CASE REPORTS. Resolution of Helicobacter pylori-associated Gastric Lymphoproliferative Disease in a Child. Case Report

Transcription

1 GASTROENTEROLOGY 1995;109: CASE REPORTS Resolution of Helicobacter pylori-associated Gastric Lymphoproliferative Disease in a Child UWE BLECKER,* TIMOTHY W. MCKEITHAN,* JOHN HART,* and BARBARA S. KIRSCHNER* Departments of *Pediatrics and *Pathology, Pritzker School of Medicine, Wyler Children's Hospital, University of Chicago, Chicago, Illinois A possible causative association between Helicobacter pylori infection and gastric lymphoproliferative disorders has recently been recognized. The case of a 14- year-old girl who was diagnosed with H. pylori gastritis and associated gastric iymphoproliferative disease of the low-grade mucosa-associated lymphoid tissue type is reported. The patient was treated only for the H. pylori infection (amoxicillin, bismuth, and metronidazole) without any adjuvant chemotherapy or surgery for her lymphoproliferative disorder. This treatment not only resulted in the eradication of the microorganism but also complete resolution of her lymphoproliferative disease. The patient was subsequently followed up for a period of 7 years. There has been no histological recurrence of H. pylori gastritis or gastric lymphoproliferative disease. It is believed that this is the first report to describe a long-term follow-up of an H. pyloriassociated gastric lymphoproliferative disorder in a pediatric patient who was exclusively treated for H. pylori infection. The observations in this report suggest that H. pylori-associated low-grade gastric lymphoproliferative disease can be completely cured by eradicating the organism. Therefore, this therapeutic approach, combined with close follow-up, should be the treatment of choice in children with this associated condition before attempting more aggressive treatments, thus potentially avoiding chemotherapy and/or (partial) gastrectomy. H elicobacterpylori has been found to be the major cause for gastroduodenal pathology, both in adultp '2 and children, s'4 This finding resulted in a new understanding and approach of chronic active gastritis, duodenal ulcers, and, to a lesser degree, gastric ulcers. The recent discovery of an association between H. pylori and gastric adenocarcinoma s'6 has intensified interest in the pathogenicity of this microorganism. Very recently, H. pylori has also been described in association with gastric lymphoproliferative disease, more specifically low-grade B-cell lymphoma (rnucosa-associated lymphoid tissue [MALT]) of the stomach/ 9 and even with gastric non-hodgkin's lymphoma, l Lymphopro- liferative disease in general and lymphomas in particular are rare in immunocompetent children. Among white children, lymphomas account for only about 10% of all malignant disease in children who are 15 years old and younger.*~ Approximately 40% of these tumors are histologically non-hodgkin's lymphomas, and one third of these non-hodgkin's lymphomas originate from the abdomen.11 In most of these cases, however, the tumor mass is predominantly in the ileum or cecum. We describe the case of a 14-year-old girl who was diagnosed with H. pylori chronic active gastritis and associated gastric lymphoproliferative disease of the lowgrade B-cell lymphoma (MALT) type. The patient was treated exclusively for her H. pylori infection. This approach not only resulted in the eradication of H. pylori but also complete remission of her lymphoproliferative disease. The patient was subsequently followed up over a period of 7 years and has not presented any signs of relapse of her lymphoproliferative disease. Case Report The patient, a 14-year-old white girl, was first referred to the Pediatric Gastroenterology Clinic at Wyler Children's Hospital in November 1987 with a history of recurrent abdominal pain for several months in combination with cachexia and pallor. The patient had noted occasional low-grade fever in the weeks before her visit, and her mother reported an 8-10 kg weight loss. On initial physical examination, the patient looked cachectic and pale. Her height was 159 cm (75th percentile) and her weight was 31 kg (<5th percentile). Vital signs included a heart rate of 120 beats/min and a blood pressure of 105/65 mm Hg. Pertinent physical findings included absence of cervical lymphadenopathy; a normal cardiopulmonary examination; and a scaphoid soft abdomen without tenderness, organomegaly, or palpable masses. A stool specimen was strongly Hemoccult positive (Smith Kline Diagnostics Inc., Sunnyvale, Abbreviations used in this paper: MALT, mucosa-associated lymphoid tissue by the American Gastroenterological Association /95/$3.00

2 974 BLECKER ETAL. GASTROENTEROLOGY Vol. 109, No. 3 Figure 1. The first antral biopsy specimen showing the infiltrate of monotonous-appearing small lymphoid cells with lymphoepithelial lesions and gland destruction (H&E; original magnification 200). CA), and blood test results showed severe anemia, low serum iron, and elevated iron-binding capacity. An upper gastrointestinal series showed markedly thickened, nodular folds and rigidity in the stomach, particularly in the antrum, but otherwise normal-appearing duodenum and small bowel, including the terminal ileum. A chest radiograph was normal and did not show any lymph node enlargement. Upper gastrointestinal endoscopy was performed that showed thickened antral folds. The mucosa was markedly friable with erosions and ulcerations. The duodenal bulb and descending duodenum were normal. The stomach biopsy specimens showed gastric mucosa with focal ulceration and a dense infiltrate of atypical lymphoid cells compatible with a lymphoproliferative disorder, highly suggestive of malignant lymphoma, and well-differentiated lymphocytic type (Figure 1). Warthin- Starry stains showed the presence of spiral-shaped organisms consistent with H. pylori. The immunohistochemical findings indicated that there was a large population of cells without B- or T-cell markers and that these cells had a highgrowth fraction. There was a relative excess of immunoglobulin M-bearing cells. Monoclonality of the mucosal infiltrate could not be documented by immunohistochemical analysis. Stains for specific markers (such as bcl-2 protein) recently shown to be associated with low-grade B-cell lymphoma lz were not performed because they were not recognized or available at that time. To investigate the presence of gene rearrangements, Southern blot analysis of the gastric antral biopsy samples was subsequently performed with probes from the immunoglobulin heavy-chain locus and 1~ light-chain locus. Two rearranged bands were found with each probe. These results are consistent with the proliferation of a single clone of B cells, comprising 25%-50% of cells in the studied samples. An abdominal computerized axial tomography scan did not identify any other abnormalities within the abdomen, and a gallium scan was unable to identify any abnormal areas of uptake. To rule out bone marrow involvement by this lymphoproliferative disease, a bone-marrow aspiration was performed that had completely normal results. Based on this extensive work-up, a diagnosis of gastric lymphoproliferative disease was made in agreement with the criteria by Dawson et a1.13 However, because of the association with H. pylori that had recently been shown to be responsible for (severe) chronic active gastritis, 2 the question was raised whether the observed lymphoproliferative disease was caused by the H. pylori gastritis. After careful consideration, a decision was made to treat the patient for her H. pylori-associated chronic active gastritis first, before attempting a more aggressive therapy, such as chemotherapy and/or (partial) gastrectomy, directly aimed at the lymphoproliferative disease. At the same time, it was decided to follow up with the patient very closely to be able to detect any worsening of her condition. She received a combination of amoxicillin (50 mg" kg-1. day-i three times a day), bismuthsubcitrate (Pepto-bismol; Procter and Gamble, Cincinnati, OH) (15 ml three times a day) and metronidazole (Flagyl; Searle and Co., San Juan, Puerto Rico) (15 mg" kg -1" day-i). Repeat endoscopy was performed 3 months later (February 1988). At that time, biopsy specimens of the antrum showed the same atypical lymphoid infiltrate that was noted in the previous biopsy specimens. This infiltrate involved the lamina propria and submucosa, with focal glandular invasion and destruction (lymphoepithelial lesions). Warthin-Starry stains of the antral biopsy specimens showed no evidence of H. pylori at this time. Endoscopy 6 months later (August 1988) showed a microscopically normal gastric and duodenal mucosa. H. pylori organisms were still absent. By this time, the patient had gained 35 lbs and had no abdominal complaints. However, because of the unusual association between H. pylori infection and gastric lymphoma, the triple therapy was continued (amoxicillin 500 mg twice daily every other day) for another year, at which time the amoxicillin therapy was discontinued. Metronidazole (15 mg/kg every other day) and bismuthsubcitrate (15 ml three times a day) were continued until repeat gene-rearrangement studies showed normal results. In June 1990, gastric biopsy specimens were sent for repeat gene-rearrangement studies that no longer showed any rearranged bands. The patient was examined most recently in October 1994, and she remained symptom free. An esophagogastroduodenoscopy was performed at that time, and biopsy specimens were sent for histological analysis and repeat immunoglobulin generearrangement studies. Histological analysis showed a normal gastric and duodenal mucosa, and no gene rearrangements were detected. Discussion H. pylori has been recognized as a major cause of gastroduodenal disease. 14 Epidemiological data suggest that H. pylori is acquired in early childhood 15'16 and that the prevalence of H. pylori infection increases with advancing age. 17 H. pylori infection causes the vast majority

3 September 1995 RESOLUTION OF GASTRIC LYMPHOMA 975 of cases of chronic gastritis) 8 With the eradication of this microorganism, chronic inflammation decreases and the density of submucosal lymphocytes dramatically declines. ~9 Because most gastric lymphomas arise in areas of chronic inflammation, 2 it seems likely that prior H. pylori infection and gastric lymphoproliferative disease are linked. Circumstantial evidence suggests that infection with H. pylori may increase the risk of gastric non-hodgkin's lymphoma. Indeed, 60% of gastric non-hodgkin's lymphomas evolve from chronic gastritis, a lesion usually caused by H. pylori. 2 In a study of adenocarcinoma, an unexpected link between H. pylori infection and the subsequent development of gastric non-hodgkin's lymphoma was identified) Furthermore, a region in Northeastern Italy with a high incidence of gastric non-hodgkin's lymphoma had a higher rate of H. pylori infection than a region with a low incidence of gastric non-hodgkin's lymphoma. 2~ Parsonnet et al. found that patients with gastric non- Hodgkin's lymphoma were substantially more likely to have had immunologic evidence of prior H. pylori infection than were matched controls (odds ratio of 6.3). Sixtysix percent of gastric lymphomas could be attributed to H. pylori infection in this population, whereas no association was found between nongastric non-hodgkin's lymphoma and prior H. pylori infection (odds ratio of 1.2). 1 Two studies have shown high rates of H. pylori infection in patients with gastric non-hodgkin's lymphoma, 7'22 one of which linked infection to a specific type of tumor derived from MALT] Lymphomas caused by MALT have been described first in the early 1980s when Isaacson and Wright noted that the histology of certain low-grade B-cell gastrointestinal lymphomas was unlike that of comparable low-grade nodal lymphomas but instead was similar to that of MALT. 23'24 In the stomach, lymphoid tissue is acquired as a result of the colonization of the gastric mucosa by H. pylori. ~5'26 Wotherspoon et al. showed that this H. pylori-associated lymphoid tissue is of MALT type] They subsequently suggested that MALT acquired in response to H. pylori infection provides the background on which other, as yet unidentified, factors act, which then lead to the development of lymphoma in a small proportion of cases. Very recently, Hussell et al. showed that cellular proliferation of low-grade B-cell gastric lymphomas caused by MALT to H. pylori is dependent on H. pylori-specific T cells and their products rather than on the bacteria themselves. Therefore, gastric lymphomas derived from MALT are associated with certain strains of H. pylori. 8 In low-grade gastric lymphoma derived from MALT, blast transformation, 2v subepithelial plasma cell differentiation, 2v the specific colonization of lymphoid follicle centers by neoplastic cells, 28 and the binding of specific antibodies 9 suggest that the tumor is immunotogically responsive. Given the close association between gastric lymphoma caused by MALT and H. pylori, this organism may be evoking the immunologic response, and eradication of H. pylori may inhibit the tumor. Wotherspoon et al. suggest that the eradication of H. pylori causes regression of low-grade B-cell gastric lymphomas derived from MALT and that anti-h, pylori treatment should be administered for this type of lymphoma. 29 They conclude that compared with surgery (partial gastrectomy) or chemotherapy, antibiotic treatment for H. pylori in lymphomas derived from MALT is "harmless and inexpensive." They suggest that anti-h, pylori treatment should be the first line of treatment. In a recent abstract, Bayerd6rffer et al. report that an apparent cure of MALT lymphoma occurred in half of the patients in whom H. pylori was eradicated) To our knowledge, there have been two previously described pediatric patients with H. pylori-associated lymphoproliferative disease. Ashorn et al. report that an l 1-year-old boy with prolonged abdominal symptoms was diagnosed as having a concomitant gastric non- Hodgkin's lymphoma and H. pylori-associated chronic active gastritis) 1 After a course of antibiotics (amoxicillin, metronidazole, in association with bismuth) and 6 months of chemotherapy, the patient was disease flee. Horstmann et al. describe a 16-year-old girl with chronic, recurrent epigastric pain, who was diagnosed with H. pylori-associated low-grade B-cell lymphoma of MALT) z Although the patient's clinical condition improved after a course of omeprazole and ampicillin, the investigators decided to give her chemotherapy combined with radiation therapy. This regimen led to full regression of the lymphoma. The present case report describes the association between H. pylori gastritis, peptic ulcer disease, and gastric lymphoproliferative disease in a 14-year-old girl presenting with recurrent abdominal pain and cachexia. The histological appearance of the gastric (antral) biopsy specimens and immunoglobulin gene rearrangements are compatible with primary low-grade B-cell gastric lymphoma of MALT type. Although the patient's gastric biopsy specimens presented both histological and immunohistochemical markers compatible with gastric lymphoproliferative disease, a decision was made to treat the H. pylori gastritis first before considering a more classical but also more aggressive approach of treating the lymphoproliferative disease. At the time of diagnosis, the association between H. pylori colonization of the stomach and

4 976 BLECKERETAL. GASTROENTEROLOGY Vo1.109, No. 3 chronic active gastritis (but not lymphoma derived from MALT) had recently been recognized, originally in adults 3~ and shortly thereafter in children. 3<35 For this reason, a therapeutic attempt was made to eradicate the microorganism first. This approach resulted in the eradication of H. pylori and the subsequent (complete) disappearance of any markers of lymphoproliferative disease, as assessed by repeat endoscopies with biopsy specimens. These findings are consistent with previous reports of a possible cause-relationship between H. pylori colonization of the antral mucosa and gastric lymphoproliferative disease and show that local H, pylori infection may be a predisposing factor for gastric lymphoproliferative disease, even in children. To our knowledge, this is the first report to describe a long-term follow-up of a pediatric patient with gastric lymphoproliferative disease who was exclusively treated for her H, pylori infection without adjuvant chemotherapy or surgery. Seven years later, she remains asymptomatic and without histological evidence of the lymphoproliferative disease. This observation documents that H, py/ori-associated low-grade gastric lymphoproliferative disease can be cured nonaggressively by eradicating H, pylori with excellent long-term remission. Although the former has been described recently in adult patients with low-grade lymphoma of the stomach, no long-term follow-up has ever been reported in adults or children. In the future, H. pylori therapy may be the initial step in the treatment of proven or suspected gastric lymphoproliferative disease. Moreover, our observations suggest that once H. pylori eradication and remission of the lymphoproliferative disorder are achieved, the latter is not likely to relapse. References 1. Buck GE, Gourley WK, Lee WK, Subramanyam K, Latimer JM, DiNuzzo AR. Relation of Campylobacter pyloridis to gastritis and peptic ulceration. J Inf Dis 1986; 153: Marshall B J, McGeehie DB, Rogers PA, Glancy RJ. Pyloric Campy- Iobacter infection and gastroduodenal disease. Med J Aust 1985; 142: Drumm B, O'Brien A, Cutz E, Sherman P. Campylobacter pyloridis-associated gastritis in children. Pediatrics 1987;80: Vandenplas Y, Blecker U, Devreker T, Keppens E, Nijs J, Cadranel S, Pipeleers-Madchal M, Goossens A, Lauwers S. Contribution of the 13C-urea breath test to the detection of Helicobacter pylori gastritis in children. Pediatrics 1992;90: Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK. Helicobacter pylori infection and the risk of gastric carcinoma. 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5 September 1995 RESOLUTION OF GASTRIC LYMPHOMA 977 zation in B-cell lymphoma of mucosa-associated lymphoid tissue. Am J Surg Pathol 1991; 15: Wotherspoon AC, Doglioni C, Diss TC, Langxing P, Moschini A, de Boni M. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of He/icobacter pylori. Lancet 1993;342: BayerdOrffer E, Neubauer A, Eidt S, Lehn N, Thiede C, Rudolph B, Seifert E, Schultz H, Sommer A, Heidt H, Stolte M. Doubleblind treatment of early gastric malt-lymphoma patients by H. py/ori eradication (abstr). Gastroenterology 1994;106:A Ashorn P, L~hde PL, Ruuska T, MSkipernaa A. Gastric lymphoma in an 11-year~ld boy: a case report. Med Pediatr Oncol 1994; 22: Horstmann M, Erttmann R, Winkler K. Relapse of MALT lymphoma associated with Helicobacter py/ori after antibiotic treatment. Lancet 1994;343: Marshall B J, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1: Drumm B, Sherman P, Cutz E, Karmali M. Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children. N Engl J Med 1987;316: Czinn S J, Dahms BB, Jacobs GH, Kaplan B, Rothstein FC. Campy- Iobacter-like organisms in association with symptomatic gastritis in children. J Pediatr 1986; 109: Received December 1, Accepted March 22, Address requests for reprints to: Uwe Blocker, M.D., Division of Pediatric Gastroenterology, Academic Children's Hospital, Free University of Brussels, Laarbeeklaan 101, 1090 Brussels, Belgium. Fax: (32) Dr. Blocker is the recipient of a scholarship from the Johnny Genna Foundation. The authors thank Dr. James R. Vardiman for his help and comments with diagnosis and follow-up of this patient.