Seminars in Oncology
Volume 37, Issue 3 , Pages 183-187, June 2010

Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Article Outline

 

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.

Gloria J. Morris, MD, PhD

Current Clinical Practice Feature Editor

According to the World Health Organization (WHO) classification,1 gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a form of marginal zone lymphoma (MZL), a very heterogeneous group of disorders consisting of extranodal MALT, nodal MZL, and splenic MZL.2 It occurs in areas of prolonged proliferation of lymphoid tissue in mucosal sites,3 and can be classified into gastric and non-gastric types.3 Gastric MALT may typically develop in the stomach, with Helicobacter pylori infection playing a major role in the pathogenesis of the disease; eradication of H pylori can culminate in tumor regression.4 Other bacterial infections also have been implicated in the pathogenesis but are not consistently borne out in the literature.5, 6, 7

The typical immunophenotype associated with MZL is CD5−, CD10−, CD20+, CD23−/+, CD43−/+, cyclin D1−, and negative for bcl-2 follicles. The t(11;18)(q21;q21) chromosomal translocation is the most common cytogenetic abnormality found in gastric MALT lymphoma, observed in 18% to 53% of cases.3 This translocation can confer antibiotic resistance, and is associated with disseminated disease. Some MALT lymphomas can transform into diffuse large B-cell lymphoma (DLBCL) with a more aggressive course; however, this change is not associated with the t(11;18) translocation.

Gastric MALT lymphoma usually has an indolent course, with epigastric discomfort and dyspepsia being the most common symptoms, but gastric bleeding is a rare occurrence.3 Diagnosis of gastric MALT lymphoma requires direct endoscopic assessment of the gastrointestinal tract and testing for the presence of H pylori organisms; the endoscopic appearance is often similar to benign chronic conditions such as gastritis or peptic ulcer.8 Staging of the lymphoma can include endoscopic ultrasound to determine the depth of invasion into the gastric wall; computed tomography (CT) scan of the chest, abdomen, and pelvis and bone marrow biopsy are performed to determine the full extent of the disease.

Treatment for gastric MALT lymphoma includes eradication of H pylori via one of several antibiotic regimens, usually in combination with a proton-pump inhibitor to block gastric acid secretion, unless positivity for t(11;18) translocation necessitates alternative therapy. This includes involved-field radiation therapy (IFRT),9 rituximab, or chemoimmunotherapy.10 IFRT also is considered for disease that extends to the muscularis layer or to adjacent organs.9 Re-evaluation with endoscopy post-treatment is helpful after 3-month intervals, and if recurrence is demonstrated, patients are treated the same as those with follicular lymphoma, following national guidelines.

We present a case of gastric MALT lymphoma confined to the gastric antrum for which multidisciplinary treatment recommendations are sought for the following questions: (1) What treatment approaches would you recommend at the time of diagnosis? (2) What follow-up strategies would you recommend? (3) What further treatment would you recommend in the event of recurrence?

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The Problem 

A 53-year-old woman who took daily aspirin but no other nonsteroidal anti-inflammatory drugs (NSAIDs) as an outpatient presented to the hospital emergency room with weakness, dizziness, hypotension, and history of dark stools over 2 weeks and frank melena for 2 days. She was found to have orthostatic hypotension, and a low hemoglobin, initially 9.4, which dropped to 7.4 after hydration, requiring red blood cell transfusion. She underwent endoscopy, which showed a punched out 1.5 × 2 cm ulcer with raised edges in the mid body of the stomach along the greater curvature. Active bleeding continued despite epinephrine injection around the ulcer, and heater probe cautery. The patient then underwent emergency exploratory laparotomy and partial gastrectomy for persistent bleeding ulcer. The area of the ulcer was identified surrounded by a mass; both were dissected with a wedge resection of the upper body of the stomach, and sent for pathologic evaluation. Both specimens contained a diffuse, nodular infiltration by lymphoid cells with predominantly small, slightly irregular nuclei and minimal cytoplasm, as well as minimal mitotic activity (Figure 1 A, B, C). The tumor cells diffusely infiltrated the mucosal, submucosal, and muscular layers of the gastric tissue. The tumor cells were diffusely positive with CD20 (Figure 1D) and CD79a (Figure 1E), with scattered positive reactivity with CD43 (Figure 1F) and CD5 (Figure 1G), and no reactivity with CD10 (Figure 1H), CD23 (Figure 1I), CD45Ro, or cyclin D1 (Figure 1J). The specimen was therefore consistent with a low-grade B-cell MALT lymphoma with focal moderate numbers of H pylori identified on the immunohistochemical stains. There was no other evidence of systemic lymphadenopathy on a CT scan of the chest, abdomen, or pelvis, or on an outpatient positron emission tomography (PET) scan. Upon recovery from surgery, the patient was started on a triple-antibiotic regimen against H pylori, and considered for local radiation treatment.

  • View full-size image.
  • Figure 1. 

    (A) Gastric mucosa, hematoxylin and eosin stain (H&E), 4X magnification. (B) Gastric mucosa, H&E, 40X magnification. (C) Gastric mucosa, H&E, 60X magnification. (D) Antibody to CD20, 40X magnification. (E) Antibody to CD79a, 40X magnification. (F) Antibody to CD43, 40X magnification. (G) Antibody to CD5, 40X magnification. (H) Antibody to CD10, 40X magnification. (I) Antibody to CD23, 40X magnification. (J) Antibody to cyclin D1, 40X magnification. (K) Identification of H pylori organisms by immunohistochemical stain, 40X magnification. (L) Identification of H pylori organisms by immunohistochemical stain, 60X magnification.

Courtesy of Dr. Thomas R. Himes, Department of Pathology, Community Medical Center, Scranton, PA.

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Hematologists' Opinion 

This patient has a somewhat unusual presentation of low-grade B-cell MALT, also known as extranodal marginal zone B-cell lymphoma, in that she had significant bleeding and has undergone surgical resection. More commonly patients are identified at upper endoscopy for symptoms of gastritis or gastro-esophageal reflux disease (GERD).

MALT lymphomas can arise in different epithelial tissues including stomach, salivary glands, lung, and small bowel, and they represent about 5% of all cases of non-Hodgkin lymphoma.11 MALT lymphoma is the most common type of primary gastrointestinal lymphoma worldwide. Within the gastrointestinal tract they are most commonly found in the stomach, but they can be found throughout the entire gastrointestinal tract.

MALT lymphoma of the stomach is thought to originate from lymphatic tissue that develops in the setting of chronic infection or other persistent immune stimulation. Epidemiologic studies found strong association between the findings of H pylori infection in the presence of MALT lymphoma.12 Moreover, therapy for eradication of H pylori infection can result in regression of early lesion of MALT lymphoma in most cases.13 Other predisposing factors to MALT lymphoma include history of autoimmune disorders, such as Sjögren's syndrome with salivary gland MALT or Hashimoto's thyroiditis with thyroid MALT. MALT lymphoma develops from marginal zone B-lymphocytes, which demonstrate a typical immunophenotype with positivity to B-cell antigens (CD19, CD20, CD79a) and antigens typical for marginal zone (CD35, CD21). The cells are usually negative for CD5, CD10, CD23, and cyclin D1. Multiple recurrent chromosomal translocations have been found associated with MALT lymphoma, including t(11;18)(q21;q21)—fusion of the apoptosis inhibitor-2 gene (API2) and the MALT1 gene; t(14;18)(q32;q21)—fusion of the MALT1 and IgH genes; and t(1;14)(p22;q32)—fusion of the BCL-10 and IgH genes. These chromosomal alterations results in activation of nuclear factor (NF)-κB transcription factor leading to an overexpression of BCL-10, which induces a survival advantage in B cells. Tumors carrying these genetic abnormalities were shown to be less responsive to H pylori eradication. Another transformation t(3;14)(p13;q32) results in the fusion of the FOXP1 and IgH genes, which increases nuclear levels of the FOXP1 transcription factor. This transformation was found to correlate with poor prognosis and high rates of aggressive transformation.

MALT lymphomas commonly present with nonspecific manifestations such as peptic ulcer disease or gastritis, abdominal pain, or an asymptomatic mass. Lymph node, blood or bone marrow involvement, and presence of B symptoms are quite rare. Gastrointestinal bleeding is seen in 20% to 30% of cases, although gastric perforation is infrequent.11 Diagnosis is usually made through endoscopic biopsy, which demonstrates the classic polymorphous infiltrate of small lymphocytes. Endoscopic ultrasound can be useful for estimating the depth of invasion, since deep invasion is associated with a higher likelihood of adjacent lymph node involvement. Staging should be completed with CT scans of the chest, abdomen, and pelvis to exclude systemic lymphatic involvement. The use of PET CT is controversial in MALT lymphoma, and can frequently be negative due to the indolent nature of the disease.

The initial therapy for early localized MALT lymphoma is aimed at eradication of H pylori with a combination of antibiotics and proton pump inhibitors. Eradication of H pylori can result in long-term remission in the majority of patients with H pylori−positive MALT lymphoma. Antibiotic therapy should be used in patients with localized disease involving the mucosa/submucosa that is nonbulky and without evidence of metastasis or lymph node involvement. Patients with evidence of diffuse large B-cell lymphoma should be treated aggressively with anthracycline-based chemotherapy. As noted earlier, some genetic abnormalities can predict response to H pylori eradication. Patients who achieve a complete response will not benefit from additional chemotherapy, and should be followed expectantly.

Due to the indolent nature of the disease, a treatment trial of antibiotics is often recommended even if the patient appears to be negative for H pylori, as H pylori can be difficult to identify. For patients who do not respond to antibiotic therapy, the treatment of choice is radiation to the stomach and perigastric lymph nodes, which provides high rates of durable response with minimal toxicity. Given that the infiltrative nature of the disease requires total gastrectomy for long-term disease control, and that relatively low doses of radiation provide such control with little impact on quality of life, surgery is generally reserved for uncontrolled bleeding or perforation. Effective cytotoxic agents include oral alkylating agents (chlorambucil and cyclophosphamide) and purine analogues (fludarabine and cladribine). Combination chemotherapy regimens are effective yet rarely used due to the indolent course of the disease. Rituximab is effective as a single agent with about 70% response rates, and is currently under investigation in combination with chlorambucil by the International Extranodal Lymphoma Study Group (IELSG).

Eradication of H pylori should be documented by breath test a few months following therapy. Endoscopy with gastric biopsies is recommended 3 to 6 months following the completion of treatment in order to document histologic remission. The frequency of follow-up endoscopy is not data-driven. Common recommendations are to repeat the study every 6 months for the first 2 years and yearly afterwards to identify early recurrent disease. Post-treatment biopsies often display minimal residual disease with small amounts of monoclonal B cells, especially if highly sensitive techniques such as flow cytometry or polymerase chain reaction are used. However, the clinical significance of this finding is unclear, and most physicians recommend no additional therapy other than close follow-up in this setting. Thus, the role of frequent endoscopies in asymptomatic patients is not clear. If, however, persistent symptomatic and/or progressive disease is identified after H pylori eradication, then radiation therapy is advised. As relapse post-radiation is rare, the role of follow-up endoscopies after radiation is even less clear.

In the case before us, the patient was diagnosed with gastric MALT lymphoma following surgical gastric resection due to uncontrolled bleeding ulcer. The patient does not have any evidence of distant lymph nodes involvement on imaging scan and thus will be a candidate for local therapy. Antibiotic therapy for eradication of H pylori is indicated with close follow-up afterwards. In this case, given the symptomatic presentation of her disease, we would have a low threshold for recommending IFRT if the disease persists after H pylori eradication.

Efrat Dotan, MD

Fellow

Mitchell R. Smith, MD, PhD

Director, Lymphoma Service

Fox Chase Cancer Center

Philadelphia, PA

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Hematologist's Opinion 

In this case of a patient with previously undiagnosed gastric MALT, the patient presented to an emergency room with gastric bleeding, which had been chronic, followed by an acute phase. The disease was difficult to control with local attempts, signifying that this malignancy involved more than just the mucosa and justifying the emergent surgery. The disease was primarily resected, although we do not know if there was disease remaining after surgery. At pathologic examination, only small cells were observed, with no evidence of large cells, and immunohistochemical stains were typical for the disease, with nothing to suggest follicular lymphoma (CD10−) or mantle cell lymphoma (cyclin D1−), two other lymphomas that can involve the stomach. H pylori was recovered, so the patient received antibiotics following surgery.

This is a relatively rare presentation of MZL, although the stomach is the most common site for MALT, and more is known about the etiology, diagnosis, and therapy of this disease than any other presentation of marginal zone lymphoma. In the past, this disease was considered a “pseudolymphoma” because of its chronicity in many patients, and because it pathologically appeared to be a lymphoma, but did not “behave” like a malignancy in many patients. When the disease was found to harbor gene rearrangements, it was fully recognized as a malignancy, and the discovery that it was often induced by H pylori and could be treated with antibiotics gave rise to a search for other pathogen-induced lymphomas. Interestingly, investigators disagree on guidelines for staging of the disease; in one series, more than one third of patients with apparently isolated extranodal MZL had presence of the disease at two or more sites, suggesting that patients should undergo complete staging, including marrow biopsies, and possible colonoscopy. The benefit of PET staging remains controversial, and can not be used to predict outcome, since most patients with extranodal MZL may well eventually die of other illnesses. The disease can “transform,” as with follicular lymphomas, but investigators are not sure how often this occurs, and cases with “increased numbers of large cells” in the biopsy are sometimes difficult to identify as being “indolent” diseases.

Surgery should no longer be considered as initial therapy for the disease, unless mitigating circumstances call for it, as in the case in point. However, antibiotic therapy is indicated, according to the National Comprehensive Cancer Network guidelines, even for patients whose biopsies do not demonstrate H pylori, since such treatment is associated with limited side effects and often effective. In one ongoing study, antibiotic therapy was effective at control of the disease in the majority of cases; in this trial, patients occasionally developed infiltrates that harbored gene rearrangements, but these did not mean that therapy for relapse was necessary. Importantly, since H pylori also is associated with gastric carcinoma, these investigators have continued to follow their patients with gastroscopy, and have reported that gastric cancer can occur in these patients, even when their stomachs no longer harbor H pylori, and they may be at risk for the development of secondary lymphomas, unrelated to the original malignancy.

Radiotherapy has been reported to be excellent therapy for patients with gastric MZL, with long-term remissions observed. Careful evaluation may be necessary to determine the appropriateness of such treatment, including gastric mapping via ultrasound, biopsies of potentially involved nodes, and careful pathologic interpretation, since some cases also may harbor large cell lymphoma. Rituximab monotherapy may well be good initial therapy for such patients, although those with “bulkier” or more extensive disease may best be treated with rituximab-based chemotherapy. The proper chemotherapy is unknown: it is likely that alkylator- and purine-based therapies are similarly effective, and investigators have not yet determined the pros and cons of either type.

Based on the assumption that this patient has no other evidence of disease, and that the disease has been completely resected, I would not administer additional therapy beyond treatment for the H pylori. Of course, if additional biopsies demonstrated that there were more local disease present that was not eradicated by antibiotic therapy, then additional radiotherapy might be indicated. If there was more disease at restaging, then therapy with rituximab or rituximab-based chemotherapy should be considered.

Frederick B Hagemeister Jr, MD

University of Texas M.D. Anderson Cancer Center

Houston, TX

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Radiation Oncologists' Opinion 

I would treat the H pylori and then repeat a gastroscope with biopsy at about 2 to 3 months. If the lymphoma was not present pathologically then I would simply follow the patient, and probably repeat the gastroscopy with biopsy at 6 to 12 months. If the lymphoma was still present at that time, I would treat with whole gastric portal with irradiation of 3,060 cGy in 180-cGy fractions.

Harmar D. Brereton, MD

Director, Northeast Radiation Oncology Center

Dunmore, PA

The Commonwealth Medical College

Scranton, PA

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Summary and Assessment 

We present the case of a 53-year-old woman who was found to have a stage I gastric MALT lymphoma from a bleeding ulcer bed, and who underwent wedge resection of the gastric antrum. Postoperatively, she underwent antibiotic treatment against H pylori and subsequent endoscopic surveillance. Decisions toward radiation therapy and chemotherapy were withheld until signs of recurrence or disease progression. Radiation therapy can be anecdotally added early in the treatment algorithm for locally advanced or incompletely resected tumors after primary surgical excision is accomplished© and is usually well tolerated, with a low risk for second malignancies.11 While data on the use of chemotherapy is limited, incorporation of anti-CD20 radioimmunoconjugates as specifically targeted therapy is also an intriguing option if recurrence or progression should be detected in the future.14 (Figure 1).

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References 

  1. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Am J Surg Pathol. 1997;21:114–121
  2. Non-Hodgkins' lymphomas (National Comprehensive Cancer Network Practice Guidelines in Oncology, v.2.2009). www.nccn.org
  3. Cohen SM, Petryk M, Varma M, et al. Non-Hodgkins' lymphoma of mucosa-associated lymphoid tissue. Oncologist. 2006;11:1100–1117
  4. Isaacson PG, Spencer J. Gastric lymphoma and Helicobacter pylori. Important Adv Oncol. 1996;111–121
  5. Roggero E, Zucca E, Mainetti C, et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol. 2000;31:263–268
  6. Lecuit M, Abachin E, Martin A, et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med. 2004;350:239–248
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  8. Taal BG, Boot H, van Heerde P, et al. Primary non-Hodgkins lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept. Gut. 1996;39:556–561
  9. Castrillo JM, Montalban C, Obeso G, et al. Gastric B-cell mucosa associated lymphoid tissue lymphoma: a clinicopathological study in 56 patients. Gut. 1997;33:1307–1311
  10. Ranaldi R, Goteri G, Baccarini MG, et al. A clinicopathologic study of 152 surgically treated primary gastric lymphomas with survival analysis of 109 high grade tumors. J Clin Pathol. 2002;55:346–351
  11. Shani A, Schutt AJ, Weiland LH. Primary gastric malignant lymphoma followed by gastric adenocarcinoma: report of 4 cases and review of the literature. Cancer. 1978;42:2039–2044
  12. Ferrucci P, Zucca E. Primary gastric lymphoma pathogenesis and treatment: what has changed over the past 10 years?. Br J Haematol. 2006;136:521–538
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  14. Bayerdorffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection (MALT Lymphoma Study Group). Lancet. 1995;345:1591

PII: S0093-7754(10)00078-3

doi:10.1053/j.seminoncol.2010.05.013

Seminars in Oncology
Volume 37, Issue 3 , Pages 183-187, June 2010

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