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© 2001 American Society for Clinical Oncology Complete Remission of Primary High-Grade B-Cell Gastric Lymphoma After Cure of Helicobacter pylori InfectionFrom Medical Department I, Technical University of Dresden, Dresden; Medical Department II, Klinikum Aschaffenburg, Aschaffenburg; Medical Department I, Krankenhaus Neuperlach, Munich; Institute for Pathology, University of Würzburg, Würzburg; Medical Department, Virchow Klinikum, Humboldt University, Berlin; Centre for Internal Medicine, University of Marburg, Marburg; and Institute for Pathology, Klinikum Bayreuth, Bayreuth, Germany. Supported in part by Deutsche Krebshilfe (grant no. 70-551-Ne1).Address reprint requests to Andrea Morgner, MD, Medical Department I, Technical University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany; email: andrea.morgner{at}t-online.de
PURPOSE: Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases. The effect that cure of the infection has on the course of a primary high-grade gastric lymphoma is largely uncertain. The aim of this study was to report the effect of cure of H pylori infection exerted in patients with high-grade B-cell gastric lymphoma. PATIENTS AND METHODS: Eight patients (4 males and 4 females; age range, 26 to 85 years) with H pylori infection and high-grade lymphoma received eradication therapy before planned treatment. The effect of H pylori eradication on the course of high-grade lymphoma was assessed by analysis of surgical specimens (n = 2) or endoscopic biopsies (n = 6). RESULTS: H pylori eradication was successful in all patients and led to complete remission of the lymphoma in seven patients. One patient has experienced partial remission. Two patients were referred to surgery, one of whom (stage II1E) had lymph node involvement, and the histologic work-up of the resected stomach revealed residual infiltrates of a low-grade lymphoma, which prompted consolidation chemotherapy. In one patient (initially stage I1E), abdominal lymphoma developed 6 months after eradication therapy, which regressed completely after chemotherapy. In four patients, no further treatment was given. Six patients continue in complete remission (range, 6 to 66 months). CONCLUSION: Primary high-grade B-cell gastric lymphoma in stages IE through IIE1 associated with H pylori may regress completely after successful cure of the infection. Prospective trials are needed to investigate this treatment in larger numbers of patients.
NON-HODGKIN’S LYMPHOMA of mucosa-associated lymphoid tissue (MALT) type is a distinct disease entity with characteristic histologic presentation and clinical behavior.1,2 Recognition of the role of chronic Helicobacter pylori infection in the pathogenesis of gastric MALT lymphoma is increasing rapidly. Initial evidence for a causal relationship between H pylori and the development of gastric MALT lymphoma was provided in 1991, when Wotherspoon et al3 demonstrated the presence of H pylori infection in 92% of patients with primary low-grade gastric MALT lymphoma. Since then, several lines of evidence have indicated that the development and proliferation of B-cell MALT lymphoma depends on the immunologic stimulus provided by the presumptive causative antigen H pylori.4,5 The Revised European-American Lymphoma classification designates MALT lymphomas as marginal zone B-cell lymphomas of MALT type, because these lymphomas arise from B cells found in the marginal zone of organized lymphoid tissue.6 This classification makes a clear distinction between histologic or cytologic grade and clinical aggressiveness. Histologic grade is based on cell morphology. Thus, low-grade lymphomas are composed of small cells with dense nuclear chromatin and a low proliferation fraction; the converse is true for high-grade tumors. In high-grade disease, the lymphoma infiltrate consists of large, transformed blastic cells. Destruction of gastric glands by high-grade cell invasion is rare. As part of their natural history, many lymphoma entities may transform from low- to high-grade disease and can present as either low- or high-grade lesions. In gastric MALT lymphomas, this high-grade transformation is associated with p53 abnormalities, deletions of p16 and t(8;14), or Bcl-6 overexpression.7 Large-cell transformation is clinically significant and represents a significant adverse impact on prognosis. It is important to select patients who may benefit from H pylori eradication as single-modality treatment and patients who need classic anticancer therapy. In 1997, de Jong et al8 analyzed the percentage of diffuse large-cell components as an objective criterion for discrimination of low- and high-grade MALT lymphoma in pretreatment biopsy specimens, with the goal to predict ultimate prognosis and outcome. Within their group of patients, the prevalence of low-grade MALT tumors was 68.4%; the prevalence of high-grade lymphomas with low-grade components was 21.6% (n = 73; secondary high-grade MALT lymphoma). In 31.3% of patients (n = 106), no low-grade components within the high-grade lymphoma were observed, which probably represented diffuse large-cell lymphoma de novo. In the absence of low-grade components, the MALT origin cannot be proven formally in high-grade disease, and the lymphoma cannot be distinguished from diffuse large B-cell lymphoma. It seems likely that at least some high-grade gastric lymphomas, especially in patients younger than 50 years of age, do not originate from high-grade transformation of low-grade MALT lymphomas.9 In recent years and on the basis of many clinical studies, the diagnosis and treatment have been developed for primary gastrointestinal non-Hodgkin’s lymphomas of the stomach, and histologic diagnosis and classification have been improved. New information has been discovered regarding pathogenesis, and the treatment of low-grade gastric MALT lymphomas by the eradication of H pylori has changed the management of this disease dramatically. An analysis of published reports on the results of antibiotic treatment of H pylori-associated low-grade gastric MALT lymphoma reveals a complete remission rate of 78% in 209 patients.10-19 Although regression in single cases of primary high-grade gastric lymphoma after cure of H pylori infection had been reported, this uncommon finding has not attracted attention.20-25 Standard current therapeutic approaches include gastric surgery, chemotherapy, and/or radiotherapy. H pylori eradication therapy in high-grade lymphoma has been performed only to influence possible low-grade components of the tumor and prevent subsequent later low-grade lymphoma relapse.20 To elucidate the relationship between H pylori infection and primary high-grade gastric lymphoma, presumably of the MALT type, we retrospectively analyzed the effect of H pylori eradication therapy in eight patients with primary high-grade gastric lymphoma and H pylori infection.
Patients We studied eight patients (four males and four females) aged 26 to 85 years who had primary high-grade gastric lymphomas that were diagnosed between March 1993 and August 1998. All patients (patient nos. 1 to 8) consulted their physicians with moderate to severe abdominal pain, and two patients experienced massive weight loss (patient nos. 1 and 7). One patient had a history of recurrent gastric ulcers (patient no. 3). The patients underwent endoscopic examinations, and histologic analysis of the biopsy specimens obtained during this examination revealed H pylori infection and high-grade B-cell gastric lymphoma in seven patients (patient nos. 2 to 8). Additional immunohistochemical analysis was performed in three patients (patient nos. 2, 3, and 5). One patient had both low-grade and high-grade MALT lymphoma components in the initial biopsy (patient no. 7). One patient (patient no. 1) was initially diagnosed with a low-grade MALT lymphoma, but histologic analysis of biopsy specimens obtained during a check endoscopy performed 4 weeks after antimicrobial therapy demonstrated additional infiltrates of a high-grade MALT lymphoma and persistent H pylori infection. In all patients, H pylori eradication was performed before planned conventional treatment. These data are summarized in Table 1.
Histology Endoscopic biopsy specimens were placed in neutral buffered formalin. Sections were cut (4 µm thick) and stained with hematoxylin and eosin to diagnose high- and low-grade lymphoma and Warthin-Starry silver stain to reveal H pylori colonization. Diagnostic criteria for low- and/or high-grade MALT lymphoma were assessed in accordance with the criteria proposed by Isaacson and Spencer.26 The diagnostic requirements for a low-grade MALT lymphoma are clear evidence of lymphoid destruction of the glands or the gastric foveolae and replacement of glands by uniform infiltrates comprising centrocyte-like cells. A high-grade MALT lymphoma is composed of sheets of cells resembling centroblasts, and fewer follicles are observed than in the low-grade counterpart. Because the centroblast-like cells rarely infiltrate the glands, clear evidence of lymphoepithelial destruction usually is absent ( Fig 1A).27 Complete lymphoma remission was diagnosed on the basis of an empty lamina propria and only small remnant T-lymphocyte aggregates.
Therapy Eradication treatment consisted of a dual regimen of omeprazole 40 mg tid and amoxicillin 750 mg tid for 14 days28 or a triple regimen of omeprazole 20 mg bid, clarithromycin 250 mg bid, and metronidazole 400 mg bid for 7 days.29 One patient (patient no. 8) was treated initially with pantoprazole 40 mg bid, clarithromycin 500 mg bid, and metronidazole 500 mg bid. Six months thereafter, the patient demonstrated H pylori reinfection and the dual regimen was administered.
Clinical Tumor Staging
With the use of dual therapy in three patients (patient nos. 1, 3, and 4) and triple therapy in five patients (patient nos. 2 and 5 to 8), H pylori eradication was achieved in all patients except patient no. 1. In this patient, a second course of treatment using the triple regimen finally cured the infection. One patient (patient no. 8) experienced H pylori reinfection 6 months after initial treatment. Use of the dual regimen as second line therapy eliminated the infection, but it recurred 2 months later. We are investigating the strain resistance profile before we make a third attempt to cure the infection. The diagnosis of high-grade lymphoma was established on the basis of the histologic work-up in eight patients and additional immunohistochemical examination in three patients (patient nos. 2,3, and 5) that revealed positivity for CD20 and a high proliferation activity, with a Ki-67 index greater than 70% (Fig 1a-c) Histologic analysis was performed by H. M-H. (Institute of Pathology, University of Würzburg) and M.S. (Institute for Pathology, Klinikum Bayreuth, Germany). In six patients, the gastric lymphoma was in an early stage (three patients in I1E and three patients in I2E). Two patients demonstrated an advanced clinical stage (II1E) with enlarged paragastric and pancreatic lymph nodes up to 15 mm. Initial endoscopic findings revealed ulcers or ulcerative lesions in five patients (patient nos. 1, 3, 5, 7, and 8), erythematous mucosa in one patient (patient no. 2), and an atypical mucosa relief in patient nos. 4 and 6. H pylori eradication led to complete lymphoma remission in seven cases, and one patient currently is in partial lymphoma remission. Because the symptoms improved and the lymphoma was in an early stage, patient nos. 1 and 2 received no immediate additional treatment after eradication. Instead, a check endoscopy including endoscopic ultrasound was performed 12 weeks (patient no. 1) and 4 weeks (patient no. 2) after eradication, and this demonstrated complete remission of both high- and low-grade components (patient no. 1). During the 66-month follow-up period of patient no. 1 and the 12-month follow-up period of patient no. 2, no relapse of either low- or high-grade lymphoma or H pylori reinfection was observed. Patient no. 3 was referred to surgery without confirmation that H pylori infection was cured. The diagnosis of complete remission of the high-grade lymphoma was established by histologic analysis 3 months after eradication and after a two-thirds resection of the stomach. No evidence of lymph node involvement was found. This patient has been in continuous complete remission for 12 months with no relapse of the infection or the lymphoma. Patient no. 4, an HIV-positive woman, achieved complete remission of the high-grade gastric lymphoma 4 weeks after eradication treatment, as confirmed by endoscopy and histology. Six months later, the patient developed abdominal lymphoma infiltrates with no relapse of the gastric lymphoma. She received dose-reduced chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) and achieved complete remission of the abdominal lymphoma. One year after the high-grade gastric lymphoma had regressed completely, the patient died of HIV-associated progressive leukoencephalopathy. Patient no. 5 was referred to surgery without confirmation that the infection had been cured. Because of the advanced lymphoma stage (II1E) with multiple enlarged lymph nodes (10 mm in diameter) in the pancreatic head area, he was sent for gastric and splenic resection 4 weeks after eradication. The histologic work-up of the resected stomach revealed complete remission of the high-grade lymphoma (Fig 1 D and 1 E) but also infiltrates of a low-grade MALT lymphoma. After he recovered from surgery, the patient received chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) as planned; after six courses of treatment, complete remission of the lymph node manifestations was achieved. During a follow-up period of 48 months, no lymphoma relapse has occurred, and the patient remains in good health. Because of the improvement in symptoms and the advanced age of patient no. 6, additional chemotherapeutic treatment was postponed. Despite an initially advanced lymphoma stage (II1E) and multiple enlarged paragastric lymph nodes (15 mm in diameter), eradication treatment led to complete histologic remission of the lymphoma. Endoscopy, endoscopic ultrasound, and abdominal ultrasound revealed macroscopic regression of the lymphoma, normalization of the structure of the gastric wall, and partial remission of the enlarged paragastric lymph nodes. At 6 months after eradication treatment, partial remission of the high-grade lymphoma had been achieved. The patient is scheduled to undergo the next endoscopic examination in 6 months. In patient no. 7, eradication treatment cured the infection and healed the ulcerative lesions 2 months after treatment. Histologic analysis revealed residual infiltrates of both high- and low-grade MALT lymphoma. Clinical tumor staging, including endoscopy, was performed after another 2 months because additional chemotherapy was planned. This examination revealed complete remission of both high- and low-grade MALT lymphoma. During the subsequent follow-up period of 6 months, no relapse of either low- or high-grade lymphoma or H pylori reinfection was observed. Patient no. 8 received eradication treatment and achieved complete remission of the high-grade lymphoma 4 weeks after the infection was cured; at that point, the planned consolidation chemotherapy was postponed. A check endoscopy biopsy performed 6 months later revealed continuous complete remission of the lymphoma histologically but reinfection with H pylori. The patient received a second course of antibiotic treatment with the high-dose dual regimen. A check endoscopy performed another 2 months later demonstrated failed eradication, with no relapse of the lymphoma. The patient has been in continuous complete lymphoma remission for 15 months with no sign of tumor relapse despite H pylori reinfection. She is scheduled to receive a third course of antibiotic treatment after the strain is resistance tested. However, the lymphoma remission seems stable (data summarized in Table 2).
The overall follow-up period of the patients ranges from 6 to 66 months. Six patients are in continuous complete lymphoma remission, one patient died of causes unrelated to lymphoma (patient no. 4), and one patient (patient no. 6) has achieved partial lymphoma remission. One patient remains H pylori positive despite two courses of antibiotic treatment (patient no. 8).
Treatment choices for patients with primary gastric marginal zone B-cell lymphomas of the MALT type include gastric surgery or stomach-conserving radiotherapy, chemotherapy, or antibiotic treatment. The selection of therapy should be based on an accurate histopathologic diagnosis, grading, and clinical staging. The value of any lymphoma classification, and its impact on the choice of treatment, depends largely on its histopathologic reproducibility. Gastric MALT lymphomas are difficult to grade, and disagreement can occur among pathologists. The presence of diffuse large-cell lymphoma in patients with low-grade MALT lymphoma usually is associated with an accelerated clinical course and shorter survival. Therefore, histologic criteria, as reported by de Jong et al8 can adequately stratify gastric MALT lymphomas according to prognosis and treatment approaches. In the natural history of low-grade gastric MALT lymphomas, a prolonged indolent phase of the disease may be observed by clinical progression toward intermediate and high-grade disease triggered by interaction with an antigen (H pylori) and stepwise accumulation of genetic abnormalities. If this theory holds true, most gastric MALT lymphomas should be of low-grade morphology. From March 1993 to August 1998, we documented 351 patients with gastric lymphoma at our Institute for Pathology in Bayreuth, Germany. Of those 351 patients, 271 patients (77.2%) had low-grade morphology, and 80 patients (22.7%) were diagnosed with high-grade lymphoma. Fifty-three patients (15%) with high-grade lymphoma did not demonstrate any low-grade tumor components, whereas 27 patients (7.7%) had lymphoma of mixed morphology. Ohashi et al31 reported a series of 23 patients; 66% of gastric MALT lymphomas were of low-grade morphology, and 33.3% were of secondary high-grade morphology with low-grade components. In their study, the overall prevalence of diffuse large-cell lymphomas without proof of MALT origin was 21.7%. These and our own prevalence data are in agreement with the data presented from the Netherlands,8 and they support the contention that most gastric MALT lymphomas arise in MALT acquired in response to H pylori and develop by stepwise accumulation of genetic abnormalities (the H pylori theory). Findings by Yoshino et al9 suggest that lymphoma patients younger than 50 years of age are more likely to have a de novo high-grade lymphoma; ie, these lymphomas do not originate from low-grade MALT lymphoma, because high-grade transformation may require at least one decade. In our series, three patients were younger than 50 years of age (patient nos. 2, 7, and 8). One of these patients (patient no. 7) demonstrated a mixed lymphoma morphology. This lymphoma was secondarily high-grade of MALT origin; it was responsive to antigen and therefore would fit into the H pylori theory. Because no such low-grade component was found in patient nos. 2 and 8, these lymphomas were probably diffuse large-cell lymphomas ab initio. With regard to the H pylori theory, it is also possible that the prevalence rates of diffuse large-cell lymphomas are too high, and that the number of high-grade lymphomas that originate from low-grade MALT lymphomas is much higher and probably is underestimated. However, the clonal link between the low- and high-grade components has not been established at the genetic level. High-grade gastric lymphoma is considered independent of antigen stimulation, and like any autonomous process it therefore is not amenable to growth reversal by removal of the antigenic stimulus. On the basis of the H pylori theory, the stepwise acquisition of genetic abnormalities can be divided into early and later molecular events. Early molecular events in the evolution of gastric MALT lymphoma include trisomy 3 (33% of low-grade MALT lymphomas), but this event does not seem to play a major role in progression.32 The t(11;18)(q21;q21) chromosome translocation is also an early, frequent, and specific aberration in low-grade MALT lymphomas.33-35 Of interest, this translocation seems to be absent in high-grade lymphomas, which suggests that low-grade MALT lymphomas that are positive for the t(11;18)(q21;21) translocation may represent a subgroup with low risk for progression to high-grade disease. Another molecular event in the early phase of lymphomagenesis is Bcl-2 protein overexpression. Therefore, inhibition of apoptosis seems to be involved in oncogenesis.31 Expression of p53 protein is inversely correlated to Bcl-2 expression, and it is more common in high-grade tumors. Therefore, mutations of the p53 gene may be related to histologic transformation of low- to high-grade lymphoma, as reported previously.31,36,37 At this early stage in lymphomagenesis, the growth of the lymphoma is driven by the contact between the neoplastic B cells and the H pylori-specific intratumoral T cells. Eradication of the antigenic stimulus H pylori causes the tumor to regress completely in approximately 80% of cases. Later molecular events, such as Bcl-10 gene mutation (t(1;14)(p22;q32)),38 interstitial deletion of 8(q13;p22),39 or mutation of Bcl-6 proto-oncogene,37 seem to be linked to a capacity for autonomous growth, loss of sensitivity to H pylori, and dissemination of the lymphoma beyond the stomach and gastric lymph nodes. As demonstrated here as well as in anecdotal case reports,20-25 antibiotic therapy alone can lead to complete remission of high-grade lymphoma. In two cases, the risk of a false-negative complete remission diagnosis was minimized by the complete histologic work-up of the resected stomachs. In the other cases in which the diagnosis of complete remission was obtained by histologic examination of biopsy specimens, sampling error, although unlikely, cannot be excluded. Additional endoscopic ultrasound examinations in these patients revealed no thickening of the gastric wall after histologic documentation of complete remission. Follow-up examinations confirmed continuous complete remission for up to 66 months. Therefore, successful cure of H pylori infection in patients with primary high-grade gastric lymphoma seems to influence low-grade tumor components, and it may also induce complete remission of the high-grade lymphoma. These findings require confirmation in prospective controlled clinical studies before any definite conclusions can be drawn. Until then, standard therapy for high-grade gastric lymphoma remains chemotherapy with or without local radiation.40 Proliferation of low-grade MALT lymphoma in vitro depends on the presence of H pylori-specific tumor-infiltrating T cells.4,5 In only a single case, cells of a high-grade gastric lymphoma failed to proliferate in vitro in response to H pylori.5 This finding supports the contention that high-grade lymphomas are antigen independent, and cure of H pylori infection does not influence tumor growth, which has been discussed as a reason for failed response of low-grade MALT lymphoma to eradication therapy.12,18 In some of these cases, subsequent surgery revealed infiltrates of a high-grade lymphoma in deeper parts of the gastric wall, which were considered the reason for treatment failure. The presence of activated, CD56+ natural killer T cells in high-grade lymphoma indicates that the chronic inflammation triggered by the antigen may still be present in vivo; therefore, eradication of the bacteria may result in complete remission of even high-grade lymphoma. As suggested by Guidoboni et al,41 these cells might have immunoregulatory functions, including the ability to modulate both humoral and cell-mediated immune response. Natural killer cells may contribute to limit the extent of autoreactive responses elicited by H pylori. In general, T-cell biology in H pylori-associated MALT low- or high-grade lymphoma seems to play a key role in the determination of antigen responsiveness as well as the subsequent response to eradication therapy; this requires further investigation. It has been demonstrated that complete remission of low-grade MALT lymphoma after cure of H pylori infection depends on the depth of lymphoma infiltration, the involvement of regional lymph nodes, and the degree of malignancy of the tumor.42,43 Although the most of these low-grade MALT lymphomas have been treated at an early stage, there is evidence that more advanced stages also may demonstrate at least partial, and sometimes even complete, remission.12,44 In this study, our observations in high-grade lymphomas were similar. Six patients demonstrated early stages I1E (patient nos. 1, 4, and 7) and I2E (patient nos. 2, 3, and 8), and two patients presented with an advanced stage II1E (patient nos. 5 and 6). Patient no. 5 underwent surgery, and received planned chemotherapy because of pancreatic lymph node involvement. The other patient with an advanced II1E stage tumor and enlarged paragastric lymph nodes currently has achieved partial lymphoma remission. Therefore, it would seem that high-grade gastric lymphomas in the advanced II1E stage also might respond with complete or partial remission to cure of H pylori infection. Because most of these advanced lymphomas are associated with lymph node involvement, however, complete remission of the high-grade lymphoma would seem achievable only with additional chemotherapy targeted to lymph node involvement. The remnant infiltrates of a low-grade gastric MALT lymphoma after complete remission of the high-grade lymphoma (patient no. 5), which also has been reported by others,20 were an unexpected observation, at least from the standpoint of the commonly accepted model of MALT lymphoma progression from a low-grade, H pylori-dependent lesion to a high-grade lymphoma. One possible explanation for this uncommon finding could be that the initial low-grade lymphoma was presented by two different clones of malignant B cells; however, this was not investigated. One clone might have been positive for t(11;18)(q21;q21), which probably represents a subgroup of low-grade MALT lymphomas that do not progress to high-grade disease. The other clone probably was negative for this translocation and represented the origin of the high-grade lymphoma diagnosed in the biopsy of patient no. 5. Therefore, it is possible that the low-grade clone associated with the high-grade transformation also regressed after the eradication therapy, and the low-grade infiltrate diagnosed in the resection material represented the translocation-positive clone that did not respond to the antibiotic therapy and did not progress to high-grade disease.
In summary, our data suggest that H pylori-associated primary high-grade gastric B-cell lymphomas in stages I1E, I2E, and II1E may respond with complete or partial lymphoma remission after successful cure of the infection. A combination of stomach-conserving therapies, such antimicrobial therapy and chemotherapy, in advanced tumors (
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
II1E) might be a promising approach to the management of this disease and should be considered in future prospective clinical trials. Until further data are available, these tumors must be considered aggressive. Standard therapy for lymphomas probably should consist of chemotherapy with or without local radiation. Further characterization of these tumors requires careful clinicopathologic documentation in large series, which should be assisted greatly by additional molecular genetic and immunohistochemical analyses. 
