Monoclonal Immunoglobulin Production Is a Frequent Event in Patients with Mucosa-Associated Lymphoid Tissue Lymphoma

Vol. 10, 7179–7181, November 1, 2004 Clinical Cancer Research 7179

Featured Article Monoclonal Immunoglobulin Production Is a Frequent Event in Patients with Mucosa-Associated Lymphoid Tissue Lymphoma

Stefan Wo¨hrer,1 Berthold Streubel,2 INTRODUCTION Rupert Bartsch,1 Andreas Chott,2 and Production of a monoclonal immunoglobulin/paraprotein Markus Raderer1,3 (PP) by lymphoma cells is a well-known phenomenon associated with various types of B-cell non-Hodgkin’s lymphomas 1Department of Medicine I, Division of Oncology, 2Department of Pathology, and 3Center of Excellence for Clinical and Experimental (NHLs; ref. 1). Extranodal marginal zone (MZ) B-cell lym- Oncology, Medical University, Vienna, Austria phoma of mucosa-associated lymphoid tissue (MALT) is a distinct clinicopathological entity initially defined by Isaacson and Wright in 1983 (2), which has been incorporated into the ABSTRACT recent World Health Organization classification of hematologic Purpose: Mucosa-associated lymphoid tissue (MALT) malignancies (3). MALT lymphoma comprises 7% of all newly lymphoma comprises 7% of all newly diagnosed non- diagnosed NHLs and is therefore among the most common Hodgkin’s lymphomas and is therefore among the most lymphoma entities (3). common lymphoma entities. Monoclonal gammopathy due The postulated cell of origin of MALT lymphoma is the MZ to production of a monoclonal immunoglobulin by lym- B cell corresponding to a post germinal center B cell with re- phoma cells is a well-known phenomenon associated with arranged and mutated immunoglobulin heavy and light chain genes various types of B-cell non-Hodgkin’s lymphomas. The ob- (3). MZ cells are thought to capture, process, and present antigens jective of the present study was to evaluate the incidence and and deliver costimulatory signals to T cells. In addition, they clinical relevance of paraprotein (PP) production in patients apparently display the capacity to differentiate into plasma cells, with MALT lymphoma. and most early antibody-secreting cells are thought to originate Experimental Design: Fifty two patients were prospec- from MZ B-cell precursors (4). In keeping with this hypothesis, tively evaluated with regard to differentiation of the MALT MALT lymphomas often include high numbers of plasma cells, a lymphoma cells, t(11;18) translocation, monoclonal immu- phenomenon termed plasmacytic differentiation (3). This feature is noglobulin production, Helicobacter pylori (HP) status, especially prominent in a special, albeit rare, type of MALT lym- stage, treatment, and clinical outcome. phoma termed immunoproliferative small intestinal disease (5, 6), Results: Nineteen of 52 MALT lymphoma patients but it may also explain cases initially described as extramedullary (36%) had PP (8 IgM␬, 6 IgG␬, 4 IgM␭, and 1 IgA␬). The plasmacytoma within classical MALT organs such as the gastro- histologic feature of plasmacytic differentiation correlated intestinal tract, which might in fact be MALT lymphomas with .No extreme plasmacytic differentiation .(0.001 ؍ significantly with the production of PP (P correlation was found between PP and clinical stage, HP The close relationship of MZ B cells with plasma cells sug- status, and t(11;18) status. PP was, however, negatively gests a potential for immunoglobulin production by MALT lym- associated with response to eradication of HP in gastric phoma cells, which has been reported by various authors, albeit in MALT lymphoma, and PP levels declined significantly in anecdotal form (7–10). To date, however, no systematic investiga- patients responding to chemotherapy or radiation. Impor- tions to assess the frequency of monoclonal immunoglobulin/PP tantly, both immunofixation and serum electrophoresis have production have been performed in patients with MALT lym- to be performed to detect low PP levels. phoma. Therefore, the objective of the present analysis was to study Conclusions: In conclusion, PP levels may probably be the incidence and clinical relevance of PP in MALT lymphoma used as a potential prognostic tool for response to HP erad- patients diagnosed and treated at our institution. ication, and serial measurements may also allow for noninvasive assessment of response to radiation or chemotherapy PATIENTS AND METHODS in patients with MALT lymphoma. All patients with histologically verified, previously untreated MALT lymphoma admitted at our institution since the beginning of 2001 were prospectively evaluated. Histopathological diagnosis was established according to the Received 4/24/04; revised 7/14/04; accepted 8/2/04. criteria defined by Isaacson and Wright (2), initially adopted in The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked the revised european american lymphoma and later adopted in the advertisement in accordance with 18 U.S.C. Section 1734 solely to recent World Health Organization classification for MALT lym- indicate this fact. phoma (11). In all patients, immunologic phenotyping on paraffin Requests for reprints: Markus Raderer, Department of Medicine I, sections was done for demonstration of heavy and light chain Division of Oncology, Medical University Vienna, Waehringer Guertel ϩ Ϫ Ϫ Ϫ 18-20, A-1090 Vienna, Austria. Phone/Fax: 43-1-40400-2296; E-mail: restriction and for the phenotype CD20 CD5 CD10 cyclinD1 , [email protected]. which, in context with the microscopic appearance, is consistent ©2004 American Association for Cancer Research. with MALT lymphoma. Plasmacytic differentiation was defined

as the presence of sheets of light chain-restricted plasma cells. Table 2 Changes in median serum PP during therapy All samples were evaluated by a single reference hemato- PP before PP after pathologist (A. C.) to avoid a potential bias caused by interob- PP therapy therapy Difference server variability. In addition, reverse transcription-polymerase Patients with treatment response chain reaction on paraffin-embedded biopsy sections for assess- IgG 21.1 (11.9–36.5) 14.9 (10.8–18.6) Ϫ6.2 (Pϭ0.028) ment of the t(11;18) translocation was performed. IgM 28.7 (9.5–47.9) 13.2 (8.7–39.5) Ϫ15.5 (Pϭ0.043) Clinical information evaluated included the following: lo- ⌺ 21.4 (9.5–47.9) 14.4 (8.7–39.5) Ϫ7(P ϭ0.003) calization of the lymphoma, clinical stage, both serum electro- Patients without treatment response IgM 13.9 (13.7–15.0) 16.0 (13.5–19.1) 2.1 (PϾ0.05) phoresis (Olympus Hite 630; Goffin Meyvis, Etten-Leur, the IgA 16.1 16.5 0.4 (PϾ0.05) Netherlands) and serum immunofixation (Hydragel 9 IF; Sebia, NOTE. Values represent serum PP in g/liter; range is shown in Norcross, GA) according to standard methods in all patients, parentheses. quantitative levels of serum immunoglobulins (IgG, IgM, and Abbreviation: ⌺, IgG ϩ IgM. IgA), the presence of an underlying autoimmune disease, Heli- cobacter pylori (HP) status, treatment, response to therapy, follow-up time, and survival. an underlying autoimmune disease, i.e., Sjogren’s syndrome, RESULTS also had evidence of PP. Among the 21 patients with gastric MALT lymphoma, 15 (71%) had signs of HP infection. Overall, Fifty two consecutive patients with previously untreated no correlation between PP and HP status was found because 5 of MALT lymphoma (31 patients with extragastric lymphoma and 21 7 patients (71%) with PP and 10 of 14 patients (71%) without patients with gastric lymphoma) were evaluable for analysis (see PP were HP positive. Table 1), and PP production was found in 19 of 52 patients (36%). None of the seven gastric MALT lymphoma patients with Eight of these 19 patients (42%) had IgM␬, 6 of 19 patients PP responded to eradication of HP, whereas four PP-negative (31%) had IgG␬, 4 of 19 patients (21%) had IgM␭,and1of19 patients showed remission of the lymphoma after antibiotic patients (5%) had IgA␬. The serum PP corresponded with the treatment. Three of the 7 nonresponders were positive for t(11; light chains detected on biopsy specimens in all patients, and a 18). The t(11;18) translocation did not correlate with the pres- 79% correspondence with the immunohistochemical results for ence of PP. In addition, none of these seven cases had evidence heavy chains was found. Two of the patients with discordance of an underlying autoimmune disease. between serum PP and the heavy chains on biopsy specimens As expected, plasmacytic differentiation correlated signif- had IgG␬, one had IgM␬, and one had IgA␬. Interestingly, 4 of icantly (P ϭ 0.001) with the presence of PP because 10 of 19 the 19 patients (21%) with PP had a positive immunofixation patients (53%) with detectable PP were found to have plasma- but a normal serum electrophoresis pattern. The levels of unin- cytic differentiation as opposed to 3 of 33 patients (9%) without volved immunoglobulin were depressed in 5 of 19 (26%) pa- PP. In total, 13 of 52 patients (25%) had plasmacytic differen- tients with serum PP (IgG and IgM in two patients each and IgA tiation, including 3 of 21 patients (14%) with gastric lymphoma in one patient). and 10 of 31 patients (32%) with extragastric lymphoma. Inter- Twelve of 31 patients (39%) with extragastric MALT estingly, plasmacytic differentiation was present in only 1 of 11 lymphoma and 7 of 21 patients (33%) with gastric lymphoma patients with Sjogren’s syndrome, but this patient had no evi- had PP. The presence of PP was not indicative of clinical stage: dence of PP production. 12 of 19 patients (63%) had stage I or II disease, and 7 of 19 Overall, good correlation was noted between PP and ther- patients (37%) had stage IV disease. Only 1 of 11 patients with apeutic response in patients undergoing serial evaluation of PP levels. A decrease of PP corresponded to a clinical response, and the median level decreased significantly (P ϭ 0.003) from 21.4 g/liter (range, 9.5–47.9 g/liter) before treatment to 14.2 g/liter Table 1 Patient characteristics (range, 8.7–39.5 g/liter) after treatment, but it did not reach No. of patients 52 normal levels in the patients for whom quantitative assessment Median age (yrs) (range) 57 (22–85) was possible (see Table 2). One patient who had a normal serum No. of patients with t(11;18) 13 (45 Pat.ev.) electrophoresis but showed an indication of PP on immunofix- No. of patients with HP 30 infection ation became PP negative after successful treatment resulting in No. of patients with PP 19 complete remission as judged by conventional staging. Median survival (mo) ϩ204 (not reached) No. of patients with stage I 29 disease DISCUSSION No. of patients with stage II 11 Production of a serum PP has been reported repeatedly in disease patients with various forms of NHL (1, 12–14) but has been No. of patients with stage III 1 judged to be a rare event in patients with MALT lymphoma disease No. of patients with stage IV 11 (15). However, no systematic investigations on this topic are disease available in the recent literature, which has prompted us to No. of patients with plasmacytic 13 prospectively study all patients with untreated MALT lym- differentiation phoma admitted at our institution as of the beginning of 2001. Abbreviation: Pat. ev., evaluable patients. Our analysis disclosed a detectable serum PP in 19 of 52

patients (36%) evaluated by both serum electrophoresis and im- (P ϭ 0.003) from 21.4 g/liter (range, 9.5–47.9 g/liter) before munofixation, which is one of the highest frequencies of PP pro- treatment to 14.2 g/liter (range, 8.7–39.5 g/liter) after treatment (see duction in lymphoma documented to date. As opposed to this, Table 2), and one patient with PP detectable only on immunofix- lower frequencies have been published for various other types of ation became negative after successful treatment resulting in com- NHL (1, 12–14), and a recent report has documented the occur- plete remission. rence of PP in 20.2% of patients with indolent types of NHL (12), In conclusion, our data suggest that monoclonal gammopathy whereas it appears to be rare in aggressive lymphomas. In our is a common phenomenon in patients with MALT lymphoma, most cohort, the serum PP corresponded with the light chains detected on probably due to PP production by the clonal lymphoplasmacytic biopsy specimens in all patients, and a 79% correspondence with cells. However, it is important to perform both immunofixation and the immunohistochemical results for heavy chains was found. conventional serum electrophoresis to detect even low levels of According to this striking correspondence, the most likely expla- monoclonal immunoglobulins. PP levels may not only be used as nation for PP in our patients is the production of the immunoglobu- a potential prognostic tool for response to HP eradication, but serial lins by the clonal lymphoplasmocytic cells. In four patients, how- measurements may also allow for noninvasive assessment of re- ever, a discordance between serum PP and heavy chains was found, sponse to radiation or chemotherapy. suggesting a possible coincidence of MALT lymphoma and monoclonal gammopathy of undetermined significance. Because a like- lihood of 3% for monoclonal gammopathy of undetermined sig- REFERENCES nificance (15) has been reported in elderly patients, such an 1. Alexanian R. Monoclonal gammopathy in lymphoma. Arch Intern association appears to be possible, especially in patients with IgG␬ Med 1975;135:62–6. (which was indeed present in two of four cases). The fact that all 2. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer (Phila) patients were negative for the MALT lymphoma-specific t(11;18) 1983;52:1410–6. further supports this notion. 3. Isaacson P, Mu¨ller-Hermelink HK, Piris MA, et al. 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Stefan Wöhrer, Berthold Streubel, Rupert Bartsch, et al.

Clin Cancer Res 2004;10:7179-7181.

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