Regression of Duodenal Mucosa Associated Lymphoid Tissue Lymphoma After Eradication of Helicobacter pylori

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1 GASTROENTEROLOGY 1996;111: Regression of Duodenal Mucosa Associated Lymphoid Tissue Lymphoma After Eradication of Helicobacter pylori RYUICHI NAGASHIMA,* HIROAKI TAKEDA,* KUNIHIKO MAEDA, SHIGERU OHNO,* and TSUNEO TAKAHASHI* *Second Department of Internal Medicine and Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan E vidence links Helicobacter pylori gastritis with the development of lymphoma of mucosa-associated lymphoid tissue (MALT) in the stomach, 1 3 and some studies have suggested that such low-grade MALT lymphoma may regress after eradication of H. pylori infection. 4 6 However, little is known about lymphoma arising in the duodenum because it is so rare. 7 9 The relationship between H. pylori infection and duodenal lymphoma and the possible therapeutic efficacy of H. pylori eradication are still obscure. A patient with an MALT lymphoma in the duodenal bulb who was treated with antibiotics is described. Case Report A 58-year-old man who had been undergoing diet therapy for diabetes mellitus for 7 years had a 3-day episode of diarrhea and colicky pain in the epigastrium unrelated to meals. Initial upper gastrointestinal endoscopy showed multiple small erosions and diffuse erythema in the duodenal bulb. A diagnosis of duodenal lymphoma was made based on findings of biopsy specimens, and the patient was referred to our institution for treatment. It is rare for low-grade lymphoma of mucosa-associated lymphoid tissue (MALT) to affect the duodenum, and no reports have mentioned any relationship between this disease and Helicobacter pylori infection. This case report describes a patient with multiple small ero- sions and diffuse erythema in the duodenal bulb diagnosed histopathologically as MALT lymphoma. Immunoglobulin (Ig) heavy-chain gene rearrangement was detected, and monotypic plasma cell proliferation (IgGk) was shown by immunohistochemistry. The le- sion was localized to the duodenal bulb. Antibiotic ther- apy for H. pylori resulted in resolution of the morphological features of the lymphoma, as confirmed by endoscopic and pathological examination. Moreover, the gene rearrangement could not be detected after eradication of the bacterium. Although additional fol- low-up is needed, it is suggested that H. pylori eradication therapy may be effective for patients with MALT lymphoma in the duodenum as well as the stomach. At the time of evaluation, the patient had no abdominal pain and his diarrhea had improved. He had no abdominal tenderness, lymphadenopathy, or hepatosplenomegaly. The level of serum immunoglobulin (Ig), including IgG, IgM, and IgA, was normal, and no M protein or Bence Jones proteins were found by immunoelectrophoresis of the serum and urine. Examination of the sternal marrow showed no abnormalities. Radiological examination of the upper gastrointestinal tract revealed multiple small barium flecks and small nodular pro- trusions in the duodenal bulb but not in the stomach. Upper gastrointestinal endoscopy showed erosion, erythema, small nodular elevations, and fold convergence in the duodenal bulb (Figure 1A). There were no such findings in the stomach or in other parts of the duodenum. Gallium scintigraphy, computed tomographic scan, total colonoscopy, and small intestinal roentgenography using peroral barium with pneumocolon showed no abnormal findings. The findings of histopathologic and genetic studies of endo- scopic biopsy specimens suggested that low-grade lymphoma of MALT was an appropriate diagnosis. This lesion was considered to have arisen primarily in the duodenal bulb. Surgical treatment was offered, but the patient refused it. Although the serum IgG titer for H. pylori, estimated using Pylicaplate G Helicobacter (Biomerica, Newport Beach, CA), was considered equivocal, biopsy specimens from the gastric mucosa were used to confirm H. pylori infection by Giemsa staining, immunohis- tochemistry using a rabbit anti H. pylori antibody (Dakopatts, Glostrup, Denmark), and a rapid urease test (CLOtest; Delta West, Bentley, Western Australia). Bacterial eradication ther- apy was initiated with oral lansoprazole (30 mg every day) and clarithromycin (200 mg twice daily). After 4 weeks of therapy, H. pylori was found to persist in biopsy specimens from the gastric mucosa using light microscopy. The patient was given a 14-day course of amoxicillin (250 mg three times daily), metronidazole (250 mg three times daily), and polaprezinc (0.5 g twice daily; Promac; Zeria Pharmaceutical Co., Ltd., Tokyo, Japan), which is one of the mucosal protective drugs. Upper gastrointestinal endoscopy performed 1 month after the second course of eradication therapy failed to show H. pylori Abbreviations used in this paper: CCL, centrocyte-like; MALT, mucosa-associated lymphoid tissue by the American Gastroenterological Association /96/$3.00

2 December 1996 DUODENAL MALT LYMPHOMA 1675 Figure 1. Endoscopic view of a duodenal bulb in a patient with MALT lymphoma (A) before antibiotic treatment and (B) after eradication of H. pylori. by either the CLOtest or light microscopy, and improvement of the lymphoma lesion was observed. Three months later, regression of the duodenal lesion was obvious, and only slight erythema remained in the bulb (Figure 1B). At the time of the latter examination, no pathological change was evident in Figure 2. Photomicrographs of initial biopsy specimens from the duodenal lesion. (A) Dense mononuclear cell proliferation in the duodenal mucosa. (B) A lymphoepithelioid lesion. (C) CCL cells are proliferating with many plasma cells (H&E; original magnifications: 161 [A], 1601 [B], 1001 [C]).

3 1676 NAGASHIMA ET AL. GASTROENTEROLOGY Vol. 111, No. 6 scribed previously. 10 As primary antibodies, we used rabbit polyclonal anti-human CD3, IgA, IgG, IgM, IgD, IgE, k, and l chains and mouse monoclonal anti-human CD20/cy (L26), CD45RO (UCHL-1) (Dakopatts, Glostrup, Denmark), and CD43 (MT-1) (Bio-Science, Emmenbrücke, Switzerland). Figure 3. Photomicrographs showing immunoreactivity for (A) IgG, (B) IgM, (C) k light-chain, and (D) l light-chain in the lymphoma lesion. Plasma cells in this focus continue to show monotypic staining for IgG and k light-chain (avidin-biotin peroxidase immunolabeling; original magnification 501). Molecular Study Rearrangements of the Ig heavy-chain gene and T-cell b receptor were studied using Southern blot hybridization as described previously. 11 Digestion was performed to completion with the restriction enzymes BamHI and HindIII, and 32 P- labeled probes for the Ig heavy chain joining region (Oncor, Gaithersburg, MD), and 32 P-labeled CTb probes (Oncor) were used for hybridization. Results Histopathologic and Molecular Studies Initial biopsy specimens from the duodenal lesion showed a diffuse, dense mononuclear cell proliferation expanding in the duodenal mucosa (Figure 2A). These cells, which infiltrated the duodenal epithelial layer (Figure 2B), were medium sized with clear cytoplasm resembling centrocyte-like (CCL) cells; in addition, many plasma cells were associated with them (Figure 2C). These CCL cells had a clear cell or monocytoid B cell form. We could not find large cells or blast-like CCL cells. In several biopsy specimens, follicle-like lymphoid aggregations were found. Some of them had germinal centers. However, the specimens from the gastric mucosa showed no such findings. Neither gastric mucosal metaplasia, ectopic gastric mucosa, nor H. pylori infection could be seen in specimens from the duodenal bulb. Proliferating CCL cells were positive for CD20/cy; associated plasma cells revealed monotypic IgG and k chain the biopsy specimens, and gene rearrangement could not be found. H. pylori was still negative according to upper gastrointestinal endoscopy. Four months after the second course of therapy, the serum IgG titer was regarded negative. A urea breath test performed 7 months later was negative for H. pylori. This patient still shows no evidence of MALT lymphoma 13 months after eradication of H. pylori. Laboratory Methods Immunohistochemical labeling. Biopsy specimens were fixed in 10% formalin and processed routinely to obtain conventional paraffin sections. Immunohistochemical labeling was performed using the avidin-biotin peroxidase method de- Figure 4. A photomicrograph of biopsy specimens from the duodenal mucosa after eradication of H. pylori (H&E; original magnification 161).

4 December 1996 DUODENAL MALT LYMPHOMA 1677 proliferation (Figure 3). The CCL cells were not positive References for T cell markers such as CD4, CD43, and CD45RO. 1. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Heli- Rearrangement of the Ig heavy chain joining region cobacter pylori associated gastritis and primary B-cell gastric gene, but not of the T-cell receptor b gene, was revealed lymphoma. Lancet 1991;338: by Southern blot analysis of biopsy specimens from the 2. Eidt S, Stolte M. Prevalence of lymphoid follicles and aggregates in Helicobacter pylori gastritis in antral and body mucosa. J Clin duodenal lesion. Pathol 1993;46: Biopsy specimens obtained 3 months after eradication 3. Greiner A, Marx A, Heesemann J, Leebmann J, Schmaußer B, of H. pylori showed only mild, apparently reactive infiland B cell in Helicobacter pylori associated chronic gastritis. Müller-Hermelink HK. Idiotype identity in a MALT-type lymphoma tration of lymphocytes and plasma cells in the duodenal Lab Invest 1994;70: mucosa (Figure 4). We were unable to detect monotypic 4. Bayerdörffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt proliferation for IgG or k light chain. Gene analysis S, Stolte M. Regression of primary gastric lymphoma of mucosaassociated lymphoid tissue type after cure of Helicobacter showed no monoclonal bands. pylori infection. Lancet 1995;345: Roggero E, Zucca E, Pinotti G, Pascarella A, Capella C, Savio A, Pedrinis E, Paterlini A, Venco A, Cavalli F. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1995;122: Discussion MALT lymphoma is a B-cell malignant neoplasm morphologically characterized by CCL cell proliferation, lymphoepithelial lesions, and lymphoid follicles. 12 In the 6. Weber DM, Dimopoulos MA, Anandu DP, Pugh WC, Steinbach G. stomach, this neoplasm is believed to arise in chronic Regression of gastric lymphoma of mucosa-associated lymphoid gastritis as a result of H. pylori infection 1 3 through a T tissue with antibiotic therapy for Helicobacter pylori. Gastroenter- ology 1994;107: cell mediated reaction. 13 Accordingly, distinction from 7. Fischbach W, Kestel W, Kirchner T, Mössner J, Wilms K. Maligreactive change is important in the diagnosis of MALT nant lymphomas of the upper gastrointestinal tract. Results of lymphoma, and B-cell monoclonality must be confirmed a prospective study in 103 patients. Cancer 1992;70: by searching for rearrangement of the Ig heavy-chain 8. Muchmore JH, Haddad CG, Goldwag S. Primary non-hodgkin s gene. 14,15 lymphoma of the duodenum. Am Surgeon 1994;60: In the duodenum, MALT lymphoma is a rare condi- 9. Al Mofleh IA. Endoscopic features of primary upper gastrointestinal lymphoma. J Clin Gastroenterol 1994;19: tion, 16 and its relationship with H. pylori infection is still 10. Cattoretti G, Berti E, Schiro R, D Amato L, Valeggio C, Rilke F. obscure. There are reports of chronic lymphocytic cell Improved avidin-biotin-peroxidase complex (ABC) staining. Histoinfiltration in the duodenal mucosa of patients with gas- chem J 1988;20: tric H. pylori infection, 17,18 and it is suggested that this 11. Katz RL, Hirsch-Ginsberg C, Childs C, Dekmezian R, Fanning T, inflammatory condition is related to the occurrence of Ordonez N, Cabanillas F, Sneige N. The role of gene rearrange- ments for antigen receptors in the diagnosis of lymphoma obduodenal lymphoma. It is well known that H. pylori tained by fine-needle aspiration. A study of 63 cases with coninfects the ectopic or metaplastic gastric mucosa of the comitant immunophenotyping. Am J Clin Pathol 1991;96:479 duodenum. 19,20 However, in our patient, neither ectopic 490. gastric mucosa nor gastric mucosal metaplasia was eviated lymphoid tissue. A distinctive B cell lymphoma. Cancer 12. Isaacson PG, Wright DH. Malignant lymphoma of mucosa associ- dent in biopsy specimens from the duodenal lesion and 1983;52: H. pylori was not detected in the bulb. It is suggested 13. Hussell T, Isaacson PG, Crabtree EJ, Spencer JO. The response that H. pylori infection in the stomach was intrinsically of cells from low-grade B-cell gastric lymphomas of mucosa-asso- ciated lymphoid tissue to Helicobacter pylori. Lancet 1993;342: related to the occurrence of MALT lymphoma in the bulb, which is interesting in relation to the reaction of 14. Sigal SH, Saul SH, Auerbach HE, Raffensperger E, Kant JA, duodenal MALT to H. pylori infection. Brooks JJ. Gastric small lymphocytic proliferation with immuno- There are no reports of bacterial eradication therapy globulin gene rearrangement in pseudolymphoma versus lymphoma. Gastroenterology 1989;97: for duodenal MALT lymphoma. On the other hand, many 15. Trainor KJ, Brisco MJ, Story CJ, Morley AA. Monoclonality in B- articles have described that eradication of H. pylori from lymphoproliferative disorders detected at the DNA level. Blood patients with gastric MALT lymphoma has resulted in 1990;75: tumor regression. 5,6,21 Recently, a larger study to estabscopic features of mucosa-associated lymphoid tissue lym- 16. Wang HH, Lin JT, Chiu CC, Chiang IP, Wu MS, Wang TH. Endolish the efficacy of this therapy was performed. 4 Although phoma of the duodenum. Gastrointest Endosc 1995;41:258 further follow-up is needed to show whether such lesions 261. regress completely or are actually cured, our present case 17. Shabib SM, Cutz E, Drumm B, Sherman PM. Association of gas- tric metaplasia and duodenitis with Helicobacter pylori infection suggests that eradication may be effective for the treatin children. Am J Clin Pathol 1994;102: ment of MALT lymphoma in both the duodenum and 18. Madsen JE, Vetvik K, Aase S. Helicobacter pylori and chronic the stomach. active inflammation of the duodenum and stomach in duodenal

5 1678 NAGASHIMA ET AL. GASTROENTEROLOGY Vol. 111, No. 6 ulcer patients treated with ranitidine, misoprostol, or an acid- Treatment of low-grade gastric MALT lymphoma with Helicobacter neutralizing agent. Scand J Gastroenterol 1991;26: pylori eradication. Lancet 1995;345: Mégraud F, Lamouliatte H. Helicobacter pylori and duodenal ulcer. Evidence suggesting causation. Dig Dis Sci 1992;37: Received March 25, Accepted August 19, Wyatt JI, Rathbone GJ, Dixon MF, Heatley RV. Campylobacter Address requests for reprints to: Ryuichi Nagashima, M.D., Second pyloridis and acid-induced gastric metaplasia in the pathogenesis Department of Internal Medicine, Yamagata University School of of duodenitis. J Clin Pathol 1987;40: Montalban C, Manzanal A, Boixeda D, Redondo C, Bellas C. Medicine, Iida-Nishi, Yamagata , Japan. Fax: (81)