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Journal of Clinical Oncology, Vol 24, No 9 (March 20), 2006: pp. 1370-1375 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.9025 Antibiotic Treatment Is Not Effective in Patients Infected With Helicobacter pylori Suffering From Extragastric MALT Lymphoma
From the Departments of Medicine I and IV, Pathology, and Otorhinolaryngology, Medical University Vienna, Vienna, Austria Address reprint requests to Markus Raderer, MD, Department of Medicine I, Division of Oncology, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; e-mail: markus.raderer{at}meduniwien.ac.at
PURPOSE: Apart from anecdotal reports implicating Helicobacter pylori (HP) in the development of extragastric mucosa associated lymphoid tissue (MALT) lymphoma, no large scale prospective studies have been performed on this topic. PATIENTS AND METHODS: A total of 77 patients with extragastric MALT lymphoma were prospectively studied. The presence or absence of HP was tested by histology, urease breath test, and serology. Patients were also tested for hepatitis A, B, and C and autoimmune conditions along with assessment of MALT lymphoma-specific genetic changes. RESULTS: Evidence for infection with HP was present in 35 of 77 patients (45%), and three of 75 patients tested (4%) were positive for hepatitis C and one for hepatitis B. All patients with HP-infection underwent eradication, 16 before initiation of further therapy. Apart from one patient with lymphoma involving parotid and colon, who achieved regression of the colonic lesions, none of these 16 patients showed regression of the lymphoma after a median follow-up of 14 months (range, 8 to 48+ months) before initiation of definitive treatment. No correlation between HP-status, localization, stage, autoimmune diseases, and genetic findings was seen. CONCLUSION: In our series, HP-eradication was ineffective for treatment of extragastric MALT lymphomas. This finding, along with an infection rate of 45%—as could also be expected in the general Austrian population—suggests that HP does not play a role in the development of these lymphomas. Antibiotic treatment targeting HP should, therefore, be discouraged in patients with extragastric MALT lymphomas.
Mucosa associated lymphoid tissue (MALT) lymphoma accounts for 7% of all newly diagnosed lymphomas and is, therefore, among the more common types of lymphoma.1 It arises in lymphoid tissue acquired in the course of chronic antigenic stimulation or chronic infection,2 while physiologic MALT, as exemplified by the Peyer's patches, is not prone to the development of lymphoma. Following the definition of gastric MALT lymphoma by Isaacson and Wright in 1983,3 Isaacson et al4 soon extended their concept of MALT lymphoma to lymphomas with similar histology arising in various organs throughout the human body. The identification of a causative role of Helicobacter pylori (HP) in the development of gastric MALT lymphoma has resulted in early attempts by the same investigators to use antibiotic eradication of the bacteria to treat gastric MALT lymphoma.5 These early successes could consistently be reproduced by large scale trials and have revolutionized the approach to gastric MALT lymphoma by defining HP eradication as the standard management for disease restricted to the stomach. In addition to HP, various other infectious agents have also been reported to be related to the development of MALT lymphoma such as Borrelia burgdorferi in cutaneous,6 Chlamydia psittaci in orbital,7 and Campylobacter jejuni8 in small intestinal lymphoma. In addition, a recent series has found a high rate of hepatitis C infection in patients with MALT lymphoma in general but especially in lymphoma of the salivary glands.8,9 Scattered reports throughout the literature, however, have also linked infection with HP to MALT lymphoma arising in extragastric organs, and regressions of extragastric manifestations following HP eradication have anecdotally been reported.10 To date, no systematic prospective investigation on the role of HP infection in patients with primary extragastric MALT lymphomas has been performed. To assess the role of HP infection in patients with MALT lymphoma of extragastric origin, we have prospectively studied 77 patients by histology, urease breath test, and serologic testing for HP antibodies. As infection with hepatitis, especially hepatitis C, has been reported to be associated with development of MALT lymphoma,9,11 we also tested patients for hepatitis A, B, and C as well as the presence of autoimmune conditions to rule out a confounding factor. This was accompanied by investigation of MALT lymphoma-associated genetic changes.
A total of 77 consecutive patients with MALT lymphoma of extragastric origin were included in this analysis. Histologic diagnosis of MALT lymphoma was established by a reference hematopathologist (A.C.) in all cases according to the criteria outlined in the WHO classification of lymphoid malignancies. Immunologic phenotyping on paraffin sections was done for demonstration of light chain restriction and the phenotype CD20+CD5-CD10-cyclinD1- which, in context with the microscopic appearance, is consistent with MALT lymphoma. Before initiation of therapy, all patients underwent staging for assessment of extent of disease and to rule out a gastric origin of MALT lymphoma. Minimum staging for inclusion in this series required gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal (GI) tract, computed tomography of thorax and abdomen, and a bone marrow biopsy. The presence or absence of HP was assessed by urease breath test, histology, and serologic testing for immunoglobulin G (IgG) antibodies against HP. Patients were considered HP-positive if they had direct histologic evidence of HP, a positive breath test, or elevated antibody titers. This definition was chosen as HP detection by histologic and immunohistochemical examination is less sensitive and often affected by the quality and nature of biopsies. Patients also underwent serologic testing for infection with hepatitis A, B, and C. In case of suspected hepatitis C infection, polymerase chain reaction had to be performed for definitive diagnosis. In addition, all patients were screened for the presence of an underlying autoimmune condition, ie, Sjogren's syndrome (SS) and Hashimoto's thyroiditis (HT). The diagnosis of SS was based on characteristic clinical symptoms, ie, presence of mouth- and/or eye-dryness as well as additional features such as a positive lip biopsy or serologic changes as required in the recently updated US-EU (United States–European) criteria.12 Routine assessment of TSH, T3, T4, and thyroid autoantibodies was performed for assessment of HT. Paraffin embedded biopsy samples were tested for MALT lymphoma-specific genetic aberrations including t(11;18)(q21;q21), t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32), t(3;14)(q14;q32) involving FOXP1 and IGH and trisomies three and 18. T11,18(q21;q21) involving API2 and MALT1 was assessed by reverse transcriptase polymerase chain reaction, t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) involving BCL10 and IGH, t(3;14)(q14;q32) involving FOXP1 and IGH and trisomies three and 18 were investigated by fluorescence in situ hybridization, as previously published.13 These genetic studies were carried out on representative biopsies, if enough material was available.
Statistical analyses were done with the SPSS 12.0 program (SPSS Inc, Chicago, IL). The association between the categoric variables was calculated either with the Breslow-Day
A total of 77 consecutive patients with extragastric MALT lymphomas were analyzed; 42 were female and 35 were male with a median age of 56 years (range, 33 to 91 years). An additional six patients presented with MALT lymphoma of the lung (two patients), the colon (three patients), and the terminal ileum (one patient) but turned out to have gastric involvement with MALT lymphoma as well during staging. As the exact origin of the lymphoma, ie, gastric versus nongastric, could not be established with certainty in these patients, they were not included in the analysis. Further, in two patients, staging also showed additional gastric MALT lymphoma along with involvement of the lung, both parotid and lacrimal glands in one and lymphoma in both parotids and the lung in the other (Table 1). Both patients, however, had a history of prior MALT lymphoma (in the lung 6 years prior and the parotid gland 4 years prior, respectively). At the time of initial presentation, no sign of additional lymphoma deposits had been detected during staging, including gastroscopy, so both patients were included in the analysis as primary extragastric lymphomas with secondary spread to the stomach.
For detailed patients' characteristics see Table 1. Twenty-six patients had lymphoma originating in the parotid, two in the submandibular gland, eight in the lacrimal gland, six of the orbit, three of the conjunctiva, 10 of the lung, seven of the thyroid gland, and six of the colon, while four patients had lymphoma of the breast, two of the kidney, two of the liver, and one of the esophagus and the skin, respectively. A total of 35 patients (45%) had evidence of HP infection. Among the patients found positive for HP, 13 patients (17%) had a MALT lymphoma of the parotid, five (6%) of the lung, four (5%) each of the colon and the lacrimal gland, two (3%) each of the conjunctiva, orbit, and the thyroid gland, and one had the primary location in the submandibular gland, the kidney, and the breast. After a median follow-up of 44 months (range, 31 to 57 months), 11 patients have died, and median survival has not been reached. No difference in survival was seen between HP-positive and HP-negative patients (Fig 1), and also progression-free survival was not different between the two groups of patients (data not shown).
All patients with evidence of HP infection underwent antibiotic eradication using clarithromycin, metronidazole, and the proton-pump inhibitor pantoprazole. In 19 patients, treatment with chemotherapy or radiation was given concomitantly, or eradication was performed after oncologic treatment, but 16 patients were not put on further therapy for a median time-span of 14 months (Table 1). All of these patients, except one, had advanced disease not amenable to local treatment or radiation and were watched for signs of disease progression by regular follow-up every 8 to 12 weeks, while the remaining patient had a second local relapse in the lung, following resection and surgery, and refused any form of therapy except antibiotics. Antibiotic treatment with clarithromycin, metronidazole, and pantoprazole resulted in successful eradication of the bacteria in 15 of these patients, while one patient received a second antibiotic course with amoxicillin and omeprazole for eradication of HP. These 16 patients were followed for a median time of 14 months (range, 9 to 48+ months) without further therapeutic intervention. One patient, who was diagnosed with MALT lymphoma involving the parotid and the colon, had undergone removal of the parotid lymphoma for diagnostic reasons. Six months after HP eradication, a control colonoscopy disclosed no evidence of MALT lymphoma. However, he developed an enlarged submandibular gland 5 months later, which, on biopsy, showed infiltration with MALT lymphoma. Of the remaining 15 patients, none responded to antibiotic treatment in terms of lymphoma regression. Five patients had progressive disease and 11 patients had stable disease, resulting in initiation of oncologic treatment in 14 patients. Two patients, including the patient with second relapse of lung lymphoma, however, refused further intervention as a result of stable disease and are still undergoing regular follow-up for stable disease 36 and 48 months after antibiotic therapy. Of 75 patients in whom results of tests for hepatitis were available, only four patients were found to be positive. Three patients (4%) had hepatitis C (two patients with orbital and one with parotid lymphoma), while one patient with MALT lymphoma of the lung had hepatitis B. All patients were screened for the presence of an underlying autoimmune condition. Twelve patients (16%) suffered from SS, five patients (7%) had HT, and one patient had severe chronic polyarthritis (Table 1). Sufficient material for analysis of chromosomal aberrations was available from 58 patients (75%). Among these patients, genetic aberrations were detected in 34 (69%; Table 1). In our statistical analyses, we found no correlation between HP infection and localization of the lymphoma, extent of disease, autoimmune conditions, or genetic aberrations.
This is the first large-scale study to systematically address the potential role of HP in patients with extragastric MALT lymphoma. In total, 83 patients initially presented with MALT lymphoma diagnosed at an extragastric site, but six patients were excluded from our analysis because of the detection of gastric MALT lymphoma during staging. Of interest is the fact that four of these excluded patients had their initial presentation at another GI site, ie, the colon or terminal ileum, while two initially presented with MALT lymphoma in the lung. In patients with clinically apparent MALT lymphoma of the salivary glands, the lacrimal glands, or the thyroid, gastric involvement was virtually absent. In fact, only one patient with a history of isolated parotid lymphoma and who relapsed 4 years after irradiation in both parotids, showed gastric involvement (along with sites in the lung) during staging. This patient, however, was included in the analysis as having primary extragastric lymphoma because a gastroscopy performed at the initial diagnosis had been normal. Taken together, these findings are again in keeping with the notion that lymphoid trafficking within MALT organs appears to be different for GI sites versus supradiaphragmatic organs.15,16 In addition, these data question the necessity of gastroscopy in the staging of patients presenting with MALT lymphoma in the parotid, lacrimal, or thyroid gland because of the almost absent risk of gastric involvement in such patients. In total, 35 of 77 patients studied (45%) were found to be positive for HP. As opposed to gastric MALT lymphomas, where infection-rates of up to 90% have been published, this percentage appears to be relatively moderate.17-19 In fact, it corresponds to the percentage found in a healthy Austrian population in a previous study performed at our institution. In this study, investigating HP infection in pancreatic cancer as opposed to healthy patient controls, 45% of healthy volunteers had signs of HP infection,20 which equals the infection rate found in the present study. No correlation between HP status and localization, extent of disease, underlying autoimmune condition, and genetic findings could be demonstrated in our study. Our series as a whole again confirms the excellent prognosis of such patients, with the median survival not being reached at a median follow-up time of 44 months (Fig 1, left panel). This excellent outcome is in keeping with previous reports by Zucca et al21 and Thieblemont et al,22 in whose series median survival was also not reached after a median follow-up of 3.4 years and 52 months, respectively. In our patients, no difference in survival was found between the group of HP-positive and HP-negative patients (Fig 1, right panel), and HP status did not affect progression-free survival. To rule out a potential confounding factor, we have also analyzed the presence of hepatitis infection in our patients, as especially hepatitis C has been linked with development of MALT lymphoma. Serologic results were available from 75 patients, and three patients (4%) tested positive for hepatitis C and one for hepatitis B. This is in contrast to results published in two Italian series, both of which have reported a much higher rate of infection in patients with MALT lymphoma.9,11 These differences, however, probably may be explained by geographic differences in hepatitis C incidence. In terms of clinical relevance, however, the most important finding from our series was probably the absence of efficacy of HP eradication on the course of extragastric MALT lymphoma. While all patients with signs of HP infection were given HP eradication, 16 patients underwent HP eradication as the sole initial management of extragastric MALT lymphoma and were only watched without further therapy for a prolonged time. In fact, none of these 16 patients responded to antibiotic therapy. Only one patient achieved regression of discrete colonic lesions following HP eradication after the large parotid lymphoma had been removed. Disappearance of colonic lymphoma had been verified by multiple biopsies from the colon 6 months after HP eradication. Five months later, however, he developed an enlarged submandibular gland, which was verified as MALT lymphoma by excisional biopsy. In addition, this short-lasting response has to be interpreted with some caution. As the colonic infiltration diagnosed after histologic assessment of multiple biopsies had been minor, it might have been missed because of a sampling bias during recolonoscopy despite the fact that mapping biopsies from the whole colon had been taken. In addition, these scattered lymphomatous infiltrates might simply have constituted a transient circulatory phenomenon of lymphoma cells within a mucosal environment15 rather than real lymphoma growth. Of the remaining 15 patients, none responded to treatment with clarithromycin, metronidazole, and pantoprazole, despite successful HP eradication. This is opposed to scattered reports were lymphoma regression was seen following HP eradication in thyroid, colorectal, and urinary tract localizations.10,23,24 In some cases, however, an underlying gastric lymphoma had been present, or no gastroscopy to rule out a gastric origin of the disease had been performed. In addition, other bacteria have also been implicated in the development of MALT lymphoma of various sites, which might explain the effect of antibiotic treatment in some cases. While one has to be aware that these results do not constitute a real prospective trial of HP eradication in extragastric MALT lymphoma, this cohort of 16 patients allows an estimation of the efficacy of HP eradication and, to our knowledge, is the largest series reported in the current literature. Some caveats in interpreting the results regarding the absence of efficacy of HP eradication have to be kept in mind. First of all, a sufficient follow-up time is imperative when assessing lymphoma-regression following HP eradication, as has repeatedly been shown in gastric MALT lymphoma. In our series, however, the median follow-up was 14 months (range, 9 to 48+ months), which exceeds the range considered necessary in gastric lymphoma, where 12 months are thought to constitute a reasonable cutoff to judge efficacy of antibiotic therapy. A potential drawback in our series is the fact that the majority of patients had advanced disease not amenable to local treatment (Table 1), while patients with localized disease were immediately referred to potentially curative treatment. When extrapolating from gastric MALT lymphoma, one might argue that the presence of advanced disease per se is an adverse prognostic factor impairing the success of antibiotic therapy. This has indeed been demonstrated by Sackmann et al, 25 who found that patients with gastric MALT lymphoma restricted to mucosa and submucosa had a significantly higher response rate when compared with more advanced disease. As opposed to this, however, regression of gastric MALT lymphoma involving other organs has been reported following HP eradication. In addition, early-stage disease is exceedingly hard to diagnose in extragastric MALT lymphoma because of the impaired accessibility of eg, the parotid or the ocular adnexa as opposed to the gastric mucosa. In such cases, MALT lymphoma is almost always a by-chance finding in patients undergoing surgery for other reasons than suspected lymphoma. Early diagnosis of MALT lymphoma is further hampered by the fact that predisposing factors such as SS may result in polycystic glandular changes that are virtually indistinguishable from lymphoma by noninvasive means. Nevertheless, one would expect at least some activity in a cohort of 16 patients even at advanced stage in case of a causative role of HP. While we cannot exclude a potential role of HP eradication in a selected group of patients with early MALT lymphoma, our data suggest that the large majority of patients with extragastric MALT lymphoma will not benefit from HP eradication. Thus, its clinical use outside of a clearly defined clinical trial should strongly be discouraged.
The authors indicated no potential conflicts of interest.
Conception and design: Andreas Chott, Markus Raderer Administrative support: Stefan Wöhrer, Andreas Puespoek, Michael Haefner, Michael Hejna, Markus Raderer Provision of study materials or patients: Berthold Streubel, Michael Formanek, Ventzislav Petkov, Andreas Puespoek, Michael Haefner, Michael Hejna, Ulrich Jaeger, Markus Raderer Collection and assembly of data: Birgit Grünberger, Stefan Wöhrer, Berthold Streubel, Michael Formanek, Ventzislav Petkov, Andreas Puespoek, Michael Haefner, Michael Hejna, Andreas Chott, Markus Raderer Data analysis and interpretation: Birgit Grünberger, Stefan Wöhrer, Berthold Streubel, Michael Haefner, Michael Hejna, Ulrich Jaeger, Andreas Chott, Markus Raderer Manuscript writing: Birgit Grünberger, Andreas Puespoek, Markus Raderer Final approval of manuscript: Birgit Grünberger, Stefan Wöhrer, Berthold Streubel, Michael Formanek, Ventzislav Petkov, Andreas Puespoek, Michael Haefner, Michael Hejna, Ulrich Jaeger, Andreas Chott, Markus Raderer
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Isaacson P, Müller-Hermelink HK, Piris MA, et al: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), in Jaffe ES, Harris NL (eds): Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001, pp 157-160 2. Isaacson PG, Norton AJ: Mucosa-associated lymphoid tissue (MALT) and the MALT-lymphoma concept, in Isaacson PG, Norton AJ (eds): Extranodal Lymphomas. Edinburgh, UK, Churchill Livingston, 1994, pp 5-14 3. Isaacson P, Wright DH: Malignant lymphoma of mucosa-associated lymphoid tissue: A distinctive type of B-cell lymphoma. Cancer 52:1410-1416, 1983[CrossRef][Medline] 4. Isaacson P, Wright DH: Extranodal malignant lymphoma arising from mucosa associated lymphoid tissue. Cancer 53:2515-2524, 1984[CrossRef][Medline] 5. Wotherspoon AC, Doglioni C, Diss TC, et al: Regression of primary low grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori. Lancet 342:575-577, 1993[CrossRef][Medline] 6. 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 31:263-268, 2000[CrossRef][Medline] 7. Ferreri AJ, Guidoboni M, Ponzoni M, et al: Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96(8):571-573, 2004 8. Al-Saleem T, Al-Mondhiry H: Immunoproliferative small intestinal disease (IPSID): A model for mature B-cell neoplasms. Blood 105(6):2274-2280, 2005 9. Ambrosetti A, Zanotti R, Pattaro C, et al: Most cases of primary salivary mucosa-associated lymphoid tissue lymphoma are associated either with Sjoegren syndrome or hepatitis C virus infection. Br J Haematol 126:43-49, 2004[CrossRef][Medline] 10. Arima N, Tsudo M: Extragastric mucosa-associated lymphoid tissue lymphoma showing regression by Helicobacter pylori eradication therapy. Br J Haematol 120(5):790-792, 2003 11. Luppi M, Longo G, Ferrari MG, et al: Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br J Haematol 94:373-375, 1996[CrossRef][Medline] 12. Vitali C, Bombardieri S: The European classification criteria for Sjögren's syndrome (SS): Proposal for a modification of the rules for classification suggested by the analysis of the receiver operating characteristic (ROC) curve of the criteria performance. J Rheumatol 24:S50, 1997 13. Streubel B, Simonitsch-Klupp I, Müllauer L, et al: Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722-1726, 2004[CrossRef][Medline] 14. Cochran WG: Some methods for strengthening the common Chi-squared tests. Biometrics 10:417-451, 1954[CrossRef] 15. Brandtzaeg P, Farstad I, Haraldsen G: Regional specialization of the mucosal immune system: Primed cells do not always home along the same track. Immunol Today 20:267-277, 1999[CrossRef][Medline] 16. Raderer M, Vorbeck F, Formanek M, et al: Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 83:454-457, 2000[CrossRef][Medline] 17. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al: Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338:1175-1176, 1991[CrossRef][Medline] 18. Doglioni C, Wotherspoon AC, Moschini A, et al: High incidence of primary gastric lymphoma in Northeastern Italy. Lancet 339:834-835, 1992[CrossRef][Medline] 19. Parsonnet J, Hansen S, Rodriguez L, et al: Helicobacter pylori infection and gastric lymphoma. N Engl J Med 330:1267-1271, 1994 20. Raderer M, Wrba F, Kornek G, et al: Association between Helicobacter pylori infection and pancreatic cancer. Oncology 55:16-19, 1998[CrossRef][Medline] 21. Zucca E, Conconi A, Pedrinis E, et al: Nongastric marginal zone B-cell lymphoma of mucosa associated lymphoid tissue. Blood 101:2489-2495, 2003 22. Thieblemont C, Bastion Y, Berger F, et al: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: Analysis of 108 patients. J Clin Oncol 15:1624-1630, 1997[Abstract] 23. Raderer M, Pfeffel F, Pohl G, et al: Regression of colonic low grade B cell lymphoma of the mucosa associated lymphoid tissue type after eradication of Helicobacter pylori. Gut 46:133-135, 2000 24. van den Bosch J, Kropman RF, Blok P, et al: Disappearance of a mucosa-associated lymphoid tissue (MALT) lymphoma of the urinary bladder after treatment for Helicobacter pylori. Eur J Haematol 68(3):187-188, 2002 25. Sackmann M, Morgner A, Rudolph B, et al: Regression of gastric MALT lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging: MALT Lymphoma Study Group. Gastroenterology 113(4):1087-1090, 1997[CrossRef] Submitted May 30, 2005; accepted January 9, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, the Fisher's exact test, or with contingency tables. All tests were used according to the recommendations of Cochran.
