Published online May 7, 2010. doi: 10.3748/wjg.v16.i17.2158
Revised: February 10, 2010
Accepted: February 17, 2010
Published online: May 7, 2010
AIM: To investigate treatment outcome of Helicobacter pylori (H. pylori)-negative low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma.
METHODS: In this study, we retrospectively reviewed the clinical outcome and clinicopathologic factors of stage IE H. pylori-negative low-grade gastric MALT lymphoma cases from August 1998 to June 2009.
RESULTS: A total of eleven patients with H. pylori-negative low-grade gastric MALT lymphoma were enrolled in the study and received anti-H. pylori eradication treatment and/or radiotherapy or excisional therapy. Complete remission (CR) of gastric MALT lymphoma was achieved in all patients. The time to CR was 1-66 mo (median, 1 mo).
CONCLUSION: Eradication therapy may be offered as an initial treatment option even in cases of localized H. pylori-negative gastric MALT lymphoma.
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Citation: Park HS, Kim YJ, Yang WI, Suh CO, Lee YC. Treatment outcome of localized
Helicobacter pylori -negative low-grade gastric MALT lymphoma. World J Gastroenterol 2010; 16(17): 2158-2162 - URL: https://www.wjgnet.com/1007-9327/full/v16/i17/2158.htm
- DOI: https://dx.doi.org/10.3748/wjg.v16.i17.2158
Mucosa-associated lymphoid tissue (MALT) lymphoma, first described in 1983 by Isaacson and Wright[1], has been recently re-classified as extranodal marginal zone lymphoma of MALT-type, in the Revised European-American Classification of Lymphoid Neoplasms (REAL)/World Health Organization (WHO) Classification of Lymphoid Neoplasms. An important feature of MALT lymphoma is the presence of lymphoepithelial lesions formed by the invasion of individual glands by aggregates of lymphoma cells[2].
In previous studies, Helicobacter pylori (H. pylori) infection was suggested to be causally associated with primary gastric MALT lymphoma[3,4]. Indeed, H. pylori provides the antigenic stimulus, which is mediated by mucosal T cells, for sustaining the growth of gastric MALT lymphoma[5]. The regression of gastric MALT lymphoma after the eradication of H. pylori was first reported in 1993 by Wotherspoon et al[3]. H. pylori eradication led to complete remission in 80% of stage IE, low-grade gastric MALT lymphoma patients, with a yearly recurrence rate of approximately 5%[6]. Currently, eradication of H. pylori is considered the accepted initial therapy in cases of localized, stage IE low-grade gastric MALT lymphoma[7].
However, there are no treatment guidelines for the management of patients who are unresponsive to antibiotic treatment or for the subset of patients who present with stage IE low-grade gastric MALT lymphoma but are H. pylori-negative and understandably do not respond to antibiotic treatment[8]. In these cases, treatment choices include the known, conventional therapeutic approaches such as surgery, chemotherapy or radiotherapy[9]. Because of the ambiguity of treatment in H. pylori-negative patients, further studies are required to clarify a treatment strategy for H. pylori-negative MALT lymphoma. In this study, we evaluated the treatment outcome of eleven H. pylori-negative low-grade gastric MALT lymphoma patients to offer therapeutic guidelines for treating H. pylori-negative low-grade gastric MALT lymphoma.
We retrospectively studied eleven patients with H. pylori-negative low-grade gastric MALT lymphoma diagnosed at the Severance Hospital from August 1998 to June 2009. All patients were confirmed by pathology to have low-grade gastric MALT lymphoma without a diffuse large B-cell lymphoma (DLBCL) component. Histological diagnosis of MALT lymphoma was performed according to the criteria outlined in the WHO classification, and histological assessment was performed by a reference pathologist (Yang WI). Immunological phenotyping of paraffin sections was performed to demonstrate light chain restriction and the CD20+CD5-CD10-cyclinD1- phenotype which was microscopically consistent with the presence of low-grade MALT lymphoma. The study was approved by our institutional review board, and informed consent was not required.
None of the patients had evidence of H. pylori infection as judged by histology, a urea breath test, a rapid urease test (CLOTM, Delta West, Bentley, Western Austria) and serological testing. The gross phenotype for each patient was classified into five types according to endoscopic features: (1) ulcerative: one or more ulcerations; (2) protruding: elevated or polypoid; (3) granular: small nodules on the lesion; (4) infiltrative: mucosal infiltration; and (5) mixed.
Determination of the stage of disease included a detailed physical examination, chest X-ray, abdominal computed tomography (CT), endoscopic ultrasonography (EUS), bilateral bone marrow examination, and 18F-FDG PET scan.
Treatment modalities included anti-H. pylori eradication therapy, radiotherapy, and excisional therapy (one endoscopic mucosal resection and one subtotal gastrectomy). The most common treatment was radiotherapy (six patients), followed by anti-H. pylori eradication only (three patients). Prior to radiotherapy, three of the six radiotherapy patients received anti-H. pylori eradication therapy which consisted of amoxicillin (2 × 1000 mg/d), clarithromycin (2 × 500 mg/d), and esomeprazole (2 × 40 mg/d) or pantoprazole (2 × 20 mg/d) for 7 or 14 d. Radiotherapy was performed at a total dose ranging from 30 Gy to 36 Gy on an outpatient basis. Two patients underwent local excision therapy, including one subtotal gastrectomy and one endoscopic mucosal resection (EMR).
The median time for follow-up after remission was 25 mo (range: 5-76 mo). Complete remission (CR) was defined as the total disappearance of clinical evidence for lymphoma and an absence of histologic evidence for lymphoma on biopsy specimens. Partial remission (PR) was defined as a tumor reduction of at least 50%, and stable disease (SD) was defined as variation within either a 50% decrease or 25% increase in tumor size. In cases with complete remission, endoscopic examinations and biopsies were performed at regular intervals.
The male to female patient ratio in this study was 1:1.2. The mean age of the patients was 55.7 (36-73) years. Four patients were symptomatic at presentation indicating abdominal pain (two cases), abdominal discomfort (one case), and GI bleeding (one case). Lymphoma was most often localized in the body and the antrum in 36% of the patients. Endoscopic lesions were characterized as ulcerative (five cases), infiltrative (one case), protruding (two cases), granular (one case) and mixed (two cases). Initial endoscopic findings are summarized in Table 1. Initial clinical staging with EUS and/or CT scans and BM examinations revealed all the cases to be stage IE.
| H. pylori negative MALT lymphoma (n = 11) | |
| Age (yr, mean) | 55.7 (36-73) |
| Sex | |
| Men | 5 (45) |
| Women | 6 (55) |
| Site | |
| Cardia | 1 (9) |
| Fundus | 1 (9) |
| Body only | 3 (27) |
| Body & antrum | 4 (36) |
| Diffuse | 2 (18) |
| Endoscopy | |
| Ulcerative | 5 (45) |
| Infiltrative | 1 (9) |
| Protruding | 2 (18) |
| Granular | 1 (9) |
| Mixed | 2 (18) |
Complete remission (CR) of gastric MALT lymphoma was achieved in all patients (Table 2). The time to CR ranged from one to 66 mo (median, 1 mo). Anti-H. pylori eradication therapy was performed in six of the eleven patients. Three of six patients, who completed the follow-up endoscopic examination 1 or 2 mo later, had complete remission of gastric MALT lymphoma. However, two patients refused to wait for the treatment response evaluation and subsequently underwent radiotherapy for definitive treatment. The remaining patient had stable disease for 2 mo before being referred for radiotherapy. All three of these patients showed complete remission of gastric MALT lymphoma 1 mo after the cessation of radiotherapy based on histological evidence. None of the 11 patients showed local or distant recurrence after a median follow-up time of 25 mo (range: 5-76 mo).
| Age (yr)/sex | Stage | Treatment | Response | Time to CR(mo) | Follow up time after remission (mo) | |
| Case 1 | 54/F | IE | Eradication | CR | 1 | 6 |
| Case 2 | 60/F | IE | Eradication | CR | 1 | 27 |
| Case 3 | 52/F | IE | Eradication | CR | 2 | 25 |
| Case 4 | 36/M | IE | RTx | CR | 1 | 76 |
| Case 5 | 58/F | IE | RTx | CR | 2 | 17 |
| Case 6 | 69/M | IE | RTx | CR | 1 | 47 |
| Case 7 | 41/F | IE | Eradication + RTx | CR | 1 | 7 |
| Case 8 | 62/M | IE | Eradication + RTx | CR | 1 | 8 |
| Case 9 | 55/M | IE | Eradication -> RTx | CR | 1 | 5 |
| Case 10 | 73/F | IE | STG | CR | 66 | 54 |
| Case 11 | 53/M | IE | EMR | CR | 2 | 69 |
The prevalence of H. pylori in patients with low-grade gastric MALT lymphoma is variable[10]. It is possible that a reduced number of H. pylori organisms present in the infection may account for the negative H. pylori diagnostic test result in some cases, and false-negative results may also be obtained when only one diagnostic method is employed[11]. The European Guidelines generally take the gold standard to be represented by at least two tests[12]. When appropriate diagnostic methods are used, the prevalence of H. pylori infection in low-grade MALT lymphoma is high, at nearly 90%[10]. In our study, four diagnostic tests were performed and showed that true H. pylori-negative patients were included. However, additional tests, such as culture with polymerase chain reaction, would allow the detection and identification of other infective organism[13].
Due to the excellent clinical outcome of H. pylori eradication treatment, the eradication of H. pylori with antibiotics should be employed as the sole initial treatment in the localized form (confined to the stomach) of gastric MALT lymphoma[14]. However, in advanced stages with H. pylori-positive gastric MALT lymphoma and in H. pylori-negative lymphoma, definitive treatment guidelines are not yet available despite the numerous published clinical research papers[8,14,15].
Antibiotic treatment for H. pylori-negative gastric MALT lymphoma has been described in a limited number of patients. We collectively reviewed a series of four published studies including patients treated solely with the anti-H. pylori antibiotic regimen as the initial treatment for H. pylori-negative stage IE gastric MALT lymphoma (Table 3). A total of 31 patients were included in these studies, and ten patients (32%) were shown to respond to this treatment alone. Raderer et al[16] reported that five of six patients with H. pylori-negative gastric MALT lymphoma responded to antibiotic treatment (one partial remission and four complete remissions). However, Steinbach et al[17] and Ye et al[18] experienced a 0% response rate. In other words, marked variation in treatment response rate was noted. Nevertheless, instituting anti-H. pylori treatment showed satisfactory clinical outcomes and allowed for gastric preservation in a significant number of cases with H. pylori-negative gastric MALT lymphoma. Although seemingly contradictory, anti-H. pylori treatment may be advised as the first-line therapy in H. pylori-negative localized gastric MALT lymphoma. Unfortunately, the effectiveness of anti-H. pylori treatment could not be confirmed in this study, as only four out of the six patients who received the anti-H. pylori eradication regimen waited long enough to receive the follow-up endoscopic examination which was used to confirm the complete remission status of MALT lymphoma. The other two patients proceeded to radiation therapy due to various clinical and psychosocial issues. In addition, previous studies also included patients with advanced stages of disease, including IIE1 (Table 3). However, it was not possible from the available data to categorize lymphoma regression according to tumor stage (IE vs IIE1). Therefore, additional studies are needed to define the role of anti-H. pylori eradication therapy in advanced stages of gastric MALT lymphoma such as stages IIE, IIIE or IV.
| Author | Yr | No. of patients | Stage | Follow-up after treatment (mo) | Response rate |
| Steinbach et al[17] | 1999 | 6 | IE | 5 or more | 0 (0) |
| Ye et al[18] | 2003 | 5 | IE | 4-12 | 0 (0) |
| Raderer et al[16] | 2006 | 6 | IE | 12-19 | 5 (83) |
| Stathis et al[23] | 2009 | 14 | IE | Not described | 51 (35) |
| Ruskone-Fourmestraux et al[24] | 2001 | 10 | IE, IIE1 | 2-21 | 0 (0) |
| Nakamura et al[25] | 2006 | 7 | IE, IIE1 | 1-15 | 2 (29) |
| Akamatsu et al[21] | 2006 | 9 | IE, IIE1 | 6 or more | 1 (11) |
| Terai et al[26] | 2008 | 4 | IE, IIE1 | Not described | 1 (25) |
There is still no explanation for the effectiveness of anti-H. pylori treatment in H. pylori-negative gastric MALT lymphoma[16]. However, it has been speculated that another infective organism, Helicobacter heilmannii[19], might be involved in the development of gastric MALT lymphoma. Also, one cannot rule out the possibility that unknown bacterial agents capable of surviving in the stomach might play a role in the development of rare H. pylori-negative gastric MALT lymphomas[16]. Another possibility is that low bacterial counts[20] and urease-negative H. pylori mutant strains may escape detection by the diagnostic tests that are currently available. If this assumption is correct, one might expect the noted H. pylori-negative gastric MALT lymphoma patient response to broad-spectrum antibiotic therapy. Also, MALT lymphoma is to some extent an immunologically driven disease, therefore an additional hypothesis may involve the potential immunomodulatory effects of the antibiotic agents used[16].
Disease control using radiotherapy alone has been previously reported in the literature, which supports the use of a modest dose of involved-field radiotherapy for patients with stages IE-IIE MALT lymphoma of the stomach without evidence of H. pylori infection[14]. Table 4 summarizes these previously reported cases. Including our cases, 35 of 35 cases responded to radiotherapy. One of the 35 patients reported by Akamatsu et al[21] had a partial remission, while the others all had a complete remission. Based on these results, it is prudent to say that radiotherapy is suitable in early stage (IE or IIE) H. pylori-negative gastric MALT lymphoma. In addition, excisional treatments such as endoscopic mucosal resection or laparoscopic gastric resection may represent another therapeutic option in the case of localized forms of gastric MALT lymphoma in individuals who are not suitable for, or who refuse, standard therapeutic approaches[15,20,22]. In the past, surgical treatment has often been advocated to establish accurate diagnosis, staging, and management of early-stage gastric lymphoma, which has about a 90% 5-year survival rate, but leads to significant morbidity[22]. In our study, two patients received endoscopic mucosal resection and subtotal gastrectomy, respectively. There has been no local or distant recurrence during the follow-up period of 54 to 69 mo.
In our series, therapeutic measures such as anti-H. pylori eradication, radiotherapy and excisional therapy achieved complete remission in all cases. Nevertheless, antibiotic treatment is simple, inexpensive, less harmful and H. pylori negative low grade MALT lymphoma shows a favorable long-term outcome[22]. Therefore we suggest that H. pylori eradication therapy may be an initial treatment option for localized H. pylori-negative gastric MALT lymphoma. In addition, further studies on eradication therapy are required to help in the establishment of strategies for patients with localized H. pylori-negative gastric MALT lymphoma.
Eradication of Helicobacter pylori (H. pylori) is a well-accepted initial therapy in cases of localized (stage IE) low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with H. pylori infection. However, there are no treatment guidelines for the management of H. pylori-negative low-grade gastric MALT lymphoma.
Previous studies revealed the effectiveness of radiotherapy for localized H. pylori-negative low grade gastric MALT lymphoma. However, H. pylori eradication therapy is still a controversial treatment modality, although this treatment is simple and less harmful than other treatments.
With the exception of this study, only 31 H. pylori-negative patients have received eradication therapy (response rate 32%). However, treatment response was variable. The authors’ study enrolled a small number of patients, but they all had complete remission.
The findings from this study suggest that H. pylori eradication therapy may be an initial treatment option for localized H. pylori-negative gastric MALT lymphoma. Their study adds information which helps in the establishment of strategies for patients with localized H. pylori-negative gastric MALT lymphoma.
This is an interesting paper that may be beneficial for patients with H.pylori-negative gastric MALT lymphoma.
Peer reviewer: Philippe Lehours, MD, PhD, University Bordeaux 2, INSERM U853, Bat 2B RDC Zone Nord, 146 rue Léo Saignat, Bordeaux cedex, 33076, France
S- Editor Tian L L- Editor Webster JR E- Editor Ma WH
| 1. | Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52:1410-1416. [Cited in This Article: ] |
| 2. | Cavalli F, Isaacson PG, Gascoyne RD, Zucca E. MALT Lymphomas. Hematology Am Soc Hematol Educ Program. 2001;241-258. [Cited in This Article: ] |
| 3. | Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, Isaacson PG. 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. [Cited in This Article: ] |
| 4. | Parsonnet J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, Jellum E, Orentreich N, Vogelman JH, Friedman GD. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994;330:1267-1271. [Cited in This Article: ] |
| 5. | 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;342:571-574. [Cited in This Article: ] |
| 6. | Stolte M, Bayerdörffer E, Morgner A, Alpen B, Wündisch T, Thiede C, Neubauer A. Helicobacter and gastric MALT lymphoma. Gut. 2002;50 Suppl 3:III19-III24. [Cited in This Article: ] |
| 7. | Fischbach W. Primary gastric lymphoma of MALT: considerations of pathogenesis, diagnosis and therapy. Can J Gastroenterol. 2000;14 Suppl D:44D-50D. [Cited in This Article: ] |
| 8. | Psyrri A, Papageorgiou S, Economopoulos T. Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management. Ann Oncol. 2008;19:1992-1999. [Cited in This Article: ] |
| 9. | 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. 2009;Epub ahead of print. [Cited in This Article: ] |
| 10. | Asenjo LM, Gisbert JP. [Prevalence of Helicobacter pylori infection in gastric MALT lymphoma: a systematic review]. Rev Esp Enferm Dig. 2007;99:398-404. [Cited in This Article: ] |
| 11. | Gisbert JP, Aguado B, Luna M, Nistal S, Asenjo LM, Reina T, Acevedo A, Arranz R. Gastric MALT lymphoma: clinical characteristics and prevalence of H. pylori infection in a series of 37 cases. Rev Esp Enferm Dig. 2006;98:655-665. [Cited in This Article: ] |
| 12. | Ricci C, Holton J, Vaira D. Diagnosis of Helicobacter pylori: invasive and non-invasive tests. Best Pract Res Clin Gastroenterol. 2007;21:299-313. [Cited in This Article: ] |
| 13. | Liu H, Rahman A, Semino-Mora C, Doi SQ, Dubois A. Specific and sensitive detection of H. pylori in biological specimens by real-time RT-PCR and in situ hybridization. PLoS One. 2008;3:e2689. [Cited in This Article: ] |
| 14. | Zucca E, Dreyling M. Gastric marginal zone lymphoma of MALT type: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19 Suppl 2:ii70-ii71. [Cited in This Article: ] |
| 15. | Fischbach W, Keller R, Englert D. Unusual treatment of a gastric marginal zone B-cell lymphoma of MALT type. Z Gastroenterol. 2007;45:383-386. [Cited in This Article: ] |
| 16. | 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. [Cited in This Article: ] |
| 17. | Steinbach G, Ford R, Glober G, Sample D, Hagemeister FB, Lynch PM, McLaughlin PW, Rodriguez MA, Romaguera JE, Sarris AH. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial. Ann Intern Med. 1999;131:88-95. [Cited in This Article: ] |
| 18. | Ye H, Liu H, Raderer M, Chott A, Ruskone-Fourmestraux A, Wotherspoon A, Dyer MJ, Chuang SS, Dogan A, Isaacson PG. High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood. 2003;101:2547-2550. [Cited in This Article: ] |
| 19. | Morgner A, Lehn N, Andersen LP, Thiede C, Bennedsen M, Trebesius K, Neubauer B, Neubauer A, Stolte M, Bayerdörffer E. Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Gastroenterology. 2000;118:821-828. [Cited in This Article: ] |
| 20. | Yang YY, Lo SS, Li FY, Lin HC, Lee FY, Chang FY, Lee SD. Helicobacter pylori-negative low-grade extranodal B-cell primary gastric mucosa-associated lymphoid tissue lymphoma. J Chin Med Assoc. 2007;70:121-125. [Cited in This Article: ] |
| 21. | 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. [Cited in This Article: ] |
| 22. | Chung SJ, Kim JS, Kim H, Kim SG, Kim CW, Jung HC, Song IS. Long-term clinical outcome of helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma is comparable to that of h. pylori-positive lymphoma. J Clin Gastroenterol. 2009;43:312-317. [Cited in This Article: ] |
| 23. | Stathis A, Chini C, Bertoni F, Proserpio I, Capella C, Mazzucchelli L, Pedrinis E, Cavalli F, Pinotti G, Zucca E. 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. [Cited in This Article: ] |
| 24. | 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. [Cited in This Article: ] |
| 25. | Nakamura S, Matsumoto T, Ye H, Nakamura S, Suekane H, Matsumoto H, Yao T, Tsuneyoshi M, Du MQ, Iida M. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a clinicopathologic and molecular study with reference to antibiotic treatment. Cancer. 2006;107:2770-2778. [Cited in This Article: ] |
| 26. | Terai S, Iijima K, Kato K, Dairaku N, Suzuki T, Yoshida M, Koike T, Kitagawa Y, Imatani A, Sekine H. Long-term outcomes of gastric mucosa-associated lymphoid tissue lymphomas after Helicobacter pylori eradication therapy. Tohoku J Exp Med. 2008;214:79-87. [Cited in This Article: ] |
| 27. | Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol. 1998;16:1916-1921. [Cited in This Article: ] |