ter- terms of lymphoma classification that had hampered Iminology used at that time, this was regarded as a communication across the Atlantic for some decades.5 In variant of intermediate lymphocytic lymphoma that pro- particular, the American and European ILSG members liferated as wide mantles around non-neoplastic appear- agreed on the existence of a tumor derived from mantle ing germinal centers (GC). One year later, Swerdlow et al. B cells that was consequently termed mantle-cell lym- found that the pattern described above was part of the phoma (MCL). The criteria for its recognition were draft- spectrum of the centrocytic lymphoma of the Kiel ed and included 2 years later in the Revised European- Classification and might correspond to initial lymph American Lymphoma Classification that led the way to node involvement by the tumor.2,3 In 1985, Pileri et al. the latest edition of the World Health Organization reported on 18 cases of small B-cell lymphomas display- (WHO) Classification of Tumours of Haematopoietic ing a mantle-fashion growth around reactive GC, which and Lymphoid Tissues.6,7 The present article will focus on turned out to be quite heterogeneous on closer examina- the diagnosis and bio-pathology of MCL in the light of tion.4 In fact, at disease presentation 13 of the 18 cases the criteria of the WHO Classification7 and recent reports displayed cytological and immunological findings consis- in the literature including those of Quintinilla-Martinez et tent with centrocytic lymphoma, while the remaining al., Mozos et al. and Dictor et al. in this issue of the jour- ones corresponded to neoplasms that nowadays would nal.8-10 It will not include the still ongoing debate on the be diagnosed as marginal zone lymphoma. Interestingly, multiple options proposed for the treatment of MCL the centrocytic lymphomas were CD5+, FMC7+ and patients, which often have limited efficacy (comprehen- CD10– and showed progression to a diffuse growth pat- sively reviewed by Ghielmini et al.).11 tern in follow-up biopsies. Two important conclusions were reached: (i) the mantle-fashion growth was pro- Definition duced by different types of B-cell lymphoma and could MCL is a distinct entity, representing from 3-10% of not be used as a diagnostic criterion, and (ii) conversely non-Hodgkin’s lymphomas and more frequently affect- to what is reported in the Kiel Classification,3 centrocyt- ing middle-aged to older males (male:female ratio = 2- ic lymphomas are derived from a normal counterpart 7:1).7,12 It is listed among peripheral B-cell lymphomas, is other than GC, possibly related to mantle cells. In 1992, usually composed of small to medium-sized elements the International Lymphoma Study Group (ILSG) made with irregular nuclear contours and CCDN1 transloca- | 1488 | haematologica | 2009; 94(11) Editorials and Perspectives tion, and is thought to stem from peripheral B cells of rarely representing morphological progression of the the inner mantle-zone of secondary follicles, mostly of disease. The small cell variant is composed of small, naïve pre-GC type.7,12 MCL is generally regarded as an round lymphocytes with more clumped chromatin, aggressive, incurable disease with the median survival mimicking chronic lymphocytic leukemia/small lym- of affected patients being 3-4 years.12 phocytic lymphoma. Occasionally, the small lym- phomatous elements can be almost exclusively restrict- Clinical features ed to the inner mantle zones or to narrow mantles, a MCL more often presents in stage III-IV with lym- pattern termed in situ MCL and thought to have a more phadenopathy, hepatosplenomegaly, bone-marrow indolent behavior.15 Finally, the marginal zone-like sub- involvement, and leukemic spread.7,12 The latter two type displays prominent foci of cells with abundant pale findings can be missed by morphological studies alone cytoplasm resembling marginal zone or monocytoid B- and are shown by, respectively, immunohistochemistry elements.7,12 Notably, these cases are at times character- and FACS analysis in most if not all instances.7,12 ized by splenomegaly, intrasinusoidal bone-marrow Waldayer’s ring and the gastro-intestinal tract are fre- infiltration and a leukemic picture in the absence of quently affected.7,12 Most cases of multiple lymphoma- lymph node involvement. They can be easily confused tous polyposis correspond to MCL. with splenic marginal zone lymphoma and seem to have a very indolent course. As for in situ MCL, the diag- Morphology nosis of this rare form of the tumor is feasible only upon MCL usually consists of small to medium-sized lym- immunohistochemical detection of cyclin D1 (see phoid elements with irregular nuclear contours, some- below). what dispersed chromatin, inconspicuous nucleoli, and scant cytoplasm.7,12,13 Within this context, centroblasts, Immunophenotype immunoblasts, prolymphocytes and para-immuno- MCL is characterized by expression of the B-cell blasts are not encountered. This is relevant for the dif- markers CD19, CD20, CD22, CD79a and ferential diagnosis from follicular lymphoma, lympho- BSAP/PAX5.7,12,13 Notably, CD20 is strongly expressed plasmacytic lymphoma and chronic lymphocytic on the surface of neoplastic cells, a feature that can be leukemia/small lymphocytic lymphoma, which by def- useful for the differential diagnosis from chronic lym- inition, contain centroblasts, immunoblasts and prolym- phocytic leukemia/small lymphocytic lymphoma, phocytes/para-immunoblasts, respectively. Comprised which shows weak CD20 positivity in the small cell within the neoplastic population, hyaline small vessels component.13 The search for immunoglobulin (Ig) heavy and/or epithelioid histiocytes are frequently found. and light chains usually reveals IgM/D positivity with Clusters of plasma cells can be seen: they are usually more frequent lambda restriction.7,12 Neoplastic cells are reactive
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