The Prognostic Role of Genetic Aberrations in Mantle Cell Lymphoma: A Literature Review and Clinical Experience

EV Kleina1, SV Voloshin1,2, YuS Vokueva1, OD Petukhova1, EV Motyko1, MP Bakai1, DV Kustova1, AN Kirienko1, SYu Linnikov1, EV Karyagina3, OS Uspenskaya4, IS Zyuzgin5, SV Sidorkevich1, IS Martynkevich1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva ul., Saint Petersburg, Russian Federation, 194044

3 Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205

4 Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

5 NN Petrov National Medical Cancer Research Center, 68 Leningradskaya ul., Pesochnyi pos., Saint Petersburg, Russian Federation, 197758

For correspondence: Elizaveta Vyacheslavovna Kleina, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; e-mail:

For citation: Kleina EV, Voloshin SV, Vokueva YuS, et al. The Prognostic Role of Genetic Aberrations in Mantle Cell Lymphoma: A Literature Review and Own Experience. Clinical oncohematology. 2023;16(2):213–26. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-213-226


Mantle cell lymphoma (MCL) is a type of peripheral B-cell non-Hodgkin’s lymphoma characterized by constitutive cyclin D1 overexpression leading to cell-cycle dysregulation and disruption of DNA damage repair. Apart from the typical translocation t(11;14)(q13;q32) and more rare variants, such as t(2;11)(p11;q13) and t(11;22)(q13;q11), a considerable number of patients quite often show secondary molecular and chromosomal aberrations underlying heterogeneity of the clinical course of MCL. Among a wide range of molecular genetic abnormalities, particular attention during the last years has been concentrated on studying the so-called double-hit MCL within a subgroup of patients with translocations involving CCND1 and MYC genes. Double-hit MCL is distinguished with rapid progression and tumor generalization at the time of diagnosis. Poor prognosis and low survival rates in most MCL patients call for the fastest possible diagnosis. Morphological and immunohistochemical as well as genetic methods (standard cytogenetic technique and fluorescence in situ hybridization) contribute to improving the quality of evidence-based diagnosis. The results of comprehensive diagnostic studies optimize prognosis assessment and treatment decision making in clinic.

Keywords: mantle cell lymphoma, double-hit MCL, karyotype, genetic aberrations, prognostic factors.

Received: August 16, 2022

Accepted: February 27, 2023

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  1. Kallen ME, Rao NP, Kulkarni SK, et al. B-lymphoblastic transformation of mantle cell lymphoma/leukemia with “double hit” changes. J Hematopathol. 2015;8(1):31–6. doi: 10.1007/s12308-014-0229-9.
  2. Geling Li, Zhou Yi, Sindhu Ch, et al. An unusual case of co-existing classic mantle cell lymphoma and transformed lymphoma with Burkitt-like features with leukemic presentation. J Hematopathol. 2016;9(2):91–9. doi: 10.1007/s12308-016-0274-7.
  3. Delas A, Sophie D, Brousset P, Laurent C. Unusual concomitant rearrangements of Cyclin D1 and MYC genes in blastoid variant of mantle cell lymphoma: Case report and review of literature. Pathol Res Pract. 2013;209(2):115–9. doi: 10.1016/j.prp.2012.12.001.
  4. Sarkozy C, Terre C, Jardin F, et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index. Genes Chromosomes Cancer. 2014;53(1):106–16. doi: 10.1002/gcc.22123.
  5. Oka K, Ohno T, Kita K, et al. PRAD1 gene over-expression in mantle-cell lymphoma but not in other low-grade B-cell lymphomas, including extranodal lymphoma. Br J Haematol. 1994;86(4):786–91. doi: 10.1111/j.1365-2141.1994.tb04830.x.
  6. Rule S. The modern approach to mantle cell lymphoma. Hematol Oncol. 2019;37(1):66–9. doi: 10.1002/hon.2596.
  7. 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(8):1530–3. doi: 10.1182/blood-2009-08-236570.
  8. Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806–13. doi: 10.1002/ajh.24797.
  9. Ladha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its management: where are we now? Exp Hematol Oncol. 2019;8:2. doi: 10.1186/s40164-019-0126-0.
  10. Sander B, Quintanilla-Martinez L, Ott G, et al. Mantle cell lymphoma – a spectrum from indolent to aggressive disease. Virchows Arch. 2016;468(3):245–57. doi: 10.1007/s00428-015-1840-6.
  11. Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647–56. doi: 10.1182/blood-2018-03-791392.
  12. Hoster E, Dreyling M, Klapper W, et al. German Low Grade Lymphoma Study Group (GLSG); European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558–65. doi: 10.1182/blood-2007-06-095331.
  13. Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Haematol. 1974;3:39–45.
  14. Miao Y, Lin P, Wang W, et al. CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma. Am J Clin Pathol. 2016;146(6):747–52. doi: 10.1093/ajcp/aqw194.
  15. Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. doi: 10.1186/s13045-020-00914-1.
  16. Reya T, O’Riordan M, Okamura R, et al. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity. 2000;13(1):15–24. doi: 10.1016/s1074-7613(00)00004-2.
  17. Tandon B, Peterson L, Gao J, et al. Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas. Mod Pathol. 2011;24(11):1433–43. doi: 10.1038/modpathol.2011.103.
  18. Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol. 2015;68(6):473–8. doi: 10.1136/jclinpath-2015-202862.
  19. Walther N, Ulrich A, Vockerodt M, et al. Aberrant lymphocyte enhancer-binding factor 1 expression is characteristic for sporadic Burkitt’s lymphoma. Am J Pathol. 2013;182(4):1092–8. doi: 10.1016/j.ajpath.2012.12.013.
  20. Mozos A, Royo C, Hartmann E. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94(11):1555–62. doi: 10.3324/haematol.2009.010264.
  21. Lord M, Wasik AM, Christensson B, et al. The utility of mRNA analysis in defining SOX11 expression levels in mantle cell lymphoma and reactive lymph nodes. Haematologica. 2015;100(9):369–72. doi: 10.3324/haematol.2015.123885.
  22. Ek S, Dictor M, Jerkeman M, et al. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008;111(2):800–5. doi: 10.1182/blood-2007-06-093401.
  23. Wang X, Asplund AC, Porwit A. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br J Haematol. 2008;143(2):248–52. doi: 10.1111/j.1365-2141.2008.07329.x.
  24. Royo C, Salaverria I, Hartmann EM, et al. The complex landscape of genetic alterations in mantle cell lymphoma. Semin Cancer Biol. 2011;21(5):322–34. doi: 10.1016/j.semcancer.2011.09.007.
  25. Klapper W, Hoster E, Determann O, et al. Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network. J Hematop. 2009;2(2):103–11. doi: 10.1007/s12308-009-0036-x.
  26. Jares P, Colomer, D, Campo E, et al. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012;122(10):3416–23. doi: 10.1172/JCI61272.
  27. Ishigaki T, Sasaki K, Watanabe K, et al. Amplification of IGH/CCND1 fusion gene in a primary plasma cell leukemia case. Cancer Genet Cytogenet. 2010;201(1):62–5. doi: 10.1016/j.cancergencyto.2010.05.006.
  28. Lovec H, Grzeschiczek A, Kowalski MB, et al. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J. 1994;13(15):3487–95. doi: 10.1002/j.1460-2075.1994.tb06655.x.
  29. Wang L, Tang G, Medeiros LJ, et al. MYC rearrangement but not extra MYC copies is an independent prognostic factor in patients with mantle cell lymphoma. Haematologica. 2021;106(5):1381–9. doi: 10.3324/haematol.2019.243071.
  30. Espinet B, Salaverria I, Bea S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosomes Cancer. 2010;49(5):439–51. doi: 10.1002/gcc.20754.
  31. Nordstrom L, Sernbo S, Eden P, et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma–a Nordic Lymphoma Group study. Br J Haematol. 2014;166(1):98–108. doi: 10.1111/bjh.12854.
  32. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319–31. doi: 10.1182/blood-2010-09-297879.
  33. Boerma EG, Siebert R, Kluin PM, et al. Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge. Leukemia. 2009;23(2):225–34. doi: 10.1038/leu.2008.281.
  34. Gruszka-Westwood AM, Atkinson S, Summersgill BM, et al. Unusual case of leukemic mantle cell lymphoma with amplified CCND1/IGH fusion gene. Genes Chromosomes Cancer. 2002;33(2):206–12. doi: 10.1002/gcc.1216.
  35. Greenwell IB, Staton AD, Lee MJ, et al. Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy. Cancer. 2018;124(11):2306–15. doi: 10.1002/cncr.31328.
  36. Halldorsdottir AM, Lundin A, Murray F, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011;25(12):1904–8. doi: 10.1038/leu.2011.162.
  37. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27(8):1209–13. doi: 10.1200/JCO.2008.19.6121.
  38. Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017;28(10):2489–95. doi: 10.1093/annonc/mdx333.
  39. Adam P, Schiefer AI, Prill S, et al. Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues. Mod Pathol. 2012;25(12):1629–36. doi: 10.1038/modpathol.2012.117.
  40. Espinet B, Ferrer A, Bellosillo B, et al. Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry. Clin Cancer Res. 2014;20(4):1007–19. doi: 10.1158/1078-0432.CCR-13-1077.
  41. Lecluse Y, Lebailly P, Roulland S, et al. t(11;14)-positive clones can persist over a long period of time in the peripheral blood of healthy individuals. Leukemia. 2009;23(6):1190–3. doi: 10.1038/leu.2009.31.
  42. Karube K, Scarfo L, Campo E, Ghia P. Monoclonal B cell lymphocytosis and “in situ” lymphoma. Semin Cancer Biol. 2014;24:3–14. doi: 10.1016/j.semcancer.2013.08.003.
  43. Racke F, Simpson S, Christian B, et al. Evidence of Long Latency Periods Prior to Development of Mantle Cell Lymphoma. Blood. 2010;116(21):323. doi: 10.1182/blood.V116.21.323.323.
  44. Edlefsen KL, Greisman HA, Yi HS, et al. Early lymph node involvement by mantle cell lymphoma limited to the germinal center: report of a case with a novel “follicular in situ” growth pattern. Am J Clin Pathol. 2011;136(2):276–81. doi: 10.1309/AJCP6KFFGTC8PLVR.
  45. Chapman-Fredricks J, Sandoval-Sus J, Vega F, et al. Progressive leukemic non-nodal mantle cell lymphoma associated with deletions of TP53, ATM, and/or 13q14. Ann Diagn Pathol. 2014;18(4):214–9. doi: 10.1016/j.anndiagpath.2014.03.006.