Helicobacter pylori Infection and MALT Lymphoma

  • Xavier SagaertEmail author


Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphoma, is an indolent B-cell non-Hodgkin lymphoma, arising in lymphoid infiltrates that are induced by chronic inflammation in extranodal sites. The stomach is the most commonly affected organ, where MALT lymphomagenesis is clearly associated with Helicobacter pylori gastroduodenitis. Outside the stomach, the role of infectious agents is less clearly defined. In recent years, gastric MALT lymphoma became the focus of attention because of the involvement of its genetic aberrations in the nuclear factor kappa B (NF-κB) pathway, currently one of the most investigated pathways in the fields of immunology and oncology. This chapter presents gastric MALT lymphoma as an outstanding example of the close pathogenic link between Helicobacter pylori-induced chronic inflammation and tumour development. It also presents gastric MALT lymphoma as one of the best models of how genetic events initiate oncogenesis, determine tumour biology, dictate clinical behaviour and represent viable therapeutic targets. Moreover, in view of the association of gastric MALT lymphoma with deregulation of the NF-κB pathway, the latter signalling pathway is also discussed in depth in both physiological and pathological conditions.


Helicobacter pylori MALTlymphoma NF-κB pathway Carcinogenesis 


  1. Achuthan R et al (2000) Novel translocation of the BCL10 gene in a case of mucosa associated lymphoid tissue lymphoma. Genes Chromosomes Cancer 29:347–349PubMedCrossRefGoogle Scholar
  2. Akagi T et al (1999) A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18:5785–5794PubMedCrossRefGoogle Scholar
  3. Allister-Lucas LM et al (2001) Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappa B induction. J Biol Chem 276:30589–30597CrossRefGoogle Scholar
  4. Alpen B et al (2000) Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection. Blood 95:4014–4015PubMedGoogle Scholar
  5. Aviles A, Nambo MJ, Neri N, Talavera A, Cleto S (2005) Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach – results of a controlled clinical trial. Med Oncol 22:57–62PubMedCrossRefGoogle Scholar
  6. Baens M, Steyls A, Geboes K, Marynen P, Wolf-Peeters C (2000) The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 156:1433–1439PubMedPubMedCentralCrossRefGoogle Scholar
  7. Baens M et al (2006) Selective expansion of marginal zone B cells in E mu-API2-MALT1 mice is linked to enhanced I kappa B kinase gamma polyubiquitination. Cancer Res 66:5270–5277PubMedCrossRefGoogle Scholar
  8. Bahler DW, Miklos JA, Swerdlow SH (1997) Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood 89:3335–3344PubMedGoogle Scholar
  9. Banham AH et al (2001) The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 61:8820–8829PubMedGoogle Scholar
  10. Banham AH et al (2005) Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res 11:1065–1072PubMedGoogle Scholar
  11. Barrans SL, Fenton JAL, Banham A, Owen RG, Jack AS (2004) Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 104:2933–2935PubMedCrossRefGoogle Scholar
  12. Bayerdorffer E et al (1995) Regression of primary gastric lymphoma of mucosa-associated lymphoid-tissue type after cure of Helicobacter-pylori infection. Lancet 345:1591–1594PubMedCrossRefGoogle Scholar
  13. Bertin J et al (2001) CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B. J Biol Chem 276:11877–11882PubMedCrossRefGoogle Scholar
  14. Bonizzi G, Karin M (2004) The two NF-kappa B activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288PubMedCrossRefGoogle Scholar
  15. Brigden ML, Pattullo AL (1999) Prevention and management of overwhelming postsplenectomy infection – an update. Crit Care Med 27:836–842PubMedCrossRefGoogle Scholar
  16. Cogliatti SB et al (1991) Primary B-cell gastric lymphoma – a clinicopathological study of 145 patients. Gastroenterology 101:1159–1170PubMedGoogle Scholar
  17. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedPubMedCentralCrossRefGoogle Scholar
  18. De Re V et al (2000) Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood 96:3578–3584PubMedGoogle Scholar
  19. Derringer GA et al (2000) Malignant lymphoma of the thyroid gland – a clinicopathologic study of 108 cases. Am J Surg Pathol 24:623–639PubMedCrossRefGoogle Scholar
  20. Dierlamm J et al (1999) 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 93:3601–3609PubMedGoogle Scholar
  21. Doglioni C, Wotherspoon AC, Moschini A, Deboni M, Isaacson PG (1992) High-incidence of primary gastric lymphoma in northeastern Italy. Lancet 339:834–835PubMedCrossRefGoogle Scholar
  22. Du M et al (1996a) Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 10:1190–1197PubMedGoogle Scholar
  23. Du MQ et al (1996b) Intestinal dissemination of gastric malt lymphoma occurs following antigen mediated tumour clonal expansion. Blood 88:2673Google Scholar
  24. Enno A et al (1995) Maltoma-like lesions in the murine gastric-mucosa after long-term infection with Helicobacter-felis – a mouse model of Helicobacter-pylori-induced gastric lymphoma. Am J Pathol 147:217–222PubMedPubMedCentralGoogle Scholar
  25. Ferreri AJM et al (2004) Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96:586–594PubMedCrossRefGoogle Scholar
  26. Franco EL et al (2004) Role and limitations of epidemiology in establishing a causal association. Semin Cancer Biol 14:413–426PubMedCrossRefGoogle Scholar
  27. Fredricks DN, Relman DA (1996) Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 9:18PubMedGoogle Scholar
  28. Gaide O et al (2001) Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappa B activation. FEBS Lett 496:121–127PubMedCrossRefGoogle Scholar
  29. Gaide O et al (2002) CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation. Nat Immunol 3:836–843PubMedCrossRefGoogle Scholar
  30. Goossens T, Klein U, Kuppers R (1998) Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci U S A 95:2463–2468PubMedPubMedCentralCrossRefGoogle Scholar
  31. Grunberger B et al (2006a) Antibiotic treatment is not effective in patients infected with Helicobacter pylori suffering from extragastric MALT lymphoma. J Clin Oncol 24:1370–1375PubMedCrossRefGoogle Scholar
  32. Grunberger B et al (2006b) ‘Blind’ antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa. Ann Oncol 17:484–487PubMedCrossRefGoogle Scholar
  33. Han SL et al (2009) FOXP1 expression predicts polymorphic histology and poor prognosis in gastric mucosa-associated lymphoid tissue lymphomas. Dig Surg 26:156–162PubMedCrossRefGoogle Scholar
  34. Hans CP et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282PubMedCrossRefGoogle Scholar
  35. Hara Y et al (2001) Immunoglobulin heavy chain gene analysis of ocular adnexal extranodal marginal zone B-cell lymphoma. Invest Ophthalmol Vis Sci 42:2450–2457PubMedGoogle Scholar
  36. Haralambieva E et al (2006) Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. Leukemia 7:1300–1303CrossRefGoogle Scholar
  37. Ho L et al (2005) MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 105:2891–2899PubMedCrossRefGoogle Scholar
  38. Hosokawa Y, Suzuki H, Nakagawa M, Lee TH, Seto M (2005) AP12-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappa B binding elements: evidence for a positive feed-back loop pathway resulting in unremitting NF-kappa B activation. Biochem Biophys Res Commun 334:51–60PubMedCrossRefGoogle Scholar
  39. Hu H et al (2006) Foxp1 is an essential transcriptional regulator of B cell development. Nat Immunol 7:819–882PubMedCrossRefGoogle Scholar
  40. Hussell T, Isaacson PG, Crabtree JE, Spencer J (1993a) The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid-tissue to Helicobacter-pylori. Lancet 342:571–574PubMedCrossRefGoogle Scholar
  41. Hussell T, Isaacson PG, Crabtree JE, Dogan A, Spencer J (1993b) Immunoglobulin specificity of low-grade B-cell gastrointestinal lymphoma of mucosa-associated lymphoid-tissue (Malt) type. Am J Pathol 142:285–292PubMedPubMedCentralGoogle Scholar
  42. Hyjek E, Isaacson PG (1988) Primary B-cell lymphoma of the thyroid and its relationship to Hashimotos thyroiditis. Hum Pathol 19:1315–1326PubMedCrossRefGoogle Scholar
  43. Hyjek E, Smith WJ, Isaacson PG (1988) Primary B-cell lymphoma of salivary-glands and its relationship to myoepithelial sialadenitis. Hum Pathol 19:766–776PubMedCrossRefGoogle Scholar
  44. Jaffe E, Harris N, Stein H, Vardiman J (2008) World Health Organisation classification of tumours: pathology and genetics: tumours of haemopoietic and lymphoid tissues. IAR Press, LyonGoogle Scholar
  45. Kalla J et al (2000) Heterogeneity of the AP12-MALT1 gene rearrangement in MALT-type lymphoma. Leukemia 14:1967–1974PubMedCrossRefGoogle Scholar
  46. Kruschinski C, Zidan M, Debertin AS, Von Horsten S, Pabst R (2004) Age-dependent development of the splenic marginal zone in human infants is associated with different causes of death. Hum Pathol 35:113–121PubMedCrossRefGoogle Scholar
  47. Lecuit M et al (2004) Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350:239–248PubMedCrossRefGoogle Scholar
  48. Li QT, Verma IM (2002) NF-kappa B regulation in the immune system. Nat Rev Immunol 2:725–734PubMedCrossRefGoogle Scholar
  49. Liu HX et al (2001a) Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 357:39–40PubMedCrossRefGoogle Scholar
  50. Liu HX et al (2001b) T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 98:1182–1187PubMedCrossRefGoogle Scholar
  51. Lucas P et al (2001) Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 276:19012–19019PubMedCrossRefGoogle Scholar
  52. Martin F, Kearney JF (2002) Marginal-zone B cells. Nat Rev Immunol 2:323–335PubMedCrossRefGoogle Scholar
  53. Martinelli G et al (2005) 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 23:1979–1983PubMedCrossRefGoogle Scholar
  54. Montalban C et al (1995) Gastric B-cell mucosa-associated lymphoid-tissue (Malt) lymphoma – clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 6:355–362PubMedGoogle Scholar
  55. Morgan JA et al (1999) Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res 59:6205–6213PubMedGoogle Scholar
  56. Morgner A et al (2000) Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Gastroenterology 118:821–828PubMedCrossRefGoogle Scholar
  57. Motegi M et al (2000) API2-MALT1 chimeric transcripts involved in mucosa-associated lymphoid tissue type lymphoma predict heterogeneous products. Am J Pathol 156:807–812PubMedPubMedCentralCrossRefGoogle Scholar
  58. Muller-Hermelink HK (2003) Genetic and molecular genetic studies in the diagnosis of B-cell lymphomas: marginal zone lymphomas. Hum Pathol 34:336–340PubMedCrossRefGoogle Scholar
  59. Nakagawa M et al (2005) MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. Blood 106:4210–4216PubMedCrossRefGoogle Scholar
  60. Packham G (2008) The role of NF-kappa B in lymphoid malignancies. Br J Haematol 143:3–15PubMedCrossRefGoogle Scholar
  61. Parsonnet J et al (1994) Helicobacter-pylori infection and gastric lymphoma. N Engl J Med 330:1267–1271PubMedCrossRefGoogle Scholar
  62. Pillai S, Cariappa A, Moran ST (2005) Marginal zone B cells. Ann Rev Immunol 23:161–196CrossRefGoogle Scholar
  63. Pomerantz JL, Baltimore D (2002) Two pathways to NF-kappa B. Mol Cell 10:693–695PubMedCrossRefGoogle Scholar
  64. Qin YF et al (1995) Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma. Blood 86:3528–3534PubMedGoogle Scholar
  65. Rawlings DJ, Sommer K, Moreno-Garcia ME (2006) The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6:799–812PubMedCrossRefGoogle Scholar
  66. Remstein ED, James CD, Kurtin PJ (2000) Incidence and subtype specificity of AP12-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. Am J Pathol 156:1183–1188PubMedPubMedCentralCrossRefGoogle Scholar
  67. Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW (2004) Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia 18:156–160PubMedCrossRefGoogle Scholar
  68. Roggero E et al (2000) Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol 31:263–268PubMedCrossRefGoogle Scholar
  69. Roy N et al (1997) The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. Blood 90:2645Google Scholar
  70. Royer B et al (1997) Lymphomas in patients with Sjogren’s syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood 90:766–775PubMedGoogle Scholar
  71. Ruefli-Brasse AA, French DM, Dixit VM (2003) Regulation of NF-kappa B-dependent lymphocyte activation and development by paracaspase. Science 302:1581–1584PubMedCrossRefGoogle Scholar
  72. Ruland J et al (2001) Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappa B and neural tube closure. Cell 104:33–42PubMedCrossRefGoogle Scholar
  73. Ruland J, Duncan GS, Wakeham A, Mak TW (2003) Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19:749–758PubMedCrossRefGoogle Scholar
  74. Sagaert X et al (2006a) Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma. J Clin Oncol 24:2490–2497PubMedCrossRefGoogle Scholar
  75. Sagaert X, Laurent M, Baens M, Wlodarska I, De Wolf-Peeters C (2006b) MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells. Mod Pathol 19:225–232PubMedCrossRefGoogle Scholar
  76. Schmelz R et al (2005) Helyx study part I & II: treatment of low-grade gastric non-Hodgkin’s lymphoma of mucosa-associated lymphoid tissue (MALT) type stages I & III, an interim analysis. Gastroenterology 128:A295Google Scholar
  77. Siebenlist U, Brown K, Claudio E (2005) Control of lymphocyte development by nuclear factor-kappa B. Nat Rev Immunol 5:435–445PubMedCrossRefGoogle Scholar
  78. Starostik P et al (2002) Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways. Blood 99:3–9PubMedCrossRefGoogle Scholar
  79. Stefanovic A, Lossos IS (2009) Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114:501–510PubMedPubMedCentralCrossRefGoogle Scholar
  80. Streubel B et al (2003) T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 101:2335–2339PubMedCrossRefGoogle Scholar
  81. Streubel B et al (2004) Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722–1726PubMedCrossRefGoogle Scholar
  82. Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A (2005) T(3;4)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 19:652–658PubMedGoogle Scholar
  83. Sugiyama T et al (2001) API2-MALT1 chimeric transcript is a predictive marker for the responsiveness of H-pylori eradication treatment in low-grade gastric MALT lymphoma. Gastroenterology 120:1884–1885PubMedCrossRefGoogle Scholar
  84. Sun LJ, Deng L, Ea CK, Xia ZP, Chen ZJJ (2004) The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 14:289–301PubMedCrossRefGoogle Scholar
  85. Thieblemont C et al (2000) Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood 95:802–806PubMedGoogle Scholar
  86. Thome M (2004) CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol 4:348–359PubMedCrossRefGoogle Scholar
  87. Tsang RW et al (2003) Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21:4157–4164PubMedCrossRefGoogle Scholar
  88. Uren AG et al (2000) Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 6:961–967PubMedGoogle Scholar
  89. Wang D et al (2004) CD3/CD28 costimulation-induced NF-{kappa}B activation is mediated by recruitment of protein kinase C-{theta}, Bcl10, and I{kappa}B kinase {beta} to the immunological synapse through CARMA1. Mol Cell Biol 24:164–171PubMedPubMedCentralCrossRefGoogle Scholar
  90. Willis TG et al (1999) Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96:35–45PubMedCrossRefGoogle Scholar
  91. Wlodarska I et al (2005) FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 19:1299–1305PubMedCrossRefGoogle Scholar
  92. Wotherspoon AC, Ortizhidalgo C, Falzon MR, Isaacson PG (1991) Helicobacter-pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338:1175–1176PubMedCrossRefGoogle Scholar
  93. Wotherspoon AC, Pan LX, Diss TC, Isaacson PG (1992) Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid-tissue. Cancer Genet Cytogenet 58:35–38PubMedCrossRefGoogle Scholar
  94. Wotherspoon AC et al (1993) Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid-tissue type after eradication of Helicobacter-pylori. Lancet 342:575–577PubMedCrossRefGoogle Scholar
  95. Wotherspoon AC, Doglioni C, Deboni M, Spencer J, Isaacson PG (1994) Antibiotic-treatment for low-grade gastric malt lymphoma. Lancet 343:1503PubMedCrossRefGoogle Scholar
  96. Ye HT et al (2000) BCL10 expression in normal and neoplastic lymphoid tissue – nuclear localization in MALT lymphoma. Am J Pathol 157:1147–1154PubMedPubMedCentralCrossRefGoogle Scholar
  97. Ye HT et al (2003) 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 102:1012–1018PubMedCrossRefGoogle Scholar
  98. Ye HT et al (2005) MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol 205:293–301PubMedCrossRefGoogle Scholar
  99. Zhou HL, Du MQ, Dixit VM (2005) Constitutive NF-kappa B activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 7:425–431PubMedCrossRefGoogle Scholar
  100. Zucca E et al (2000) Prevalence of Helicobacter pylori and hepatitis C virus infections among non Hodgkin’s lymphoma patients in Southern Switzerland. Haematologica 85:147–153PubMedGoogle Scholar
  101. Zullo A et al (2009) Eradication therapy for Helicobacter pylori in patients with gastric MALT lymphoma: a pooled data analysis. Am J Gastroenterol 104:1932–1937PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  1. 1.Department of PathologyUniversity Hospital K.U.LeuvenLeuvenBelgium

Personalised recommendations