Korean J Gastroenterol.  2019 Dec;74(6):304-313. 10.4166/kjg.2019.74.6.304.

Diagnosis and Treatment of Gastric Mucosa-associated Lymphoid Tissue Lymphoma

• Gong EJ
• Choi KD

• KMID: 2469904
• DOI: http://doi.org/10.4166/kjg.2019.74.6.304

Abstract

The stomach is the most common primary site of an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type, which is characterized by an indolent clinical course. A diagnosis of gastric MALT lymphoma requires an endoscopic biopsy that should be confirmed by an experienced pathologist. Gastric MALT lymphoma shows a variable endoscopic appearance, including erosion, erythema, discoloration, atrophy, ulcer, and subepithelial lesion. The distribution is often multifocal. Therefore, clinical suspicion and multiple biopsies are essential for an accurate diagnosis. Gastric MALT lymphoma is almost invariably associated with a Helicobacter pylori (H. pylori) infection. H. pylori eradication therapy is the mainstay of treatment, which must be delivered to all patients regardless of the H. pylori infection status or stage. For patients who have failed to achieve remission following eradication therapy, radiotherapy or chemotherapy can be considered. Radiotherapy is an effective treatment modality for a localized stage and shows excellent outcomes. In the presence of disseminated or advanced disease, chemotherapy and/or immunotherapy with the anti-CD20 monoclonal antibody, rituximab, can be applied. Treatment should be individualized according to the stage and symptoms, as well as the patients' preference. Given that the clinical course of gastric MALT lymphoma is usually indolent, watchful waiting may be an adequate strategy in selected cases where scheduled follow-up is guaranteed.

Keyword

Diagnosis; Helicobacter pylori; Lymphoma, B-cell, marginal zone; Therapeutics

MeSH Terms

Atrophy
Biopsy
Diagnosis*
Drug Therapy
Erythema
Follow-Up Studies
Helicobacter pylori
Humans
Immunotherapy
Lymphoma, B-Cell, Marginal Zone*
Radiotherapy
Rituximab
Stomach
Ulcer
Watchful Waiting
Rituximab

Figure

• 

  Fig. 1 Various endoscopic findings of gastric MALT lymphoma. (A) MALT lymphoma mimicking erythematous gastritis, (B) ulcer scar, (C) polyp, (D) ulcer, (E) mass, and (F) thickened fold. MALT lymphoma, mucosa-associated lymphoid tissue lymphoma.

• 

  Fig. 2 Suggested management algorithm for gastric MALT lymphoma. MALT lymphoma, mucosa-associated lymphoid tissue lymphoma; H. pylori, Helicobacter pylori.

Reference

1. Nakamura S, Matsumoto T, Iida M, Yao T, Tsuneyoshi M. Primary gastrointestinal lymphoma in Japan: a clinicopathologic analysis of 455 patients with special reference to its time trends. Cancer. 2003; 97:2462–2473.

2. Ferrucci PF, Zucca E. Primary gastric lymphoma pathogenesis and treatment: what has changed over the past 10 years? Br J Haematol. 2007; 136:521–538.

3. Psyrri A, Papageorgiou S, Economopoulos T. Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management. Ann Oncol. 2008; 19:1992–1999.

4. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009; 523–531.

5. Wotherspoon AC, Doglioni C, Isaacson PG. Low-grade gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT): a multifocal disease. Histopathology. 1992; 20:29–34.

6. NCCN guidelines® & clinical resources. NCCN guidelines®. [Internet]. Plymouth Meeting (PA): National Comprehensive Cancer Network;cited 2019 Aug 28. Available from: https://www.nccn.org/professionals/physician_gls.

7. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991; 338:1175–1176.

8. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994; 330:1267–1271.

9. Eck M, Schmausser B, Haas R, Greiner A, Czub S, Müller-Hermelink HK. MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein. Gastroenterology. 1997; 112:1482–1486.

10. Zucca E, Bertoni F, Roggero E, Cavalli F. The gastric marginal zone B-cell lymphoma of MALT type. Blood. 2000; 96:410–419.

11. Kim JS, Chung SJ, Choi YS, et al. Helicobacter pylori eradication for low-grade gastric mucosa-associated lymphoid tissue lymphoma is more successful in inducing remission in distal compared to proximal disease. Br J Cancer. 2007; 96:1324–1328.

12. Zullo A, Hassan C, Andriani A, et al. Primary low-grade and high-grade gastric MALT-lymphoma presentation. J Clin Gastroenterol. 2010; 44:340–344.

13. Taal BG, Boot H, van Heerde P, de Jong D, Hart AA, Burgers JM. Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept. Gut. 1996; 39:556–561.

14. Yokoi T, Nakamura T, Nakamura S. Differential diagnosis of gastric MALT lymphomas. Stomach Intest. 2001; 36:13–20.

15. Choi MK, Kim GH. Diagnosis and treatment of gastric MALT lymphoma. Korean J Gastroenterol. 2011; 57:272–280.

16. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993; 342:575–577.

17. Zucca E, Copie-Bergman C, Ricardi U, et al. Gastric marginal zone lymphoma of MALT type: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6:vi144–vi148.

18. Raderer M, Wöhrer S, Streubel B, et al. 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; 24:3136–3141.

19. Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000; 95:802–806.

20. Ruskoné-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut. 2011; 60:747–758.

21. Janssen J. The impact of EUS in primary gastric lymphoma. Best Pract Res Clin Gastroenterol. 2009; 23:671–678.

22. Palazzo L, Roseau G, Ruskone-Fourmestraux A, et al. Endoscopic ultrasonography in the local staging of primary gastric lymphoma. Endoscopy. 1993; 25:502–508.

23. Fujishima H, Misawa T, Maruoka A, Chijiiwa Y, Sakai K, Nawata H. Staging and follow-up of primary gastric lymphoma by endoscopic ultrasonography. Am J Gastroenterol. 1991; 86:719–724.

24. Nakamura S, Matsumoto T, Suekane H, et al. Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori. Gut. 2001; 48:454–460.

25. Min BH, Park JY, Kim ER, et al. Limited role of bone marrow aspiration and biopsy in the initial staging work-up of gastric mucosa-associated lymphoid tissue lymphoma in Korea. Gut Liver. 2014; 8:637–642.

26. Gong EJ, Ahn JY, Jung HY, et al. Bone marrow involvement is not associated with the clinical outcomes of gastric mucosa-associated lymphoid tissue lymphoma. Scand J Gastroenterol. 2016; 51:942–948.

27. Park JY, Kim SG, Kim JS, Jung HC. Bone marrow involvement is rare in superficial gastric mucosa-associated lymphoid tissue lymphoma. Dig Liver Dis. 2016; 48:81–86.

28. Choi SI, Kook MC, Hwang S, et al. Prevalence and implications of bone marrow involvement in patients with gastric mucosa-associated lymphoid tissue lymphoma. Gut Liver. 2018; 12:278–287.

29. Park SH, Chi HS, Park SJ, Jang S, Park CJ, Huh JR. Prognostic impact of Helicobacter pylori infection and eradication therapy in gastric mucosa-associated lymphoid tissue lymphoma. Korean J Lab Med. 2010; 30:547–553.

30. Thieblemont C, Zucca E. Clinical aspects and therapy of gastrointestinal MALT lymphoma. Best Pract Res Clin Haematol. 2017; 30:109–117.

31. Treglia G, Zucca E, Sadeghi R, Cavalli F, Giovanella L, Ceriani L. Detection rate of fluorine-18-fluorodeoxyglucose positron emission tomography in patients with marginal zone lymphoma of MALT type: a meta-analysis. Hematol Oncol. 2015; 33:113–124.

32. Hwang JW, Jee SR, Lee SH, Kim JH, Seol SY, Lee SM. Efficacy of positron emission tomography/computed tomography in gastric mucosa-associated lymphoid tissue lymphoma. Korean J Gastroenterol. 2016; 67:183–188.

33. Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, et al. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet. 2001; 357:39–40.

34. Lehours P, Ruskone-Fourmestraux A, Lavergne A, Cantet F, Mégraud F. Groupe d'Etude des Lymphomes Digestifs (GELD) for the Fédération Française de Cancérologie Digestive (FFCD). Which test to use to detect Helicobacter pylori infection in patients with low-grade gastric mucosa-associated lymphoid tissue lymphoma? Am J Gastroenterol. 2003; 98:291–295.

35. Koch P, del Valle F, Berdel WE, et al. Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German multicenter study GIT NHL 01/92. J Clin Oncol. 2001; 19:3874–3883.

36. Fischbach W. MALT lymphoma: forget surgery? Dig Dis. 2013; 31:38–42.

37. Zullo A, Hassan C, Andriani A, et al. Eradication therapy for Helicobacter pylori in patients with gastric MALT lymphoma: a pooled data analysis. Am J Gastroenterol. 2009; 104:1932–1937.

38. Zullo A, Hassan C, Cristofari F, et al. Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma. Clin Gastroenterol Hepatol. 2010; 8:105–110.

39. Hong SS, Jung HY, Choi KD, et al. A prospective analysis of low-grade gastric malt lymphoma after Helicobacter pylori eradication. Helicobacter. 2006; 11:569–573.

40. Wündisch T, Thiede C, Morgner A, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol. 2005; 23:8018–8024.

41. Sugizaki K, Tari A, Kitadai Y, et al. Anti-Helicobacter pylori therapy in localized gastric mucosa-associated lymphoid tissue lymphoma: a prospective, nationwide, multicenter study in Japan. Helicobacter. 2018; 23:e12474.

42. Nakamura S, Sugiyama T, Matsumoto T, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut. 2012; 61:507–513.

43. Steinbach G, Ford R, Glober G, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial. Ann Intern Med. 1999; 131:88–95.

44. Ruskoné-Fourmestraux A, Lavergne A, Aegerter PH, et al. Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment. Gut. 2001; 48:297–303.

45. Ye H, Liu H, Raderer M, et al. High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood. 2003; 101:2547–2550.

46. Raderer M, Streubel B, Wöhrer S, Häfner M, Chott A. Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas. Gut. 2006; 55:616–618.

47. Akamatsu T, Mochizuki T, Okiyama Y, Matsumoto A, Miyabayashi H, Ota H. Comparison of localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma with and without Helicobacter pylori infection. Helicobacter. 2006; 11:86–95.

48. Nakamura S, Matsumoto T, Ye H, et al. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a clinicopathologic and molecular study with reference to antibiotic treatment. Cancer. 2006; 107:2770–2778.

49. Nakamura T, Seto M, Tajika M, et al. Clinical features and prognosis of gastric MALT lymphoma with special reference to responsiveness to H. pylori eradication and API2-MALT1 status. Am J Gastroenterol. 2008; 103:62–70.

50. Terai S, Iijima K, Kato K, et al. Long-term outcomes of gastric mucosa-associated lymphoid tissue lymphomas after Helicobacter pylori eradication therapy. Tohoku J Exp Med. 2008; 214:79–87.

51. Sumida T, Kitadai Y, Hiyama T, et al. Antibodies to Helicobacter pylori and CagA protein are associated with the response to antibacterial therapy in patients with H. pylori-positive API2-MALT1-negative gastric MALT lymphoma. Cancer Sci. 2009; 100:1075–1081.

52. Stathis A, Chini C, Bertoni F, et al. Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann Oncol. 2009; 20:1086–1093.

53. Asano N, Iijima K, Terai S, et al. Eradication therapy is effective for Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma. Tohoku J Exp Med. 2012; 228:223–227.

54. Choi YJ, Kim N, Paik JH, et al. Characteristics of Helicobacter pylori-positive and Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma and their influence on clinical outcome. Helicobacter. 2013; 18:197–205.

55. Ryu KD, Kim GH, Park SO, et al. Treatment outcome for gastric mucosa-associated lymphoid tissue lymphoma according to Helicobacter pylori infection status: a single-center experience. Gut Liver. 2014; 8:408–414.

56. Raderer M, Wöhrer S, Kiesewetter B, et al. Antibiotic treatment as sole management of Helicobacter pylori-negative gastric MALT lymphoma: a single center experience with prolonged follow-up. Ann Hematol. 2015; 94:969–973.

57. Gong EJ, Ahn JY, Jung HY, et al. Helicobacter pylori eradication therapy is effective as the initial treatment for patients with H. pylori-negative and disseminated gastric mucosa-associated lymphoid tissue lymphoma. Gut Liver. 2016; 10:706–713.

58. Kim JS, Kang SH, Moon HS, Sung JK, Jeong HY. Clinical outcome of eradication therapy for gastric mucosa-associated lymphoid tissue lymphoma according to H. pylori infection status. Gastroenterol Res Pract. 2016; 2016:6794848.

59. Kuo SH, Yeh KH, Wu MS, et al. First-line antibiotic therapy in Helicobacter pylori-negative low-grade gastric mucosa-associated lymphoid tissue lymphoma. Sci Rep. 2017; 7:14333.

60. Nakamura T, Nakamura S, Yonezumi M, Seto M, Yokoi T. The t(11;18)(q21; q21) translocation in H. pylori-negative low-grade gastric MALT lymphoma. Am J Gastroenterol. 2000; 95:3314–3315.

61. Morgner A, Lehn N, Andersen LP, et al. Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Gastroenterology. 2000; 118:821–828.

62. Fox JG. The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases. Gut. 2002; 50:273–283.

63. Zullo A, Hassan C, Ridola L, et al. Eradication therapy in Helicobacter pylori-negative, gastric low-grade mucosa-associated lymphoid tissue lymphoma patients: a systematic review. J Clin Gastroenterol. 2013; 47:824–827.

64. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma. Ann Oncol. 2013; 24:857–877.

65. Park W, Chang SK, Yang WI, et al. Rationale for radiotherapy as a treatment modality in gastric mucosa-associated lymphoid tissue lymphoma. Int J Radiat Oncol Biol Phys. 2004; 58:1480–1486.

66. Ahn JS, Nam TK. The role of radiotherapy for the treatment of gastric MALT lymphoma. Korean J Med. 2012; 83:712–717.

67. Aleman BM, Haas RL, van der Maazen RW. Role of radiotherapy in the treatment of lymphomas of the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010; 24:27–34.

68. Tsang RW, Gospodarowicz MK. Radiation therapy for localized low-grade non-Hodgkin's lymphomas. Hematol Oncol. 2005; 23:10–17.

69. Tsang RW, Gospodarowicz MK, Pintilie M, et al. Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol. 2003; 21:4157–4164.

70. Abe S, Oda I, Inaba K, et al. A retrospective study of 5-year outcomes of radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication therapy. Jpn J Clin Oncol. 2013; 43:917–922.

71. Martinelli G, Laszlo D, Ferreri AJ, et al. 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; 23:1979–1983.

72. Park Y. Role of chemotherapy in gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. Korean J Med. 2012; 83:706–711.

73. Thieblemont C, Cascione L, Conconi A, et al. A MALT lymphoma prognostic index. Blood. 2017; 130:1409–1417.

74. Salar A, Domingo-Domenech E, Panizo C, et al. Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood. 2017; 130:1772–1774.

75. Hong J, Cho J, Ko YH, Kim SJ, Kim WS. Validation of the marginal zone lymphoma international prognostic index. Ann Hematol. 2019; 98:457–464.

76. Urakami Y, Sano T, Begum S, Endo H, Kawamata H, Oki Y. Endoscopic characteristics of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori. J Gastroenterol Hepatol. 2000; 15:1113–1119.

77. Ishihara R, Tatsuta M, Iishi H, Uedo N, Narahara H, Ishiguro S. Usefulness of endoscopic appearance for choosing a biopsy target site and determining complete remission of primary gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori infection. Am J Gastroenterol. 2002; 97:772–774.

78. Copie-Bergman C, Gaulard P, Lavergne-Slove A, et al. Proposal for a new histological grading system for post-treatment evaluation of gastric MALT lymphoma. Gut. 2003; 52:1656.

79. Copie-Bergman C, Wotherspoon AC, Capella C, et al. Gela histological scoring system for post-treatment biopsies of patients with gastric MALT lymphoma is feasible and reliable in routine practice. Br J Haematol. 2013; 160:47–52.

80. 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; 53:34–37.

81. Choi JY, Lee GH, Ahn JY, et al. The role of abdominal CT scan as follow-up after complete remission with successful Helicobacter pylori eradication in patients with H. pylori-positive stage I(E1) gastric MALT lymphoma. Helicobacter. 2011; 16:36–41.

82. Fischbach W, Goebeler ME, Ruskone-Fourmestraux A, et al. Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series. Gut. 2007; 56:1685–1687.