Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma

Arnold S Freedman, MD
Jon C Aster, MD
Section Editor
Andrew Lister, MD, FRCP, FRCPath, FRCR
Deputy Editor
Alan G Rosmarin, MD


Mantle cell lymphoma (MCL) is one of the mature B cell non-Hodgkin lymphomas (NHL) [1-5]. (See "Classification of the hematopoietic neoplasms".) While it is often discussed together with the clinically indolent forms of NHL, its behavior is more often that of an aggressive disease.

MCL has been previously referred to as intermediate lymphocytic lymphoma, mantle zone lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation [6,7]. In the Rappaport and Working Formulation classifications, the majority of cases of diffuse small cleaved cell lymphomas on re-review were found to be MCLs; however, cases were also found in the small lymphocytic and follicular categories [2]. These misclassifications stemmed from cases with ambiguous morphologies, emphasizing the importance of immunophenotyping in the diagnosis of MCL. (See 'Immunophenotype' below.)

The epidemiology, clinical presentation, pathology, diagnosis, and prognosis of MCL will be discussed here. The pathobiology and treatment of this NHL variant are presented separately. (See "Initial treatment of mantle cell lymphoma" and "Pathobiology of mantle cell lymphoma".)


Mantle cell lymphoma comprises about 7 percent of adult non-Hodgkin lymphomas in the United States and Europe with an incidence of approximately 4 to 8 cases per million persons per year [3,8-12]. Incidence increases with age and appears to be increasing overall in the United States [13]. Approximately three-quarters of patients are male and Caucasians are affected almost twice as frequently as Blacks. Median age at diagnosis is 68 years.


Mantle cell lymphoma (MCL) is thought to have two distinct cellular origins, each giving rise to different forms of the disease [14]:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Nov 02, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361.
  2. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835.
  3. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16:2780.
  4. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  6. Weisenburger DD, Kim H, Rappaport H. Mantle-zone lymphoma: a follicular variant of intermediate lymphocytic lymphoma. Cancer 1982; 49:1429.
  7. Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood 1987; 69:1617.
  8. Lennert K. Malignant lymphomas other than Hodgkin's disease, Springer-Verlag, New York 1978.
  9. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89:3909.
  10. Shivdasani RA, Hess JL, Skarin AT, Pinkus GS. Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma. J Clin Oncol 1993; 11:802.
  11. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116:3724.
  12. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 2011; 105:1684.
  13. Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer 2008; 113:791.
  14. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 2012; 122:3416.
  15. Argatoff LH, Connors JM, Klasa RJ, et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 1997; 89:2067.
  16. Romaguera JE, Medeiros LJ, Hagemeister FB, et al. Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer 2003; 97:586.
  17. Ferrer A, Salaverria I, Bosch F, et al. Leukemic involvement is a common feature in mantle cell lymphoma. Cancer 2007; 109:2473.
  18. Isaacson PG, MacLennan KA, Subbuswamy SG. Multiple lymphomatous polyposis of the gastrointestinal tract. Histopathology 1984; 8:641.
  19. Chim CS, Hu WH, Loong F, et al. GI manifestations of mantle cell lymphoma. Gastrointest Endosc 2003; 58:931.
  20. Ruskoné-Fourmestraux A, Delmer A, Lavergne A, et al. Multiple lymphomatous polyposis of the gastrointestinal tract: prospective clinicopathologic study of 31 cases. Groupe D'étude des Lymphomes Digestifs. Gastroenterology 1997; 112:7.
  21. Pittaluga S, Verhoef G, Criel A, et al. "Small" B-cell non-Hodgkin's lymphomas with splenomegaly at presentation are either mantle cell lymphoma or marginal zone cell lymphoma. A study based on histology, cytology, immunohistochemistry, and cytogenetic analysis. Am J Surg Pathol 1996; 20:211.
  22. Oinonen R, Franssila K, Elonen E. Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 1999; 78:145.
  23. Gill S, Herbert KE, Prince HM, et al. Mantle cell lymphoma with central nervous system involvement: frequency and clinical features. Br J Haematol 2009; 147:83.
  24. Cheah CY, George A, Giné E, et al. Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann Oncol 2013; 24:2119.
  25. Zukerberg LR, Medeiros LJ, Ferry JA, Harris NL. Diffuse low-grade B-cell lymphomas. Four clinically distinct subtypes defined by a combination of morphologic and immunophenotypic features. Am J Clin Pathol 1993; 100:373.
  26. Lardelli P, Bookman MA, Sundeen J, et al. Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations. Am J Surg Pathol 1990; 14:752.
  27. Ott MM, Ott G, Kuse R, et al. The anaplastic variant of centrocytic lymphoma is marked by frequent rearrangements of the bcl-1 gene and high proliferation indices. Histopathology 1994; 24:329.
  28. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol 1992; 16:637.
  29. Dorfman DM, Pinkus GS. Distinction between small lymphocytic and mantle cell lymphoma by immunoreactivity for CD23. Mod Pathol 1994; 7:326.
  30. Bosch F, López-Guillermo A, Campo E, et al. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer 1998; 82:567.
  31. Kaptain S. CD5-negative mantle cell lymphoma. Mod Pathol 1998.
  32. DiRaimondo F, Albitar M, Huh Y, et al. The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease. Cancer 2002; 94:1721.
  33. Stein H, Lennert K, Feller AC, Mason DY. Immunohistological analysis of human lymphoma: correlation of histological and immunological categories. Adv Cancer Res 1984; 42:67.
  34. Harris NL, Nadler LM, Bhan AK. Immunohistologic characterization of two malignant lymphomas of germinal center type (centroblastic/centrocytic and centrocytic) with monoclonal antibodies. Follicular and diffuse lymphomas of small-cleaved-cell type are related but distinct entities. Am J Pathol 1984; 117:262.
  35. Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 2009; 94:1555.
  36. Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res 2012; 72:5307.
  37. Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. Blood 2013; 121:1394.
  38. Mynster T, Hultberg B, Bülow S. Multiple lymphomatous polyposis of the colon and rectum. Report of a case and review of the literature. Scand J Gastroenterol 1994; 29:545.
  39. Hashimoto Y, Nakamura N, Kuze T, et al. Multiple lymphomatous polyposis of the gastrointestinal tract is a heterogenous group that includes mantle cell lymphoma and follicular lymphoma: analysis of somatic mutation of immunoglobulin heavy chain gene variable region. Hum Pathol 1999; 30:581.
  40. Yang WI, Zukerberg LR, Motokura T, et al. Cyclin D1 (Bcl-1, PRAD1) protein expression in low-grade B-cell lymphomas and reactive hyperplasia. Am J Pathol 1994; 145:86.
  41. Zukerberg LR, Yang WI, Arnold A, Harris NL. Cyclin D1 expression in non-Hodgkin's lymphomas. Detection by immunohistochemistry. Am J Clin Pathol 1995; 103:756.
  42. Swerdlow SH, Yang WI, Zukerberg LR, et al. Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene. Hum Pathol 1995; 26:999.
  43. Cheuk W, Wong KO, Wong CS, Chan JK. Consistent immunostaining for cyclin D1 can be achieved on a routine basis using a newly available rabbit monoclonal antibody. Am J Surg Pathol 2004; 28:801.
  44. Liu Z, Dong HY, Gorczyca W, et al. CD5- mantle cell lymphoma. Am J Clin Pathol 2002; 118:216.
  45. Yatabe Y, Suzuki R, Tobinai K, et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood 2000; 95:2253.
  46. de Boer CJ, Vaandrager JW, van Krieken JH, et al. Visualization of mono-allelic chromosomal aberrations 3' and 5' of the cyclin D1 gene in mantle cell lymphoma using DNA fiber fluorescence in situ hybridization. Oncogene 1997; 15:1599.
  47. Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 2007; 109:4599.
  48. Wlodarska I, Dierickx D, Vanhentenrijk V, et al. Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas. Blood 2008; 111:5683.
  49. Lovec H, Grzeschiczek A, Kowalski MB, Möröy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994; 13:3487.
  50. Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood 2005; 106:4315.
  51. Walsh SH, Thorsélius M, Johnson A, et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma. Blood 2003; 101:4047.
  52. Camacho FI, Algara P, Rodríguez A, et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations. Blood 2003; 101:4042.
  53. Hummel M, Tamaru J, Kalvelage B, Stein H. Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood 1994; 84:403.
  54. Bertoni F, Zucca E, Cotter FE. Molecular basis of mantle cell lymphoma. Br J Haematol 2004; 124:130.
  55. Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol 1999; 36:115.
  56. Tsujimoto Y, Yunis J, Onorato-Showe L, et al. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 1984; 224:1403.
  57. De Wolf-Peeters C, Pittaluga S. Mantle-cell lymphoma. Ann Oncol 1994; 5 Suppl 1:35.
  58. Boehm T, Baer R, Lavenir I, et al. The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. EMBO J 1988; 7:385.
  59. Panayiotidis P, Kotsi P. Genetics of small lymphocyte disorders. Semin Hematol 1999; 36:171.
  60. Vandenberghe E, De Wolf-Peeters C, van den Oord J, et al. Translocation (11;14): a cytogenetic anomaly associated with B-cell lymphomas of non-follicle centre cell lineage. J Pathol 1991; 163:13.
  61. Rosenberg CL, Wong E, Petty EM, et al. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci U S A 1991; 88:9638.
  62. Bertoni F, Rinaldi A, Zucca E, Cavalli F. Update on the molecular biology of mantle cell lymphoma. Hematol Oncol 2006; 24:22.
  63. Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 2012; 119:1963.
  64. Quintanilla-Martinez L, Davies-Hill T, Fend F, et al. Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis. Blood 2003; 101:3181.
  65. Hofmann WK, de Vos S, Tsukasaki K, et al. Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood 2001; 98:787.
  66. Delfau-Larue MH, Klapper W, Berger F, et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood 2015; 126:604.
  67. Parry-Jones N, Matutes E, Morilla R, et al. Cytogenetic abnormalities additional to t(11;14) correlate with clinical features in leukaemic presentation of mantle cell lymphoma, and may influence prognosis: a study of 60 cases by FISH. Br J Haematol 2007; 137:117.
  68. Greiner TC, Moynihan MJ, Chan WC, et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87:4302.
  69. Ott G, Kalla J, Ott MM, et al. Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. Blood 1997; 89:1421.
  70. Dreyling MH, Bullinger L, Ott G, et al. Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res 1997; 57:4608.
  71. Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 2017; 130:1903.
  72. Tirier C, Zhang Y, Plendl H, et al. Simultaneous presence of t(11;14) and a variant Burkitt's translocation in the terminal phase of a mantle cell lymphoma. Leukemia 1996; 10:346.
  73. Nagy B, Lundán T, Larramendy ML, et al. Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol 2003; 120:434.
  74. Cuneo A, Bigoni R, Rigolin GM, et al. Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features. Blood 1999; 93:1372.
  75. Espinet B, Solé F, Woessner S, et al. Translocation (11;14)(q13;q32) and preferential involvement of chromosomes 1, 2, 9, 13, and 17 in mantle cell lymphoma. Cancer Genet Cytogenet 1999; 111:92.
  76. Monni O, Oinonen R, Elonen E, et al. Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma. Genes Chromosomes Cancer 1998; 21:298.
  77. Martinez-Climent JA, Vizcarra E, Sanchez D, et al. Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma. Blood 2001; 98:3479.
  78. Allen JE, Hough RE, Goepel JR, et al. Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization. Br J Haematol 2002; 116:291.
  79. Sun T, Nordberg ML, Cotelingam JD, et al. Fluorescence in situ hybridization: method of choice for a definitive diagnosis of mantle cell lymphoma. Am J Hematol 2003; 74:78.
  80. Schraders M, Pfundt R, Straatman HM, et al. Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide array-based comparative genomic hybridization. Blood 2005; 105:1686.
  81. Ghobrial IM, McCormick DJ, Kaufmann SH, et al. Proteomic analysis of mantle-cell lymphoma by protein microarray. Blood 2005; 105:3722.
  82. Rubio-Moscardo F, Climent J, Siebert R, et al. Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. Blood 2005; 105:4445.
  83. Rizzatti EG, Falcão RP, Panepucci RA, et al. Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways. Br J Haematol 2005; 130:516.
  84. Rinaldi A, Kwee I, Taborelli M, et al. Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br J Haematol 2006; 132:303.
  85. Salaverria I, Zettl A, Beà S, et al. Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature. J Clin Oncol 2007; 25:1216.
  86. Kienle D, Katzenberger T, Ott G, et al. Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors. J Clin Oncol 2007; 25:2770.
  87. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  88. Carvajal-Cuenca A, Sua LF, Silva NM, et al. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior. Haematologica 2012; 97:270.
  89. Barna G, Reiniger L, Tátrai P, et al. The cut-off levels of CD23 expression in the differential diagnosis of MCL and CLL. Hematol Oncol 2008; 26:167.
  90. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 2008; 111:558.
  91. Møller MB, Pedersen NT, Christensen BE. Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index. Br J Haematol 2006; 133:43.
  92. Fisher RI, Dahlberg S, Nathwani BN, et al. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 1995; 85:1075.
  93. Meusers P, Engelhard M, Bartels H, et al. Multicentre randomized therapeutic trial for advanced centrocytic lymphoma: anthracycline does not improve the prognosis. Hematol Oncol 1989; 7:365.
  94. Berger F, Felman P, Sonet A, et al. Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood 1994; 83:2829.
  95. Matutes E, Parry-Jones N, Brito-Babapulle V, et al. The leukemic presentation of mantle-cell lymphoma: disease features and prognostic factors in 58 patients. Leuk Lymphoma 2004; 45:2007.
  96. Andersen NS, Jensen MK, de Nully Brown P, Geisler CH. A Danish population-based analysis of 105 mantle cell lymphoma patients: incidences, clinical features, response, survival and prognostic factors. Eur J Cancer 2002; 38:401.
  97. Räty R, Franssila K, Jansson SE, et al. Predictive factors for blastoid transformation in the common variant of mantle cell lymphoma. Eur J Cancer 2003; 39:321.
  98. Tiemann M, Schrader C, Klapper W, et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol 2005; 131:29.
  99. Hartmann E, Fernàndez V, Moreno V, et al. Five-gene model to predict survival in mantle-cell lymphoma using frozen or formalin-fixed, paraffin-embedded tissue. J Clin Oncol 2008; 26:4966.
  100. Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood 2010; 115:1530.
  101. Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol 2014; 32:1338.
  102. Furtado M, Shah N, Levoguer A, et al. Abnormal serum free light chain ratio predicts poor overall survival in mantle cell lymphoma. Br J Haematol 2013; 160:63.
  103. Katzenberger T, Petzoldt C, Höller S, et al. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 2006; 107:3407.
  104. Garcia M, Romaguera JE, Inamdar KV, et al. Proliferation predicts failure-free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabine. Cancer 2009; 115:1041.
  105. Hoster E, Rosenwald A, Berger F, et al. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. J Clin Oncol 2016; 34:1386.