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Ongoing Monoclonal B-Cell Proliferation Is Not Common in Gastric B-Cell Lymphoma After Combined Radiochemotherapy

From the Departments of Internal Medicine, Hematology, Oncology, and Immunology, Hospital of the Philipps-University, Marburg; Department of Hematology, St Georg Hospital, Hamburg; Institute for Hematopathology, University of Kiel, Kiel; Institute for Pathology, University of Würzburg, Würzburg; and Institute for Pathology, Hospital Bayreuth, Bayreuth, Germany

Address reprint requests to Andreas Neubauer, MD, Hospital of Philipps University, Department of Hematology, Oncology and Immunology, Baldinger Straße, 35033 Marburg, Germany; e-mail: neubauer{at}mailer.uni-marburg.de

	ABSTRACT

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PURPOSE: Gastric marginal-zone B-cell lymphoma (MZBCL) of the mucosa-associated lymphoid tissue (MALT) is associated with chronic Helicobacter pylori gastritis. Stable complete remission (CR) can be induced by H pylori eradication. Whether this is paralleled by cure of the lymphoma remains unclear. Persisting monoclonal bands for immunoglobulin heavy chain variable region (V_H) representing the lymphoma clone have been described in up to 50% of patients in CR. This retrospective study investigated whether this phenomenon also occurs after radiochemotherapy.

PATIENTS AND METHODS: Biopsy samples of 20 patients receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone and irradiation were analyzed before and after therapy. Study patients had Ann Arbor stage I/II primary gastric cancer, including four cases of MZBCL of MALT type, 12 cases of diffuse large-cell lymphomas (DLCL), and four cases of mixed MALT type/DLCL. Polymerase chain reaction (PCR) for V_H rearrangement was performed. Monoclonal PCR products were cloned and sequenced.

RESULTS: Fourteen of 20 patients had a monoclonal or oligoclonal band distribution at diagnosis converted into polyclonal pattern after radiochemotherapy. Of the remaining six patients, two were lost to follow-up. One patient did not respond and died of progressive disease. PCR in this patient showed persistent B-cell clonality. In three patients, the initial PCR showed a polyclonal pattern and thus could not be evaluated during follow-up.

CONCLUSION: In contrast with H pylori eradication alone, radiochemotherapy results in clearing of monoclonal cells during follow-up. This may result in better elimination of residual lymphoma cells. Further study is needed to determine whether this translates into lower risk of relapse.

	INTRODUCTION

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Lymphomas arising from the mucosa-associated lymphoid tissue (MALT) have been regarded as a special entity, both clinically and biologically.¹ They are typically found in organs that are primarily free of lymphoid tissue, like the salivary glands or the stomach. The acquisition of lymphoid tissue in these organs is caused by an infection or an autoimmune reaction and is a prerequisite for MALT lymphoma development. The strong association between gastric marginal-zone B-cell lymphomas (MZBCL) of MALT type and a chronic infection with Helicobacter pylori has been recognized.² The lymphoma cell-specific immunoglobulin receptor is directed against auto-antigens of the gastric mucosa.³ Hussel et al⁴ showed convincingly that the proliferation of MALT lymphoma B cells in vitro depends on H pylori–specific T cells. Thus the proliferation of MALT lymphoma cells does not seem to be autonomous. On the contrary, the stimulation of a possibly autoimmune clonal B cell on the background of reactive inflammatory infiltration can be responsible for the tumor initiation. The hypothesis of a still controlled although malignant behavior of MALT lymphomas is supported by the clinical course of early low-grade MALT lymphoma. In keeping with this observation, Wotherspoon et al⁵ reported complete regressions of low-grade gastric MALT lymphomas after H pylori eradication therapy. These data were corroborated in larger cohorts by others.^6-10 In longer follow-up studies, remissions were reported to be stable.^10-12

The analysis of the rearranged variable region (V_H) of the immunoglobulin heavy chain gene by means of polymerase chain reaction (PCR) can be used as a marker for the monoclonal proliferation of B-lymphoma cells.¹³ Furthermore, the sequence analysis of the characteristic immunoglobulin heavy chain gives insight into the lymphoma biology. The finding of somatic hypermutations indicates the postgerminal center origin of low-grade MALT lymphoma cells.^14,15 Concomitant to the clinical evaluation after H pylori eradication in low-grade gastric MALT lymphoma, several study groups carried out analysis of the immunoglobulin heavy chain during follow-up. In up to 50% of patients, a persisting monoclonal PCR band was observed, although a histologic complete remission was diagnosed.^9-11,16 Whether this observation points to a higher relapse risk because of quiescent lymphoma cells in the gastric mucosa remains unclear. Possibly the cure of H pylori infection induces remission of early low-grade MALT lymphomas by withdrawing the stimulating antigen but does not lead to a complete eradication of the lymphoma cells in these PCR-positive patients. In addition, sequence analysis of samples with persisting monoclonal PCR bands showed ongoing somatic hypermutations during follow-up.¹² This was interpreted as a sign of antigen stimulation and antigen selection after cure of H pylori infection (ie, that the proliferation of lymphoma cells seems to be antigen-dependent).^12,15

In this study, we examined whether the persistence of monoclonal bands is a common finding after treatment of gastric lymphomas. We therefore analyzed samples of patients with gastric B-cell non-Hodgkin's lymphoma (NHL) and who were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–based chemotherapy and irradiation.¹⁷

	PATIENTS AND METHODS

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Patients
Biopsy specimens from 20 retrospective patients suffering from gastric B-cell lymphoma were investigated. Diagnosis was made by one of the reference pathologists (R.P., M.S., H.K.M.-H.) by standard procedures as described previously.¹⁶

In four patients, an MZBCL of MALT type was diagnosed. Twelve patients suffered from a diffuse large B-cell lymphoma (DLCL). An MZBCL with portions of a DLCL was diagnosed in four patients. Median patient age was 58 years (range, 28 to 77 years). A summary of patient characteristics is included in Table 1.

DNA Extraction
Formalin-fixed paraffin-embedded tissue was available for all biopsy samples. Thirty- to 100-µm sections were treated with xylene and ethanol. DNA was extracted from the dried pellet using a commercially available kit as recommended by the manufacturer (QiaAmp DNA Tissue Kit; Qiagen, Hilden, Germany).

PCR for the Rearranged Immunoglobulin Heavy Chain V_H and Genescan Analysis
The B-cell clonality in the gastric biopsy samples was investigated using a seminested PCR protocol for the V_H of the rearranged immunoglobulin heavy chain gene as described previously.¹⁸ Briefly, the oligonucleotide primers were directed against the framework 2 region (FR2) and the 3' part of the CDRIII coding JH region. The sequence of the oligonucleotide primers for the seminested PCR were as follows: FR2 (sense) 5'-Tgg (A/G)TC Cg(A/C) CAg (C/G)C(C/T) (C/T)C(A/C/G/T) gg-3', LJH (antisense, first round) 5'-TgA ggA gAC ggT gAC C-3', VLJH (antisense, second round) 5'-gTg ACC Agg gT(A/C/G/T) CCT Tgg CCC CAg-3'. Cross contamination was avoided by strictly separating pre- and post-PCR sections and by using aerosol resistant filter tips. The final reaction volume of 50 µL of the first-round PCR reaction mix contained 200 µmol/L of deoxynuleotide-triphosphates, 0.001% gelatin, 50 mmoles/L of KCl, 1.5 mmoles/L of MgCl₂, 10 mmoles/L of Tris-HCl, 500 nmoles/L of Fr2a and LJH primers, and 100 ng of genomic DNA. To perform a hot start, 1 U of Taq polymerase (Perkin Elmer Cetus; Foster City, CA) was added to the paraffin-oil covered reaction mixture after incubation at 94°C for 5 minutes. Twenty-nine cycles, with 94°C for 60 seconds, 55°C for 60 seconds, and 72°C for 60 seconds, were carried out by means of a PE480 thermal cycler (Perkin Elmer), whereby in the first cycle, the denaturation took 180 seconds. The reaction was completed by a final extension step of 94°C for 60 seconds and 60°C for 10 minutes. One microliter of 1:100 diluted preamplified PCR product was used for the seminested PCR with the same reaction conditions as described above. The VLJH primer was used instead of the LJH primer. The Fr2a primer of the second reaction was stained with FAM fluorescence dye. The analysis of the PCR amplification was carried out on an automated DNA sequencer ABI 377 (Perkin Elmer Cetus). Therefore, the PCR products were diluted in gel-loading buffer consisting of Dextran blue/EDTA and deionized formamid as well as a ROX stained size standard and denaturated at 90°C for 2 minutes. After direct storage on ice, 1.5 µL of each sample was loaded on a 5% denaturating polyacrylamide gel, and the electrophoresis was carried out for 2 hours and 25 minutes. The electrophoresis results were analyzed using the Genescan software (Applied Biosystems, Foster City, CA). One sharp peak in the Genescan analysis led to the assumption of a monoclonal B-cell population in the sample. Bi- or triclonal populations showed two or three peaks, respectively. A pattern of more than three but isolated peaks was assumed to result from an oligoclonal B-cell population. A band distribution resulting in a curve similar to a cockscomb was designated as polyclonal (Fig 1). The integrity of each DNA sample was controlled by PCR for interferon beta as reference gene as described previously.¹⁹

View larger version (15K): [in this window] [in a new window]   Fig 1. Molecular genetic follow-up in a patient with a diffuse large B-cell lymphoma. The Genescan polymerase chain reaction for the rearranged immunoglobulin heavy chain variable region of patient 15 showed a biclonal band distribution at diagnosis. During follow-up, oligoclonal pattern switched to a polyclonal distribution.

Sequencing
The Sequencing analysis was carried out as described previously.¹² Briefly, DNA sequencing of the plasmids was performed on a 377 automatic DNA sequencer (Perkin Elmer) using Taq FS dye terminator Cycle Sequencing Kit (Perkin Elmer) as recommended by the manufacturer. For forward and backward sequencing, T7 and M13 reverse primers were used. Eight to 10 clones were sequenced for each patient sample. The sequences were compared with published germline sequences for the rearranged immunoglobulin heavy chain V_H.^20,21 Alignments were made using the Lasergene software for Windows (DNASTAR, Boston, MA).

	RESULTS

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Clinical Data
Nineteen of 20 patients received the scheduled CHOP-based chemotherapy. In one case, five cycles of CHOP were followed by two cycles of chemotherapy with cyclophosphamide, epirubicin, vinblastine, and prednisone.

Chemotherapy was combined with irradiation in 18 patients. One patient (patient 9) refused radiation therapy. Patient 19 experienced relapse at the beginning of irradiation therapy and thus did not receive irradiation. Radiation was discontinued; the patient left the country and was lost to follow-up. Although data were obtained retrospectively, we carried out an intent-to-treat analysis on all patients and evaluated all patients further.

Eighteen of 20 patients achieved a complete remission (CR). Patient 5 achieved a partial remission and was lost to follow-up. Patient 20 did not respond to treatment and died of general tumor progression.

Two of 18 patients experienced relapse. In addition to patient 19 mentioned above, one patient (patient 14) experienced relapse 2 years after obtaining CR with a lymphoma in the ileum and involvement of local lymph nodes. The stomach was not investigated at this time. After surgery and 13 additional cycles of monotherapy with cyclophosphamide, no lymphoma activity has been detectable for 15 months, and the patient is in ongoing remission.

One patient (patient 15) died in CR because of metabolic acidosis with no sign of lymphoma relapse. Table 1 summarizes the obtained data.

PCR for the Rearranged Immunoglobulin Heavy Chain V_H
We and others have previously reported that after cure of H pylori infection, monoclonal B cells are detectable on PCR analysis in a significant percentage of patients.^9-11,16 To compare the retrospective molecular data of the patients treated in this study with these previous data, we used the PCR technique as described, but with fluorescence-labeled primers for Genescan analysis.¹⁸ In addition, the PCR samples were sequenced for more detailed analysis (see following section).

The PCR technique for the rearranged immunoglobulin heavy chain V_H may reveal a polyclonal pattern (Fig 1, lane 8), indicating a polyclonal B-cell infiltration, an oligoclonal B-cell proliferation (Fig 1, lane 5), or the presence of bi- or monoclonal B cells (Fig 1, lane 1).

At diagnosis, the results were as follows: in 10 patients, a monoclonal band was detected. In one patient, a biclonal distribution of PCR bands was detected. In six patients, an oligoclonal pattern was shown. In three patients (patient nos. 3, 4, and 6) polyclonal PCR bands were determined in the Genescan analysis at diagnosis (Table 2).

View larger version (25K): [in this window] [in a new window]   Fig 2. Schematic illustration of the Genescan analysis in the patients at diagnosis and during follow-up at various time points. Patient 9 did not receive radiation therapy and thus is not shown. In patients18 and 19, only one sample at diagnosis was available, and thus the data are not presented here as well.

In the subgroup of eight patients with MZBCL (n = 4) and MZBCL with fractions of DLCL (n = 4), no patients revealed persisting clonality during a median follow-up of 48 months (range, 14 to 68 months).

V(D)J Sequences at Diagnosis
To prove the clonality of the obtained PCR results, we used DNA sequence analysis for the rearranged immunoglobulin heavy chain allele. Samples that showed a monoclonal or biclonal PCR result in the Genescan analysis were investigated by DNA sequence analysis. Sequencing analysis was performed in 10 patients at diagnosis. In all samples, the investigated clones were classified to known V_H alleles.¹⁸ In two of these samples (patient Nos. 15 and 17), two independent clones were determined. The distribution of the detected V_H alleles is shown in detail in Table 2. For one clone of patient 15, a 100% homology to the V4-59 allele was observed. In all other sequences, somatic hypermutations were detected (not shown).

Sequence Analysis During Follow-Up After Treatment
Although a polyclonal distribution of the PCR bands was detected during follow-up, the samples of five patients showed a monoclonal PCR band in two to three consecutive samples (median, two samples) at the beginning of follow-up (Fig 2). For four of these samples, sequencing analyses were performed during follow-up. In three patients, the same V_H allele was determined as in the diagnosis sample. The identical somatic hypermutations were detected in these samples as initially described. No additional ongoing mutations were observed (not shown). However, in one patient, completely different alleles were detected in one follow-up sample. As mentioned above, the sequence analysis for the last follow-up sample of patient 7 revealed a polyclonal distribution of V_H alleles, although the Genescan PCR showed one monoclonal peak.

	DISCUSSION

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Many authors believe that cure of H pylori infection has been established as first-line therapy for early gastric MZBCL of MALT type stage I E1.^{5,7,8,10,11,22} Nevertheless, we and others have reported the persistence of a monoclonal PCR band for the rearranged variable region of the immunoglobulin heavy chain gene during follow-up.^9-12,16 This observation may point to resting lymphoma cells and a potential higher relapse risk. The present study was performed to investigate whether the finding of persisting monoclonal PCR bands is a common feature after lymphoma regression of gastric lymphomas induced by radiochemotherapy.

We investigated the molecular follow-up in patients with gastric B-cell NHL at Ann Arbor stage I/II after radiochemotherapy by means of a PCR assay for the rearranged immunoglobulin heavy chain V_H over a median follow-up time of 37 months (range, 5 to 69 months). Only one patient showed a persistence of clonal PCR bands, but this patient did not achieve CR and died because of disease progression. These results suggest that radiochemotherapy leads to a complete eradication of lymphoma cells in gastric lymphoma. In contrast, H pylori eradication therapy induces a minimal residual disease in approximately 45% to 50% of patients, possibly as a result of immunoregulation of the disease.^9,10,16 Whether this is associated with a higher risk of relapse still remains unclear. Although MALT lymphoma cells show rather slow progression, relapses were observed after H pylori eradication. Thus lifelong endoscopic follow-up is indicated to detect early relapses, which could be treated with salvage therapy either via conventional radiotherapy^23-25 or via therapy with anti-CD20 monoclonal antibody.²⁶

In the present retrospective investigation, not only gastric MALT lymphoma patients were evaluated, but also patients with diffuse large B-cell lymphomas and patients with composite lymphomas consisting of low-grade MALT lymphomas and large-cell fractions. Thus all patients in this study and the patients investigated for minimal residual disease in other studies^9-11,16 are not completely comparable. However, in the present study, four patients suffered from gastric MALT lymphomas and another four from low-grade MALT lymphomas with large-cell fractions. None of these eight patients revealed persisting clonality during follow-up. Because these patients are comparable to the patients analyzed after cure of H pylori infection,^9-11,16 we believe the data suggest that chemoradiotherapy induces an improved clearing of residual gastric lymphoma cells as compared with H pylori eradication alone.

Yahalom et al²⁷ recently reported a series of nine patients with stage I/IIE MALT lymphoma receiving radiotherapy alone and showed, in seven of nine cases, an ongoing PCR monoclonality at a median follow-up time of 28 months. Because clone-specific primers were used for this PCR analysis, these results are not directly comparable to ours. Nevertheless, the patients we investigated received not only local therapy (ie, radiotherapy) but also chemotherapy. It seems possible that the systemic effect of chemotherapy leads to eradication of distantly residing lymphoma cells, which therefore are no longer contributing to a repopulating of the gastric mucosa by homing. As shown by Du et al,²⁸ gastric MALT lymphoma cells preferentially disseminate to the marginal zone in case of splenic involvement, indicating their normal homing properties.

In our study sequence, analyses were performed for the monoclonal immunoglobulin heavy chain fragment before therapy and during follow-up. The consecutive samples of one patient showed V_H alleles that were completely unrelated to the initially detected allele. This may be caused by a heterogeneous distribution of two or even more lymphoma clones within one tumor, which were detected when the follow-up biopsy samples were taken from different areas. The follow-up samples in three patients showed identical allele-sequences. No further ongoing mutations were observed. The occurrence of somatic hypermutations may be interpreted as a marker for antigen selection, because mutations in the immunoglobulin receptor gene may lead to a better antigen recognition. Ongoing mutations of the immunoglobulin receptor gene were described in samples of patients with persisting monoclonal PCR bands after H pylori eradication therapy.^12,15 The absence of ongoing mutations in patient's samples after chemotherapy and irradiation may point to a less important influence of immunoregulation for the eradication of lymphoma cells after conventional therapy. Whether this is necessarily of benefit for the patients remains unclear at present.

In summary, conservative therapy of gastric lymphomas involving chemotherapy and radiation therapy leads to clearing of monoclonal B cells in all responding patients. This is in contrast to therapy of curing H pylori infection, which frequently shows monoclonal B cells as a sign for ongoing minimal residual disease.^9,10,16

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Deutsche Krebshilfe (grant No. 70-2251, Ne1).

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

	REFERENCES

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

 
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Submitted August 27, 2003; accepted April 29, 2004.

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