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Nuclear Expression of BCL10 or Nuclear Factor Kappa B Predicts Helicobacter pylori–Independent Status of Early-Stage, High-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphomas

From the Departments of Oncology, Internal Medicine, and Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine; Cancer Research Center, Graduate Institute of Clinical Medicine, and Graduate Institute of Microbiology, National Taiwan University College of Medicine; Division of Cancer Research, National Health Research Institutes; Department of Pathology, Taipei Medical University, Taipei; and Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Address reprint requests to Ann-Lii Cheng, MD, PhD, Department of Internal Medicine and Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan S Rd, Taipei, Taiwan; e-mail: andrew{at}ha.mc.ntu.edu.tw

	ABSTRACT

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PURPOSE: A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H pylori–independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-B) is useful in predicting H pylori–independent status in patients with stage IE high-grade gastric MALT lymphomas.

PATIENTS AND METHODS: Twenty-two patients who had participated in a prospective study of H pylori eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-B in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript.

RESULTS: Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H pylori–independent and in none of 14 H pylori–dependent high-grade gastric MALT lymphomas (P < .001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-B, compared with only two of 15 patients without nuclear BCL10 expression (P = .002). As a single variable, the frequency of nuclear expression of NF-B was also significantly higher in H pylori–independent tumors than in H pylori–dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P = .002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H pylori–independent lymphomas.

CONCLUSION: Nuclear expression of BCL10 or NF-B is highly predictive of H pylori–independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.

	INTRODUCTION

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Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) of the stomach has recently been recognized as a distinct entity of non-Hodgkin's lymphoma.¹ Helicobacter pylori infection of the gastric mucosa plays an important role in the development and progression of gastric MALT lymphoma,^2-5 and eradication of H pylori results in durable tumor regression in approximately 70% of patients with localized low-grade gastric MALT lymphomas.^5-7 However, high-grade gastric MALT lymphomas, in contrast to their low-grade counterpart, are believed to consist of highly transformed cells, the growth of which is independent of H pylori.^8-11

Recently, our group and other investigators have demonstrated that a substantial portion of early-stage, high-grade gastric MALT lymphomas remain H pylori dependent and can potentially be cured by H pylori eradication.^12-14 Although the tumor response to H pylori eradication is almost as good as in its low-grade counterpart, early-stage, high-grade gastric MALT lymphomas may rapidly progress if they are unresponsive to H pylori eradication therapy. Therefore, identification of cellular or molecular markers that can help predict the H pylori–independent status of newly diagnosed high-grade gastric MALT lymphomas is mandatory. It is noteworthy that markers relevant to H pylori–independent status may be different between high-grade and low-grade gastric MALT lymphomas. For example, t(11;18)(q21;q21), one of the most important predictors of H pylori independence in low-grade gastric MALT lymphomas, is rarely found in high-grade gastric lymphomas.^15-17 Other markers that help predict the H pylori–independent status of high-grade gastric MALT lymphomas must be sought.

t(1;14)(p22;q32) is another genetic aberration implicated in the development of MALT lymphoma. t(1;14)(p22;q32) juxtaposes BCL10 of chromosome 1 to an immunoglobulin gene locus of chromosome 14, and results in strong expression of a truncated BCL10 protein in the nuclei and cytoplasm, in contrast to the weak cytoplasmic expression of BCL10 in normal germinal center B cells.^18,19 It is noteworthy that t(1;14)(p22;q32) was detected in less than 5% of low-grade gastric MALT lymphomas, whereas moderate nuclear expression of BCL10 was found in 30% to 40% of these tumors.¹⁹ In contrast, BCL10 nuclear expression was found to be more closely associated with the genetic aberration t(11;18)(q21;q21) and advanced tumor stages, two of the conditions predictive of H pylori–independent status in low-grade gastric MALT lymphoma.²⁰ The physiologic function of BCL10 in B lymphocytes remains unclear. The mechanism and biologic significance of BCL10 nuclear expression in lymphoma cells without BCL10 gene mutation are largely unknown. In T lymphocytes, BCL10 normally resides in the cytoplasm and specifically relays antigen-receptor–mediated signals to activate nuclear factor kappa B (NF-B).²¹ We hypothesized that upregulation of BCL10 may trigger a constitutive NF-B activation signal, and therefore contribute to antigen-independent growth and the progression of the gastric MALT lymphoma. Under this condition, expression patterns of NF-B and BCL10 may be useful markers for predicting H pylori independence of high-grade gastric MALT lymphoma.

In this study, we compared the expression patterns of BCL10 and NF-B in 14 H pylori–dependent and eight H pylori–independent high-grade gastric MALT lymphomas. We found that these two markers are highly useful in predicting H pylori status of high-grade gastric MALT lymphoma.

	PATIENTS AND METHODS

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Patients, Treatment, and Evaluation of the Tumors
Twenty-two patients who had participated in a prospective study of H pylori eradication for stage IE high-grade gastric MALT lymphomas at our institutions from June 1995 through June 2002 were included in the study. The clinicopathologic features of the initial 16 patients have been reported previously.¹⁴ The diagnosis of high-grade gastric MALT lymphoma was made according to the histologic criteria described by Chan et al²² based on the presence of confluent clusters or sheets of large cells resembling centroblasts or lymphoblasts within predominantly low-grade centrocyte-like cell infiltrate, or the predominance of high-grade lymphoma with only a small residue, low-grade foci, and/or the presence of lymphoepithelial lesions. The histopathologic characteristics of all tumor specimens were independently reviewed by two experienced hematopathologists. Staging was classified according to Musshoff's modification of the Ann Arbor staging system.²³ All patients consented to a brief trial of an H pylori eradication therapy.

At the beginning of the study, the eradication regimen consisted of amoxicillin 500 mg and metronidazole 250 mg qid with either bismuth subcitrate 120 mg qid or omeprazole 20 mg bid for 4 weeks, which was changed to amoxicillin 500 mg qid, clarithromycin 500 mg bid, plus omeprazole 20 mg bid for 2 weeks after March 1996. Patients were scheduled to undergo first follow-up upper gastrointestinal endoscopic examination 4 to 6 weeks after completion of antimicrobial therapy, and follow-up was then repeated every 6 to 12 weeks until histologic evidence of remission was found. At each follow-up examination, four to six biopsy specimens were taken from the antrum and body of the stomach for the evaluation of H pylori infection, and a minimum of six biopsy specimens were taken from each of the tumors and suspicious areas for histologic evaluation. Diagnosis of H pylori infection was based on histologic examination, biopsy urease test, and bacterial culture. Tumor regression after eradication therapy was histologically evaluated according to the criteria of Wotherspoon et al.⁵ Tumors that resolved to Wotherspoon grade 2 or less after H pylori eradication were considered H pylori dependent; other tumors were considered H pylori independent.

Immunohistochemistry and Confocal Laser Scanning Microscopy
Formalin-fixed, paraffin-embedded sections cut at a thickness of 4 µm were deparaffinized and rehydrated through xylenes and a graded alcohol series. After antigen retrieval by heat treatment in 0.1 M citrate buffer at pH 6.0, endogenous peroxidase activity was blocked by 3% H₂O₂. Briefly, slides were incubated for 30 minutes in 2.5% normal donkey serum or goat serum. The slides were then incubated overnight at 4°C either with polyclonal goat antihuman BCL10 (1:10; sc-9560; Santa Cruz Biotechnology, Santa Cruz, CA) or polyclonal rabbit antihuman RelA (p65; 1:100; sc-7151; Santa Cruz Biotechnology) and incubated with secondary antibodies (BCL10, donkey antigoat immunoglobulin; RelA, goat antirabbit immunoglobulin; Santa Cruz Biotechnology) according to the manufacturer's instructions. Finally, antibody binding was detected with the avidin-biotin-peroxidase method. Reaction products were developed using 3', 5'-diaminobenzidine (Dako, Glostrup, Denmark) as a substrate for peroxidase. Sections were counterstained with Mayer's hematoxylin. All of the washes were performed in phosphate-buffered saline (pH 7.4). Staining was considered as positive for BCL10 or NF-B when the protein was detected in more than 10% of tumor cells with nuclear staining. A semiquantitative method was used to determine the level of expression of RelA. Reactive spleen and lymph node tissue sections were used as controls.

For double-immunolabeling studies, fluorescein isothiocyanate–labeled donkey antigoat immunoglobulin G (IgG) or rhodamine-labeled goat antirabbit IgG was incubated as a secondary antibody for 60 minutes at room temperature in the dark. The sections were further evaluated under a confocal laser scanning microscope (model TC-SP; Leica, Heidelberg, Germany) equipped with argon and argon-krypton laser sources.

Multiplex Reverse Transcriptase Polymerase Chain Reaction for the API2-MALT1 Fusion Transcript
Given that t(11;18)(q21;q21), which results in chimeric API2-MALT1 fusion protein, is not only the most important predictor of H pylori–independent status but also is closely associated with BCL10 nuclear expression in low-grade gastric MALT lymphoma, we examined our patients for the presence of this genetic aberration. Eight patients with low-grade gastric MALT lymphoma were also studied for comparison. Total cellular RNA was extracted from formalin-fixed, paraffin-embedded tissues using an Ambion RNA isolation kit (AMS Biotechnology, Oxon, United Kingdom). Briefly, two to three pieces of 10-µm paraffin sections were deparaffinized in xylene. The tissue was digested with proteinase K (Roche Diagnostics, Mannheim, Germany) for 1 hour at 45°C and solubilized in a guanidinium-based buffer. RNA extracted from the paraffin-embedded tissues was analyzed for API2-MALT1 fusion using multiplex reverse transcriptase polymerase chain reaction (RT-PCR), as described previously.¹⁷ RNA was subjected to first-round multiplex one-tube RT-PCR, then to second-round nested multiplex PCRs (three parallel: second PCR-A, second PCR-B, and second PCR-C). The final PCR products were run on 3% agarose gel and stained with ethidium bromide. The band size ranged from 80 to 179 bp. PCR of low-grade gastric MALT lymphoma samples known to possess API2-MALT1 fusion was used as a positive control. Beta-actin (190 bp) was amplified in parallel as an internal control. Where indicated, PCR products of the API2-MALT1 transcript were either directly sequenced or cloned into a vector (TOPO TA Cloning Kit; Invitrogen, Paisely, United Kingdom) and sequenced with vector primers using dye-labeled terminators (BigDye Terminators; Applied Biosystems, Foster City, CA) and analyzed on a DNA sequencer (model 310; Applied Biosystems).

Statistical Analysis
Fisher's exact test and the ² test were used to analyze the correlation between the H pylori–independent status of MALT lymphomas with BCL10 and NF-B expression patterns.

	RESULTS

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Patients and Tumor Response
There were 14 patients with H pylori–dependent and eight patients with H pylori–independent tumors. The clinicopathologic features of these patients are summarized in Table 1. The median duration between H pylori eradication and complete histologic remission was 5.6 months (range, 1.5 to 17.7 months). At a median follow-up of 57.5 months (range, 8.6 to 81.8 months), all 14 patients who had achieved complete histologic remission after eradication of H pylori were alive and free of lymphoma. One patient (patient 22) had residual high-grade lymphoma cells, whereas low-grade lymphoma cells were completely resolved. In contrast, another patient (patient 3) had residual low-grade components with complete remission of the high-grade components. Six patients whose tumors grossly increased in size or had microscopic findings of increased large-cell fraction and one patient whose tumor remained grossly stable at the first follow-up endoscopic examination were immediately referred for systemic chemotherapy.

View this table: [in this window] [in a new window]   Table 1. Clinicopathologic Features of the Patients and Tumor Expression of BCL-10, NF-B, and API2-MALT1

Correlation of Nuclear Expression of BCL10 and NF-B With Tumor Response to H pylori Eradication

View larger version (169K): [in this window] [in a new window]   Fig 1. BCL10 and nuclear factor kappa B (NF-B) protein expression in high-grade gastric mucosa-associated lymphoid tissue lymphoma. (A, B, C) BCL10; (D, E, F) NF-B; (A, D) nuclear BCL10 and NF-B expression in Helicobacter pylori–independent patients; (B, E) cytoplasmic BCL10 and NF-B expression in H pylori–dependent patients; (C, F) cytoplasmic BCL10 expression and nuclear NF-B expression in two H pylori–dependent patients. Original magnification x400.

View larger version (59K): [in this window] [in a new window]   Fig 2. Colocalization of BCL10 and nuclear factor kappa B (NF-B). Nuclear expression of BCL10 (A), NF-B (B), and co-expression of BCL10 and NF-B (C) in the tumor cells of Helicobacter pylori–independent patients analyzed by confocal microscopy. Original magnification x400.

View larger version (30K): [in this window] [in a new window]   Fig 3. Detection of API2-MALT1 fusion transcript by multiplex reverse transcriptase polymerase chain reaction (RT-PCR). (B) Second PCR-B. (C) Second PCR-C; lane N, negative control (normal lymph node); lane 1, Helicobacter pylori–independent high-grade gastric MALT lymphoma (positive); lanes 2 to 5, H pylori–independent low-grade gastric MALT lymphoma (positive); lanes 6 to 9, H pylori–independent high-grade gastric MALT lymphoma (negative). Beta-actin mRNA is amplified in all cases.

	DISCUSSION

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BCL10 protein is expressed in the cytoplasm of normal lymphoid tissues, whereas the protein partially localizes to the nucleus in a fraction of MALT lymphoma with or without t(1;14)(p22;q32).¹⁹ It has been shown that t(1;14)(p22;q32) or other BCL10 gene mutation is absent in the majority of MALT lymphoma with nuclear expression of BCL10.^24-26 Moreover, two recent studies clearly demonstrated that genomic BCL10 mutations are not responsible for the nuclear localization of BCL10 protein in gastric MALT lymphoma cells.^27,28 However, several researchers have shown that nuclear BCL10 expression is highly correlated with the presence of API2-MALT1 fusion in low-grade gastric MALT lymphomas.²⁰ In addition, nuclear expression of BCL10 in low-grade gastric MALT lymphoma is closely associated with advanced-stage diseases, particularly those invading beyond the serosa.²⁰ Given that t(11;18)(q21;q21) is rarely found in high-grade gastric MALT lymphoma, the mechanisms and biologic significance of the aberrant nuclear expression of BCL10 in these tumors are intriguing. In our study, we found that BCL10 nuclear translocation seems to be a major independent event that predicts H pylori independence of high-grade gastric MALT lymphoma. We confirmed that BCL10 nuclear translocation was independent of t(11;18)(q21;q21) in the majority of patients with high-grade gastric MALT lymphoma. Nuclear expression of BCL10 may also be detected in some low-grade gastric MALT lymphomas without t(11;18)(q21;q21).^29-31 These findings suggest that the direct interaction between BCL10 and API2-MALT1 fusion protein may not occur in most MALT lymphomas. Additional investigation of the molecular interaction and biologic consequences of nuclear translocation of BCL10 in gastric MALT lymphoma is needed.

BCL10 is an intracellular protein that positively regulates lymphocyte proliferation by linking antigen receptor stimulation to constitutively activate NF-B signaling.^21,32 Because NF-B is known to mediate cell survival and antiapoptotic signals, it has been speculated that upregulation of NF-B may contribute to the malignant transformation of H pylori–independent growth of MALT lymphomas. In normal lymphoid cells, NF-B was weakly expressed in the cytoplasm.²⁸ In contrast, our results showed that NF-B was strongly expressed in the cytoplasm and/or nucleus in a substantial portion of high-grade gastric MALT lymphoma cells. Furthermore, the nuclear expression of NF-B was closely associated with the aberrant nuclear expression of BCL10, comparable to the findings of a recent study by Ohshima et al.²⁸ Interestingly, the nuclear expression of NF-B was also closely associated with the H pylori–independent status of high-grade gastric MALT lymphomas.

In this series, API2-MALT1 was detected in only one patient with H pylori–independent high-grade gastric MALT lymphoma. This patient had residual low-grade components with complete remission of the high-grade counterpart. Although high-grade MALT lymphoma is generally believed to be transformed from its low-grade counterpart,³³ recent reports suggest that the high-grade components may evolve independently from coexisting low-grade MALT lymphoma.^34,35 We suspect that this patient may have had coexisting H pylori–dependent API2-MALT1–negative high-grade MALT lymphomas and H pylori–independent API2-MALT1–positive low-grade MALT lymphomas originating from two different clones. Although we failed to examine API2-MALT1 separately in these two different components of lymphomas, we were able to demonstrate that low-grade and high-grade lymphoma of this patient displayed different pattern of rearranged IgH genes, indicating different clonal origin of the low-grade and high-grade lymphomas in this patient. Our results suggest that high-grade gastric MALT lymphoma may not necessarily evolve by transformation of a low-grade MALT lymphoma.

In conclusion, a substantial portion of early-stage, high-grade gastric MALT lymphomas remains H pylori dependent and can potentially be cured by H pylori eradication. Detection of nuclear expression of either BCL10 or NF-B can identify H pylori–independent patients and help select patients for either cytotoxic or H pylori eradication therapy.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by research grants NSC91-3112-B-002-009 from the National Science Council, NHRI-91A1-CANT-1 from the National Health Research Institutes, and NTUH 93-N012 from National Taiwan University Hospital, Taiwan.

S.-H.K. and L.-T.C. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted October 10, 2003; accepted June 1, 2004.

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