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High Relapse Rate in Patients with MALT Lymphoma Warrants Lifelong Follow-up

Authors' Affiliations: ¹ Clinical Division of Oncology, Departments of Medicine I, ² Pathology, ³ Medicine IV, and ⁴ Otorhinolaryngology, Medical University Vienna, and ⁵ Center of Excellence in Clinical and Experimental Oncology (CLEXO), Vienna, Austria

Requests for reprints: Markus Raderer, Division of Oncology, Department of Medicine I, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-2296; E-mail: markus.raderer{at}meduniwien.ac.at.

	Abstract

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Background: B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is thought to be an indolent disease, with a good prognosis following various forms of treatment. Little, however, is known about the rate and pattern of relapse following successful treatment.

Patients and Methods: We have analyzed time to and pattern of relapse in patients with MALT lymphoma, along with investigation of t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) involving IGH/MALT1, trisomy 3, and trisomy 18. Eighty-six patients achieving complete remission (CR) after initial therapy with sufficient follow-up data were available. Primary site of disease was the stomach (n = 36), salivary gland (n = 19), ocular adnexa/orbit (n = 12), lung (n = 8), thyroid (n = 5), breast (n = 3), liver (n = 2), and skin (n = 1).

Results: Thirty-two patients (37%) relapsed between 14 and 307 months (median 47 months) after initial CR. Ten relapses were local, whereas the remaining patients relapsed in a distant organ. Eight of 36 gastric versus 24 of 50 nongastric MALT lymphomas (P = 0.02) relapsed. Five patients had a second recurrence 26 to 56 months after a second CR. Relapse rates were not related to forms of initial treatment. Chromosomal aberrations were detected in 14 of 28 (50%) relapsing patients, and chromosomal alterations were identical at diagnosis and relapse. No significant association of any of the genetic changes investigated with relapse was found. Interestingly, patients with t(11;18)(q21;q21) had a significantly longer median time to relapse (76 months) than patients without this translocation (29 months; P = 0.012).

Conclusions: In view of the late relapses seen in our series, lifelong observation of all patients treated for MALT lymphoma seems to be required.

Key Words: MALT lymphoma • follow-up • relapse

MALT lymphoma irrespective of origin is thought to be an indolent disease as reflected by the good general prognosis of patients (6). There is widespread consensus that MALT lymphomas remain localized to their mucosal environment for a prolonged period of time (2, 3) due to exclusive interaction between lymphoma cells and mucosal adhesion molecules (7, 8). This immunologic trafficking nevertheless seems to be slightly different for mucosal sites within the gastrointestinal tract as opposed to nongastrointestinal sites (8).

In the past, local therapies including surgery and radiation have preferentially been applied. Although resulting in good local control, distant relapses have repeatedly been reported in the literature, in some cases even after decades following initial treatment (9–11). To date, there are no data on the relapse pattern of MALT lymphomas and the optimal duration of follow-up after successful therapy. Therefore, we have analyzed all patients with MALT lymphoma treated at our institution who achieved complete remission (CR) following initial therapy. In addition, we have investigated samples from all patients for chromosomal aberrations common in MALT lymphoma including t(11;18), t(1;14), and t(14;18) involving IGH/MALT1, trisomy 3, and trisomy 18 to assess whether these changes might influence relapses.

	Patients and Methods

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A retrospective analysis of patients with MALT-lymphoma diagnosed and treated at our institution was done. Only patients who had undergone extensive staging according to our standard protocol (12), who had achieved CR after therapy, and in whom follow-up data of at least 24 months after initial treatment were available, were included. Histologic diagnosis of MALT-lymphoma was done according to the criteria outlined in the WHO classification (13), and histologic (re-) assessment was done by a reference hematopathologist (A.C.). 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.

Information extracted from patients' charts and analyzed included diagnosis and localization on initial presentation, extent of staging, treatment, response to treatment, duration of response (calculated from CR to histologic diagnosis of relapse), site of relapse, and time to relapse. In all patients referred to our institution for relapsing MALT lymphoma, the original biopsies were also reassessed, and patients were only included if these, along with information on initial treatment, staging, and response, were available.

t(11;18)(q21;q21) involving API2 and MALT1 was assessed by reverse transcription-PCR, t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) involving BCL10 and IGH, and trisomies 3 and 18 were investigated by fluorescence in situ hybridization as previously published (14). These genetic studies were carried out on representative biopsies both at diagnosis and at relapse in all patients.

	Results

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A total of 86 patients with MALT lymphoma treated at our institution and achieving CR were identified for our analysis. The large majority of patients (n = 36) had gastric lymphoma; the remaining primary sites of disease were salivary gland (n = 19), ocular adnexa/orbit (n = 12), lung (n = 8), thyroid (n = 5), breast (n = 3), liver (n = 2), and skin (n = 1).

Different forms of treatment (or combinations thereof) including surgery, radiation and chemotherapy, and Helicobacter pylori eradication were applied (see Table 1). Treatment modalities applied did not differ between the group of patients with relapse and those without recurrence (data not shown).

Taken together, 8 of 36 patients with gastric lymphoma versus 24 of 50 nongastric MALT lymphomas (P = 0.02) relapsed. Only one of our patients showed transformation to diffuse large B-cell lymphoma on relapse (see Table 1). Ten relapses were local, whereas the remaining patients relapsed in a distant organ. The large majority of these recurrences occurred in another MALT organ, as only three patients developed recurrent disease in lymph nodes (for details, see Table 1), and only one had (additional) bone marrow involvement.

In total, seven patients have died: two of three relapsing patients from lymphoma progression (including the patient with transformation) and one from myocardial infarction, whereas four have died in CR from causes unrelated to lymphoma.

The median follow-up was 56 months (range, 30-315) in relapsing patients and 53 months (range, 33-130) for the nonrelapsing patients. The median time to relapse was 47 months, ranging from 14 to 307 months. Five of these 31 patients had another relapse following a second CR; these relapses occurred 26, 43, 49, and 56 months (in two patients) after the first recurrence. The occurrence of relapses and their pattern, however, seemed not to be influenced by the treatment modality employed for reaching CR (P > 0.2, data not shown).

Analysis of chromosomal aberrations could be carried out successfully in 28 of 32 relapsing patients. No chromosomal aberrations were detected in 14 of 28 relapsing patients (50%). A total of seven relapsing patients (25%) had evidence of t(11;18)(q21;q21), which was the sole aberration in all cases. Two cases were found positive for t(14;18)(q32;q21) along with trisomy 3; an additional three patients harbored trisomy 3 as the sole aberration; and two patients had both trisomy 3 and trisomy 18. Taken together, trisomy 3 was present at the same frequency (25%) as the t(11;18)(q21;q21) in our cohort of relapsing patients. No differences were found between genetic changes present in the initial samples and material obtained on relapse in the 32 patients developing recurrences.

In the patients in continuous CR during follow-up, aberrations could be investigated in 43 of 55 cases. A t(11;18)(q21;q21) was found in 7 of 43 (16%), and trisomy 3 was present in 8 cases (18.6 %). The differences between relapsing and nonrelapsing patients, however, were not statistically significant for both t(11;18)(q21;q21) (P = 0.822) and trisomy 3 (P = 0.732). Interestingly, t(11;18)(q21;q21)+ patients had a significantly longer median time to relapse (76 versus 29 months, P = 0.012) as compared with patients without this translocation.

Due to the small sample size in various localizations, comparative analysis was done only in gastric lymphoma, where sufficient material for analysis of genetic changes was available in 29 patients. In total, 9 of 29 (31%) were found positive for t(11;18)(q21;q21), including 4 of 8 (50%) relapsing and 5 of 21 (24%) nonrelapsing patients (P > 0.2). Trisomy 3 was present in only 2 of 21 patients (in one case accompanied by trisomy 18) in continuous CR as opposed to 0 of 8 gastric lymphoma patients with recurrence.

	Discussion

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This is the first series to systematically address the rate and pattern of relapse in patients with MALT lymphoma achieving CR after initial therapy. Judging from our data, the rate of recurrences seems to be substantial, with the median time to relapse being 47 months (range, 14-307 months). Only 4 of the 32 patients (12%) with relapse had been referred to our institution after recurrence had been diagnosed. This relatively small percentage suggests that our data do indeed reflect a real clinical phenomenon in patients with MALT lymphoma rather than being caused by a referral bias.

Eight of 36 patients with gastric lymphoma versus 24 of 50 nongastric MALT lymphomas (P = 0.02) relapsed, suggesting a higher risk of relapse for extragastric MALT lymphoma. This is also in keeping with previous results documenting a higher rate of initial multiorgan involvement in MALT lymphomas arising outside the stomach (12). The large majority of these recurrences occurred in another MALT organ, which is in keeping with the notion of a common mucosal immunity and homing of MALT lymphoma cells within their original environment (2, 8) and again underscores the importance of extensive staging of patients with MALT lymphoma (12). In addition, only one patient developed transformation to diffuse large B-cell lymphoma, suggesting that the risk of subsequent transformation is small in patients with MALT lymphoma. This fact has already been reported for MALT lymphomas harboring the t(11;18)(q21;q21), which seem to have a relatively stable karyotype with a lack of transformation (15). Judging from our data, the apparent risk for transformation to diffuse large cell lymphoma is also extremely low for cases without this specific translocation.

In our cohort of patients, the relapse rate was not related to the initial stage of the disease or to the treatment modality applied for reaching CR. As with other series available in the literature (3), however, interpretation of this finding is impaired by the fact that no uniform treatment strategies were applied in our patients due to the different localizations of the lymphoma and the absence of a standard chemotherapeutic regimen.

Genetic changes commonly found in patients with MALT lymphoma could be investigated in the large majority of patients (28 of 32 relapsing patients and 43 of 55 patients in ongoing CR), and sufficient material was available for genetic assessment in the 28 relapsing patients also from the time of initial diagnosis. Of interest is the fact that no differences were found between genetic changes present in the initial samples and material obtained on relapse in the 28 evaluable patients developing recurrences. These data are the first indication that relapses in MALT lymphoma are not triggered/accelerated by accumulation of additional MALT lymphoma-associated genetic changes in the course of the disease. It has to be emphasized, however, that only a very limited number of genetic aberrations were investigated.

None of the aberrations investigated were predictive of relapse, as differences between relapsing and nonrelapsing patients, however, were not statistically significant for both t(11;18)(q21;q21) (P = 0.822) and trisomy 3 (P = 0.732). Interestingly, t(11;18)(q21;q21)+ patients had a significantly longer median time to relapse (76 versus 29 months, P = 0.012) as compared with patients without this translocation. This finding is in contrast to recent results which have associated t(11;18)(q21;q21)+ MALT lymphomas at least of gastric origin with more advanced stage, suggestive of a more aggressive clinical course (16). Our data are the first to suggest that MALT lymphomas with t(11;18)(q21;q21) might run a more indolent clinical course and might be characterized by a significantly longer time to relapse.

Taken together, our findings suggest that patients with MALT lymphoma should undergo lifelong follow-up after successful initial treatment irrespective of treatment modality or genetic changes present on diagnosis.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 8/04; revised 2/ 3/05; accepted 2/10/05.

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