Skip to main content

Advertisement

SpringerLink
Log in

The Role of Infectious Agents, Antibiotics, and Antiviral Therapy in the Treatment of Extranodal Marginal Zone Lymphoma and Other Low-Grade Lymphomas

  • Lymphoma (JW Sweetenham, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

There is strong evidence to corroborate the association with Helicobacter pylori (Hp) to gastric extranodal marginal zone lymphoma (ENMZL) and hepatitis C virus (HCV) to splenic/nodal marginal zone lymphoma. Koch’s postulates generally hold for these two associations and eradication of the infectious agent is well supported. Hp eradication (HPE) is recommended as front-line therapy for early stage gastric ENMZL regardless of Hp status. Complete response (CR) rate for Hp-negative patients is not as high as for Hp-positive patients; however, the benign nature of HPE and high rates of salvage allow this strategy to be safe while sparing some Hp-negative patients from systemic therapy or radiation. Similarly for HCV-seropositive patients, treatment with antivirals should be strongly considered as first-line for those who do not require immediate cytoreductive therapy or at some point even after completing chemoimmunotherapy. The controversy regarding the role for antibiotics is greatest for primary ocular adnexal lymphoma (POAL). Considering the low incidence of Chlamydia psittaci (Cp) infection with OAL and the challenges to reliably identifying Cp, we typically do not consider doxycycline in POAL treatment. Involved-field radiotherapy (IFRT) remains the treatment of choice for most with unilateral POAL. However, if reliable detection of Cp is available and Cp is identified, patients with unilateral low tumor stage POAL who do not require immediate radiotherapy could be considered for doxycycline as front-line treatment. Other infectious associations to indolent lymphomas have been made, including Borrelia borgdorferi (Bb) in cutaneous lymphoma and Campylobacter in immunoproliferative small intestinal disease (IPSID), but these associations are not as strong and primary treatment targeting the infectious agents is not recommended.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bracci PM, Benavente Y, Turner JJ, et al. Medical history, lifestyle, family history, and occupational risk factors for marginal zone lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014;48:52–65. This study pooled data from 1052 MZL cases and 13766 controls to identify risk factors associated with the development of MZL.

  2. 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(8):3034–44.

    Article  CAS  PubMed  Google Scholar 

  3. Gradmann C. A spirit of scientific rigour: Koch’s postulates in twentieth-century medicine. Microbes Infect. 2014;16(11):885–92.

    Article  PubMed  Google Scholar 

  4. 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(12):2770–8.

    Article  PubMed  Google Scholar 

  5. Zucca E, Copie-Bergman C, Ricardi U, Thieblemont C, Raderer M, Ladetto M. Gastric marginal zone lymphoma of MALT type: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Supplement 6):vi144–8. This study outlines current practice guidelines for gastric ENMZL.

  6. 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(2):105–10.

    Article  PubMed  Google Scholar 

  7. 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(4):507–13. This is a large study that confirmed the long-term efficacy associated with first-line HPE for gastic MALT lymphoma, similar to the results shown by an early meta-analysis [5].

  8. Wündisch T, Dieckhoff P, Greene B, et al. Second cancers and residual disease in patients treated for gastric mucosa-associated lymphoid tissue lymphoma by Helicobacter pylori eradication and followed for 10 years. Gastroenterology. 2012;143(4):936–42.

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Zullo A, Hassan C, Ridola L, et al. Eradication therapy in Helicobacter pylori-negative gastric low-grade MALT lymphoma patients: a systemic review. J Cinical Gastroenterol. 2013;47(10):824–7. This is the largest systemic review that demonstrates the impact of HPE in Hp-negative gastric ENMZL and suggests a select group of these patients can be successfully treated with antibiotics alone.

  11. Al-Taie O, Al-Taie E, Fischbach W. Patients with Helicobacter pylori negative gastric marginal zone b-cell lymphoma (MZBCL) of MALT have a good prognosis. Z Gastroenterol. 2014;52(12):1389–93.

    Article  CAS  PubMed  Google Scholar 

  12. 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

  13. Engels EA, Chatterjee N, Cerhan JR, et al. Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI-SEER multi-center case-control study. Int J Cancer. 2004;111(1):76–80.

    Article  CAS  PubMed  Google Scholar 

  14. Nieters A, Kallinowski B, Brennan P, et al. Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH. Gastroenterology. 2006;131(6):1879–86.

    Article  CAS  PubMed  Google Scholar 

  15. De Sanjose S, Benavente Y, Vajdic CM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol. 2008;6(4):451–8.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Morton LM, Slager SL, Cerhan JR, et al. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014;48:130–44. This is a very large study that pooled data from 17,471 NHL cases and 23,096 controls to identify risk factors associated with different NHL subtypes. This study overcomes the limitations associated with smaller studies and showed the increased risk of HCV with certain NHL subtypes.

  17. Kawamura Y, Ikeda K, Arase Y, et al. Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med. 2007;120(12):1034–41.

    Article  CAS  PubMed  Google Scholar 

  18. Mazzaro C, De Re V, Spina M, et al. Pegylated-interferon plus ribavirin for HCV-positive indolent non-Hodgkin lymphomas. Br J Haematol. 2009;145(2):255–7.

    Article  CAS  PubMed  Google Scholar 

  19. Vallisa D, Bernuzzi P, Arcaini L, et al. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol. 2005;23(3):468–73.

    Article  CAS  PubMed  Google Scholar 

  20. Kelaidi C, Rollot F, Park S, et al. Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia. 2004;18(10):1711–6.

    Article  CAS  PubMed  Google Scholar 

  21. Tursi A, Brandimarte G, Torello M. Disappearance of gastric mucosa-associated lymphoid tissue in hepatitis C virus-positive patients after anti-hepatitis C virus therapy. J Gastroenterol. 2004;38(4):360–3.

    Google Scholar 

  22. Arcaini L, Merli M, Volpetti S, Rattotti S, Gotti M, Zaja F. Indolent B-cell lymphomas associated with HCV infection: clinical and virological features and role of antiviral therapy. Clin Dev Immunol. 2012;2012:638185.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Saadoun D, Suarez F, Mariette X, et al. Brief report splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood. 2005;105(1):74–6.

    Article  CAS  PubMed  Google Scholar 

  24. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384(9941):403–13.

    Article  CAS  PubMed  Google Scholar 

  25. Flamm SL, Lawitz E, Jacobson I, et al. Boceprevir with peginterferon alfa-2a-ribavirin is effective for previously treated chronic hepatitis C genotype 1 infection. Clin Gastroenterol Hepatol. 2013;11(1):81–7.

    Article  CAS  PubMed  Google Scholar 

  26. Arcaini L, Vallisa D, Rattotti S, et al. Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. Ann Oncol. 2014;25(7):1404–10. This is currently the largest study demonstrating the efficacy of first- or second-line AT in HCV-related indolent NHL that correlated to HCV-RNA clearance.

  27. Michot J-M, Canioni D, Driss H, et al. Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol. 2015;90(3):197-203. This study reinforces the results of [26] and also demonstrated favorable OS benefits associated with AT therapy.

  28. Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol. 2007;31(2):170–84.

    Article  PubMed  Google Scholar 

  29. Portell CA, Aronow ME, Rybicki LA, Macklis R, Singh AD, Sweetenham JW. Clinical characteristics of 95 patients with ocular adnexal and uveal lymphoma: treatment outcomes in extranodal marginal zone subtype. Clin Lymphoma Myeloma Leuk. 2014;14(3):203–10.

    Article  PubMed  Google Scholar 

  30. Aronow ME, Portell CA, Rybicki LA, Sweetenham JW, Singh AD. Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system. Ophthalmology. 2013;120(9):1915–9.

    Article  PubMed  Google Scholar 

  31. Harada K, Murakami N, Kitaguchi M, et al. Localized ocular adnexal mucosa-associated lymphoid tissue lymphoma treated with radiation therapy: a long-term outcome in 86 patients with 104 treated eyes. Int J Radiat Oncol Biol Phys. 2014;88(3):650–4.

    Article  PubMed  Google Scholar 

  32. Ohga S, Nakamura K, Shioyama Y, et al. Radiotherapy for early-stage primary ocular adnexal mucosa-associated lymphoid tissue lymphoma. Anticancer Res. 2013;33(12):5575–8.

    PubMed  Google Scholar 

  33. Fung CY, Tarbell NJ, Lucarelli MJ, et al. Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes. Int J Radiat Oncol. 2003;57(5):1382–91.

    Article  Google Scholar 

  34. Lim S-H, Kang M, Son J. Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type of the ocular adnexa: retrospective single institution review of 95 patients. Indian J Ophthalmol. 2011;59(4):273–7.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Olszewski AJ, Desai A. Radiation therapy administration and survival in stage I/II extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Int J Radiat Oncol Biol Phys. 2014;88(3):642–9. This is a large population-based analysis extracting data on 7774 patients with stage I/II MALT lymphoma from the SEER database and showed excellent survival in most sites of origin and negligible lymphoma-related death for ocular lymphoma.

  36. Ferreri AJM, Guidoboni M, Ponzoni M, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst. 2004;96(8):586–94.

    Article  PubMed  Google Scholar 

  37. Ruiz A, Reischl U, Swerdlow SH, et al. Extranodal marginal zone B-cell lymphomas of the ocular adnexa: multiparameter analysis of 34 cases including interphase molecular cytogenetics and PCR for Chlamydia psittaci. Am J Surg Pathol. 2007;31(5):792–802.

    Article  PubMed  Google Scholar 

  38. Carugi A, Onnis A, Antonicelli G, et al. Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular adnexal lymphomas: a comparison between Italian and African samples. Hematol Oncol. 2010;28(1):20–6.

    CAS  PubMed  Google Scholar 

  39. Chanudet E, Zhou Y, Bacon CM, et al. Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J Pathol. 2006;209(3):344–51.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang D, Dong L, Li H, et al. Ocular adnexal mucosa-associated lymphoid tissue lymphoma in Northern China: high frequency of numerical chromosomal changes and no evidence of an association with Chlamydia psittaci. Leuk Lymphoma. 2010;51(11):2031–8.

    Article  PubMed  Google Scholar 

  41. Rosado MF, Byrne GE, Ding F, et al. Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci. Blood. 2006;107(2):467–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Husain A, Roberts D, Pro B, McLaughlin P, Esmaeli B. Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics. Cancer. 2007;110(4):809–15.

    Article  PubMed  Google Scholar 

  43. Ferreri AJM, Dolcetti R, Dognini GP, et al. Chlamydophila psittaci is viable and infectious in the conjunctiva and peripheral blood of patients with ocular adnexal lymphoma: results of a single-center prospective case-control study. Int J Cancer. 2008;123(5):1089–93.

    Article  CAS  PubMed  Google Scholar 

  44. Ferreri AJM, Govi S, Pasini E, et al. 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(24):2988–94. This is prospective multi-center trial that showed OAL regression with first-line doxycycline in Cp-positive patients and has introduced the possibility of treating a very select group of these patients with antibiotics.

  45. Han JJ, Kim TM, Jeon YK, et al. Long-term outcomes of first-line treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell lymphoma. Ann Hematol. 2015;94(4):575–81.

  46. Lee MJ, Min B-J, Choung H-K, Kim N, Kim YA, Khwarg SI. Genome-wide DNA methylation profiles according to Chlamydophila psittaci infection and the response to doxycycline treatment in ocular adnexal lymphoma. Mol Vis. 2014;20:1037–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Ferreri AJM, Ponzoni M, Guidoboni M, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006;98(19):1375–82.

    Article  CAS  PubMed  Google Scholar 

  48. Boudova L, Kazakov DV, Sima R, et al. Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients. Am J Dermatopathol. 2005;27(5):375–86.

    Article  PubMed  Google Scholar 

  49. Colli C, Leinweber B, Müllegger R, Chott A, Kerl H, Cerroni L. Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases. J Cutan Pathol. 2004;31(3):232–40.

    Article  PubMed  Google Scholar 

  50. De la Fouchardiere A, Vandenesch F, Berger F. Borrelia-associated primary cutaneous MALT lymphoma in a nonendemic region. Am J Surg Pathol. 2003;27(5):702–3.

    Article  PubMed  Google Scholar 

  51. Cerroni L, Zoohling N, Piitz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol. 1997;24(8):457–61.

    Article  CAS  PubMed  Google Scholar 

  52. Goodlad JR, Davidson MM, Hollowood K, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the highlands of Scotland. Am J Surg Pathol. 2000;24(9):1279–85.

    Article  CAS  PubMed  Google Scholar 

  53. Bertolotti A, Pham-Ledard A, Petrot D, et al. Two cases of proliferation of monoclonal and monotypic lymphocytes and plasma cells corresponding to acrodermatitis chronica atrophicans. Ann Dermatol Venereol. 2014;141(6–7):452–7.

    Article  CAS  PubMed  Google Scholar 

  54. Fühler M, Ottmann KW, Tronnier M. Cutaneous marginal zone lymphoma (SALT) and infection with Borrelia burgdorferi. Hautarzt. 2010;61(2):145–7.

    Article  PubMed  Google Scholar 

  55. Roggero E, Zucca E, Mainetti C, et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol. 2000;31(2):263–8.

    Article  CAS  PubMed  Google Scholar 

  56. Ponzoni M, Ferreri AJM, Mappa S, et al. Prevalence of Borrelia burgdorferi infection in a series of 98 primary cutaneous lymphomas. Oncologist. 2011;16(11):1582–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Kodama K, Massone C, Chott A, Metze D, Kerl H, Cerroni L. Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients. Blood. 2005;106(7):2491–7.

    Article  CAS  PubMed  Google Scholar 

  58. Goteri G, Ranaldi R, Simonetti O, et al. Clinicopathological features of primary cutaneous B-cell lymphomas from an academic regional hospital in central Italy: no evidence of Borrelia burgdorferi association. Leuk Lymphoma. 2007;48(11):2184–8.

    Article  PubMed  Google Scholar 

  59. Kempf W, Kazakov DV, Buechner SA, et al. Primary cutaneous marginal zone lymphoma in children: a report of 3 cases and review of the literature. Am J Dermatopathol. 2014;36(8):661–6.

    Article  PubMed  Google Scholar 

  60. Monari P, Farisoglio C, Calzavara Pinton PG. Borrelia burgdorferi-associated primary cutaneous marginal-zone B-cell lymphoma: a case report. Dermatology. 2007;215(3):229–32.

    Article  CAS  PubMed  Google Scholar 

  61. Takino H, Li C, Hu S, et al. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States. Mod Pathol. 2008;21(12):1517–26.

    Article  CAS  PubMed  Google Scholar 

  62. Li C, Inagaki H, Kuo T-T, Hu S, Okabe M, Eimoto T. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 Asian cases. Am J Surg Pathol. 2003;27(8):1061–9.

    Article  PubMed  Google Scholar 

  63. Wood GS, Kamath NV, Guitart J, et al. Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States. J Cutan Pathol. 2001;28(10):502–7.

    Article  CAS  PubMed  Google Scholar 

  64. Ben-Ayed F, Halphen M, Najjar T, et al. Treatment of alpha chain disease. Results of a prospective study in 21 Tunisian patients by the Tunisian-French Intestinal Lymphoma Study Group. Cancer. 1989;63(7):1251–6.

    Article  CAS  PubMed  Google Scholar 

  65. Akbulut H, Soykan I, Yakaryilmaz F, et al. Five-year results of the treatment of 23 patients with immunoproliferative small intestinal disease: a Turkish experience. Cancer. 1997;80(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  66. Pervez S, Mumtaz K, Ullah SS, Akhtar N, Ali N, Aaqil H. Immunoproliferative small intestinal disease (IPSID). J Coll Physicians Surg Pak. 2011;21(1):57–8.

    PubMed  Google Scholar 

  67. Lecuit M, Suarez F, Lortholary O. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. Médecine Sci. 2004;20(6–7):638–40.

    Article  Google Scholar 

  68. Mesnard B, De Vroey B, Maunoury V, Lecuit M. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. Dig Liver Dis. 2012;44(9):799–800.

    Article  PubMed  Google Scholar 

  69. Coeuret S, de La Blanchardiere A, Saguet-Rysanek V, et al. Campylobacter coli cultured from the stools of a patient with immunoproliferative small intestinal disease. Clin Microbiol Infect. 2014;20(9):908–11.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Laahn H. Foster and Craig A. Portell declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, University of Virginia School of Medicine, PO Box 800716, Charlottesville, VA, 22908-0716, USA

    Laahn H. Foster MD & Craig A. Portell MD

Authors
  1. Laahn H. Foster MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig A. Portell MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig A. Portell MD.

Additional information

This article is part of the Topical Collection on Lymphoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Foster, L.H., Portell, C.A. The Role of Infectious Agents, Antibiotics, and Antiviral Therapy in the Treatment of Extranodal Marginal Zone Lymphoma and Other Low-Grade Lymphomas. Curr. Treat. Options in Oncol. 16, 28 (2015). https://doi.org/10.1007/s11864-015-0344-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-015-0344-6

Keywords

Search

Navigation