＊: corresponding author Part I.
Expression of nuclear BCL10 is highly correlated with the expression of nuclear NF-B and is predictive of Helicobacter pylori-independent status in early-stage high-grade gastric MALT lymphoma.
Sung-Hsin Kuo, Li-Tzong Chen, Pei-Yen Yeh, Chi-Long Chen, Ih-Jen Su , Jaw-Town Lin2, and Ann-Lii Cheng＊. Eur J Cancer 2002: 38, Suppl 7; S161 (abstr. 540) poster presentation.
Manuscripts have been submitted for publication.
Abstract content:
Background:
We have recently demonstrated that around 60% of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas are rendered durable tumor remission by eradication of H pylori (J Clin Oncol 2001; 19:4245 -51).
However, the histologic and molecular features that help predict the H pylori -dependent state of these tumors remains elusive. The intracellular signal protein BCL10 was identified by its direct involvement in t(1;14)(p22;q32) of MALT lymphomas, and is a putative regulator of antigen-receptor-mediated NF-B activation. Upregulation of BCL10 may trigger a constitutive NF-B signal from the antigen receptor, and therefore may contribute to antigen-independent growth and progression of gastric MALT lymphoma.
Purpose:
The present study sought to investigate the correlation between nuclear BCL10 expression and nuclear NF-B expression, and the correlation of their expression with the tumor resistance to H pylori eradication therapy in patients with stage IE
high-grade gastric MALT lymphoma.
Materials and Methods:
Lymphoma biopsies of all patients, who had participated in a prospective study of H pylori-eradication for stage IE high-grade gastric MALT lymphoma, were collected.
The H pylori-dependent status was verified by the results of the prospective clinical trials. There were 16 patients with H pylori-dependent, and 7 patients with H pylori-independent high-grade gastric MALT lymphoma. The expression of BCL10 and NF-B in pre-treatment paraffin-embedded lymphoma tissues was determined by immunohistochemistry with anti- BCL10 antibody (polyclonal; 1:10; Santa Cruz Biotechnology) and anti-NF-B RelA (p65; 1:150; Santa Cruz Biotechnology). A semi-quantitative method was used to determine the level of expression of RelA.
Reactive spleen and lymph nodes tissue sections were used as the control. The co-expression of nuclear BCL10 and NF-B activity was further analyzed by a confocal immunofluorescence microscopy.
Results:
The aberrant nuclear BCL10 expression was detected in six (86%) of 7 H pylori-independent high-grade gastric MALT lymphomas but none in 13 H
pylori-dependent cases (P<0.001). All six patients with nuclear BCL10 expression had co-expression of nuclear NF-B, while only two of 16 patients without nuclear BCL10 expression did so (P=0.002). Interestingly, the latter two patients were found to have tumor invasion of the gastric muscularis propria. There was a significant correlation between nuclear expression of BCL10 and NF-B activation (P<0.001). Furthermore, the nuclear co-localization of RelA and BCL10 was confirmed by confocal immunofluorescence microscopy. The frequency of nuclear translocation of RelA was also significantly higher in H pylori-independent tumors than those H pylori-dependent tumors (6 of 7=86% versus 2 of 16=12.5%, P=0.002).
Conclusion:
The results of this study suggest that nuclear BCL10 expression is closely
associated with the nuclear NF-B expression and support the hypothesis that nuclear BCL10 may activate NF-B. Detection of the nuclear expression of either BCL10 or NF-B is highly useful in the prediction of H pylori-dependent state of early-stage high-grade gastric MALT lymphoma. (This work was supported by grants from NSC91-3112-B-002-009, NHRI-91A1-CANT-1 and NTUH 91-N007)
Part II.
Increased Infiltration of NK Cells in Tumor Tissues and Increased Expression of CD86 on lymphoma cells are Associated with Helicobacter pylori-dependent state of High-Grade Gastric MALToma
Sung-Hsin Kuo 1,4, Li-Tzong Chen5, Hui-Chen Hsu1,4, Pei-Yen Yeh1,4, Chi-Long Chen6, Ih-Jen Su 3, Jaw-Town Lin 2, and Ann-Lii Cheng1, 2,4, *
1Departments of Oncology, 2Internal Medicine, and 3Pathology, National Taiwan University Hospital; 4Cancer Research Center, National Taiwan University College of Medicine; 5Division of Cancer Research, National Health Research Institutes;
6Department of Pathology, China Medical College Hospital
Proc Am Assoc Cancer Research 2003, abstract:2329, poster presentation
Abstract content:
Background:
We have recently demonstrated that around 60% of early-stage high-grade gastric mucosa-associated lymphoid tissue lymphoma (MALToma) remains Helicobacter pylori (HP)-dependent and can be cured by HP eradication (J Clin Oncol 2001;
19:4245-51). However, the histologic and molecular features that help predict the HP -dependent state of these tumors remains elusive. Proliferation of neoplastic B-cells of MALToma depends at least partly on the stimulation of HP-specific intratumoral T-cells. CD56 (+) nature killer (NK) cells are thought to limit the
autoreactive T cell-dependent B cell proliferation. Further, the presence of co-stimulatory marker CD86 (B7.2) on lymphoma cells may promote functional T-cell-mediated neoplastic B cell proliferation.
Purpose:
To investigate whether the infiltration of NK cells in tumor tissues and the
expression of CD86 on lymphoma cells may be associated with HP-dependent state of stage IE high-grade gastric MALToma.
Materials and Methods:
Lymphoma biopsies of all patients, who had participated in a prospective study of HP -eradication for stage IE high-grade gastric MALT lymphoma, were collected.
There were 14 patients with HP -dependent, and 6 patients with HP -independent high-grade gastric MALToma. The infiltration of CD56 (+) NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry with anti-CD56 antibody (NCL-CD56-1B6,
1:100, Novacastra) and anti-CD86 antibody (AF-141-NA, R and D Systems,
Abingdon, UK). A minimum of 1000 cells (normal and neoplastic) were counted for each single determination and reported as the percentage of CD56 (+) NK cells in total mononuclear cells (as described by Guidoboni et al, Am J Pathol
1999;155:823-29). Staining was considered as positive for CD86 when the protein was detected in more than 10% of tumor cells.
Results:
HP -dependent high-grade gastric MALToma contained significantly higher numbers of CD56 (+) NK cells than HP -independent cases (2.7 ±1.2% versus 0.80±0.70%; p=0.005, nonparametric Mann- Whitney U test ). The expression of CD86 was detected in 9 (64%) of 14 HP-dependent high-grade gastric MALTomas but in none of 6 HP -independent cases (p=0.010).
Conclusion:
Increased infiltration of NK cells in tumor tissues and the expression of co-stimulatory marker CD86 on lymphoma cells are associated with HP-dependent state of early-stage high-grade gastric MALToma. Our data support the hypotheses that increased infiltration of NK cells may suppress the growth of HP- related
autoreactive and neoplastic B lymphoid cells of the stomach, and loss of co-stimulatory markers may preclude functional tumor-B-cell/reactive T-cell interaction and therefore contribute to the transition into the antigen-independent status of high-grade gastric MALToma. (This work was supported by grants from NSC91-3112-B-002-009, NHRI-91A1-CANT-1 and NTUH 91-N007)
Part III.
BCL-2 Expression is Associated with Poor Response to Chemotherapy and Poor Prognosis of Primary High-Grade Gastric Lymphoma
Sung-Hsin Kuo 1,3, Chiun Hsu1,3, Li-Tzong Chen 4, Han-Ting Liu1, Chi-Long Chen5, Chang-Ming Jan6, and Ann-Lii Cheng1, 2,3,*
1Departments of Oncology, and 2Internal Medicine, National Taiwan University Hospital; 3Cancer Research Center, National Taiwan University College of Medicine;
4Division of Cancer Research, National Health Research Institutes; 5Department of Pathology, China Medical College Hospital; Department of Pathology, 6Kaohsiung Medical College Hospital
Proc Am Soc Clin Oncol 2003, abstract:2320, poster discussion
Abstract content:
Background:
Recent data suggest that systemic chemotherapy alone is a highly effective treatment for localized primary large cell lymphoma of stomach. The oncoprotein BCL-2 is a potent suppressor of apoptotic cell death and represses cell death triggered by a variety of anticancer agents, and contributes to chemoresistance of nodal
lymphomas and several other malignancies.
Purpose:
The present study sought to clarify the role of BCL-2 protein expression in predicting chemosensitivity and prognosis of patients with primary high-grade gastric lymphoma.
Materials and methods:
We reviewed the pathologic materials of all patients who had a diagnosis of primary large cell lymphoma of the stomach and who had been treated primarily by systemic chemotherapy in our institutions between January 1, 1988 through
December 31,1999. The expression of BCL-2 in pre-treatment paraffin-embedded lymphoma tissues was determined by immunohistochemistry with anti-BCL-2 antibody (1:25; Dako, Glostrup,Denmark). Staining was considered as positive for BCL-2 when the protein was detected in more than 10% of tumor cells. Tumors were considered chemosensitive if complete remission was documented after chemotherapy.
Results:
All patients received standard systemic chemotherapy including
anthracyclines or anthracenedione, mostly CHOP (40 cases) and CEpiOP (3 cases).
BCL-2 was expressed in 10 (71.4%) of 14 chemoresistant patients but in only 7(21.9%) of 32 chemosensitive patients (P=0.002). The 3-year failure-free survival for tumors with versus without BCL-2 expression was 76% versus 29% (P<0.001, by log-rank test). The median survival time was 16 months in the 17 patients with BCL-2 expression, but it had not yet been reached in the 29 patients without BCL-2
expression. The 3-year overall survival rate was 35 % for patients with BCL-2 expression and 82% for those without (P<0.001, by log-rank test).
Conclusion:
BCL-2 expression of tumor cells is associated with a poor response to systemic chemotherapy and a poor survival of the patients with primary high-grade gastric lymphoma. This work was supported by grants from NSC91-3112-B-002-009, NHRI-91A1-CANT-1 and NTUH 91-N007.