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Originally published as JCO Early Release 10.1200/JCO.2005.92.007 on June 20 2005 © 2005 American Society of Clinical Oncology.
Another Piece of the MALT Lymphomas JigsawOncology Institute of Southern Switzerland, Bellinzona, Switzerland In this issue, Ferreri et al1 add to the fascinating story of mucosa-associated lymphoid tissue (MALT) lymphomas, whose growth is stimulated by chronic inflammatory processes, showing that Chlamydia psittaci–eradicating antibiotic therapy can be followed by histologic regression of marginal-zone lymphomas of ocular adnexa. MALT lymphoma was first described in 1983 by Isaacson and Wright,2 who recognized a striking histologic similarity between cases of immunoproliferative small intestinal disease (IPSID) and gastric low-grade lymphoma. The histologic features were close to those of the Peyer's patches, and it soon became evident that similar cases can be found at other mucosal sites, and the term mucosa-associated lymphoid tissue was proposed. Later, it was demonstrated that the B cells of MALT lymphoma share the cytologic features and immunophenotype of marginal-zone B-cell lymphomas; therefore, the WHO lymphoma classification of 2001 designated this lymphoma as the "extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)"3; and IPSID is now considered a MALT lymphoma variant that involves mainly the proximal small intestine.4 Since the 1970s, it has been known that certain cases of stage A IPSID may regress after antibiotic therapies eliminating unknown organism(s).5 However, it was the demonstration that Helicobacter pylori infection is a risk factor for gastric MALT lymphoma6 and that eradication of the microorganism can result in histologic lymphoma regression in more than half of the treated patients7 that made this tumor a popular model of antigen-driven lymphomagenesis. Primary gastric MALT lymphoma is the most common MALT lymphoma and the most widely studied to date. In the stomach, where lymphocytes are not normally present, the onset of MALT lymphoma is preceded by the acquisition of MALT as a result of H pylori infection,8 and the regression of gastric MALT lymphoma can be achieved after anti-Helicobacter therapy.7 The association of H pylori with gastric MALT lymphoma has led to the hypothesis that the microorganism may provide the antigenic stimulus for sustaining the growth of the lymphoma in the stomach.9 However, the tumor-derived immunoglobulins usually do not recognize H pylori, but recognize various autoantigens.10 Sequence analysis of the immunoglobulin genes expressed by the gastric MALT lymphoma B cells shows a pattern of somatic hypermutation, indicating that the tumor cell has undergone antigen selection in germinal centers.11 Ongoing mutations of the immunoglobulin genes can also be found, suggesting that clonal expansion of tumor cells continues to be at least partially driven by a long-term antigen stimulation. It can be postulated that the interaction of host T-cell and antigen-presenting cells with bacterial antigens leads to a cascade of complex events, which finally results in autonomous clonal B-cell expansion and proliferation, bearing specific genomic aberrations. Extranodal lymphomas of the MALT are relatively rare, accounting for approximately 8% of all non-Hodgkin's lymphomas.12 On the contrary, H pylori can be found in the stomach of more than one half of the world population.13 Thus, both bacterial and host individual additional factors have to interact to cause lymphoma. Polymorphisms affecting genes, such as IL1RN and GSTT1, are involved in inflammatory responses. Therefore, antioxidative capacity may represent at least part of the genetic background for the lymphomagenesis in individual H pylori–infected persons.14 Free radicals are likely to play a role in development of B-cell genomic damages in the chronic gastritis, and their presence is increased in the presence of the cytotoxin-associated antigen A (CagA) -positive strains of H pylori.15 Until now, at least three recurrent translocations have been described in MALT lymphomas; these translocations are t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21). The most common aberration is t(11;18), which results in a fusion of the apoptosis inhibitor gene API2 on chromosome 11q21 with the MALT1 gene on chromosome 18q21.16 t(11;18) is present in at least one third of patients with extranodal marginal-zone B-cell lymphoma of MALT type but not in patients with nodal marginal-zone lymphoma, splenic marginal-zone lymphoma, or mucosal diffuse large-cell lymphoma. It is often the sole cytogenetic alteration, which is a hint of a major pathogenetic role. The frequency of t(11;18) in MALT lymphoma is site related; it is more frequent in the gastrointestinal tract and in the lung, less common in conjunctiva and orbit, and absent or almost absent in salivary glands, thyroid, liver, and skin.15,17 t(1;14)(p22;q32) is much more rarely detected, and it deregulates the expression of the survival-related gene BCL10, which is highly expressed in the nucleus of the neoplastic B cells of MALT lymphomas carrying this translocation.18,19 Interestingly, nuclear expression of BLC10 is also present in t(11;18)-positive MALT lymphomas, indicating that nuclear localization of BCL10 can occur as the result of two apparently independent cytogenetic events.15,20,21 Instead, BCL10 is expressed only in the cytoplasm in MALT lymphomas without these translocations as well as in non-neoplastic germinal center and marginal-zone B cells.22 The t(14;18)(q32;q21) translocation, which is cytogenetically identical to the translocation involving BCL2 in follicular lymphoma but here involving MALT1 (which is localized approximately 5 million base pairs centromeric of BCL2), has been also described in approximately 20% of MALT lymphomas.17,23,24 This translocation seems to be more common at the level of ocular adnexal, liver, and skin than in the gastrointestinal tract and lung. In contrast to t(11;18), t(14;18)(q32;q21) is often associated with additional genetic abnormalities, such as trisomies of chromosomes 3 and 12.
The three seemingly disparate translocations that target BCL10 and MALT1 seem to affect the same signaling pathway, resulting in the activation of nuclear factor kappa-B (NF Three individual structural chromosomal aberrations all leading to the same histology might be considered as a hint of the presence of different disease entities or can suggest that site-specific pathogenetic pathways may sustain the growth of MALT lymphomas at different anatomic locations. In the stomach, H pylori infection and the related chronic inflammation seem to be the major causative factors, possibly inducing the occurrence of the t(11;18). The search of other infections associated with the growth of MALT lymphoma has been somehow elusive. Borrelia burgdorferi27 and Campylobacter jejuni4 have been associated with marginal-zone lymphomas arising in the skin and small intestine, respectively. The last entry in the list of bacterial infections associated with MALT lymphomas is C psittaci, which has been found in 80% of lymphomas of ocular adnexa28 and whose eradication has been shown to cause lymphoma regression.1 Thus, different infection agents resulting in chronic inflammatory processes at different anatomic sites may ultimately result in the development of marginal-zone lymphoma. Similarly, chronic autoimmune disorders, such as Hashimoto thyroiditis and Sjögren syndrome, may be another background for the development of marginal-zone lymphoma in the thyroid and salivary glands, respectively.3 A similar event might be the development of mixed cryoglobulinemia and (splenic) marginal-zone lymphoma associated with hepatitis C virus infection.29 As noted earlier, surprisingly different chromosomal translocations have been found that are apparently mutually exclusive, site associated, and all acting on the same biologic pathway. All malignant lymphomas are derived from cells of the immune system and, as recently shown by molecular profiling of follicular lymphomas,30 the functional interaction of lymphoma cells with the immune system is very important in defining tumor behavior and development. The MALT lymphoma is an excellent example of this. The important data reported by Ferreri et al1 will obviously need to be reproduced in larger series of patients and in different geographical areas to obtain confirmation of this new, cheap, and well-tolerated therapeutic approach for ocular adnexal lymphomas. They also underscore the need to answer the following urgent questions. What are the links among the different genetic abnormalities and the different infections and anatomic sites? Does t(14;18), which has a high incidence in ocular adnexal lymphomas and is often associated with a certain degree of aneuploidy,24 affect the response rate to antibiotics? What about the presence of nuclear BCL10, which has been reported to be frequent in ocular adnexal lymphomas and not related to t(11;18)?31 Hopefully, time will tell. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Ferreri AJM, Ponzoni M, Guidoboni M, et al: Regression of ocular adnexal lymphoma after Chlamydia psittaci–eradicating antibiotic therapy. J Clin Oncol 23: 5067-5073, 2005 2. 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] 3. Isaacson PG, Muller-Hermelink HK, Piris MA, et al: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), in Jaffe ES, Harris NL, Stein H, et al (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, International Agency for Research on Cancer Press, 2001, pp 157-160
4. Al-Saleem T, Al-Mondhiry H: Immunoproliferative small intestinal disease (IPSID): A model for mature B-cell neoplasms. Blood 105: 2274-2280, 2005 5. 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 63: 1251-1256, 1989[CrossRef][Medline]
6. Parsonnet J, Hansen S, Rodriguez L, et al: Helicobacter pylori infection and gastric lymphoma. N Engl J Med 330: 1267-1271, 1994 7. Zucca E, Cavalli F: Are antibiotics the treatment of choice for gastric lymphoma? Curr Hematol Rep 3: 11-16, 2004[Medline]
8. Zucca E, Bertoni F, Roggero E, et al: Molecular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Engl J Med 338: 804-810, 1998 9. Hussell T, Isaacson PG, Crabtree JE, et al: The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 342: 571-574, 1993[CrossRef][Medline] 10. Hussell T, Isaacson PG, Crabtree JE, et al: Immunoglobulin specificity of low grade B cell gastrointestinal lymphoma of mucosa-associated lymphoid tissue (MALT) type. Am J Pathol 142: 285-292, 1993[Abstract] 11. Du M, Diss TC, Xu C, et al: Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 10: 1190-1197, 1996[Medline]
12. The Non-Hodgkin's Lymphoma Classification Project: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood 89: 3909-3918, 1997
13. Parsonnet J: Helicobacter pylori: The size of the problem. Gut 43: S6-S9, 1998 (suppl 1)
14. Rollinson S, Levene AP, Mensah FK, et al: Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood 102: 1007-1011, 2003
15. Ye H, Liu H, Attygalle A, et al: Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: Significant association with CagA strains of H. pylori in gastric MALT lymphoma. Blood 102: 1012-1018, 2003
16. Dierlamm J, Baens M, Wlodarska I, et al: The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93: 3601-3609, 1999 17. Murga Penas EM, Hinz K, Roser K, et al: Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas. Leukemia 17: 2225-2229, 2003[CrossRef][Medline] 18. Zhang Q, Siebert R, Yan M, et al: Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1; 14)(p22;q32). Nat Genet 22: 63-68, 1999[CrossRef][Medline] 19. Willis TG, Jadayel DM, Du MQ, et al: Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96: 35-45, 1999[CrossRef][Medline]
20. Liu H, Ye H, Dogan A, et al: T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 98: 1182-1187, 2001
21. Kuo SH, Chen LT, Yeh KH, et al: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22: 3491-3497, 2004
22. Ye H, Dogan A, Karran L, et al: BCL10 expression in normal and neoplastic lymphoid tissue: Nuclear localization in MALT lymphoma. Am J Pathol 157: 1147-1154, 2000
23. Sanchez-Izquierdo D, Buchonet G, Siebert R, et al: MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 101: 4539-4546, 2003 24. Streubel B, Lamprecht A, Dierlamm J, et al: T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 101:2335-2339, 2003
25. Lucas PC, Yonezumi M, Inohara N, et al: Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 276: 19012-19019, 2001 26. Ho L, Davis RE, Conne B, et al: MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 105: 2891-2899, 2004 27. 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]
28. Ferreri AJ, Guidoboni M, Ponzoni M, et al: Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96: 586-594, 2004
29. Hermine O, Lefrere F, Bronowicki JP, et al: Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347: 89-94, 2002
30. Dave SS, Wright G, Tan B, et al: Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351: 2159-2169, 2004 31. Adachi A, Tamaru JI, Kaneko K, et al: No evidence of a correlation between BCL10 expression and API2-MALT1 gene rearrangement in ocular adnexal MALT lymphoma. Pathol Int 54: 16-25, 2004[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B), a transcription factor with a central role in immunity, inflammation, and apoptosis.
