Expression of nuclear BCL10 is highly correlated with the expression of nuclear NF-kB and is predictive of helicobacter pylori-dependent status in early-stage high-grade gastric malt lymphoma

AbstractLow-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection. The eradication of H pylori using antibiotics is successful in 60% to 80% of affected patients. In contrast to the previous paradigm, we and other investigators have shown that a certain proportion of patients with H pylori–positive early-stage diffuse large B-cell lymphoma (DLBCL) of the stomach with histological evidence of MALT lymphoma, including high-grade transformed gastric MALT lymphoma and gastric DLBCL(MALT), achieved long-term complete pathological remission (pCR) after first-line H pylori eradication therapy, indicating that the loss of H pylori dependence and high-grade transformation are separate events in the progression of gastric lymphoma. In addition, patients with H pylori–positive gastric DLBCL without histological evidence of MALT (gastric pure DLBCL) may also respond to H pylori eradication therapy. A long-term follow-up study showed that patients who achieved pCR remained lymphoma free. Gastric MALT lymphoma is indirectly influenced by H pylori infection through T-cell stimulation, and recent studies have shown that H pylori–triggering chemokines and their receptors, H pylori–associated epigenetic changes, H pylori–regulated miRNA expression, and tumor infiltration by CD4+CD25+ regulatory T cells contribute to lymphomagenesis of gastric MALT lymphoma. Recent studies have also demonstrated that the translocation of CagA into B lymphocytes inhibits apoptosis through p53 accumulation, BAD phosphorylation, and the up-regulation of Bcl-2 and Bcl-XL expression. In gastric MALT lymphoma, CagA may stimulate lymphomagenesis directly, through the regulation of signal transduction, and intracellular CagA is associated with H pylori dependence. These findings represent a substantial paradigm shift compared with the classical theory of H pylori–reactive T cells contributing indirectly to the development of MALT lymphoma. In conclusion, a wide range of H pylori–related gastric lymphomas have been identified. The use of antibiotics as the sole first-line therapy for early-stage gastric pure DLBCL requires validation in a prospective study. The clinical and biological significance of the CagA oncoprotein in the lymphomagenesis of gastric MALT lymphoma warrants further study.

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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

Journal of Clinical Oncology ◽

10.1200/jco.2004.10.087 ◽

2004 ◽

Vol 22 (17) ◽

pp. 3491-3497 ◽

Cited By ~ 44

Author(s):

Sung-Hsin Kuo ◽

Li-Tzong Chen ◽

Kun-Huei Yeh ◽

Ming-Shiang Wu ◽

Hui-Chen Hsu ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Lymphoid Tissue ◽

Nuclear Factor Kappa B ◽

Early Stage ◽

Gastric Malt Lymphoma ◽

Nuclear Factor ◽

High Grade ◽

Nuclear Expression ◽

H Pylori

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-κB) 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-κB 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-κB, compared with only two of 15 patients without nuclear BCL10 expression (P = .002). As a single variable, the frequency of nuclear expression of NF-κB 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-κB 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.

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