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Originally published as JCO Early Release 10.1200/JCO.2006.05.6150 on April 24 2006 © 2006 American Society of Clinical Oncology. Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium Address reprint requests to Sagaert Xavier, MD, Department of Morphology and Molecular Pathology, Katholieke Universiteit Leuven, Minderbroederstraat 12, B-3000 Leuven, Belgium; e-mail: xavier.sagaert{at}uz.kuleuven.ac.be
PURPOSE: Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas. PATIENTS AND METHODS: All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected. RESULTS: We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18. CONCLUSION: The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.
Among the genetic aberrations reported to occur in mucosa-associated lymphoid tissue (MALT) lymphomas, the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) are well known because they seem to be specific for or at least closely related to this type of B-cell non-Hodgkin's lymphoma; these translocations result in the API2-MALT1, IGH-BCL10, and IGH-MALT1 rearrangements, respectively.1-6 Two of these affected genes, BCL10 and MALT1, play a crucial role in the antigen receptor signaling pathway leading to activation of nuclear factor-kappa B.7-9 Recently, forkhead box protein P1 (FOXP1) was identified as a translocation partner of IGH in MALT lymphomas as well as in diffuse large B-cell lymphoma (DLBCL).10,11 The FOXP1 gene is located at 3p13 (www.ensembl.org) and codes for a member of the FOX family of transcription factors.12 This family includes numerous proteins that take part in a wide range of normal developmental events, including the control of cellular differentiation and proliferation, immune regulation, and signal transduction.13 Spontaneous mutations of these molecules have been identified in various congenital disorders.14,15 FOX transcription factors are also implicated in carcinogenesis through retroviral integration, transcriptional regulation, chromosomal translocation, and gene amplification.16-22 Although the physiologic role of FOXP1 in lymphoid tissue is still unclear, it has shown to be expressed in normal activated B cells using genomic-scale expression profiling and in mantle-zone and some germinal center (GC) B cells using immunohistochemistry.23,24 The significance of FOXP1 overexpression in lymphomas is still debated, but the strong nuclear expression of FOXP1 in a subset of DLBCLs argues for a possible role in the pathogenesis of this group of aggressive B-cell lymphomas. One study found FOXP1 to be predominantly expressed in non-GC DLBCLs (71%) compared with GC DLBCLs (48%), but it did not predict clinical outcome.25 Two other studies found FOXP1 expression to be associated with inferior survival; one of the studies correlated strong nuclear FOXP1 expression to poor prognosis in BCL2-positive, t(14;18)(IGH;BCL2)–negative, non-GC DLBCLs.26,27 Recent studies also revealed FOXP1 expression in follicular center lymphoma as well as marginal zone lymphoma.11,28 In view of the recently described FOXP1 rearrangement in MALT lymphoma and the possible association of strong nuclear FOXP1 expression with worse clinical outcome in non-GC DLBCL, this study investigated FOXP1 expression in a series of MALT lymphomas in its relationship to histology, genetic aberrations, and clinical outcome. It was found that not only is FOXP1 a significant predictor of unfavorable clinical outcome, but also that FOXP1-positive MALT lymphomas, marked by a polymorphic histology and by trisomy 3 and 18, are at risk of transforming into aggressive DLBCLs. For the latter reason, 10 de novo DLBCLs (marked by FOXP1 positivity and trisomy 3 and 18) were added to this study to investigate whether this subset of DLBCLs is linked to MALT lymphoma.
Patient Selection We retrospectively studied 91 consecutive MALT lymphoma patients diagnosed between 1994 and 2004 at the University Hospital of Katholieke Universiteit Leuven. In 70 patients, formalin- and/or B5-fixed paraffin-embedded blocks, fresh tissue, and a complete clinical data set were available; only these patients were included in the study. Anatomic locations of these MALT lymphomas are listed in Table 1. Some of these patients were included in previous studies.1,2,11,29-33 All MALT lymphomas were reviewed according to the WHO criteria.34
Ten de novo DLBCL patients were added to this study. These patients were part of a large collection of DLBCL patients who were included in a previous study,35 and selection was based on a non-GC phenotype, FOXP1 positivity, and presence of trisomy 3 and 18.
Clinical Data
Morphology and Immunohistochemistry Paraffin sections were immunostained for FOXP1 with the mouse monoclonal antibody JC12 (kindly donated by A.H. Banham, University of Oxford, Oxford, United Kingdom) according to a previously published protocol.11 FOXP1 immunostainings were scored as negative (with occasional cells having weak nuclear FOXP1 expression), moderately positive (with part of the tumor cells featuring nuclear FOXP1 expression with variable intensity), or strongly positive (with nearly all tumor cells showing strong, uniform nuclear FOXP1 expression). Subdivision of DLBCLs into GC and non-GC subtypes was based on the algorithm of Hans et al25 using an immunohistochemical panel including the mouse monoclonal antibodies CD10 (Novocatra, Newcastle, United Kingdom), BCL2 (Dakocytomation, Glostrup, Denmark), BCL6 (Dakocytomation), and MUM1 (Dakocytomation).
Fluorescence in Situ Hybridization
Statistical Analysis
Patient Characteristics The mean patient age was 61 years, with a male-to-female ratio of 1.2:1. Ann Arbor stage I and II disease was present in 51 (72.8%) and four (5.7%) patients, respectively, whereas 15 patients (21.4%) presented with stage IV disease. Sixty-eight patients (97.1%) were treated with curative intent; only these patients were included in survival analysis. In one patient, a wait and see policy was adopted; the one remaining patient refused therapy. Localized therapy was applied in 34 patients; 18 were treated with surgical resection of the lymphoma site, 14 were treated with localized radiotherapy, and two were treated with a combination of both. Twelve patients received chemotherapy as single therapy, eight patients were treated with combined chemotherapy and radiotherapy, and eight patients were treated with adjuvant chemotherapy (and radiotherapy in three patients) after surgery. Of these 28 patients, 22 received anthracycline-containing combination chemotherapy, predominantly cyclophosphamide, doxorubicin, vincristine, and prednisone. Because of the correlation between gastric MALT lymphoma and Helicobacter pylori, antibiotic eradication therapy was the first-line choice in 12 patients; in six patients, eradication therapy did not result in lymphoma regression, and a gastrectomy was performed. A total of 65 patients (95.6%) achieved a complete response after initial therapy. More than 50% of the patients were observed for at least 5 years. The mean OS time was 66.8 months (range, 0 to 139 months), with a median DFS time of 61.4 months. Relapse occurred in 10 patients (14.7%), with a median DFS time in those patients of 29.3 months. Five patients (7.4%) were documented with evolution to or the simultaneous presence of a DLBCL (cytogenetically related to the primary MALT lymphoma). Fourteen patients (20.6%) died; three of these deaths resulted from lymphoma progression, and all deaths occurred within 5 years from diagnosis.
Morphology and Immunohistochemistry
In total, 20 MALT lymphomas (28.6%) displayed a nuclear positivity for the FOXP1 protein; 12 of these lymphomas were marked by moderate FOXP1 positivity (two of them featuring a polymorphic histology), and the remaining eight lymphomas showed strong FOXP1 positivity (all but one of them featuring a polymorphic histology; Fig 1C). In the FOXP1-positive polymorphic lymphomas, both smaller and larger B cells expressed FOXP1 with comparable intensity. Of the eight patients with MALT lymphomas with strong FOXP1 expression, four were documented with evolution to a DLBCL, whereas a DLBCL was present at diagnosis in a fifth patient (Table 2); all five DLBCLs featured strong nuclear FOXP1 positivity as well. In contrast, none of the 12 MALT lymphomas with moderate FOXP1 expression and none of the 50 FOXP1-negative MALT lymphomas evolved to a DLBCL, although relapse of the lymphoma was documented in four patients (33.3%) and two patients (4%), respectively. The five DLBCLs that originating from MALT lymphomas featured a similar histology, being a diffuse proliferation of large lymphoid cells with oval to round, vesicular nuclei with fine chromatin and two to four membrane-bound nucleoli (Fig 1D). In all of these DLBCLs, the neoplastic cells displayed a great variability in shape and size. The 10 de novo DLBCLs included in this study strongly resembled the five DLBCLs that developed from FOXP1-positive MALT lymphomas.
FISH The translocations t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14) (p22;q32), and t(3;14)(3p13;q32) occurred mutually exclusive and were detected in seven cases (10%), two cases (2.9%), one case (1.5%), and one case (1.5%), respectively (Table 1). In 25 patients (35.7%), an increased number of fused MALT1 and/or FOXP1 signals was found as a result of trisomy/polysomy 18 (8.6%), trisomy 3 (10%), or trisomy/polysomy 3 and 18 (17.1%). In total, 35 MALT lymphomas (50%) did not display any BCL10-, MALT1-, or FOXP1-related FISH-detectable aberrations. Numeric aberrations of chromosomes 3 and/or 18 corresponded well with a polymorphic histology (P = .0001); 12 (70.6%) of 17 polymorphic MALT lymphomas were documented with a trisomy/polysomy 3 and/or 18, whereas this was only the case for 13 (24.5%) of the 53 monomorphic MALT lymphomas. Aneuploidy of chromosomes 3 and/or 18 was observed more frequently in FOXP1-positive MALT lymphomas (10 of 20 lymphomas; 50%) than in FOXP1-negative MALT lymphomas (13 of 50 lymphomas; 26%). This percentage was even higher in the group with strong FOXP1 positivity (six of eight lymphomas; 75%) compared with the group with moderate FOXP1 positivity (four of 12 lymphomas; 33.3%). Finally, the five MALT lymphomas with strong FOXP1 expression that evolved to or presented with a DLBCL were all, except for one, characterized by trisomy 3 and 18; the remaining lymphoma featured the IGH/FOXP1 rearrangement (Table 2).
Statistical Analysis
Here, we show that FOXP1 expression has prognostic significance (with impact on relapse rate and DFS) in patients with de novo MALT lymphomas. So far, FOXP1 expression was only known to be associated with poor clinical outcome in DLBCL patients.26,27 However, although this series comprises 70 patients, the lymphomas arose at different anatomic sites, which do not all share the same clinical behavior. Therefore, our data may require further confirmation by analysis of FOXP1 expression in larger series based on single extranodal sites. Interestingly, by adding morphologic and genetic characteristics to the FOXP1 phenotype, we were able to identify a subset of MALT lymphomas with high probability of evolution to a DLBCL. Of the eight patients with MALT lymphomas with strong FOXP1 positivity, four evolved to a DLBCL, whereas a DLBCL was present at diagnosis in a fifth patient. In all of these five patients, the primary MALT lymphoma featured a polymorphic histology, and the DLBCL could be linked to the MALT lymphoma because of (cyto)genetic similarities. Four of these five MALT lymphomas were marked by trisomy 3 and 18; CR was achieved in only one patient, whereas the other three patients died because of lymphoma progression. The remaining patient did not harbor a trisomy 3 and 18 but was documented instead with a t(3;14)(p13;q32), juxtaposing FOXP1 to IGH, which explains the strong nuclear FOXP1 expression. This patient presented with a gastric MALT lymphoma and a cervical lymph node affected by a DLBCL (both lymphomas featured the IGH/FOXP1 rearrangement), and CR was achieved; this lymphoma was methotrexate associated. Although extremely rare, three other incidents of methotrexate-associated MALT lymphomas have been reported36-38; however, it remains debated whether methotrexate treatment increases the risk of lymphoma development.39,40 Although relapse was documented in four (33.3%) of 12 MALT lymphomas with moderate FOXP1 expression and in two of the FOXP1-negative MALT lymphomas (4%), none of these lymphomas evolved to a DLBCL. Among the 50 FOXP1-negative MALT lymphomas, a polymorphic histology and the presence of trisomy/polysomy 3 and/or 18 were much less frequently observed compared with the FOXP1-positive MALT lymphomas, and they were documented in only 16% and 30% of the FOXP1-negative MALT lymphomas, respectively. However, in this subgroup, just as in the FOXP1-positive subgroup, a polymorphic histology was significantly associated with aneuploidy of chromosomes 3 and/or 18 (P = .0086); trisomy/polysomy 3 and/or 18 was detected in 75% of the polymorphic FOXP1-negative lymphomas, whereas it was only observed in 21.4% of the monomorphic FOXP1-negative lymphomas. As shown in Table 3, a polymorphic morphology was also a significant predictor of an unfavorable clinical outcome; this finding is in line with observations that low-grade gastric MALT lymphomas with an increased number of large cells are associated with a more aggressive behavior.41 Therefore, on the basis of all these data, we propose that MALT lymphomas can be subdivided into the following two subgroups representing different clinicopathologic entities: monomorphic MALT lymphomas presenting with a low incidence of trisomy/polysomy 3 and/or 18 and a good prognosis (low relapse rate, favorable DFS) versus polymorphic MALT lymphomas characterized by a high incidence of trisomy/polysomy 3 and/or 18 and a poor clinical outcome (high relapse rate, unfavorable DFS). The monomorphic group predominantly affects men with early-stage disease at diagnosis, whereas the polymorphic subgroup comprises MALT lymphomas affecting mainly female patients with advanced-stage disease at diagnosis and a high coincidence of autoimmune diseases. Within the latter group, strong FOXP1 positivity defines lymphomas that are likely to transform into a DLBCL. Further classification of the five DLBCLs originating from primary MALT lymphomas presented in this study using the algorithm of Hans et al25 showed that the t(3;14)(p13;q32)–positive DLBCL belonged to the GC group, whereas the four other lymphomas (all marked by trisomy 3 and 18) displayed a non-GC DLBCL phenotype. This finding supports our previous hypothesis that a subset of non-GC DLBCLs (at least marked by trisomy 3 and 18) represents a large-cell variant of marginal zone lymphoma.11 This concept is in line with observations from other groups showing that FOXP1 expression in DLBCLs is predominantly expressed within the non-GC subgroup25-27 and that this lymphoma subset is characterized by a high incidence of complete or partial trisomies 3 and 18.11,42 Moreover, one of these studies correlated strong nuclear FOXP1 expression with poor prognosis in BCL2-positive, t(14;18)(IGH;BCL2)–negative non-GC DLBCLs27; of interest, the non-GC DLBCLs originating from FOXP1-positive, polymorphic MALT lymphomas in our series were marked by strong BCL2 expression as well (data not shown). These findings prompted us to review the morphology of 10 de novo DLBCLs selected on the basis of a non-GC phenotype, FOXP1 positivity, and presence of trisomy 3 and 18. Surprisingly, all of these DLBCLs strongly resembled the DLBCLs developing from polymorphic MALT lymphomas, and seven of these 10 lymphomas arose at extranodal sites, further supporting the close relationship between polymorphic MALT lymphomas and DLBCLs that are both marked by FOXP1 positivity and trisomy 3 and 18. In 11 of the 20 FOXP1-positive MALT lymphomas, there was no evidence of structural or numeric aberrations of the FOXP1 locus, suggesting that mechanisms other than underlying genetic alterations can upregulate FOXP1 expression. Moreover, little is known about the mechanisms by which the FOXP1 transcription factor could contribute to lymphomagenesis or to the transformation from a MALT lymphoma into a more aggressive DLBCL. Although our study does not provide insight into the oncogenic pathways involved with FOXP1, our findings nevertheless define a distinct subgroup of MALT lymphomas characterized by a polymorphic histology and presence of trisomy 3 and 18 that are at risk of transforming into a non-GC DLBCL if they show, in addition, strong nuclear FOXP1 positivity.
The authors indicated no potential conflicts of interest.
We thank Ursula Pluys, Miet Van Herck, Adriana Jablecka, and Lore Bernar for excellent technical assistance.
Supported by Grant No. G.0362.01 from the Fund for Scientific Research (FWO) Flanders; X.S. and L.L. are research fellows of FWO Flanders; and V.V. is a research fellow of the Belgian Federation Against Cancer. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Baens M, Steyls A, Geboes K, et al: The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 156:1433-1439, 2000 2. 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 3. Dierlamm J, Baens M, Stefanova-Ouzounova M, et al: Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. Blood 96:2215-2218, 2000 4. Sanchez-Izquierdo D, Buchonnet 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 5. 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 6. 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] 7. Ruefli-Brasse AA, French DM, Dixit VM: Regulation of NF-kappa B-dependent lymphocyte activation and development by paracaspase. Science 302:1581-1584, 2003 8. Ruland J, Duncan GS, Elia A, et al: Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappa B and neural tube closure. Cell 104:33-42, 2001[CrossRef][Medline] 9. Ruland J, Duncan GS, Wakeham A, et al: Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19:749-758, 2003[CrossRef][Medline] 10. Streubel B, Vinatzer U, Lamprecht A, et al: T(3;4)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 19:652-658, 2005[Medline] 11. Wlodarska I, Veyt E, De Paepe P, et al: FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 19:1299-1305, 2005[CrossRef][Medline] 12. Weigel D, Seifert E, Reuter D, et al: Regulatory elements controlling expression of the Drosophila homeotic gene fork head. EMBO J 9:1199-1207, 1990[Medline] 13. Carlsson P, Mahlapuu M: Forkhead transcription factors: Key players in development and metabolism. Dev Biol 250:1-23, 2002[CrossRef][Medline] 14. Bennett CL, Christie J, Ramsdell F, et al: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20-21, 2001[CrossRef][Medline] 15. Lai CSL, Fisher SE, Hurst JA, et al: A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413:519-523, 2001[CrossRef][Medline] 16. Borkhardt A, Repp R, Haas OA, et al: Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14:195-202, 1997[CrossRef][Medline] 17. Davis RJ, Dcruz CM, Lovell MA, et al: Fusion of Pax7 to Fkhr by the variant t(1,13)(p36,q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54:2869-2872, 1994 18. Galili N, Davis RJ, Fredericks WJ, et al: Fusion of a fork head domain gene to Pax3 in the solid tumor alveolar rhabdomyosarcoma. Nat Genet 5:230-235, 1993[CrossRef][Medline] 19. Hillion J, LeConiat M, Jonveaux P, et al: AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood 90:3714-3719, 1997 20. Katoh M: Human FOX gene family. Int J Oncol 25:1495-1500, 2004[Medline] 21. Lin L, Miller CT, Contreras JI, et al: The hepatocyte nuclear factor 3 alpha gene, HNF3 alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas. Cancer Res 62:5273-5279, 2002 22. Parry P, Wei YL, Evans G: Cloning and characterization of the T(Xii) breakpoint from a leukemic-cell line identify a new member of the forkhead gene family. Genes Chromosomes Cancer 11:79-84, 1994[Medline] 23. Banham AH, Beasley N, Campo E, et al: The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 61:8820-8829, 2001 24. Shaffer A, Rosenwald A, Staudt LM: Lymphoid malignancies: The dark side of B-cell differentiation. Nat Rev Immunol 2:920-932, 2002[CrossRef][Medline] 25. Hans CP, Weisenburger DD, Greiner TC, et al: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275-282, 2004 26. Banham AH, Connors JM, Brown PJ, et al: Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res 11:1065-1072, 2005 27. Barrans SL, Fenton JAL, Banham A, et al: Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 104:2933-2935, 2004 28. Brown PJ, Marafioti T, Kusec R, et al: The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin's lymphoma. J Mol Histol 36:249-256, 2005[CrossRef][Medline] 29. Dierlamm J, Rosenberg C, Stul M, et al: Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 11:747-758, 1997[CrossRef][Medline] 30. Dierlamm J, Pittaluga S, Stul M, et al: BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. Br J Haematol 98:719-725, 1997[CrossRef][Medline] 31. Maes B, Baens M, Marynen P, et al: The product of the t(11;18), an API2-MLT fusion, is an almost exclusive finding in marginal zone cell lymphoma of extranodal MALT-type. Ann Oncol 11:521-526, 2000 32. Maes B, Demunter A, Peeters B, et al: BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression. Blood 99:1398-1404, 2002 33. Sagaert X, Laurent M, Baens M, et al: MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells. Mod Pathol 19:225-232, 2006[CrossRef] 34. Jaffe E, Harris N, Stein H, et al: World Health Organisation Classification of Tumours: Pathology and Genetics—Tumours of Haemopoietic and Lymphoid Tissues. Lyon, France, International Agency for Research on Cancer Press, 2004 35. De Paepe P, Achten R, Verhoef G, et al: Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas. J Clin Oncol 23:7060-7068, 2005 36. Baird RD, van Zyl-Smit RN, Dilke T, et al: Spontaneous remission of low-grade B-cell non-Hodgkin's lymphoma following withdrawal of methotrexate in a patient with rheumatoid arthritis: Case report and review of the literature. Br J Haematol 118:567-568, 2002[CrossRef][Medline] 37. Prochorec-Sobieszek M, Mielnik P, Wagner T, et al: Mucosa-associated lymphoid tissue lymphoma (MALT) of salivary glands and scleroderma: A case report. Clin Rheumatol 23:348-350, 2004[Medline] 38. Thonhofer R, Gaugg M, Kriessmayr M, et al: Spontaneous remission of marginal zone B cell lymphoma in a patient with seropositive rheumatoid arthritis after discontinuation of infliximab-methotrexate treatment. Ann Rheum Dis 64:1098-1099, 2005 39. Baecklund E, Ekbom A, Sparen P, et al: Disease activity and risk of lymphoma in patients with rheumatoid arthritis: Nested case-control study. BMJ 317:180-181, 1998 40. Georgescu L, Quinn GC, Schwartzman S, et al: Lymphoma in patients with rheumatoid arthritis: Association with the disease state or methotrexate treatment. Semin Arthritis Rheum 26:794-804, 1997[CrossRef][Medline] 41. De Jong D, Boot H, VanHeerde P, et al: Histological grading in gastric lymphoma: Pretreatment criteria and clinical relevance. Gastroenterology 112:1466-1474, 1997[CrossRef][Medline] 42. Bea S, Zettl A, Wright G, et al: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that Influence tumor biology and improve gene expression-based survival prediction. Blood 106:3183-3190, 2005 Submitted January 6, 2006; accepted March 3, 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, when appropriate. Survival analysis was performed to assess the relationships between the various variables and disease-free survival (DFS) and overall survival (OS) by using the product-limit method of Kaplan-Meier. The P values for these analyses were based on the log-rank test. DFS and OS were measured from the time of initial therapy to relapse or to death, respectively. The Cox proportional hazards model was used to assess the joint effects of the variables found to be associated with OS or DFS in the Kaplan-Meier analyses. For all tests, significance was accepted when P < .05. Statistical analyses were performed using Statview 5.0.1 (SAS Institute, Cary, NC). 
