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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-10-3167.
BRIEF REPORT: CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Histopathology, University
College London, United Kingdom; Department of Internal
Medicine/Clinical Pathology, University of Vienna,
Austria; Service de Gastro-enterologie, Hotel-Dieu,
Assistance Publique Hôpitaux de Paris (AP-HP), Groupe d'Etude
des Lymphomes Dignestifs (GELD), Paris, France; Department
of Histopathology, The Royal Marsden National Health Service (NHS)
Trust, London, United Kingdom; Department of Haematology,
University of Leicester, United Kingdom; Department of
Pathology, Chi-Mei Medical Center, Taiwan.
In approximately 5% to 10% of gastric
mucosa-associated lymphoid tissue (MALT) lymphomas, evidence of
Helicobacter pylori infection is absent, and their
pathogenesis is poorly understood. We reviewed the clinical data and
histology, and we examined t(11;18)(q21;q21) and BCL10 expression
pattern in 17 such cases. In each case, the absence of H
pylori was confirmed by negative serology and
histology/immunohistochemistry. Five cases with stage IE
disease were first treated with antibiotics, and none of them showed
any endoscopic or histologic response. Review of the histology failed
to identify any apparent difference between gastric MALT lymphomas with
and without H pylori infection. Reverse
transcription-polymerase chain reaction (RT-PCR) showed t(11;18)(q21;q21) in 9 (53%) of 17 cases, more frequent in lymphomas at stage IIE or above (5 of 6) than those at stage
IE (3 of 10). Two t(11;18)(q21;q21)-positive lymphomas were
treated by partial gastrectomy and more than 16 years later showed
lymphoma relapse in the gastric stump with dissemination to other
mucosal sites, poorly responsive to therapy. BCL10 nuclear expression
was observed in 7 of 8 t(11;18)(q21;q21)-positive cases and 4 of 7 t(11;18)(q21;q21)-negative cases, including one case suspicious for a
BCL10-involved chromosomal translocation. Our results show that
t(11;18)(q21;q21) occurs at a high frequency in H
pylori-negative gastric MALT lymphomas. Translocation-positive
gastric MALT lymphomas tend to be aggressive, and patients with such
lymphomas might benefit from prompt treatment and close follow-up.
(Blood. 2003;101:2547-2550) Most gastric mucosa-associated lymphoid tissue
(MALT) lymphomas are associated with Helicobacter pylori
infection. Colonization of the gastric mucosa by the organism induces
lymphoid infiltration and formation of acquired MALT, from which the
malignant clone arises. The lymphoma growth, particularly at early
phases, critically depends on H pylori-specific
tumor-infiltrating T cells, involving CD40 and CD40L costimulating
molecules.1,2 Eradication of H pylori by
antibiotics leads to complete regression of gastric MALT lymphoma in
70% of cases and is now used as first-line therapy for this
tumor.3,4
Genetically, t(1;14)(p22;q32) and t(11;18)(q21;q21) are
implicated in the development of H pylori-associated
gastric MALT lymphoma. The t(1;14)(p22;q32) translocation occurs in
around 5% of MALT lymphomas and causes deregulation of
BCL105 that specifically relays the antigen receptor
signaling to nuclear factor The t(11;18)(q21;q21) translocation occurs in 30% of gastric MALT
lymphomas. The translocation fuses the amino terminal of the
API2 gene to the carboxyl terminal of the MALT1
gene and generates a fusion product.9 The
API2-MALT1 fusion product activates NF- In approximately 5% to 10% of gastric MALT lymphomas, there is no
evidence of H pylori infection, and their pathogenesis is poorly understood.14,15 We reviewed the clinical data and
histology of 17 such cases and examined them for t(11;18)(q21;q21) and
the pattern of BCL10 expression.
Patients and materials
Reverse-transcription and polymerase chain reaction (RT-PCR) for
detection of t(11;18)(q2l;q21)
In the remaining cases, formalin-fixed and paraffin-embedded tissues
from diagnostic biopsies were used for RNA extraction.13 Reverse-transcription was carried out using a mixture of gene-specific primers, including glucose-6-phosphate dehydrogenase (G6PD)
primers, which were specially designed for formalin-fixed
paraffin-embedded tissues. Three sets of PCR primers with one common
sense primer covering 93% of the known breakpoints on the
API2 gene and 3 antisense primers targeting all 4 breakpoints on the MALT1 gene were used for PCR of the
API2-MALT1 fusion transcript (Figure 1).13 The G6PD was amplified in parallel as a control. PCR was
performed separately with each primer set at least in duplicate, and
the PCR products were analyzed on 10% polyacrylamide gels.
Where indicated, PCR products were gel purified (QIAquick Gel
Extraction kit; Qiagen) and sequenced in both directions using dRhodamine dye terminators on an ABI Prism 377 sequencer (PE Applied Biosystems, Foster City, CA).
BCL10 immunohistochemistry
The cases used in this study were selected purely based on their absence of H pylori infection as confirmed by negative serology and histology/immunohistochemistry or urease test (CLO) and histology/immunohistochemistry. The enzyme-linked immunosorbent assay for detection of serum H pylori immunoglobulin G (IgG) antibody is sensitive, capable of detecting 95% of cases.17 In 7 cases, patient's sera were also tested for CagA antibodies and none of them were positive. CagA is highly immunogenic, and antibodies to CagA are frequently detected in patient's sera that are negative for H pylori IgG antibody.18 H pylori detection by histologic and immunohistochemical examination is less sensitive and is often affected by the quality and nature of biopsies, but nonetheless it can diagnose around 70% of cases.19 In the present series, multiple biopsies obtained at various stages of patient's treatment were available in each case, and all biopsies consistently showed absence of H pylori infection. Thus, the cases included in this study were most likely negative for H pylori infection. The cases studied were also unlikely positive for non-H pylori helicobacters, such as Helicobacter heilmannii and Helicobacter felis, which are also associated with human diseases, including gastric MALT lymphoma.20 Histologic examination of multiple biopsies in each case failed to reveal any direct evidence of presence of bacteria in the gastric mucosa. Gastric MALT lymphomas associated with H heilmannii infection have been shown to respond to antibiotic therapy.21 Of the cases studied, 5 cases with stage IE lymphoma were first treated with antibiotics, and none of them showed any endoscopic and histologic response during 4.5 to 12 months of follow-up. Of the 17 cases studied, clinical staging was available in 16 cases
(Table 1), with 10 cases at stage
IE and the remaining 6 cases at stage
IIE or above. As mentioned earlier, 5 of the 10 cases with
stage IE disease were first treated with antibiotics but
failed to respond. They were subsequently treated by total gastrectomy
or radiotherapy. Of the remaining patients, cases 1 and 2 were first
treated by partial gastrectomy because of gastric ulcer, and a review
of histology of the gastrectomy specimens showed existence of MALT
lymphoma in each case. More than 16 years later, both patients showed
occurrence of MALT lymphoma in the gastric stump and in additional
mucosal sites (lung in case 1; colon and terminal ileum in case
2). Clonal analysis of the rearranged immunoglobulin heavy
chain gene showed that the recurrent tumors were clonally related to
the original gastric MALT lymphoma in each case. Both patients were
treated with rituximab, with one patient showing only partial response
and the other stable disease. All the remaining patients were treated
with chemotherapy or partial gastrectomy on diagnosis of MALT lymphoma.
Histology was reviewed by 2 hematopathologists (P.G.I. and A.C.) to identify whether there are differences between MALT lymphoma with and without H pylori infection. As tissue biopsies were small and often distorted, we focused on the 6 cases with gastrectomy specimens, in which multiple formalin-fixed and paraffin-embedded tissues were available. In essence, H pylori-negative gastric MALT lymphomas showed similar histologic features to those associated with H pylori. Characteristic lymphoepithelial lesions, similar extents of reactive lymphoid follicles, and tumor-infiltrating T cells were seen in H pylori-negative gastric MALT lymphomas. These observations suggested that these lymphomas like H pylori-positive cases were most likely arising from acquired MALT. However, the agent that induced the acquired MALT in these cases remains enigmatic. The frequency of t(11;18)(q21;q21) in H pylori-positive gastric MALT lymphoma has been reported to range from 30% to 50%.22-26 The number of cases studied in these reports was relatively small, and the investigation was commonly based on those treated by gastrectomy, which was often biased toward the advanced cases. Thus, these studies may have overestimated the incidence of t(11;18)(q21;q21) in gastric MALT lymphoma. We recently screened for t(11;18)(q21;q21) by RT-PCR in 135 cases of H pylori-associated gastric MALT lymphoma randomly selected and found the translocation in 32 (23.7%) cases (M.-Q. D. et al, unpublished data, October 2002). By using the same RT-PCR methodology followed by sequencing confirmation of suspicious PCR products (2 from frozen tissue and one from fixed tissue), we showed that the translocation was detected in 9 (53%) of the 17 H pylori-negative gastric MALT lymphomas (Table 1). Thus, the incidence of t(11;18)(q21;q21) in H pylori-negative gastric MALT lymphoma is much higher than that of H pylori-positive cases. This finding is in line with the previous finding that the translocation has been found in 2 of 2 H pylori-negative gastric MALT lymphomas.14 Similar to H pylori-positive gastric MALT lymphoma, the occurrence of t(11;18)(q21;q21) in H pylori-negative cases was significantly associated with more advanced cases, being detected in 3 of 10 cases at stage IE but in 5 of 6 cases at stage IIE or above (P < .05, chi-square test). Notably, 2 patients with t(11;18)(q21;q21)-positive gastric MALT lymphoma (nos. 1 and 2) were initially treated by partial gastrectomy, and more than 16 years later both patients showed lymphoma relapse in the gastric stump and disseminated lesions in additional mucosal sites, which were poorly responsive to therapy with rituximab. A further case (no. 9) underwent total gastrectomy and 36 months later showed lymphoma relapse in lung. The findings highlight 2 important issues. First, it further questions the role of gastrectomy in treatment of gastric MALT lymphoma because the lymphoma cells are widely disseminated in the gastric mucosa and cannot be completely cleared by a partial gastrectomy.27 Second, t(11;18)(q21;q21)-positive cells are capable of surviving and remain dormant for a long period before forming relapse and disseminated lesions, which could impose a challenge for clinical treatment. Thus, it is tempting to speculate that effective systemic treatment administered at an earlier time could be beneficial in such patients. Of the 15 cases in which immunohistochemistry for BCL10 was performed, one case (no. 17) showed strong BCL10 nuclear expression in most of the tumor cells, similar to that seen in t(1;14)(p22;q32)-positive MALT lymphoma. In the remaining 14 cases, 7 of the 8 t(11;18)(q21;q21)-positive cases and 3 of the 6 translocation-negative cases displayed a BCL10 nuclear expression at a moderate level. The remaining cases exhibited BCL10 expression in the cytoplasm. These findings are similar to those observed in H pylori-positive gastric MALT lymphomas.8 In conclusion, t(11;18)(q21;q21) occurs at a high frequency in H pylori-negative gastric MALT lymphomas. Patients with H pylori-negative gastric MALT lymphoma should be treated with chemotherapy or radiotherapy on diagnosis. The t(11;18)(q21;q21)-positive tumors may require close follow-up.
Submitted October 18, 2002; accepted November 15, 2002.
Prepublished online as Blood First Edition Paper, November 27, 2002; DOI 10.1182/blood-2002-10-3167.
Supported by research grants from the Leukemia Research Fund, United Kingdom.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Ming-Qing Du, Department of Histopathology, Royal Free and University College Medical School, University College London, Rockefeller Building, University Street, London WC1E 6JJ, United Kingdom; e-mail: m.du{at}ucl.ac.uk.
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Top
Abstract
Introduction
B (NF-