Molecular Etiopathogenesis of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

  • Alexander JA DeutschEmail author
  • Katharina Troppan
  • Karoline Fechter
  • Peter Neumeister


Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue, also known as MALT lymphomas. MALT lymphomas arise at several different extranodal sites, with the highest frequency in the stomach, followed by the lung, ocular adnexa and thyroid, and with a low percentage in the small intestine. Interestingly, at least three different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all affecting the NF-κB signal pathway-related genes, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, i.e. the association with chronic bacterial or autoaggressive infections. This chapter mainly discusses the genetic aberration and the association with chronic infections of MALT lymphomas and summarizes recent advances in the molecular pathogenesis and therapeutic advances of MALT lymphoma.


Pylorus Eradication Malt Lymphoma Class Switching Recombination Gastric Malt Lymphoma Splenic Marginal Zone Lymphoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52:1410–6.PubMedCrossRefGoogle Scholar
  2. 2.
    The Non-Hodgkin’s Lymphoma Classification. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909–18.Google Scholar
  3. 3.
    Addis BJ, Hyjek E, Isaacson PG. Primary pulmonary lymphoma: a re-appraisal of its histogenesis and its relationship to pseudolymphoma and lymphoid interstitial pneumonia. Histopathology. 1988;13:1–17.PubMedCrossRefGoogle Scholar
  4. 4.
    Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol. 1988;19:1315–26.PubMedCrossRefGoogle Scholar
  5. 5.
    Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialadenitis. Hum Pathol. 1988;19:766–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Isaacson P, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer. 1984;53:2515–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Isaacson PG, Du M-Q. MALT lymphoma: from morphology to molecules. Nat Rev Cancer. 2004;4:644.PubMedCrossRefGoogle Scholar
  8. 8.
    Isaacson PG. WHO classification of tumours: pathology and genetics tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.Google Scholar
  9. 9.
    Isaacson PG, Wotherspoon AC, Diss T, Pan LX. Follicular colonization in B-cell lymphoma of mucosa-associated lymphoid tissue. Am J Surg Pathol. 1991;15:819.PubMedCrossRefGoogle Scholar
  10. 10.
    Cogliatti SB. Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology. 1991;101:1159.PubMedCrossRefGoogle Scholar
  11. 11.
    Thieblemont C, Berger F, Dumontet C, Moullet I, Bouafia F, Felman P, Salles G, Coiffier B. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95:802–6.PubMedGoogle Scholar
  12. 12.
    Lopez-Guillermo A, Colomo L, Jimenez M, Bosch F, Villamor N, Arenillas L, Muntanola A, Montoto S, Gine E, Colomer D, Bea S, Campo E, Montserrat E. Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin. J Clin Oncol. 2005;23:2797–804.PubMedCrossRefGoogle Scholar
  13. 13.
    Chan JK, Ng CS, Isaacson PG. Relationship between high-grade lymphoma and low-grade B-cell mucosa-associated lymphoid tissue lymphoma (MALToma) of the stomach. Am J Pathol. 1990;136:1153.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Villuendas R, Piris MA, Orradre JL, Mollejo M, Rodriguez R, Morente M. Different bcl-2 protein expression in high-grade B-cell lymphomas derived from lymph node or mucosa-associated lymphoid tissue. Am J Pathol. 1991;139:989–93.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ruskone-Fourmestraux A, Fischbach W, Aleman BM, Boot H, Du MQ, Megraud F, Montalban C, Raderer M, Savio A, Wotherspoon A, Group E. EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut. 2011;60:747–58.PubMedCrossRefGoogle Scholar
  16. 16.
    Zucca E, Copie-Bergman C, Ricardi U, Thieblemont C, Raderer M, Ladetto M, GROUP, E. G. W. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl. 6):vi144–8.PubMedGoogle Scholar
  17. 17.
    Raderer M, Wohrer S, Streubel B, Troch M, Turetschek K, Jager U, Skrabs C, Gaiger A, Drach J, Puespoek A, Formanek M, Hoffmann M, Hauff W, Chott A. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24:3136–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Ruskone-Fourmestraux A, Lavergne A, Aegerter PH, Megraud F, Palazzo L, De Mascarel A, Molina T, Rambaud JL. Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment. Gut. 2001;48:297–303.PubMedCrossRefGoogle Scholar
  19. 19.
    Musshoff K. Clinical staging classification of non-Hodgkin’s lymphomas (author’s transl). Strahlentherapie. 1977;153:218–21.PubMedGoogle Scholar
  20. 20.
    Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterology. 1992;102:1628–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Ruskone-Fourmestraux A, Dragosics B, Morgner A, Wotherspoon A, De Jong D. Paris staging system for primary gastrointestinal lymphomas. Gut. 2003;52:912–3.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Lebien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112:1570–80.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Nagasawa T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol. 2006;6:107–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Alberts B. Molecular biology of the cell. New York: Garland Science; 2002.Google Scholar
  25. 25.
    Kuppers R, Zhao M, Hansmann ML, Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 1993;12:4955–67.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Perez-Andres M, Paiva B, Nieto WG, Caraux A, Schmitz A, Almeida J, Vogt Jr RF, Marti GE, Rawstron AC, Van Zelm MC, Van Dongen JJ, Johnsen HE, Klein B, Orfao A, Primary Health Care Group of Salamanca for the Study of MBL. Human peripheral blood B-cell compartments: a crossroad in B-cell traffic. Cytometry B Clin Cytom. 2010;78(Suppl. 1):S47–60.PubMedCrossRefGoogle Scholar
  27. 27.
    Soulas-Sprauel P, Rivera-Munoz P, Malivert L, Le Guyader G, Abramowski V, Revy P, De Villartay JP. V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining. Oncogene. 2007;26:7780–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu Z, Fulop Z, Zhong Y, Evinger III AJ, Zan H, Casali P. DNA lesions and repair in immunoglobulin class switch recombination and somatic hypermutation. Ann N Y Acad Sci. 2005;1050:146–62.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Liu YJ, Malisan F, De Bouteiller O, Guret C, Lebecque S, Banchereau J, Mills FC, Max EE, Martinez-Valdez H. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity. 1996;4:241–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Stavnezer J. Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol. 2011;32:194–201.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bothmer A, Robbiani DF, Feldhahn N, Gazumyan A, Nussenzweig A, Nussenzweig MC. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J Exp Med. 2010;207:855–65.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, de Wolf-Peeters C, Hagemeijer A, Van Den Berghe H, Marynen P. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood. 1999;93:3601–9.PubMedGoogle Scholar
  33. 33.
    Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood. 2003;101:2335–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia. 2005;19(4):652–8.PubMedGoogle Scholar
  35. 35.
    Willis TG, Jadayel DM, Du M-Q, Peng H, Perry AR, Abdul-Rauf M, Price H, Karran L, Majekodunmi O, Wlodarska I. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell. 1999;96:35.PubMedCrossRefGoogle Scholar
  36. 36.
    Streubel B, Simonitsch-Klupp I, Mullauer L, Lamprecht A, Huber D, Siebert R, Stolte M, Trautinger F, Lukas J, Puspok A, Formanek M, Assanasen T, Muller-Hermelink HK, Cerroni L, Raderer M, Chott A. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia. 2004;18:1722–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Keimpema M, Gruneberg LJ, Mokry M, Van Boxtel R, Koster J, Coffer PJ, Pals ST, Spaargaren M. FOXP1 directly represses transcription of pro-apoptotic genes and cooperates with NF-kappaB to promote survival of human B-cells. Blood. 2014;124(23):3431–40.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Dierlamm J, Wlodarska I, Michaux L, Stefanova M, Hinz K, Van Den Berghe H, Hagemeijer A, Hossfeld DK. Genetic abnormalities in marginal zone B-cell lymphoma. Hematol Oncol. 2000a;18:1–13.PubMedCrossRefGoogle Scholar
  39. 39.
    Rosenwald A, Ott G, Stilgenbauer S, Kalla J, Bredt M, Katzenberger T, Greiner A, Ott MM, Gawin B, Dohner H, Muller-Hermelink HK. Exclusive detection of the t(11;18)(q21;q21) in extranodal marginal zone B cell lymphomas (MZBL) of MALT type in contrast to other MZBL and extranodal large B cell lymphomas. Am J Pathol. 1999;155:1817–21.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Takada S, Yoshino T, Taniwaki M, Nakamura N, Nakamine H, Oshima K, Sadahira Y, Inagaki H, Oshima K, Tadaatsu A. Involvement of the chromosomal translocation t(11;18) in some mucosa-associated lymphoid tissue lymphomas and diffuse large B-cell lymphomas of the ocular adnexa: evidence from multiplex reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization on using formalin-fixed, paraffin-embedded specimens. Mod Pathol. 2003;16:445–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Muller-Hermelink HK. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin’s lymphomas of the mucosa-associated lymphoid tissue (MALT-) type. Cancer Res. 1997;57:3944–8.PubMedGoogle Scholar
  42. 42.
    Liu H. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood. 2001;98:1182.PubMedCrossRefGoogle Scholar
  43. 43.
    Ye H. Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H pylori in gastric MALT lymphoma. Blood. 2003;102:1012.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu H, Hamoudi RA, Ye H, Ruskone-Fourmestraux A, Dogan A, Isaacson PG, Du M-Q. t(11;18)(q21;q21) of mucosa-associated lymphoid tissue lymphoma results from illegitimate non-homologous end joining following double strand breaks. Br J Haematol. 2004;125:318–29.PubMedCrossRefGoogle Scholar
  45. 45.
    Remstein ED, James CD, Kurtin PJ. Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. Am J Pathol. 2000;156:1183.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ye H. BCL10 expression in normal and neoplastic lymphoid tissue: nuclear localization in MALT lymphoma. Am J Pathol. 2000;157:1147.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, Chott A, Streubel B, Siebert R, Gesk S, Martin-Subero JI, Radford JA, Banerjee S, Nicholson AG, Ranaldi R, Remstein ED, Gao Z, Zheng J, Isaacson PG, Dogan A, Du MQ. MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol. 2005;205:293–301.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakagawa M, Hosokawa Y, Yonezumi M, Izumiyama K, Suzuki R, Tsuzuki S, Asaka M, Seto M. MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. Blood. 2005;106:4210–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Lucas PC. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-[kappa]B signaling pathway. J Biol Chem. 2001;276:19012.PubMedCrossRefGoogle Scholar
  50. 50.
    Uren GA. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell. 2000;6:961.PubMedGoogle Scholar
  51. 51.
    Zhou H. Bcl10 activates the NF-[kappa]B pathway through ubiquitination of NEMO. Nature. 2004;427:167.PubMedCrossRefGoogle Scholar
  52. 52.
    Sanchez-Izquierdo D. MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood. 2003;101:4539.PubMedCrossRefGoogle Scholar
  53. 53.
    Hozak RR, Manji GA, Friesen PD. The BIR motifs mediate dominant interference and oligomerization of inhibitor of apoptosis Op-IAP. Mol Cell Biol. 2000;20:1877.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Mcallister-Lucas LM. Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-[kappa]B induction. J Biol Chem. 2001;276:30589.PubMedCrossRefGoogle Scholar
  55. 55.
    Taji S, Nomura K, Matsumoto Y, Sakabe H, Yoshida N, Mitsufuji S, Nishida K, Horiike S, Nakamura S, Morita M, Taniwaki M. Trisomy 3 may predict a poor response of gastric MALT lymphoma to Helicobacter pylori eradication therapy. World J Gastroenterol. 2005;11:89–93.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Krugmann J, Tzankov A, Dirnhofer S, Fend F, Wolf D, Siebert R, Probst P, Erdel M. Complete or partial trisomy 3 in gastro-intestinal MALT lymphomas co-occurs with aberrations at 18q21 and correlates with advanced disease stage: a study on 25 cases. World J Gastroenterol. 2005;11:7384–5.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Deutsch AJ, Aigelsreiter A, Steinbauer E, Fruhwirth M, Kerl H, Beham-Schmid C, Schaider H, Neumeister P. Distinct signatures of B-cell homeostatic and activation-dependent chemokine receptors in the development and progression of extragastric MALT lymphomas. J Pathol. 2008;215:431–44.PubMedCrossRefGoogle Scholar
  58. 58.
    Chanudet E, Ye H, Ferry J, Bacon CM, Adam P, Muller-Hermelink HK, Radford J, Pileri SA, Ichimura K, Collins VP, Hamoudi RA, Nicholson AG, Wotherspoon AC, Isaacson PG, Du MQ. A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands. J Pathol. 2009;217:420–30.PubMedCrossRefGoogle Scholar
  59. 59.
    Honma K, Tsuzuki S, Nakagawa M, Karnan S, Aizawa Y, Kim WS, Kim YD, Ko YH, Seto M. TNFAIP3 is the target gene of chromosome band 6q23.3-q24.1 loss in ocular adnexal marginal zone B cell lymphoma. Genes Chromosomes Cancer. 2008;47:1–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim WS, Honma K, Karnan S, Tagawa H, Kim YD, Oh YL, Seto M, Ko YH. Genome-wide array-based comparative genomic hybridization of ocular marginal zone B cell lymphoma: comparison with pulmonary and nodal marginal zone B cell lymphoma. Genes Chromosomes Cancer. 2007;46:776–83.PubMedCrossRefGoogle Scholar
  61. 61.
    Chanudet E, Huang Y, Ichimura K, Dong G, Hamoudi RA, Radford J, Wotherspoon AC, Isaacson PG, Ferry J, Du MQ. A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma. Leukemia. 2010;24:483–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Du MQ. MALT lymphoma: many roads lead to nuclear factor-kappab activation. Histopathology. 2011;58:26–38.PubMedCrossRefGoogle Scholar
  63. 63.
    Deutsch AJ, Fruhwirth M, Aigelsreiter A, Cerroni L, Neumeister P. Primary cutaneous marginal zone B-cell lymphomas are targeted by aberrant somatic hypermutation. J Invest Dermatol. 2009;129:476–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Deutsch AJ, Aigelsreiter A, Staber PB, Beham A, Linkesch W, Guelly C, Brezinschek RI, Fruhwirth M, Emberger W, Buettner M, Beham-Schmid C, Neumeister P. MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. Blood. 2007;109:3500–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–85.PubMedCrossRefGoogle Scholar
  66. 66.
    Du M, Peng H, Singh N, Isaacson PG, Pan L. The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma. Blood. 1995;86:4587–93.PubMedGoogle Scholar
  67. 67.
    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Muto S, Tamura A, Iio M, Akatsuka Y, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, Nakahata T, Yoshino T, Kobayashi Y, Ogawa S. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459:712–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, Dave SS, Zhao H, Xu W, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Chan WC, Staudt LM. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Bi Y, Zeng N, Chanudet E, Huang Y, Hamoudi RA, Liu H, Dong G, Watkins AJ, Ley SC, Zou L, Chen R, Zhu X, Du MQ. A20 inactivation in ocular adnexal MALT lymphoma. Haematologica. 2012;97:926–30.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Li ZM, Rinaldi A, Cavalli A, Mensah AA, Ponzoni M, Gascoyne RD, Bhagat G, Zucca E, Bertoni F. MYD88 somatic mutations in MALT lymphomas. Br J Haematol. 2012;158:662–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Liu F, Karube K, Kato H, Arita K, Yoshida N, Yamamoto K, Tsuzuki S, Kim W, Ko YH, Seto M. Mutation analysis of NF-kappaB signal pathway-related genes in ocular MALT lymphoma. Int J Clin Exp Pathol. 2012;5:436–41.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Min KO, Seo EJ, Kwon HJ, Lee EJ, Kim WI, Kang CS, Kim KM. Methylation of p16(INK4A) and p57(KIP2) are involved in the development and progression of gastric MALT lymphomas. Mod Pathol. 2006;19:141–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood. 2006;107:3034–44.PubMedCrossRefGoogle Scholar
  76. 76.
    Isaacson PG, Spencer J. The biology of low grade MALT lymphoma. J Clin Pathol. 1995;48:395–7.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Cerroni L, Zochling N, Putz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol. 1997;24:457–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Parsonnet J, Isaacson PG. Bacterial infection and MALT lymphoma. N Engl J Med. 2004;350:213–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin’s lymphoma and hepatitis C virus infection: a systematic review. Int J Cancer. 2004;111:1–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Ferraccioli GF, Sorrentino D, De Vita S, Casatta L, Labombarda A, Avellini C, Dolcetti R, Di Luca D, Beltrami CA, Boiocchi M, Bartoli E. B cell clonality in gastric lymphoid tissues of patients with Sjogren’s syndrome. Ann Rheum Dis. 1996;55:311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ferreri AJ, Campo E, Ambrosetti A, Ilariucci F, Seymour JF, Willemze R, Arrigoni G, Rossi G, Lopez-Guillermo A, Berti E, Eriksson M, Federico M, Cortelazzo S, Govi S, Frungillo N, Dell'oro S, Lestani M, Asioli S, Pedrinis E, Ungari M, Motta T, Rossi R, Artusi T, Iuzzolino P, Zucca E, Cavalli F, Ponzoni M. Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma. Ann Oncol. 2004a;15:1215–21.PubMedCrossRefGoogle Scholar
  82. 82.
    Ferreri AJ, Govi S, Pasini E, Mappa S, Bertoni F, Zaja F, Montalban C, Stelitano C, Cabrera ME, Giordano Resti A, Politi LS, Doglioni C, Cavalli F, Zucca E, Ponzoni M, Dolcetti R. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J Clin Oncol. 2012;30:2988–94.PubMedCrossRefGoogle Scholar
  83. 83.
    Chanudet E, Adam P, Nicholson AG, Wotherspoon AC, Ranaldi R, Goteri G, Pileri SA, Ye H, Muller-Hermelink HK, Du MQ. Chlamydiae and mycoplasma infections in pulmonary MALT lymphoma. Br J Cancer. 2007;97:949–51.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Aigelsreiter A, Leitner E, Deutsch AJ, Kessler HH, Stelzl E, Beham-Schmid C, Beham A, Krugmann J, Dinges HP, Linkesch W, Neumeister P. Chlamydia psittaci in MALT lymphomas of ocular adnexals: the Austrian experience. Leuk Res. 2008;32:1292–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Aigelsreiter A, Gerlza T, Deutsch AJ, Leitner E, Beham-Schmid C, Beham A, Popper H, Borel N, Pospischil A, Raderer M, Kessler HH, Neumeister P. Chlamydia psittaci infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions. Am J Clin Pathol. 2011;135:70–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Du MQ. Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma. Blood. 1996b;88:4445.PubMedGoogle Scholar
  87. 87.
    Du M. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia. 1996a;10:1190.PubMedGoogle Scholar
  88. 88.
    Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet. 1993;342:571.PubMedCrossRefGoogle Scholar
  89. 89.
    Wotherspoon AC. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342:575.PubMedCrossRefGoogle Scholar
  90. 90.
    Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175–86.PubMedCrossRefGoogle Scholar
  91. 91.
    Reimer P, Fischbach W, Goebeler M-E, Kraus M, Goldmann S, Müller C, Wilhelm M. Decreased frequency of HLA-B35 in patients with gastric MALT lymphoma. Ann Hematol. 2004;83:232.PubMedCrossRefGoogle Scholar
  92. 92.
    Rollinson S, Levene AP, Mensah FK, Roddam PL, Allan JM, Diss TC, Roman E, Jack A, Maclennan K, Dixon MF, Morgan GJ. Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood. 2003;102:1007–11.PubMedCrossRefGoogle Scholar
  93. 93.
    Ogawa N, Ping L, Zhenjun L, Takada Y, Sugai S. Involvement of the interferon-gamma-induced T cell-attracting chemokines, interferon-gamma-inducible 10-kd protein (CXCL10) and monokine induced by interferon-gamma (CXCL9), in the salivary gland lesions of patients with Sjögren’s syndrome. Arthritis Rheum. 2002;46:2730–41.PubMedCrossRefGoogle Scholar
  94. 94.
    Schmid U, Helbron D, Lennert K. Development of malignant lymphoma in myoepithelial sialadenitis (Sjogren’s syndrome). Virchows Arch A Pathol Anat Histol. 1982;395:11–43.PubMedCrossRefGoogle Scholar
  95. 95.
    Bahler DW, Miklos JA, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood. 1997;89:3335–44.PubMedGoogle Scholar
  96. 96.
    Berard CW, Greene MH, Jaffe ES, Magrath I, Ziegler J. NIH conference. A multidisciplinary approach to non-hodgkin’s lymphomas. Ann Intern Med. 1981;94:218–35.PubMedCrossRefGoogle Scholar
  97. 97.
    Kipps TJ, Tomhave E, Chen PP, Fox RI. Molecular characterization of a major autoantibody-associated cross-reactive idiotype in Sjogren’s syndrome. J Immunol. 1989;142:4261–8.PubMedGoogle Scholar
  98. 98.
    Chen YW, Liang AC, Au WY, Chu KM, Wong KY, Hu X, Lu L, Tang JC, Chan KW, Beh SL, Kwong YL, Liang RH, Srivastava G. Multiple BCL6 translocation partners in individual cases of gastric lymphoma. Blood. 2003;102:1931–2. author reply 1932PubMedCrossRefGoogle Scholar
  99. 99.
    Liang R, Chan WP, Kwong YL, Xu WS, Srivastava G, Ho FC. High incidence of BCL-6 gene rearrangement in diffuse large B-cell lymphoma of primary gastric origin. Cancer Genet Cytogenet. 1997;97:114–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Neumeister P, Hoefler G, Beham-Schmid C, Schmidt H, Apfelbeck U, Schaider H, Linkesch W, Sill H. Deletion analysis of the p16 tumor suppressor gene in gastrointestinal mucosa-associated lymphoid tissue lymphomas. Gastroenterology. 1997;112:1871–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Pan LX, Ramani P, Diss TC, Liang LN, Isaacson PG. Epstein-Barr virus associated lymphoproliferative disorder with fatal involvement of the gastrointestinal tract in an infant. J Clin Pathol. 1995;48:390–2.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Starostik P, Patzner J, Greiner A, Schwarz S, Kalla J, Ott G, Muller-Hermelink HK. Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways. Blood. 2002;99:3–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Kuppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20:5580–94.PubMedCrossRefGoogle Scholar
  104. 104.
    Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Kuppers R, Dalla-Favera R. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001a;412:341–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Bodor C, Bognar A, Reiniger L, Szepesi A, Toth E, Kopper L, Matolcsy A. Aberrant somatic hypermutation and expression of activation-induced cytidine deaminase mRNA in mediastinal large B-cell lymphoma. Br J Haematol. 2005;129:373–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Dijkman R, Tensen CP, Buettner M, Niedobitek G, Willemze R, Vermeer MH. Primary cutaneous follicle center lymphoma and primary cutaneous large B-cell lymphoma, leg type, are both targeted by aberrant somatic hypermutation but demonstrate differential expression of AID. Blood. 2006;107:4926–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Gaidano G, Pasqualucci L, Capello D, Berra E, Deambrogi C, Rossi D, Maria Larocca L, Gloghini A, Carbone A, Dalla-Favera R. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood. 2003;102:1833–41.PubMedCrossRefGoogle Scholar
  108. 108.
    Halldorsdottir AM, Fruhwirth M, Deutsch A, Aigelsreiter A, Beham-Schmid C, Agnarsson BA, Neumeister P, Richard Burack W. Quantifying the role of aberrant somatic hypermutation in transformation of follicular lymphoma. Leuk Res. 2008;32(7):1015–21.PubMedCrossRefGoogle Scholar
  109. 109.
    Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG. Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008;451:841–5.PubMedCrossRefGoogle Scholar
  110. 110.
    Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, Honjo T, Morse III HC, Nussenzweig MC, Dalla-Favera R. AID is required for germinal center-derived lymphomagenesis. Nat Genet. 2008;40:108–12.PubMedCrossRefGoogle Scholar
  111. 111.
    Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM, Honjo T, Chiba T. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med. 2007;13:470–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov. 2013;12:229–43.PubMedCrossRefGoogle Scholar
  113. 113.
    Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23:410–21.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Mcallister-Lucas LM, Baens M, Lucas PC. MALT1 protease: a new therapeutic target in B lymphoma and beyond? Clin Cancer Res. 2011;17:6623–31.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ, Isaacson PG. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet. 2001;357:39–40.PubMedCrossRefGoogle Scholar
  116. 116.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50.PubMedCrossRefGoogle Scholar
  117. 117.
    Campbell DJ, Kim CH, Butcher EC. Chemokines in the systemic organization of immunity. Immunol Rev. 2003;195:58–71.PubMedCrossRefGoogle Scholar
  118. 118.
    Laurence AD. Location, movement and survival: the role of chemokines in haematopoiesis and malignancy. Br J Haematol. 2006;132:255–67.PubMedCrossRefGoogle Scholar
  119. 119.
    Bowman EP, Campbell JJ, Soler D, Dong Z, Manlongat N, Picarella D, Hardy RR, Butcher EC. Developmental switches in chemokine response profiles during B cell differentiation and maturation. J Exp Med. 2000;191:1303–18.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005;23:127–59.PubMedCrossRefGoogle Scholar
  121. 121.
    Muller G, Hopken UE, Lipp M. The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol Rev. 2003;195:117–35.PubMedCrossRefGoogle Scholar
  122. 122.
    Deutsch AJ, Steinbauer E, Hofmann NA, Strunk D, Gerlza T, Beham-Schmid C, Schaider H, Neumeister P. Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma. Mod Pathol. 2013;26:182–94.PubMedCrossRefGoogle Scholar
  123. 123.
    Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series. Gut. 2004;53:34–7.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wundisch T, Thiede C, Morgner A, Dempfle A, Gunther A, Liu H, Ye H, Du MQ, Kim TD, Bayerdorffer E, Stolte M, Neubauer A. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol. 2005;23:8018–24.PubMedCrossRefGoogle Scholar
  125. 125.
    Troch M, Woehrer S, Streubel B, Weissel M, Hoffmann M, Mullauer L, Chott A, Raderer M. Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) in patients with MALT lymphoma. Ann Oncol. 2008;19:1336–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Wohrer S, Troch M, Streubel B, Zwerina J, Skrabs C, Formanek M, Hauff W, Hoffmann M, Mullauer L, Chott A, Raderer M. MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia. 2007;21:1812–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Zullo A, Hassan C, Andriani A, Cristofari F, Bassanelli C, Spinelli GP, Tomao S, Morini S. Treatment of low-grade gastric MALT-lymphoma unresponsive to Helicobacter pylori therapy: a pooled-data analysis. Med Oncol. 2010;27:291–5.PubMedCrossRefGoogle Scholar
  128. 128.
    Wirth A, Gospodarowicz M, Aleman BM, Bressel M, Ng A, Chao M, Hoppe RT, Thieblemont C, Tsang R, Moser L, Specht L, Szpytma T, Lennard A, Seymour JF, Zucca E. Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group study. Ann Oncol. 2013;24:1344–51.PubMedCrossRefGoogle Scholar
  129. 129.
    Tsang RW, Gospodarowicz MK, Pintilie M, Wells W, Hodgson DC, Sun A, Crump M, Patterson BJ. Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol. 2003;21:4157–64.PubMedCrossRefGoogle Scholar
  130. 130.
    Hammel P, Haioun C, Chaumette MT, Gaulard P, Divine M, Reyes F, Delchier JC. Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol. 1995;13:2524–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Levy M, Copie-Bergman C, Gameiro C, Chaumette MT, Delfau-Larue MH, Haioun C, Charachon A, Hemery F, Gaulard P, Leroy K, Delchier JC. Prognostic value of translocation t(11;18) in tumoral response of low-grade gastric lymphoma of mucosa-associated lymphoid tissue type to oral chemotherapy. J Clin Oncol. 2005;23:5061–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Jager G, Neumeister P, Quehenberger F, Wohrer S, Linkesch W, Raderer M. Prolonged clinical remission in patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type treated with cladribine: 6 year follow-up of a phase II trial. Ann Oncol. 2006;17:1722–3.PubMedCrossRefGoogle Scholar
  133. 133.
    Jager G, Hofler G, Linkesch W, Neumeister P. Occurrence of a myelodysplastic syndrome (MDS) during first-line 2-chloro-deoxyadenosine (2-CDA) treatment of a low-grade gastrointestinal MALT lymphoma. Case report and review of the literature. Haematologica. 2004;89(4):ECR01.PubMedGoogle Scholar
  134. 134.
    Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol. 2005;23:1979–83.PubMedCrossRefGoogle Scholar
  135. 135.
    Conconi A, Martinelli G, Lopez-Guillermo A, Zinzani PL, Ferreri AJ, Rigacci L, Devizzi L, Vitolo U, Luminari S, Cavalli F, Zucca E, International Extranodal Lymphoma Study Group. Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG). Ann Oncol. 2011;22:689–95.PubMedCrossRefGoogle Scholar
  136. 136.
    Troch M, Jonak C, Mullauer L, Puspok A, Formanek M, Hauff W, Zielinski CC, Chott A, Raderer M. A phase II study of bortezomib in patients with MALT lymphoma. Haematologica. 2009;94:738–42.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Panwalkar A, Verstovsek S, Giles F. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies. Cancer. 2004;100:1578–89.PubMedCrossRefGoogle Scholar
  138. 138.
    Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell'oro S, Fleischhauer K, Caggiari L, Lettini AA, Dal Cin E, Ieri R, Freschi M, Villa E, Boiocchi M, Dolcetti R. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst. 2004b;96:586–94.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Alexander JA Deutsch
    • 1
    Email author
  • Katharina Troppan
    • 1
  • Karoline Fechter
    • 1
  • Peter Neumeister
    • 1
  1. 1.Division of Hematology, Department of Internal MedicineMedical University GrazGrazAustria

Personalised recommendations