Gastric MALT lymphoma in the absence of Helicobacter pylori infection presenting as an upper gastrointestinal hemorrhage.

Abstract: Gastric MALT lymphoma is almost exclusively a sequelae of Helicobacter pylori infection and rarely presents with profuse bleeding. Gastric mucosa is not normally thought to contain lymphoid tissue, yet in the presence of H pylori reactive lymphoid follicles form which are possibly throught to predispose the patient to developing lymphoma. GI bleeding from these tumors is common during treatment as a consequence of tumor regression or necrosis. We present the case of a MALT Lymphoma in a 59 year-old woman manifesting as a brisk upper GI bleed without serologic or microbiologic evidence of an H pylori infection.

Key Words: gastric MALT lymphoma, upper gastrointestinal bleeding, endoseopy, radiation therapy

Case Report

A previously well, 59-year-old woman with a history significant for GERD presented with three days of melena and one day of coffee-ground emesis with weakness. She denied fever, weight loss or night sweats. She was resuscitated with crystalloid and blood transfusions. An emergent EGD showed a pulsatile arterial bleed from an ulcerated mass in the gastric antrum (Fig. 1) and approximately 200 to 300 cc of blood in the stomach. Electrocautery, epinephrine and clipping were necessary to achieve hemostasis. Over the next two days, the patient's hematocrit and vital signs remained stable. Due to the odd appearance of the bleeding site, the decision was made to revisualize the site and obtain biopsies on hospital day three. Renewed pulsatile arterial bleeding from the original site was noted. Hemostasis was achieved with electrocautery, epinephrine, sclerosis and repeated clipping. Biopsies of the mass were obtained.

Final tissue diagnosis revealed the mass to be an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) that was CD20 and BCL2 positive (Fig. 2).

Due to the close association between this form of cancer and H pylori, (1) the patient underwent extensive and repeated workup for infection. The biopsies showed no evidence of H pylori infection by hematoxylin and eosin (HE) or Steiner staining. Additional testing revealed that the patient was H pylori negative by multiple repeat serologies. Tissue-based urease testing and urea breath tests were likewise negative.

She was referred to oncology for staging and treatment. Her bone marrow biopsy showed no lymphoid infiltrate. A CT scan of her abdomen revealed no apparent lymphatic spread. Her tumor was classified as stage [IB.sub.E].

The patient received external beam radiation to a total dose of 3,000 cGy in 20 fractions to the primary tumor site. She completed radiotherapy six months after initial presentation. EGD nine months after presentation showed no masses. Biopsy of the scar at the tumor site-showed no evidence of disease. Nine months after presenting with an arterial GI bleed from a H pylori-negative MALT lymphoma, the patient is disease free.

Discussion

In 2003 there were 53,400 cases of non-Hodgkin lymphoma reported by the American Cancer Society. (2) Of these, only an estimated 2,670 (5%) were extranodal marginal zone lymphomas. Of this small number, the majority arose in the presence of Helicobacter pylori infection. H pylori has been found to be present by histology in 90% of MALT cases and by serology in 98%. (3-5) As this patient had neither, she fell into the remaining 2% of de novo cases--statistically, one of only 53 total cases of H pylori-negative gastric MALT lymphomas in the United States in 2003.

MALT lymphomas are thought to arise from an interaction between the T-cell and H pylori antigens. As the normal stomach does not contain lymphoid tissue, the prevailing theory is that bacterial antigens are responsible for inducing lymphoid growth. These tumors are comprised mainly of B-cell lines; therefore, they express markers such as CD20. The BCL2 is thought to regulate apoptosis and has been found to be active in other types of cancer. (6) Three bacterial proteins, CagA, VacA and FldA, have been implicated as being necessary for proliferation of lymphoma versus mere chronic bacterial gastritis. (7-9) These proteins could lead to new serologic testing to determine which infections require antimicrobial therapy to prevent progression to cancer.

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Patients with gastric MALT lymphoma and active H pylori infection can usually be treated successfully with antibiotic therapy directed at the infection. Complete remission can be achieved in 80% of patients with limited disease (stage I or II) with antibiotic therapy alone. (10) Thus, the importance of identifying and treating H pylori in MALT lymphoma cannot be overstated.

Patients who are either Hpylori negative, or who fail to improve after H pylori eradication, pose a different challenge. Over the last 20 years it has become clear that this group of patients with gastric MALT lymphoma can be treated with excellent results without needing surgical intervention. Identical 5-year survival rates with chemotherapy and/or radiation versus surgery are reported at 82%. (10) Therefore surgery has been relegated to a supportive role used for the treatment of complications or for resection of resistant disease.

Gastric lymphomas in general are uncommon and usually present with less dramatic symptoms. Most patients complain of unrelenting peptic ulcer disease symptoms, early satiety, abdominal pain, fullness or feeling a mass in the epigastrium. When these lesions bleed, they usually bleed subacutely from the capillary vasculature. Hemodynamically significant bleeding from gastric malignancies is very rare--accounting for less than 1% of acute upper GI bleeding. (11) In contrast, this patient presented with hematemesis from a large arterial bleed that required blood transfusion and two procedures to achieve hemostasis. Interestingly, she had no typical warning symptoms. Per the previous discussion, this presentation in this patient population would occur in one patient every other year in the U.S. (1% of 53 per year).

Conclusion

We thus offer this very rare initial presentation of an extremely uncommon tumor and submit the following points: First, gastric MALT lymphoma can occur in the absence of H pylori infection, though this is very rare. It may present with massive upper gastrointestinal hemorrhage, though this is also unusual. Furthermore, this type of malignancy responds well to therapy with radiation alone when in stage I. Finally, clinicians should consider malignancy, including MALT lymphoma, in all patients presenting with gastric ulcers, regardless of the presence or absence of hemodynamically significant bleeding.

References

1. International Agency for Research on Cancer. Schistosomes, liver flukes and Helicobacter pylori. IARC 1994;61-177.

2. Cancer Facts and Figures 2003. Atlanta. American Cancer Society, 2003.

3. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 1991;338:1175-1176.

4. 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 Engl J Med 1998;338:804-810.

5. Eck M, Greiner A, Schmausser B, et al. Evaluation of Helicobacter pylori in gastric MALT-type lymphoma: differences between histologic and serologic diagnosis. Mod Pathol 1999;12:1148-1151.

6. Hockenbery D, Nunez G, Milliman C, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990;348:334-336.

7. Tombola F, Morbiato L, Del Giudice G, et al. The Helicobacter pylori VacA toxin is a urea permease that promotes urea diffusion across epithelia. J Clin Invest 2001;108:929-937.

8. van der Hulst RW, van der Ende A, Dekker FW, et al. Effect of Helicobacter pylori eradication on gastritis in relation to cagA: a prospective 1-year follow-up study. Gastroenterology 1997;113:25-30

9. Chang CS, Chen LT, Yang JC, et al. Isolation of Helicobacter pylori protein, FldA. associated with mucosa-associated lymphoid tissue lymphoma of the stomach. Gastroenterology 1999;117(1):82-88.

10. Yoon SS, Coit DG, Portlock CS, et al. The diminishing role of surgery in the treatment of gastric lymphoma. Ann Surg 2004;240:28-37.

11. Laine L. Multipolar electrocoagulation in the treatment of peptic ulcers with nonbleeding visible vessels. Ann Intern Med 1989;110:510-514.

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LT Dustin Roberts, MD, CDR Michael Hopkins, MD, LCDR Steven Miller, MD, and CDR T.W. Schafer, MD

From the Departments of Internal Medicine, Hematology and Oncology, Radiation Oncology, and Gastroenterology and Endoscopy, Naval Medical Center, Portsmouth, VA.

Reprint requests to T. W. Schafer, MD, Division of Gastroenterology, Naval Medical Center, 620 John Paul Jones Circle, Portsmouth, VA 23708. Email: [e-mail]

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

We are all military service members (or employee of the U.S. Government). This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that 'Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.

Accepted January 23, 2006.

RELATED ARTICLE: Key Points

* Gastric MALT lymphoma can arise in the absence of Helicobacter pylori infection, although this is rare.

* Gastric malignancies can present with massive upper GI hemorrhage, although this is also rare.

* Gastric MALT lymphoma responds well to mono-therapy with external beam radiation.