Primary gastric lymphoma is a rare disease in children, and is frequently designated as mucosa-associated lymphoid tissue (MALT) lymphoma in adults (1). The true incidence of primary gastric lymphoma in children remains unknown. Of 55 pediatric alimentary tract malignancies seen during a 45-year period at the Children's Hospital in Columbus, Ohio, only one case was seen (2). MALT lymphoma is a low-grade B-cell lymphoma that was first described by Isaacson and Wright (3) in 1983; the stomach is the most common site of involvement (4). Helicobacter pylori is believed to cause chronic gastritis and MALT lymphoma, based on epidemiologic and molecular reports (5–9). Isaacson and Spencer (10) have pointed out that primary gastric lymphoma should be categorized as an infectious disease. Most MALT lymphomas have been identified in individuals more than 50 years old, and present with indolent clinical courses (11).
We present the case of a 12-year-old boy with advanced-stage primary gastric lymphoma who is H. pylori–positive. Only two cases of primary gastric lymphoma and another two MALT lymphomas in children have been reported in the English-language literature (12–15). Three of these four cases of primary gastric lymphoma were also H. pylori–positive, but the clinical presentation of the current case is more advanced and extensive. The current presentation includes discussion of pancreatic, central-nervous-system (CNS), and spinal-cord involvement.
A 12-year-old boy was referred to Taipei Veterans General Hospital, a tertiary referral center with nearly 3000 beds, because he had coffee-ground vomiting, tarry stool passage, yellowish discoloration of the skin, and poor appetite that had persisted for more than 10 days. The boy also had a distended abdomen, general malaise, and tea-colored urine. Physical findings disclosed anemic conjunctiva and icteric sclera. Initial laboratory results revealed obstructive jaundice (total bilirubin: 4.6 mg/dL; direct form: 2.8 mg/dL); microcytic anemia (hemoglobin: 7.5 gm/dL; mean corpuscular volume: 86 fL); and elevation of hepatobiliary enzymes (alanine amino transferase: 229 U/L, aspartate amino transferase: 290 U/L, alkaline phosphatase: 223 U/L, and γ-glutamyl transferase: 885 U/L). Upper gastrointestinal endoscopy was performed and a 3-cm × 3-cm round ulcer was found in the body of the stomach, which was oozing blood (Fig. 1). Abdominal computed tomography (CT) revealed an enlarged pancreatic head with nodular appearance and dilatation of intra-and extrahepatic bile ducts. The pathology of the large stomach ulcer indicated a large B-cell lymphoma (Fig. 2), by the Revised European American Lymphoma–World Health Organization classification (16). H. pylori was noted during biopsy. Results of the urease test, Campylobacter-like organism (CLO) test (Delta West Australia) and C 13 -urea breath test (UBT) were positive. Furthermore, the boy's mother had positive results on a CLO test and a UBT.
After confirmation of the diagnosis of primary gastric lymphoma, we arranged serial examinations for staging and searched for possibly hidden primary lesions; we found no other nodal or extranodal lesions except those in the stomach and pancreas. Biopsy of the pancreatic lesion was attempted under sonographic guide but the specimen was not obtained. Bone-marrow aspiration disclosed no abnormal cells. Because of the progressive paraplegia of the boy's right lower limb, magnetic resonance imaging (MRI) of his spine was arranged; the results revealed a suspicious epidural hypodense lesion on T7-L1. A metastatic lesion of gastric lymphoma was suspected. Thereafter, radiotherapy for a total dose of 40 cGy was applied to the epidural lesion. The paraplegia improved after radiotherapy, but facial palsy with progressive consciousness change developed during the radiotherapy course. CT of the boy's brain disclosed no definite pathology, but the cerebrospinal fluid demonstrated lymphoblasts. Subsequent brain MRI remained normal.
Under the impression of primary large-cell gastric lymphoma with pancreatic, epidural, and CNS involvement, we began to treat the boy with chemotherapy (a cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] regimen). The boy's consciousness improved progressively, jaundice was relieved, and the next CT scan showed that the pancreatic lesion was smaller. The large stomach ulcer was predominately healed and only a smaller lesion could be seen in the next upper gastrointestinal endoscopy. The pathology of the repeat biopsy was free of malignant cells. Despite the clinical progress made, unfortunately, the boy's consciousness fluctuated and intrathecal chemotherapy was suggested. However, the boy's family refused and the boy was discharged from the hospital, against our advice. He died 3 weeks later. Given the evidence of pathology, the whole disease picture presented a primary diffuse large B-cell lymphoma of the stomach with pancreatic, epidural, and CNS metastasis, which led to obstructive jaundice, paraplegia, and disturbance of consciousness.
Pediatric primary gastric lymphoma, including pediatric MALT lymphoma, is extremely rare (Table 1) and there is no consensus as to its best management. Surgery, radiotherapy, chemotherapy, and combined methods have all been used for treatment. In the four previously reported pediatric cases of gastric and MALT lymphomas, H. pylori was found in three. Horstmann et al. (14) treated a 16-year-old girl who had gastric MALT lymphoma by H. pylori eradication alone and achieved complete remission of disease, but disease relapsed 6 months later. Conversely, Blecker et al. (15) successfully treated a 14-year-old girl who had gastric MALT lymphoma by H. pylori eradication; there was no recurrence of lymphoma after treatment. The relationship of H. pylori and primary gastric and MALT lymphomas in pediatric patients is not yet established, although it is well documented in adults (7).
MALT lymphoma was firstly described by Isaacson and Wright (3) in 1983. H. pylori is currently believed to be the initiating factor of the disease (5–9). Eradication of H. pylori has been the initial treatment for MALT lymphomas (17,18), but it remains controversial. In localized MALT lymphomas, H. pylori eradication is crucial as the first-line treatment because it is harmless and inexpensive (1,17). However, clinically advanced gastric lymphomas and H. pylori–negative MALT lymphomas should not be treated by H. pylori eradication, because there is a low complete remission rate (18). High-grade gastric lymphomas are likely to evolve from the initial gastric MALT lymphoma (19,20). H. pylori infection stimulates the B- and T-cells of the stomach. Stimulated B cells form an abnormal clone, possibly by trisomy-3 mutation, and can become H. pylori–dependent low-grade MALT lymphomas. Moreover, the H. pylori–dependent state can become H. pylori–independent through [t(1:14)] genetic change. H. pylori-independent low-grade MALT lymphomas can become high-grade MALT lymphomas through the influences of p53 and other factors.
The case that we present is one of a primary diffuse large B-cell lymphoma of the stomach with possible pancreatic, epidural, and CNS metastases, which is H. pylori–positive. Pathologic findings were initially confusing. Therefore, we conducted a thorough survey in an attempt to discover possibly hidden primary lesions; none were found. Although primary gastric lymphoma is extremely rare in children, we are convinced that this patient had the disease. The transformation of low-grade MALT lymphomas to high-grade lymphomas is well documented in adults (19), but not well documented in children. Because of the presence of distant metastasis, this patient should be classified as having had stage IV disease (21). The clinical presentation is different from that in previously reported cases (12–15). Previously infected H. pylori might have been the cause of this advanced primary gastric lymphoma, but the rapid progression experienced by this patient is difficult to explain. Therefore, there may be other factors in the pathogenesis of gastric lymphomas in children that accelerates the progression of H. pylori infection into gastric lymphomas, because the infection period of H. pylori is much shorter in children. Given the lack of understanding of primary gastric lymphomas in children, it is difficult to apply the knowledge of adult disease to pediatric cases with certainty, although similarities exist.
1. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987; 11: 445–62.
2. Bethel AIB, Bhattacharyya N, Hutchinson C, et al. Alimentary tract malignancies in children. J Ped Surg 1997; 32: 1004–9.
3. Isaacson PG, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. Cancer 1983; 52: 1410–6.
4. Isaacson PG, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984; 53: 2515–24.
5. Isaacson PG. The MALT lymphoma concept updated. Ann Oncol 1995; 6: 319–20.
6. Zucca E, Roggero E. Biology and treatment of MALT lymphoma: the state-of-the-art in 1996: a workshop at the 6th International Conference on Malignant Lymphoma. Ann Oncol 1996; 7: 787–92.
7. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacter pylori
-associated gastritis and primary B-cell lymphoma. Lancet 1991; 338: 1175–6.
8. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori
infection and gastric lymphoma. N Eng J Med 1994; 330: 1267–71.
9. Zucca E, Bertoni F, Roggero E, et al. Molecular analysis of the progression from Helicobacter pylori
-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Eng J Med 1998; 338: 804–10.
10. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol 1993; 24: 569–70.
11. Wotherspoon AC. Gastric lymphoma of mucosa-associated lymphoid tissue and Helicobacter pylori
. Ann Rev Med 1998; 49: 289–99.
12. Harris GJ, Laszewski MJ. Pediatric primary gastric lymphoma. South Med J 1992; 85: 432–4.
13. Ashorn P, Lahde PL, Ruuska T, et al. Gastric lymphoma in an 11-year-old boy: a case report. Med Pediatr Oncol 1994; 22: 66–7.
14. Horstmann M, Ertmann R, Winkler K. Relapse of MALT lymphoma associated with Helicobacter pylori
after antibiotic treatment. Lancet 1994; 343: 1098–9.
15. Blecker U, McKeithan TW, Hart J, et al. Resolution of Helicobacter pylori
-associated gastric lymphoproliferative disease in a child. Gastroenterol 1995; 109: 973–7.
16. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Ann Oncol 1999; 10: 1419–32.
17. Nobre-Leitao C, Lage P, Cravo M, et al. Treatment of gastric MALT lymphoma by Helicobacter pylori
eradication: a study controlled by endoscopic ultrasonography. Am J Gastroenterol 1998; 93: 732–6.
18. Steinbach G, Ford R, Glober G, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. Ann Int Med 1999; 131: 88–95.
19. Peng H, Du M, Diss TC, et al. Genetic evidence for a clonal link between high grade and low grade components in gastric MALT B cell lymphoma. Histopathology 1997; 30: 425–9.
20. Isaacson PG. Recent development in our understanding of gastric lymphomas. Am J Surg Pathol 1996; 20 (suppl1): S1–7.
21. Rohatiner A, d'Amore F, Coiffier B, et al. Report on a workup convened to discuss the pathologic and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994; 5: 397–400.