Search

Purpose: To determine whether interim F-FDG PET or interim diffusion-weighted magnetic resonance imaging (DWI) can predict the end-of-treatment (EOT) outcome after immunotherapy in patients with FDG-avid extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)., Materials and Methods: Patients with untreated MALT lymphoma prospectively underwent whole-body F-FDG PET/CT and DWI before treatment (baseline), and after three cycles (interim) of rituximab-based immunotherapy. Maximum and mean standardized uptake values (SUVmax, SUVmean), and minimum and mean apparent diffusion coefficients (ADCmin, ADCmean), were measured for up to three target lesions per patient. Rates of change between baseline and interim examinations (ΔSUVmax, ΔSUVmean, ΔADCmin, and ΔADCmean) were compared, using ANOVAs, between the four end-of-treatment (EOT, after six cycles of immunotherapy) outcomes: complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD)., Results: Fifteen patients with 25 lesions were included. Lesion-based post hoc tests showed significant differences between CR and PR for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), and ΔADCmin (P = 0.044), and between CR and SD for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), ΔADCmin (P = 0.021), and ΔADCmean (P = 0.022). No lesion showed PD at EOT., Conclusions: Both quantitative interim F-FDG PET and interim DWI may possibly be useful to predict complete remission at end-of-treatment in MALT lymphoma patients after immunotherapy.

Background: Patients with gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma require lifelong endoscopic follow-up. This study aimed to establish and evaluate confocal laser endomicroscopy (CLE) criteria for gastrointestinal MALT lymphoma., Methods: This prospective trial was conducted after IRB approval at the Medical University of Vienna. Twenty-four consecutive patients (14 males and 10 females, median age 65 years) referred for staging or follow-up of (former) gastrointestinal MALT lymphoma underwent endosonography (EUS) and CLE including white light endoscopy (WLE) and conventional biopsy sampling of the upper gastrointestinal tract. CLE criteria of the disease were based on the first five patients with histologically proven MALT lymphoma. All CLE datasets were reviewed separately by two CLE experts. The diagnostic modalities were compared using conventional histology as the gold standard., Results: Sixty-two percentages had a positive diagnosis of MALT lymphoma based on histology. The sensitivity was 80 % for EUS (0.51-0.95), 100 % for WLE (0.75-1) and 93 % for CLE (0.66-1); the specificity was 67 % for EUS (0.31-0.91), 23 % for WLE (0.04-0.60) and 100 % for CLE (0.63-1). The agreement with histology was moderate for EUS (kappa 0.47, p = 0.02), fair for WLE (kappa 0.26, p = 0.06) and almost perfect for CLE (kappa 0.91, p < 0.01). Expert evaluation identified all but one case of MALT lymphoma with excellent interobserver agreement (kappa 0.89, p < 0.01). In the case missed by CLE, MALT lymphoma involvement was restricted to deep tissue structures., Conclusions: Despite minor technical limitations, CLE is a promising alternative to conventional biopsy sampling in patients with gastrointestinal MALT lymphoma. CLINICALTRIALS., Gov Number: NCT01583699.

Purpose: To determine whether in patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue lymphoma (MALT), delayed-time-point 2-F-fluoro-2-deoxy-d-glucose-positron emission tomography (F-FDG-PET) performs better than standard-time-point F-FDG-PET., Materials and Methods: Patients with untreated histologically verified MALT lymphoma, who were undergoing pretherapeutic F-FDG-PET/computed tomography (CT) and consecutive F-FDG-PET/magnetic resonance imaging (MRI), using a single F-FDG injection, in the course of a larger-scale prospective trial, were included. Region-based sensitivity and specificity, and patient-based sensitivity of the respective F-FDG-PET scans at time points 1 (45-60 minutes after tracer injection, TP1) and 2 (100-150 minutes after tracer injection, TP2), relative to the reference standard, were calculated. Lesion-to-liver and lesion-to-blood SUVmax (maximum standardized uptake values) ratios were also assessed., Results: F-FDG-PET at TP1 was true positive in 15 o f 23 involved regions, and F-FDG-PET at TP2 was true-positive in 20 of 23 involved regions; no false-positive regions were noted. Accordingly, region-based sensitivities and specificities were 65.2% (confidence interval [CI], 45.73%-84.67%) and 100% (CI, 100%-100%) for F-FDG-PET at TP1; and 87.0% (CI, 73.26%-100%) and 100% (CI, 100%-100%) for F-FDG-PET at TP2, respectively. FDG-PET at TP1 detected lymphoma in at least one nodal or extranodal region in 7 of 13 patients, and F-FDG-PET at TP2 in 10 of 13 patients; accordingly, patient-based sensitivity was 53.8% (CI, 26.7%-80.9%) for F-FDG-PET at TP1, and 76.9% (CI, 54.0%-99.8%) for F-FDG-PET at TP2. Lesion-to-liver and lesion-to-blood maximum standardized uptake value ratios were significantly lower at TP1 (ratios, 1.05 ± 0.40 and 1.52 ± 0.62) than at TP2 (ratios, 1.67 ± 0.74 and 2.56 ± 1.10; P = 0.003 and P = 0.001)., Conclusions: Delayed-time-point imaging may improve F-FDG-PET in MALT lymphoma.

This study investigated expression profiles of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) pathway components and mechanisms underlying TRAIL-induced apoptosis in mucosa associated lymphoid tissue (MALT) lymphoma. Genetic aberrations including translocations and trisomies were assessed by reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Expression of TRAIL, death receptors 4 and 5, decoy receptors 1 and 2, and FADD-like interleukin-1β-converting enzyme (FLICE) inhibitory protein was analyzed by immunohistochemistry. All 32 patients under study showed some alterations in TRAIL pathway mainly involving loss of death receptors (37.5%), gain of decoy receptors (3.1%) or both (59.4%). Decoy receptor 2 (DcR2) was highly expressed in patients with normal cytogenetic status as compared to those with cytogenetic aberrations (p = 0.005). Moreover, DcR2 expression correlated significantly with nuclear factor-κB (NF-κB) expression (R = 0.372, p = 0.047). High expression of DcR2 in patients with normal cytogenetic status and its significant correlation with NF-κB expression provides a potential clue to evasion of immune surveillance in cytogenetically normal MALT lymphomas.

We have performed a retrospective analysis of all patients with extragastric mucosa-associated lymphoid tissue (MALT) lymphoma treated at our institution to compare the efficacy of first-line therapeutic modalities including surgery, radiation, systemic therapy, and antibiotics. One hundred eighty-five patients with extragastric MALT lymphoma with a median age of 63 (interquartile range (IQR) 50-74) years and a median follow-up time of 49 (IQR 18-103) months were retrospectively analyzed. Time to progression and time to next therapy were used as surrogate endpoints for efficacy. Patients having either surgery (100 %), chemo/immunotherapy (85.5 %), or radiation (80 %) had significantly (p = 0.01) higher response rates than patients treated with antibiotics (33.3 %). Patients who were irradiated had significantly more progressive disease, but also the longest follow-up time. Stage, elevated LDH, anemia, elevated beta-2 microglobulin, plasmacytic differentiation, monoclonal gammopathy, or autoimmune disease did not influence the rate of disease progression nor did complete remission or partial remission from initial therapy influence time to and rate of progression. There was no significant difference in the median time to progression (p = 0.141), but the estimated time to progression (p = 0.023) as well as the estimated time to next therapy (p = 0.021) was significantly different among the various cohorts favoring surgery, chemo/immunotherapy, and radiation. Our results suggest extragastric MALT lymphoma as a potential systemic disease irrespective of initial stage. Radiation, surgery, and chemo/immunotherapy seem to be equally effective in achieving remissions and prolonged progression free survivals, but a curative potential is questionable. Localized MALT lymphomas affecting the thyroid gland or the lungs have excellent long-term progression-free survivals with surgical treatment only.

Background: Orbital marginal zone B-cell lymphoma (OAML) constitutes for the most frequent diagnosis in orbital lymphoma. Relatively little data, however, have been reported in larger cohorts of patients staged in a uniform way and no therapy standard exists to date., Material and Methods: We have retrospectively analyzed 60 patients diagnosed and treated at our institution 1999-2012. Median age at diagnosis was 64 years (IQR 51-75) and follow-up time 43 months (IQR 16-92). All patients had undergone uniform extensive staging and histological diagnosis was made by a reference pathologist according to the WHO classification., Results: The majority of patients presented with stage IE (n = 40/60, 67%), three had IIE/IIIE and the remaining 17 stage IVE. Seven patients with IVE had bilateral orbital disease whereas the others showed involvement of further organs. Treatment data were available in 58 patients. Local treatment with radiotherapy (14/58, 24%) or surgery (3/58, 5%) resulted in response in 82% of patients. A total of 26 patients (45%) received systemic treatment with a response rate of 85%. Nine patients received antibiotics as initial therapy; response rate was 38%. Watchful-waiting was the initial approach in 6/58 patients. In total 28/58 patients (48%) progressed and were given further therapy. Median time-to-progression in this cohort was 20 months (IQR 9-39). There was no difference in time-to-progression after first-line therapy between the different therapy arms (p = 0.14). Elevated beta-2-microglobulin, plasmacytic differentiation, autoimmune disorder and site of lymphoma were not associated with a higher risk for progress., Conclusion: Our data underscore the excellent prognosis of OAML irrespective of initial therapy, as there was no significant difference in time-to-progression and response between local or systemic therapy. In the absence of randomized trials, the least toxic individual approach should be chosen for OAML.

Recently, the combination of rituximab and bendamustine (R-Benda) has been defined as highly active in patients with follicular lymphomas, but little is known about the efficacy of R-Benda in mucosa-associated lymphoid tissue (MALT) lymphoma. In a retrospective analysis, we have defined 14 patients with MALT lymphoma undergoing therapy with R-Benda. Seven patients were female and seven male (aged 44-88 years), and all had relapsed extragastric MALT lymphoma. R-Benda was given at first relapse in ten patients, while four patients had more than two prior forms of therapy. Bendamustine was given at a dose of 90 mg/m(2) on days 2 and 3 in ten patients and at 70 mg/m(2) in three patients, while all received 375 mg/m(2) rituximab on day 1. Ten patients received six courses of therapy, while two patients discontinued therapy after three, and one after four courses for personal reasons, while one patient had progressive disease after four courses. Tolerance of therapy was excellent, and all except one patient responded. Ten patients achieved a complete remission (CR) (71 %), three a partial remission (21 %), while one patient progressed. Toxicities were mild and mainly hematological but did not result in relevant delays or the necessity for dose reductions. After a median follow-up of 23 months (range, 4-42+), 13 patients are alive and one patient has relapsed 23 months after initial CR. Our data suggest high activity and good tolerance of R-Benda in patients with relapsed MALT lymphoma despite intensive pretreatment in some patients. In view of this, prospective studies are warranted.

Mucosa associated lymphoid tissue lymphoma shares certain features with multiple myeloma. In view of this and the activity of lenalidomide in various B-cell lymphomas, we have initiated a phase II study of lenalidomide in patients with mucosa associated lymphoid tissue lymphoma. Patients with histologically verified advanced stages of this lymphoma were included in the study. Treatment consisted of oral lenalidomide 25 mg Days 1-21, with a 7-day break after each cycle. A total of 18 patients were included in the trial: 5 had gastric and 13 had extragastric mucosa associated lymphoid tissue lymphoma, but 2 discontinued therapy during the first course of therapy. In the intent to treat analysis, an overall response rate of 61% was seen (11 of 18; 6 complete and 5 partial remissions). Three patients had stable disease while 2 progressed. Side effects were manageable and included neutropenia (grade III in 3 patients) as the leading hematotoxicity. After a median follow up of 20.3 months, one patient has died from lymphoma while the remaining patients are alive and relapse-free. These data suggest activity of lenalidomide monotherapy in mucosa associated lymphoid tissue lymphoma. The study protocol had been approved by the Ethical Board of the Medical University Vienna (EK-No.: 146/09), and before opening the trial, it had been registered at www.clinicaltrials.gov. (identifier: NCT00923663).

Currently, there is no standard systemic treatment for extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. Both rituximab and cladribine have shown some activity in this disease, but the combination has not been tested so far. In view of this, we initiated a phase II study to assess the activity and safety of rituximab and cladribine in patients with histologically verified mucosa-associated lymphoid tissue lymphoma. Treatment consisted of rituximab 375 mg/m(2) i.v. day 1 and cladribine 0.1 mg/kg s.c. days 1 - 4 every 21 days. In case of complete remission after two courses, another two cycles of therapy were administered, while patients with a partial response or stable disease were scheduled to receive six cycles of treatment. Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as scheduled while one patient died before initiation of therapy and was rated as having progressive disease in the intent-to-treat analysis. Twenty-one patients had gastric lymphoma, while 19 suffered from extragastric mucosa-associated lymphoid tissue lymphoma. Side effects consisted mainly of hematologic toxicity including leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had a complete remission (58%) and nine had a partial remission (23%) for an overall response rate of 81%, while five had stable disease (13%) and two progressed during therapy. After a median follow-up of 16.7 months (interquartile range: 15.9 - 18.7 months), 35 patients are alive (88%) while four patients have died and one patient withdrew consent and did not allow further follow up. Our data demonstrate that rituximab plus cladribine is active and safe in patients with mucosa-associated lymphoid tissue lymphoma.

Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell lymphoma that shares morphological and immunophenotypic characteristics with extranodal and splenic marginal zone lymphoma. Data on altered genes and signaling pathways are scarce in this rare tumor entity. To gain further insights into the genetic background of NMZL, seven cases were investigated by microarray analysis, G-banding, and FISH. Chromosomal imbalances were observed in 3/7 cases (43%) with gains of chromosome arms 1q, 8q, and 12q being the most frequent findings. Furthermore, we identified a translocation t(11;14)(q23;q32) involving IGH and DDX6. Chromosomal walking, expression analysis, siRNA-mediated gene knockdown and a yeast two hybrid screen were performed for further characterization of the translocation in vitro. In siRNA experiments, DDX6 appeared not to be involved in NF-κB activation as frequently observed for genes promoting lymphomagenesis but was found to interfere with the expression of BCL6 and BCL2 in an NF-κB independent manner. In conclusion, we identified several unbalanced aberrations and a t(11;14) involving IGH and DDX6 providing evidence for a contribution of DDX6 to lymphomagenesis by deregulation of BCL6 in NMZL., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Mucosa-associated lymphoid tissue (MALT) lymphoma is among the most common forms of extranodal lymphomas, but little is known about subcutaneous involvement in patients with non-primary cutaneous marginal zone lymphomas., Design and Methods: Patients with MALT lymphoma diagnosed and treated at our institution between 1999 and 2010 were analyzed for subcutaneous deposits from MALT lymphoma diagnosed in another organ. Histological, clinical and genetic findings were assessed., Results: Among 216 patients with MALT lymphoma, 12 had subcutaneous deposits from MALT lymphoma (5.5%). In two patients, these lesions were present at diagnosis, while they constituted the site of relapse at an interval between 5 to 144 months in the remaining cases. Interestingly, nine of the 12 patients with subcutaneous deposits had originally been diagnosed with MALT lymphoma of the ocular adnexa (total number=51; 20%), and the other three had MALT lymphoma in the breast (total number=5; 60%). None of the patients with gastric (n=86), salivary gland (n=32) or pulmonary (n=19) MALT lymphomas had subcutaneous involvement during a median follow-up time of 87 months (range; 4 to 119 months)., Conclusions: Our data show that subcutaneous MALT lymphoma involvement is a rare event in patients with prior non-cutaneous extranodal marginal zone lymphoma. However, it seems to be almost exclusively associated with MALT lymphoma of the ocular adnexa and the breast, suggesting as yet undefined interactions between potentially embryonically related organ systems.

Mucosa-associated lymphoid tissue (MALT) lymphomas are B cell neoplasms which commonly affect the gastrointestinal (GI) tract. Gastrointestinal MALT lymphomas rarely show plasmacytic differentiation (PCD), and limited data on the potential influence of the anti-CD20 antibody rituximab (R) on PCD exist in the current literature. We have retrospectively analyzed patients with GI MALT lymphomas treated with R-containing regimens because restaging is routinely performed by repeated biopsies with pathohistological response assessment. Twenty-one patients with GI MALT lymphoma were identified to have undergone R-containing therapy. In 19 patients, the lymphoma originated in the stomach, while the colon was the primarily affected organ in two cases. Four patients received R monotherapy and 17 combinations of R with various chemotherapeutic agents. Only two patients with gastric MALT lymphoma had PCD before initiation of therapy. In 7 of 19 patients (37%) without PCD at diagnosis, restaging revealed PCD after or while on treatment with R-containing regimens. Out of these seven patients, only one patient had a complete response as opposed to 10/12 without PCD. These data suggest that R or R-containing treatment regimens may not optimally eradicate the plasma cell component and thus lead to PCD in patients with GI MALT lymphoma. In view of this, rebiopsy and histological re-assessment appear mandatory in patients failing/relapsing after R-containing regimens.

Background: In contrast to its gastric counterpart, mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland has not been studied extensively. We analyzed the clinicopathological features and the clinical course of all patients with parotid gland MALT lymphoma diagnosed and treated at our institution., Methods: Patient characteristics including an underlying autoimmune disease, disease stage, genetic aberrations, treatment, and clinical course were assessed and evaluated. Twenty-eight patients (19 women, 9 men) were identified; median age at diagnosis was 49 years (interquartile range [IQR], 40-56), and 18 patients (64%) had an underlying autoimmune disease. Eleven had stage IE, 7 patients had stage IIE, and 10 had advanced disease (stage IV)., Results: Genetic aberrations were detected in 9 of 20 patients; 5 patients had trisomy 3, 2 patients had a t(11;18)(q21;21) translocation, 1 had trisomy 3 and 18, and 1 patient had a t(14;18)(q32;q21) translocation plus trisomy 18. After a median follow-up time of 62 months (IQR, 32-98 months), 24 patients (86%) are alive. Fifteen patients are free from lymphoma, whereas 13 patients (46%) have had a relapse., Conclusion: Our data suggest that MALT lymphoma of the parotid gland is often associated with autoimmune diseases and that trisomy 3 is the most common genetic feature of this disease. The high rate of relapse warrants further study on optimal therapy of such patients., (Copyright © 2010 Wiley Periodicals, Inc.)

We have performed a phase II study to evaluate bortezomib in patients with MALT-lymphoma. Sixteen patients entered the trial, 4 had gastric MALT-lymphoma, 7 of the ocular adnexa, one of the colon, and 2 of the parotid, and one patient each the lung and the breast. Bortezomib was given at 1.5 mg/m(2) days 1, 4, 8 and 11; repeated every 21 days. The overall response rate was 80% (13/16); 7 patients achieved complete remission (43%), 6 partial response (37%) and 3 stable disease. After a median follow-up of 23 months (range; 8-26), all patients are alive and 4 have relapsed. Fifteen patients required dose reductions due to either neuropathy (7 patients) or diarrhea (8 patients). Bortezomib appears to be active in patients with MALT-lymphoma. However, an unexpectedly high rate of toxicities was seen, warranting assessment of combination schedules with bortezomib at a lower dose than given in our study.

Purpose: The well-known translocations identified in MALT lymphomas include t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, and t(14;18)/IGH-MALT1. Molecular investigations have suggested that these three disparate translocations affect a common pathway, resulting in the constitutive activation of nuclear factor-kappaB. However, the vast majority of MALT lymphomas are negative for any of the above-mentioned translocations and the underlying pathogenesis is unclear., Experimental Design: Fresh tissue of 29 gastric and extragastric MALT lymphomas was studied for genetic aberrations by conventional karyotyping, long-distance inverse PCR (LDI-PCR), fluorescence in situ hybridization (FISH), reverse transcription-PCR (RT-PCR), and real-time quantitative RT-PCR (QRT-PCR)., Results: Conventional cytogenetics, FISH, and RT-PCR identified aberrations in 26 of 29 MALT lymphoma. Balanced translocations were found in 21 cases. IGH was rearranged in the majority of cases with balanced translocations (n = 17/21); 3 cases had t(11;18)/API2-MALT1 and 1 case had novel t(6;7)(q25;q11), respectively. IGH partner genes involved MALT1, FOXP1, BCL6, and four new chromosomal regions on chromosome arms 1p, 1q, 5q, and 9p. LDI-PCR identified three novel partner genes on 1p (CNN3), 5q (ODZ2), and 9p (JMJD2C). FISH assays were established and confirmed LDI-PCR results. QRT-PCR showed deregulation of the novel genes in the translocation-positive cases., Conclusions: Our study expands the knowledge on the genetic heterogeneity of MALT lymphomas.

Background: Autoimmune diseases have been implicated in the genesis of MALT lymphoma of various localizations. The development of thyroidal MALT lymphoma has been described as an adverse event in patients suffering from long-standing chronic autoimmune thyroiditis (CAT, Hashimoto's thyroiditis). The percentage and possible association between CAT and extrathyroidal MALT lymphoma, however, have not been assessed so far., Patients and Methods: A retrospective analysis of 80 patients with MALT lymphoma diagnosed and treated at our institution identified a total of 13 patients (16%) with MALT lymphoma suffering from an underlying CAT. Patient characteristics including site of disease, stage, genetic changes and clinical course were assessed and evaluated., Results: In total, 10 patients were female and 3 male, with the median age being 57 years (range: 31-80). Four patients suffered from thyroidal lymphoma and nine patients had extrathyroidal lymphoma (four gastric, two orbital, one small intestinal and two salivary gland lymphomas). Three patients had a long-standing history of CAT at diagnosis of MALT lymphoma, while CAT was discovered during staging and clinical work-up of MALT lymphoma in the remaining 10 patients. All 13 patients had localized disease, i.e. stage I or II. Only one of the four patients with gastric MALT lymphoma responded to antibiotic treatment against Helicobacter pylori infection. Genetic aberrations were detected in four patients, two of whom had a t(11;18)(q21;q21) translocation, one patient had trisomies 3 and 18 and one had trisomy 18., Conclusion: Our findings suggest that CAT is found in patients with not only thyroidal but also nonthyroidal MALT lymphoma. While the nature of our data does not allow for delineation of a direct association between CAT and development of extrathyroidal MALT lymphoma, further prospective studies on this issue are warranted.

Background: The feature of plasmacytic differentiation (PCD) is present in up to 30% of patients diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma. To date, the influence of PCD on the clinical course of MALT lymphoma has not been assessed., Patients and Methods: Therefore, we have retrospectively analysed the clinical characteristics and the course of the disease in 34 (25%) patients with PCD as compared with 101 (75%) MALT lymphoma patients without this histological feature., Results: Patients with PCD had significantly more extragastric lymphomas [28 of 34 (82%) versus 54 of 101 (53%), P = 0.003] and a significantly lower rate of t(11;18) [2 of 26 (8%) versus 22 of 72 (31%), P = 0.02]. There was no significant difference of age at diagnosis (62 versus 64 years, P = 0.64), relapse rate (48% versus 37%, P = 0.27), estimated median time to progression (43 versus 65 months, P = 0.14), monoclonal gammopathy (50% versus 44%, P = 0.63), t(14;18) involving IGH/MALT 1 (11% versus 8%, P = 0.68), trisomy 3 (31% versus 27%, P = 0.69), trisomy 18 (8% versus 10%, P = 0.74) and the presence of autoimmune diseases between both groups (53% versus 37%, P = 0.09)., Conclusion: In conclusion, we found that PCD is predominantly found in extragastric MALT lymphoma but has no significant impact on clinical course and prognosis.

MALT lymphoma, especially of extragastric origin, is thought to be associated with an underlying autoimmune disease (AD) in a significant proportion of patients. No systematic assessment of the clinical characteristics of MALT lymphoma arising in AD as opposed to patients without AD has been performed so far. Therefore, all patients diagnosed and treated for MALT lymphoma at our institution have prospectively undergone routine clinical and serological assessment for AD since 1997. In total, 158 patients were available for analysis, and 61 out of 158 patients (39%) were diagnosed with an underlying AD. Patients with AD were predominantly women and significantly younger at lymphoma diagnosis (56 versus 67 years, P=0.004), with a significantly higher rate of extragastric lymphomas (P=0.012). Furthermore, lymphomas in these patients showed a lower frequency of trisomy 3 (P=0.04) and a significantly lower response rate to Helicobacter pylori eradication therapy in the case of gastric lymphomas (P=0.03). All other parameters including estimated median time to relapse were comparable between both groups. Our data suggest that patients with AD develop MALT lymphoma significantly earlier in life. The clinical course, however, does not appear to be adversely influenced by the presence of AD, as neither rate of relapse nor times to relapse or survival are significantly different.

Although several recurrent genetic aberrations are known to occur in MALT lymphoma, no comprehensive study on the most prevalent MALT lymphoma-associated genetic aberrations is available. We therefore screened 252 primary MALT lymphomas for translocations t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), and trisomies 3 and 18. The above-listed translocations occurred mutually exclusively and were detected overall in 13.5, 10.8, and 1.6% of the cases; trisomy 3 and/or 18 occurred in 42.1%. The frequency at which the translocations occurred varied markedly with the primary site of disease. The t(11;18)(q21;q21) was mainly detected in pulmonary and gastric tumors, whereas the t(14;18)(q32;q21) was most commonly found in lesions of the ocular adnexa/orbit, skin, and salivary glands. Trisomies 3 and 18 each occurred most frequently in intestinal and salivary gland MALT lymphomas. Our results demonstrate that the three translocations and trisomies 3 and 18 occur at markedly variable frequencies in MALT lymphoma of different sites.

A loss of FAS (CD95) function has been proposed to constitute an important step in early mucosa-associated lymphoid tissue (MALT) lymphoma development and FAS mutations have been recognized in malignant lymphomas, in particular at extranodal sites. Since primary gastric lymphomas frequently exhibit resistance to FAS-mediated apoptosis, we investigated whether FAS is mutated in 18 gastric MALT lymphomas and 28 diffuse large B-cell lymphomas (DLBCL). We detected seven mutations in five lymphomas, one MALT lymphoma and four DLBCL; two DLBCL had two mutations. The MALT lymphoma exhibited a point mutation in the splice donor region of intron 3. Three DLBCL had missense mutations in exon 2, which encodes a signal peptide and a portion of the extracellular FAS ligand-binding domain. One DLBCL carried a point mutation in the splice donor region of intron 8, which would result in exon skipping. Two DLBCL harbored a missense mutation in exon 9, which encodes the intracellular death domain. The two death domain mutations inhibited FAS ligand-induced apoptosis in a dominant-negative mode, when transiently expressed in human T47D breast carcinoma and Jurkat T cells. A signal peptide and an extracellular domain mutation, however, failed to inhibit apoptosis in these transfection assays. They are likely to reduce apoptosis in lymphoma cells solely by a loss of function. In summary, our data show that FAS mutations are rare in primary gastric MALT lymphomas (5.6%) but occur in a subset of primary gastric DLBCL (14.3%) and suggest that these mutations contribute to the pathogenesis of gastric lymphomas by rendering lymphocytes resistant to apoptosis.