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Originally published as JCO Early Release 10.1200/JCO.2006.06.0723 on June 12 2006 © 2006 American Society of Clinical Oncology. Assessment of Disease Dissemination in Gastric Compared With Extragastric Mucosa-Associated Lymphoid Tissue Lymphoma Using Extensive Staging: A Single-Center Experience
From the Departments of Internal Medicine I and IV, Pathology, Radiology, Otorhinolaryngology, Ophthalmology, and Nuclear Medicine, University of Vienna; and the Center of Excellence in Clinical and Experimental Oncology, Vienna, Austria Address reprint requests to Markus Raderer, MD, Department of Internal Medicine I, Division of Oncology, Waehringer Guertel 18-20, A-1090 Vienna, Austria; e-mail: markus.raderer{at}meduniwien.ac.at
PURPOSE: Molecular data and preliminary clinical findings have suggested mucosa-associated lymphoid tissue (MALT) lymphoma as a multifocal disease in a high percentage of patients. We report our findings with an extensive staging routine applied in patients diagnosed with MALT lymphoma at our institution. PATIENTS AND METHODS: A total of 140 consecutive patients (61 with gastric and 79 with extragastric MALT lymphoma) underwent staging according to a standardized protocol. Staging included gastroscopy with multiple biopsies, endosonography of the upper GI tract, computed tomography of thorax and abdomen, lymph node sonography, colonoscopy with multiple biopsies, otorhinolaryngologic assessment, magnetic resonance imaging of salivary and lacrimal glands, and bone marrow biopsy. All lesions suggestive of lymphoma involvement were subjected to biopsy, if accessible, and biopsies were evaluated for MALT lymphoma–specific genetic aberrations by means of reverse transcriptase polymerase chain reaction and/or fluorescent in situ hybridization. RESULTS: Fifteen (25%) of 61 patients with gastric MALT lymphoma had multiorgan involvement, with dissemination beyond the GI tract in six patients. By contrast, significantly more patients with extragastric MALT lymphoma had dissemination to another MALT organ (37 of 79 patients, 46%; P = .045). Nine of these 37 patients had dissemination to the stomach. Only three (2%) of 140 patients had bone marrow involvement. Multifocality was significantly associated with t(11;18)(q21;q21) in gastric lymphomas (P = .045) and with trisomy 18 in extragastric lymphomas (P = .011). CONCLUSION: Our findings suggest that MALT lymphoma frequently presents as a multifocal disease. Extragastric MALT lymphomas are significantly more prone to dissemination than gastric MALT lymphomas.
Mucosa-associated lymphoid tissue (MALT) lymphoma is among the more common types of lymphoma and accounts for 7% of all newly diagnosed lymphomas at our institution.1 In terms of clinical behavior, MALT lymphoma is rated as an indolent disease, which is thought to remain confined to its original MALT environment for a prolonged time.2 In keeping with this concept, local forms of treatment, including surgery in case of gastric MALT lymphoma or radiation, have been preferentially applied until recently. In fact, application of radiotherapy has repeatedly been reported to result in excellent local control and overall outcome.3,4 In contrast, data from our institution have shown a substantial rate of systemic relapse in MALT lymphoma of the head and neck region treated with radiation alone.5 In addition, a recent analysis evaluating the pattern and rate of relapse in MALT lymphoma patients achieving complete remission has shown a relapse rate of 37%, with a median time to relapse of 47 months.6 Taken together, these findings suggest MALT lymphoma to be a systemic disease in a significant proportion of patients. That intraorgan dissemination might indeed be more widespread than suspected with conventional means has already been documented by molecular data. Wotherspoon et al7 carried out a systematic examination of five gastrectomy specimens from patients with MALT lymphoma. They could identify numerous clonally identical foci of tumor even in macroscopically unaffected tissue. Similarly, Du et al8 established the presence of tumor cells in lymphoid tissue that otherwise showed no evidence of lymphoma. In addition to widespread intraorgan dissemination, the presence of a common mucosal immune system and the preferential trafficking of MALT-primed lymphocytes to other mucosal sites9 suggest that these properties might be retained after malignant transformation and could lead to widespread dissemination among various MALT organs. This is further substantiated by anecdotal reports of synchronous occurrence of MALT lymphoma within different MALT organs or relapse within another typical MALT organ after successful local therapy of the initially affected site.6,10-12 In addition, large retrospective studies13,14 have found disease dissemination in up to one third of patients, including a substantial amount of bone marrow involvement. These considerations led us to prospectively implement a standardized staging approach for all patients with MALT lymphoma at our institution in the beginning of 1997. Accordingly, data from a pilot series including 35 patients with MALT lymphoma and transformed MALT lymphoma15 have suggested that roughly 25% of patients with MALT lymphoma have multiorgan involvement at presentation, with the rate approaching 50% in patients with primary extragastric MALT lymphomas. In view of the indolent nature and slow growth of MALT lymphoma, these findings have also led to the hypothesis that relapses occurring shortly after initial diagnosis and (local) treatment might simply have been synchronous foci of MALT lymphoma not detected in the absence of meticulous staging,15 rather than true relapses. In this article, we present our experience of 140 consecutive patients with MALT lymphoma undergoing extensive staging between January 1997 and December 2005. In addition to our initial pilot study, we have also analyzed MALT lymphoma–associated chromosomal aberrations and their influence on clinical presentation and multifocality.
Between January 1997 and December 2005, all patients with a diagnosis of MALT lymphoma underwent a standardized staging program irrespective of the site of initial presentation. Histologic diagnosis of MALT lymphoma was established by a reference hematopathologist (A.C.) in all patients according to the criteria outlined in the WHO classification of lymphoid malignancies. Immunologic phenotyping on paraffin sections was performed 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. If the initial diagnosis had been established at an outside institution, histologic samples were reassessed for verification of the diagnosis. All 140 patients underwent extensive staging before initiation of therapy; staging consisted of ophthalmologic examination, otorhinolaryngologic investigation including sonography or magnetic resonance imaging of the salivary glands and lacrimal glands, gastroscopy with multiple biopsies, endosonography of the upper GI tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen, sonography of cervical, inguinal, and axillary lymph nodes, and bone marrow biopsy. In all lesions suggestive of lymphoma involvement, biopsy was attempted (if possible), and all samples were again evaluated by the same reference hematopathologist. In the GI tract, biopsies were not only taken from macroscopically abnormal regions, but mapping biopsies from normally appearing mucosa were also obtained in the stomach, duodenum, colorectum, and terminal ileum. All samples were investigated by means of histology and immunohistochemistry; additional molecular investigations were performed from all samples diagnosed as or rated suggestive for MALT lymphoma. Paraffin-embedded biopsy samples were tested for MALT lymphoma–specific genetic aberrations including t(11;18)(q21;q21) and t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) and t(3;14)(q14;q32) involving FOXP1 and IGH, and trisomies 3 and 18. t(11;18)(q21;q21) involving API2 and MALT1 was assessed by reverse transcriptase polymerase chain reaction; t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) involving BCL10 and IGH, t(3;14)(q14;q32) involving FOXP1 and IGH, and trisomies 3 and 18 were investigated by fluorescence in situ hybridization, as published previously.16 These genetic studies were carried out in all patients who had enough tumor tissue left in the paraffin block.
Statistical analyses were performed with the SPSS 12.0 for Windows program (SPSS Inc, Chicago, IL). The associations between the categoric variables were calculated with the
A total of 140 patients underwent staging as indicated; 22 had been included in a previous publication.15 All patients were newly diagnosed and had not undergone treatment before initiation of staging. Sixty-one patients presented with gastric MALT lymphoma, whereas 79 had initially been diagnosed at an extragastric site. The majority of these patients had salivary gland lymphoma (n = 24, 30%; 22 parotid and two submandibular gland lymphomas), 17 patients had lymphoma of the orbit/lacrimal gland (20%), another 11 patients had MALT lymphoma originating in the lung (14%), and 10 patients had primary intestinal MALT lymphoma (12.5%; eight in the colorectum and two in the small intestine). The remaining patients suffered from lymphoma of the thyroid (n = 5), conjunctiva (n = 4), breast (n = 3), liver (n = 2), and kidney (n = 2). Of 140 patients, 52 (37%) were found to harbor multifocal MALT lymphoma involving multiple organs. In total, 15 (25%) of 61 patients with gastric lymphoma had multiorgan involvement. Eight of these 15 patients showed synchronous spread to the GI tract (involvement of colon and/or rectum in seven patients and small bowel in one patient), whereas six patients had disease at another non-GI site (Table 1). The organs affected included the lung in three patients and lung along with parotid, bladder plus spleen, kidney, lung plus bone marrow, and bone marrow alone in one patient each. All lesions (including the splenic manifestation) were verified by histologic assessment of biopsies.
A significantly higher percentage of patients with extragastric lymphoma (37 of 79 patients, 46%) had multiorgan involvement (P = .045). Because of the relatively small number of patients in some subgroups, statistical analysis for the influence of lymphoma origin on dissemination was only performed for parotid and ocular adnexal lymphomas, but the analysis failed to disclose a significant association. In nine (24%) of 37 patients, gastric involvement was detected by subsequent staging, but the majority of patients had another MALT lymphoma focus outside the stomach. Of these nine patients with secondary spread to the stomach, four had lymphoma originating in the lung, one patient each had lymphoma originating in the small intestine, the lacrimal gland, the parotid, the conjunctiva, and the kidney. In these nine patients, one patient had evidence of florid Helicobacter pylori (HP) gastritis, and one patient had evidence of ex-HP gastritis, whereas in the remaining seven patients the gastric mucosa was devoid of any signs of inflammatory condition or acquisition of lymphoid tissue. Bilateral MALT lymphoma affecting a paired organ as the only manifestation was found in eight patients, including parotid lymphoma in four patients, orbital MALT lymphoma in two patients, and conjunctival and pulmonary lymphoma in one patient each. All four patients with bilateral parotid lymphoma had a long-standing history of Sjogren's syndrome, whereas one patient with bilateral orbital lymphoma suffered lupus erythematosus. In the other patients, more widespread disease with dissemination to another MALT organ was noted (Table 1). Taken together, only three (2%) of 140 patients had bone marrow involvement (two with gastric origin and one with lymphoma of the lung). Apart from detection of multifocal MALT lymphoma, staging procedures resulted in the detection of four additional malignancies. Two patients were diagnosed with hitherto unknown non–small-cell lung cancer, one patient had diffuse bone marrow involvement with breast cancer, and a fourth patient was diagnosed as having both adenocarcinoma of the pancreatic head and renal cell cancer. After a median follow-up time of 49 months (interquartile range, 29 to 68 months), 23 patients have died; five patients died of progressive lymphoma, whereas the remaining 18 patients died from unrelated causes. No significant difference was found in terms of survival between patients with multifocal disease versus localized stage on diagnosis (Fig 1).
Paraffin-embedded material for genetic analysis was available in 106 patients, whereas the amount of biopsy tissue was not sufficient for reverse transcriptase polymerase chain reaction or fluorescent in situ hybridization studies in the remaining 34 patients. Genetic aberrations were detected in 63 (59%) of 106 patients, with t(11;18)(q21;q21) being present in 28 (44%) of 63 patients. In patients with gastric lymphoma, t(11;18)(q21;q21) was present in 19 (31%) of 61 patients and, thus, was found in 86% of patients with gastric lymphoma harboring a genetic aberration (19 of 22 patients). In these 19 patients, it was the sole aberration detected, whereas one patient had t(14;18) involving IGH/MALT, one patient had trisomy 3, and another patient had trisomy 3 and trisomy 18. t(11;18)(q21;q21) was significantly less common in extragastric MALT lymphomas (P = .002), where it was found in nine patients. The rate of both trisomies 3 and 18 was significantly higher in patients with extragastric lymphoma (P = .003 for trisomy 3 and P = .037 for trisomy 18), as was t(14;18) involving IGH/MALT1 (P = .036). Detailed genetic findings are listed in Table 1; genetic findings in patients with multifocal disease are listed in Table 2.
In gastric lymphoma, the presence of t(11;18)(q21;q21) was significantly associated with disease dissemination (P = .045). Trisomy 18 was significantly more common in patients with extragastric MALT lymphoma having multiorgan involvement (P = .011), with six of 35 patients with multifocality having trisomy 18 (either as sole aberration or in combination; Table 1) compared with only two of 44 patients without multifocality. No significant difference was seen for the other genetic aberrations (data not shown).
To our knowledge, this is the largest and most thoroughly staged series of patients to prospectively evaluate the dissemination pattern of MALT lymphoma on diagnosis. Of 140 patients assessed in this single-center evaluation, 52 (37%) had multiorgan involvement at presentation. However, the rate of dissemination was different between gastric MALT lymphoma (25%, 15 of 61 patients) versus extragastric MALT lymphomas, which showed multiorgan involvement in 37 (46%) of 79 patients (P = .045). These data are in keeping with a previous, albeit much smaller, pilot series performed at our institution, which suggest that one third of gastric MALT lymphomas and roughly 50% of extragastric lymphomas are disseminated.15 In addition, this study also reflects the apparently different clinical behavior of extragastric MALT lymphomas, which tend to have a shorter event-free survival2 and a higher rate of relapse6 but similar overall survival compared with gastric lymphomas. However, as also seen in other series, dissemination of the disease on diagnosis did not adversely influence survival (Fig 1). Although our series is a prospective evaluation of 140 consecutive patients staged before initiation of therapy, one still cannot rule out some selection bias in our series. Extragastric MALT lymphomas were found in 79 (56%) of 140 patients, where gastric MALT lymphomas were found in 61 (44%) of 140 patients. This distribution reflects the referral pattern at our institution between 1997 and 2005, although one would probably expect a predominance of gastric MALT lymphoma.13,18 Although the reason for the distribution in our series remains somewhat elusive, it might be explained by the fact that eradication of HP has become a standard form of treatment for gastric MALT lymphoma. Because it is not necessarily performed by specialized centers, such patients may not be referred to hemato-oncologic centers such as ours as opposed to patients thought to require chemotherapy or radiation. Another explanation might be that the widespread use of antibiotic treatment in patients with complaints and a positive breath test for HP results in accidental eradication of some gastric MALT lymphomas that thereby go undetected. Interestingly, the pattern of dissemination seemed to be different between gastric and extragastric MALT lymphomas because almost 50% of patients with gastric origin had dissemination within the GI tract. This finding might reflect a special homing pattern of lymphocytes generated within a MALT environment, which has been shown to differ between GI MALT and non-GI MALT.9 Although the majority of lymphomas with extragastric origin indeed disseminated to a non-GI site, nine (24%) of 37 patients showed secondary gastric involvement detected by extensive staging. In only two of nine patients, evidence of HP infection was detected, whereas in the remaining seven patients, the gastric mucosa appeared devoid of inflammatory changes and accumulation of lymphoid tissue, suggesting that pre-existing lymphoid tissue is not a prerequisite for secondary spread to the stomach in MALT lymphoma. However, most of these patients suffered from either lymphoma of the lung (four of 11 patients with pulmonary MALT lymphoma) or the intestine, whereas secondary gastric spread was virtually absent in parotid and orbital lymphoma. Therefore, an extensive GI work-up in the absence of clinical symptoms suggestive of lymphoma does not seem strictly necessary in patients diagnosed with MALT lymphoma of the salivary glands and the ocular adnexa. In the latter patients, however, a high rate of bilateral involvement was seen, which again underscores the potential of preferential immunologic trafficking between paired mucosal organs. All four patients with bilateral parotid MALT lymphoma had a long-standing history of Sjogren's syndrome, which might have facilitated the development of bilateral disease. An additional patient with bilateral orbital involvement had underlying lupus erythematosus. One might argue that bilateral involvement of paired organs, such as the parotid, is in fact different from dissemination to other organs and might not reflect truly widespread disease as a result of a common underlying condition. In terms of clinical relevance, however, it is still an important finding because patients with unilateral disease might be subjected to potentially curative radiation, whereas one would be rather reluctant to administer bilateral salivary gland radiation in view of the potential adverse effects. One of the major differences between our series and other large but retrospective studies on MALT lymphoma is the extremely low rate of bone marrow involvement. Although only three (2%) of 140 patients with MALT lymphoma had bone marrow involvement in our series, other studies have reported much higher percentages. In a retrospective analysis of 158 patients, Thieblemont et al14 reported a total of 31 patients with bone marrow involvement, corresponding to 19% of their total study population. Apart from a potential referral bias and the different nature of the two series (prospective v retrospective analysis), we cannot offer a definite explanation for this discrepancy. However, our data suggest that bone marrow involvement is exceedingly rare in the Austrian MALT lymphoma population, arguing against the necessity of routine bone marrow biopsy in patients with MALT lymphoma. To our knowledge, this is the first prospective study of a larger series to address the question of dissemination with regard to genetic aberrations. In keeping with recent reports, we could confirm a significant association of t(11;18)(q21;q21) with disseminated disease in the group of gastric MALT lymphomas as a whole (P = .045). As has also repeatedly been reported, t(11;18)(q21;q21) is always exclusive of other (as yet discovered) genetic aberrations,16,19 suggesting some form of genetic stabilization of the disease by the acquisition of this translocation. This might also in part explain a recent finding that t(11;18)(q21;q21)–positive MALT lymphomas have a significantly longer time to relapse after complete remission compared with lymphomas negative for this aberration (76 v 29 months).6 In addition, we could identify trisomy 18 as a predictive factor (P = .011) for disseminated disease in MALT lymphoma of extragastric origin. Because the number of patients with trisomy 18 was relatively small, evaluation of a larger series is required. If confirmed, patients with extragastric MALT lymphoma harboring trisomy 18 should undergo extensive staging to rule out multifocal disease before initiation of therapy. Taken together, our data indicate that MALT lymphoma is a multiorgan disease in 25% of gastric and 46% of extragastric patients. In terms of genetic aberrations, we could identify two subgroups with a higher risk of dissemination (ie, t(11;18)(q21;q21)–positive gastric MALT lymphomas and extragastric MALT lymphomas with trisomy 18). The extremely low rate of bone marrow involvement (2%) and the finding that parotid and ocular lymphomas hardly ever disseminate to the stomach may justify individually targeted staging in such patients based on initial localization and genetic findings.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Chott A, Raderer M: New developments in extracutaneous lymphomas. Semin Cutan Med Surg 19:149-156, 2000[Medline] 2. Thieblemont C, Bastion Y, Berger F, et al: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behaviour: Analysis of 108 patients. J Clin Oncol 15:1624-1630, 1997[Abstract] 3. Tsang R, Gospodarowicz M, Pinitilie M, et al: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21:4157-4164, 2003 4. Schechter NR, Portlock CS, Yahalom J: Treatment of mucosa associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 16:1916-1921, 1998[Abstract] 5. Wenzel C, Fiebiger W, Dieckmann K, et al: Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue of the head and neck area: High rate of recurrence following local therapy. Cancer 97:2236-2241, 2003[CrossRef][Medline] 6. Raderer M, Streubel B, Woehrer S, et al: High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 11:3349-3352, 2005 7. Wotherspoon A, Doglioni C, Isaacson PG: Low-grade gastric B-cell lymphoma of mucosa associated lymphoid tissue (MALT): A multifocal disease. Histopathology 20:29-34, 1992[Medline] 8. Du MQ, Diss TC, Dogan A, et al: Clone-specific PCR reveals wide dissemination of gastric MALT lymphoma to the gastric mucosa. J Pathol 192:488-493, 2000[CrossRef][Medline] 9. Brandtzaeg P, Farstad IN, Haraldsen G: Regional specialization in the mucosal immune system: Primed cells do not always home along the same track. Immunol Today 20:267-277, 1999[CrossRef][Medline] 10. Graziadei G, Pruneri G, Carboni N, et al: Low-grade MALT-lymphoma involving multiple mucosal sites and bone marrow. Ann Hematol 76:81-83, 1998[CrossRef][Medline] 11. Kawamata N, Miki T, Fukuda T, et al: Determination of a common clonal origin of gastric and pulmonary mucosa-associated lymphoid tissue lymphomas presenting five years apart. Intern Med 34:220-223, 1995[Medline] 12. Stephen MR, Farquharson MA, Sharp RA, et al: Sequential MALT lymphomas of the stomach, small intestine and gall bladder. J Clin Pathol 51:77-79, 1998[Abstract] 13. Zucca E, Bertoni F, Roggero E, et al: The gastric marginal zone B-cell lymphoma of MALT type. Blood 96:410-419, 2000 14. Thieblemont C, Berger F, Dumontet C, et al: Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood 95:802-806, 2000 15. Raderer M, Vorbeck F, Formanek M, et al: Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 83:454-457, 2000[CrossRef][Medline] 16. Streubel B, Simonitsch-Klupp I, Müllauer L, et al: Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722-1726, 2004[CrossRef][Medline] 17. Cochran WG: Some methods for strengthening the common Chi-squared tests. Biometrics 10:417-451, 1954[Medline] 18. Zucca E, Conconi B, Pedrinis E, et al: Nongastric marginal zone B-cell lymphoma of mucosa associated lymphoid tissue. Blood 101:2489-2495, 2003 19. 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 Submitted February 6, 2006; accepted April 20, 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, Fisher's exact test, or contingency tables. All tests were used according to the recommendations of Cochran.
