Low-grade MALT lymphoma of the stomach: a review of treatment options

Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 5, pp. 1093–1103, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter

PII S0360-3016(99)00522-2

CLINICAL REVIEW

LOW-GRADE MALT LYMPHOMA OF THE STOMACH: A REVIEW OF TREATMENT OPTIONS NAOMI R. SCHECHTER, M.D.

AND

JOACHIM YAHALOM, M.D.

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Purpose: Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (MLS) is often associated with the presence of Helicobacter pylori (H. pylori) bacteria. Eradication of the infection with antibiotic therapy may result in regression of the lymphoma. But when antibiotic treatment fails to reverse the malignant process or if H. pylori is absent, other treatment options should be considered. Because MLS is often confined to the stomach and regional lymph nodes, it is potentially curable with local therapy. Endoscopy and improved imaging, with endoscopic ultrasound (EUS) and computerized tomography (CT), have reduced the prior dependence on surgery for diagnosis and staging of gastric lymphomas. Methods and Results: This review details the advances in the diagnosis, classification, and imaging of MLS. We also describe the experience that supports the use of radiation therapy as the preferred treatment of MLS in patients who have not responded to antibiotic therapy or have not had evidence for H. pylori infection. Conclusions: Radiation therapy for MLS is not only effective and safe, but offers the significant advantage of low morbidity and gastric function preservation. © 2000 Elsevier Science Inc. Non-Hodgkin’s lymphoma, MALT, Gastric lymphoma, Stomach, Radiotherapy.

in 1983, is composed of plasma cells, reactive follicles, and centrocyte-like (CCL) cells that tend to invade mucosal epithelium and form characteristic lymphoepithelial lesions (18 –21). MALT lymphoma has been reported to develop in the gastrointestinal tract (14, 22–25), salivary glands (26 – 29), lung (26 –28, 30 –32), thyroid (33–36), Waldeyer’s ring (37), larynx (38 – 40), thymus (27), liver (41, 42), kidney (43), conjunctiva (44 – 46), bladder (47), and dura (48). Most are of B-cell origin. In Western countries, the most common site is the stomach (21). Cogliatti and colleagues (49) reported a better prognosis for patients with MLS compared with that of patients with high-grade MALT lymphoma of the stomach. Unlike high-grade B-cell lymphoma of the stomach, MLS rarely spreads beyond regional lymph nodes (21, 50), making it amenable to local therapy (51–53).

EPIDEMIOLOGY OF GASTRIC LYMPHOMA Recent data suggest that the incidence of primary gastric lymphoma is rising. Between 1978 and 1982 gastric lymphoma comprised only 3% of all gastric neoplasms; between 1983 and 1987 this percentage rose to 19% (1). Data from the surveillance, epidemiology and end results (SEER) study confirmed a true increase in the age-adjusted incidence rates of gastric lymphoma, in both men and women, limited to people over the age of 60 years. Neither difference in SEER coding practices, nor changes in diagnostic procedures, could explain these observations (2). In 1992, Doglioni and colleagues (3) reported a higher incidence of primary gastric lymphoma in Northeastern Italy than in United Kingdom communities (66 vs. 5 per 100,000 per 5 years, respectively), coincident with a higher rate of gastric H. pylori infection found on endoscopy (87% vs. 50%– 60%, respectively).

MALT LYMPHOMA

CLASSIFICATION AND STAGING OF LOW-GRADE B-CELL MALT LYMPHOMA OF THE STOMACH

The stomach does not normally contain lymphoid tissue. Low-grade B-cell gastric lymphoma arises from mucosa associated lymphoid tissue (MALT), which develops in response to stimuli such as the presence of H. pylori (4 –17). MALT lymphoma, as described by Isaacson and colleagues

MALT lymphoma of the stomach (MLS) has only recently been included in a lymphoma classification. The classical lymphoma classification systems (Rappaport, Kiel, and Lukes-Collins), as well as the working formulation, largely ignored the extra-nodal lymphomas and did not

Reprint requests to: Joachim Yahalom, M.D., 1275 York Avenue, New York, NY 10021; E-mail: [email protected] Acknowledgments—This work was supported by a grant from the Sports Foundation Against Cancer (New York, NY), the Connect-

icut Sport Foundation Inc. (New London, CT), and The Lymphoma Foundation. Dr. Schechter performed this research as a Mortimer J. Lacher Lymphoma fellow at MSKCC. Accepted for publication 15 November 1999. 1093

1094

I. J. Radiation Oncology

●

Biology

●

Physics

Volume 46, Number 5, 2000

Table 1. Staging of GI lymphomas Stage I ⫽ Tumor confined to GI tract Single primary site or multiple, noncontiguous lesions Stage II ⫽ Tumor extending into abdomen from primary GI site Nodal involvement II1 local (paragastric in cases of gastric lymphoma) II2 distant (mesenteric in the case of an intestinal primary; otherwise: para-aortic, para-caval, pelvic, inguinal) Stage IIE ⫽ Penetration of serosa to involve adjacent organs or tissues Enumerate actual site of involvement, e.g., IIE[pancreas], IIE[large intestine], IIE[post abdominal wall]. Where there is both nodal involvement and penetration to involve adjacent organs, stage should be denoted using both a subscript (1 or 2) and E, e.g., II1E[pancreas]. Stage IV ⫽ Disseminated extranodal involvement, or, a GI tract lesion with supradiaphragmatic nodal involvement

recognize the unique entity of MALT lymphoma (54). However, in the new revised European-American lymphoma (REAL) classification, MALT lymphoma was included as the most common type of the marginal zone lymphomas (55). MALT lymphoma cells typically surround reactive B-cell follicles in the distribution of the marginal zone and tend to involve the marginal zone when they involve the lymph nodes or the spleen. Furthermore, the MALT lymphoma B-cells share the cytological features and immunophenotype of marginal zone B-cells (54). The Ann Arbor staging system for extranodal lymphoma as modified by Musshoff (57) is used for gastric MALT lymphoma (56, 57). The lack of a uniform staging system has caused difficulty in the comparison of data from different studies (58). In 1994, a new staging system was suggested for gastrointestinal tract lymphoma (Table 1) (59). RECENT ADVANCES Advances in endoscopic evaluation Endoscopic biopsy techniques have significantly improved in recent years. The yield of endoscopic biopsies in patients with gastric lymphoma has steadily risen, likely due to increased experience in the use of the endoscopic biopsy procedure (60). The introduction of histologic diagnostic criteria to distinguish between benign and malignant gastric disease and between MLS and other lymphomas (18 –21) enhanced the diagnostic accuracy and consistency (61). The development of simple and inexpensive histochemical stains for H. pylori such as Alcian yellow-toluidine blue (Leung) have allowed easier determination of H. pylori infection status (62). Different endoscopic techniques may be necessary for exophytic and infiltrative tumors, but, overall, surgery is rarely necessary today to establish a diagnosis of gastric MALT lymphoma. In 1993, Seifert and colleagues (63) reviewed their experience with endoscopic evaluation of 66 patients with B-cell gastric MALT lymphoma. On gross inspection, they identified both exophytic and infiltrative growth patterns (two patients had both types). They found it easier to identify the exophytic pattern as malignancy. To aid in the diagnosis of malignancy in patients with an infiltrative pattern, Seifert and colleagues recommended the use of multiple biopsies (5–10 per endoscopy session) on

repeat occasions (at least 4-week intervals, or until healing of suspicious lesions occurred). They also recommended the use of snare biopsy in patients with large gastric folds. Of the 24 exophytic tumors, 50% were low-grade; of the 17 (of 24) resected, 70% penetrated beyond the muscularis propria. Of the 44 infiltrative tumors, 77% were low-grade; of the 34 (of 44) resected, 79% were limited to the mucosa and submucosa (63). Only one patient required surgery to establish the histologic diagnosis. Swaroop and colleagues (64) also reported the use of multiple endoscopic biopsies to be safe, sensitive, and specific in the diagnosis of primary gastric lymphoma. Advances in immunologic and genetic evaluation Molecular analysis with the polymerase chain reaction (PCR) approach may aid in the diagnosis and follow-up of gastric MALT lymphoma patients. According to AshtonKey and colleagues (65), immunohistochemical detection of H. pylori in gastric biopsy specimens is sensitive and easy to perform. When a diagnosis of lymphoma is uncertain, detection of a clonal B-cell population by Southern blot analysis or the polymerase chain reaction (PCR) can be of aid (66 –71). Detection of monoclonality may precede the histologic diagnosis of lymphoma by several months (66 – 68) and may be found, after treatment, when histologic examination is negative (68, 72). For example, Thiede and colleagues (73) used PCR in combination with the genealogic analysis of shared and unshared mutations to demonstrate ongoing mutations in three of four (75%) patients who, on histologic examination, responded to antibiotic eradication of H. pylori. Thiede and colleagues’ findings led them to question the view that primary gastric low-grade B-cell MALT lymphoma can be cured solely with H. pylori eradication. PCR cannot be used as a replacement for biopsy confirmation of disease because PCR can identify tiny benign clonal collections of lymphocytes as well as malignant collections (74); nevertheless, PCR is useful as an adjunct to monitor MALT lymphoma regression during conservative treatment (75). Reactive lymphoid hyperplasia is a diagnosis of exclusion (76). Recent advances in immunology and genetics aid in the differentiation of MALT lymphoma from mantle cell and low-grade nodal lymphomas. Bcl-1 rearrangement, and cyclin D1 protein overexpression, is characteristic of mantle

MALT lymphoma of the stomach

cell lymphoma and can aid its differentiation from lowgrade MALT lymphoma (77, 78). Also useful is the presence of CD5, which is more often present in mantle cell than low-grade MALT lymphomas (79); when CD5 is present in a MALT lymphoma, it may represent a tendency for more aggressive disease (80). Wotherspoon and colleagues (81) have detected trisomy 3 in a greater proportion of low-grade MALT lymphomas (60%) than low-grade nodal lymphomas (16%). As Auer and colleagues (82) report, the most frequently reported translocation associated with MALT lymphoma is t(11;18)(q21;q21). A role for autoimmunity is being investigated (83). Transitions between benign MALT and low- and highgrade MALT lymphoma have been related to changes at the molecular level. Banerjee and colleagues suggested that the loss of chromosome 3 might have a role in the transformation of H. pylori-associated gastric MALT into low-grade B-cell gastric MALT lymphoma (84). The accumulation of p53 abnormalities (mutation and allele loss) may be associated with the transition of primary gastric MALT lymphoma from low- to high-grade (85– 87). Nakamura and colleagues (85) have found that, of 179 patients with B-cell MALT lymphoma, 6% of the low-grade tumors, 12% of the mixed-grade tumors (low-grade with a focal high-grade component), and 31% of the high-grade tumors demonstrated p53 abnormalities (p ⬍ 0.001). Conversely, 93% of low-grade tumors, 88% of mixed-grade tumors, and 44% of high-grade tumors demonstrated bcl-2 (p ⬍ 0.001) (85). The slow growth of low-grade MALT lymphoma may be partially explained by bcl-2-mediated blockage of apoptosis (86); others have implicated the overexpression of mutant bcl-10 (88, 89). Gaidano (90) and Ominishi (91) have reported an association between rearrangements of bcl-6, mutations of p53, and high-grade MALT lymphomas. Advances in imaging In 1976, when Menuck (92) reported his criteria for distinguishing primary gastric non-Hodgkin’s lymphoma from gastric cancer and Hodgkin’s lymphoma, radiographic evaluation was, by his report, the most reliable means available for the preoperative diagnosis of gastric lymphoma. Advances in endoscopy have reduced the prior dependence on surgery for diagnosis, and focused attention on noninvasive staging procedures. Computed tomography (CT) is useful in depicting preand post-treatment gastric wall abnormalities in most patients with gastric MALT. It may also detect abnormal perigastric and mesenteric lymph nodes and assist in radiation treatment planning (93). Higher quality CT information may be obtained if the stomach is distended prior to imaging. On CT, high-grade gastric non-Hodgkin’s lymphoma commonly presents with bulky gastric disease, lymphadenopathy, and locoregional extension into adjacent organs (94). Endoscopic ultrasound (EUS) is useful for the staging of low-grade gastric MALT lymphoma. It can accurately characterize both the extent of gastric wall infiltration and ad-

●

N. R. SCHECHTER

AND

J. YAHALOM

1095

jacent lymph node involvement (95). On EUS, benign lymphomatous infiltrates have a lower density than normal gastric tissue; neoplastic tissue usually has a higher density than the adjacent gastric wall (80% of the time), or the same density (20% of the time) (96). Also, on EUS, early stage primary gastric lymphoma usually involves only the second and third layers (mucosa and submucosa), whereas advanced stages may involve all five layers (transmural involvement) (97). Taal and colleagues (95) have suggested that information acquired from EUS can be combined with CT scan data to stage a gastric lymphoma patient without laparotomy. In 1993, Caletti and colleagues (98) prospectively correlated the results of EUS with the histologic findings on 86 patients with a gross endoscopic appearance suggestive of malignancy. EUS made a correct diagnosis of lymphoma in 39 of 44 patients, with a sensitivity of 89% and specificity of 97%. In the evaluation of lymphoma depth of invasion, EUS was correct in 92% of the cases. In addition, EUS displayed perigastric lymph nodes in 8 of 18 patients, with a sensitivity of 44% and specificity of 100% (98). With increasing expertise in the use of EUS, its accuracy and acceptance will likely increase (99 –101); and, as Caletti and colleagues (98) predicted, exploratory laparotomy may no longer be necessary for the staging of a gastric lymphoma patient. TREATMENT OPTIONS Several modalites have been utilized, including surgery, antibiotic therapy, radiation therapy, and chemotherapy. In the past, primary gastric lymphoma was treated with surgery, consisting of a partial or total gastrectomy (102–109). However, low-grade B-cell gastric lymphoma of MALT has been reported to regress in response to antibiotic eradication of H. pylori bacteria, bringing into question the need for resection or cytotoxic first-line therapy for this particular type of gastric lymphoma (110 –116). When antibiotic therapy fails or is irrelevant, as in the absence of H. pylori, effective treatment options consist of surgery and radiation therapy (108, 117–127). Systemic therapy has also been considered, and responses of low-grade B-cell MALT lymphoma to chemotherapy alone have been reported (50, 128). Unfortunately, several patients achieved only a partial response, and many patients relapsed (128, 129). A survival advantage with adjuvant chemotherapy remains to be proven (50, 128 –130). Surgery Most surgical studies have organized their data by stage rather than grade, and not specifically addressed the management of low-grade gastric MALT lymphoma. In 1992, Radaszkiewicz and colleagues (56) reported a retrospective evaluation of 372 patients with primary gastrointestinal non-Hodgkin’s lymphoma (GI NHL) staged EI/EII (244 gastric; 63 intestinal); 340 patients remained available for evaluation after removal of those with MLP (malignant lymphomatous polyposis) and those lost to follow-up. Suf-

1096

I. J. Radiation Oncology

●

Biology

●

Physics

ficient clinical and follow-up data were available for analysis of 307 patients. Of these 307 patients with stage EI/EII cases of primary GI NHL, 113 were of low-grade B-cell centrocyte cell-like (CCL) or immunoblast cell-like (ICL) type (89% gastric and 11% intestinal). Of the 307 cases, 97.5% underwent tumor resection and 37% received adjuvant chemotherapy and/or radiation therapy. The mode, combination, and dose of chemotherapy agents varied widely. The total radiation dose ranged from 10 to 40 Gy and was delivered to either the site of initial involvement or to residual disease. The overall survival at 2, 5, and 10 years was 61%, 55%, and 46%, respectively. The prognosis of early stage lymphomas (substage EI) was the best, with an overall survival at 5 and 10 years of 90% and 70%, respectively. Of the 340 primary GI NHLs, only 43% (68/157) of stage EI patients and 27% (50/183) of stage EII patients were of the low-grade B cell CCL/ICL type, and their survival was not separately analyzed. Therefore, one cannot directly extrapolate from EI/EII primary GI (or even gastric) NHL data to determine the best treatment for low-grade B cell gastric lymphoma (56). Recently, Montalban and colleagues (50) reported an estimated 100% 5-year survival for patients with low-grade gastric MALT lymphoma treated with surgery alone (n ⫽ 34; median follow-up of 36 months). They did not report the disease-free survival for patients treated with surgery alone. It is of interest, however, that of the 91% of patients who achieved a complete response following treatment with either surgery alone, surgery plus chemotherapy, or chemotherapy alone, 11% relapsed in the stomach (50). Post-gastrectomy syndromes occur in up to 20% of patients. Up to 5% of patients may remain symptomatic for the duration of their lives; and 1% of patients may become permanently disabled “gastric cripples” (131). In Montalban’s review (50) of 142 gastric MALT lymphomas treated primarily with surgery, the surgical complication rate was 16% (17/142); and the operative mortality rate was 4.8%. Of the 142 patients, 77.5% had stage I–II disease. Incomplete resection of the lymphoma will still require postoperative irradiation and/or chemotherapy (50). Anti-Helicobacter Pylori therapy The development of gastric MALT and gastric MALT lymphoma is primarily based upon an immune response to H. pylori colonization of the gastric mucosa, and MLS may remain dependent on H. pylori specific T cells for proliferation. In 1989, Stolte and colleagues (4) studied the prevalence of lymphoid follicles in endoscopic biopsy specimens in 2692 patients with H. pylori antral gastritis. The numbers of lymphoid follicles and aggregates significantly correlated with the degree and activity of gastritis in the antral mucosa and with the density of H. pylori colonization. They concluded that the development of lymphoid follicles in the antral mucosa probably represented, primarily, an immune response to the colonization of the mucosa by H. pylori bacteria (4). In 1996, Hsi and colleagues (11) reported the presence of clonal heavy chain gene rearrangement in

Volume 46, Number 5, 2000

chronic active gastritis with H. pylori (CAG-Hp), supporting a role for H. pylori in the development of low-grade B-cell gastric MALT lymphoma. The association between H. pylori-associated chronic gastritis and gastric MALT lymphoma has been supported by molecular analysis; with a patient-specific PCR approach, Zucca and colleagues (132) have documented two cases in which a gastric MALT lymphoma developed from a B-cell clone at the site of chronic gastritis. Hussel and colleagues (6, 13) have reported that the response of low-grade B-cell gastric MALT lymphomas to stimulating strains of H. pylori is dependent on H. pylori specific T cells and their products rather than the bacteria themselves. Low-grade MALT B-cell proliferation is dependent on CD40 signaling in combination with T-helper cell cytokines such as IL-10. The low-grade MALT lymphomas’ proliferative response to IL-10 (a Th2-cytokine) appears to be greater than that of high-grade MALT lymphomas; but high grade MALT lymphomas appear to proliferate in response to both Th 2-type (IL-4, IL-10) and Th1-type cytokines (IL-2, interferon-gamma), and CD40 stimulation (133). Calvert and colleagues (12) studied allele imbalance at tumor-suppressor gene loci as an indicator of genetic change in gastric MALT lymphoma and found evidence to support their hypothesis that the phenotypic differences between chronic gastritis, low-grade MALT lymphoma, and high-grade MALT lymphoma are related to changes at the DNA level. The transformation to high-grade MALT lymphoma may occur when the lymphoid cells acquire a genetic lesion that removes their dependence on H. pylori for proliferation (12). Most gastric MALT lymphoma patients (67/68; 98.5%) are seropositive for H. pylori (134), but only 58% of resection specimens actually contain the H. pylori bacteria; this percentage is greater for superficial low-grade gastric MALT lymphomas (63%) than advanced high-grade MALT lymphomas (38%), thus suggesting a promotor role for the H. pylori bacteria (135). CagA protein positive strains of H. pylori are more closely associated with high-grade gastric MALT lymphomas (23/30) than low-grade gastric MALT lymphomas (17/56) (p ⬍ 0.05) and may be related to the transformation of a low-grade gastric MALT lymphoma to high grade (136). Other potential infectious cofactors in the development of low-grade B-cell MALT lymphoma include the Hepatitis C virus (HCV) and a human T-cell leukemia/lymphoma virus (HTLV-1) (137, 138); Epstein-Barr virus is unlikely to have a primary role (139). Long and colleagues (140) have reported that the endoscopic and histologic appearance of syphilis can imitate that of lymphocytic gastritis and gastric lymphoma. Antibiotic eradication of H. pylori bacteria has been able to yield regression of low-grade gastric MALT lymphoma in many patients, at least temporarily; unfortunately the response is slow, and often incomplete. Wotherspoon and colleagues (110) reported in 1993 on the treatment of six patients with biopsy-proven low-grade B-cell MALT lym-

MALT lymphoma of the stomach

phoma and H. pylori infection with antibiotic therapy alone. H. pylori was eradicated in all cases. In five, repeated biopsies showed no evidence of residual lymphoma, suggesting that the antibiotic eradication of H. pylori causes regression of low-grade B-cell gastric MALT. Four cases in this study were retrospectively diagnosed as MALT lymphoma and followed for 11–38 months without progression, suggesting that there is no urgency for radical therapy, and H. pylori therapy should be the first line of treatment (110). The MALT Lymphoma Study Group evaluated 33 patients with primary gastric low-grade MALT lymphoma associated and H. pylori gastritis treated with omeprazole (120 mg QD) and amoxycillin (2.25 g QD) for 14 days (113). PCR was used to examine the proliferation of monoclonal B-cells before treatment and during follow-up. In most of the cases, a single course was sufficient to eradicate the H. pylori; two patients required a second course. On follow-up, 23 (70%) of the patients had complete histologic regression of their lymphoma. Four (12%) had partial regression; and six (18%) had no change. One was treated with chemotherapy, and five were treated with surgery. In 13 of 16 patients investigated, PCR revealed the complete disappearance of monoclonal B-cells after cure of the H. pylori infection. During a median follow-up of 1 year, no relapse of MALT lymphoma occurred. Recently, the same investigators reported the results of a PCR-based genealogical analysis of shared and unshared mutations demonstrating ongoing mutations in three of four (75%) patients with primary MLS whose MLS completely responded to antibiotic eradication of H. pylori. Thiede and colleagues’ (73) findings have led to questions regarding the actual cure of MLS with anti-H. pylori therapy alone. In 1995, Roggero and colleagues (114) reported the results of a prospective cohort study performed in Switzerland. Antibiotic eradication of H. pylori was effective in 25 of 26 patients with primary low-grade gastric MALT lymphoma. At least partial regression of lymphoma was observed in 60% (15/25) of the evaluable patients; of these, only 53% (8/15) had evidence of regression at first follow-up biopsy (114). Steinbach and colleagues (141) at the M.D. Anderson Cancer Center treated 34 Stage I or Stage II N1 gastric MALT lymphoma patients with antibiotic therapy and followed them for a mean of 41 months (range of 18 –70 months) with repeat endoscopies every 3– 4 months. Only 50% of the 28 H. pylori-positive patients achieved a complete remission; 8 (29%) achieved a partial remission (half of whom eventually failed); and 10 (36%) did not respond (141). As Genta and colleagues (142) and Kosunen and colleagues (143) demonstrated, eradication of H. pylori might cause regression of lymphoid follicles, but the process is slow and not always complete. Even after antibiotic therapy, lymphoma may remain in deeper levels of the gastric wall (144). Relapses following antibiotics are not uncommon. Neubauer and colleagues (145) reported on 50 patients with MLS and H. pylori infection treated with antibiotics alone. Forty patients achieved a complete remission, but five even-

●

N. R. SCHECHTER

AND

J. YAHALOM

1097

tually relapsed, and 71% of assessable patients (22/31) had PCR evidence of residual monoclonal B cells on follow-up (145). The persistence of monoclonality in post-treatment biopsies without histologic evidence of MALT lymphoma suggests that eradication of H. pylori suppresses, but does not eradicate, the neoplastic clone in all cases (54).

Radiation therapy While the sensitivity of gastric lymphoma to radiation therapy has long been known, it was the move towards noninvasive staging procedures that has led to renewed interest in noninvasive treatment modalities such as radiotherapy. In the past, the primary treatment for primary gastric lymphoma was resection (126). When radiation therapy and/or chemotherapy was used, the approach tended to vary from patient to patient, leading to difficulties in data interpretation (49, 102, 103, 106, 108, 117–122, 124, 125, 127, 146 –156). Nevertheless, in some studies, a survival advantage has been demonstrated for postoperative radiation therapy (103, 117, 118, 151, 152, 157). In 1988, Burgers and colleagues (119) reported results of the Netherlands Cancer Institute where, since 1978, 24 clinical Stage I gastric NHL patients were treated with radiation therapy alone in an attempt to avoid, whenever possible, partial or complete gastrectomy. The radiation therapy consisted of WART (whole abdominal radiation therapy) of 20 Gy in 3 weeks, five fractions per week, followed by a boost to the whole stomach and para-aortic lymph nodes to L2–L3 with an additional 20 Gy in 2 weeks, for a total dose of 40 Gy. The 4-year actuarial disease-free survival rate was 83% with a median follow-up of 48 months. Unfortunately, one cannot determine from this report the specific histologies of the patients who received radiation therapy alone (119). At Memorial Sloan Kettering Cancer Center we have reported our experience in treating 17 patients with specifically low-grade B-cell gastric MALT lymphoma with primary radiation therapy to the stomach and perigastric lymph nodes (52, 53). Seventeen patients with Stage I to II2 lowgrade MALT lymphoma of the stomach without evidence of H. pylori infection or with persistent lymphoma after antibiotic therapy of associated H. pylori infection were included in this series. The median age was 69 years (range 39 – 84 years). The median total radiation dose was 30 Gy (range 28.5– 43.5 Gy) delivered in 1.5-Gy fractions within 4 weeks to the stomach and adjacent lymph nodes. Following treatment, all patients underwent endoscopic evaluation and biopsy at a median of 4 months, at 6-month intervals to 2 years, and annually thereafter. All obtained a biopsy-confirmed complete response. At a median follow-up time of 27 months (range 11– 68 months) from completion of radiotherapy, event-free survival was 100%. Treatment was well tolerated, with no significant acute side effects. All remained asymptomatic at last follow-up. These results suggest that effective treatment of MALT lymphoma of the stomach with low-dose radiation therapy alone is feasible

1098

I. J. Radiation Oncology

●

Biology

●

Physics

and safe, and allows gastric preservation. Longer follow-up evaluation will be required to determine the long-term efficacy of this treatment approach and its side effects. Further studies should clarify the indications for radiotherapy in H. pylori-negative or antibiotic-resistant cases of MALT lymphoma of the stomach (52, 53). The main argument against irradiation of the stomach has been the risk of perforation and bleeding; other concerns include renal toxicity and the induction of second malignancies. On review of the literature, these risks appear minimal. The incidence of radiation-induced perforation or bleeding is ⬍ 4%. In Mittal and colleagues’ (117) literature review, published in 1983, only 4% (3/75) developed gastric perforation; and only 1% (1/75) developed gastric perforation directly attributable to radiation therapy treatment. In 1990, Talamonti and colleagues (158) reported in the Archives of Surgery, a review of 42 patients with primary gastrointestinal lymphoma. In their report, five of the patients who did not undergo surgical resection before radiation or chemotherapy developed severe life-threatening complications resuting from progression of their primary tumor. However, none of the five patients who developed bleeding or perforation had Stage I or II gastric lymphoma: one was a 65-year-old with Stage III gastric lymphoma; one was a 61-year-old with Stage IV colonic lymphoma; one was a 61-year-old with Stage IV small intestinal lymphoma; one was a 59-year-old with Stage II small intestinal lymphoma; and one was a 64-year-old with Stage IV colonic lymphoma (158). In their review of nonsurgical approaches to gastric lymphoma, Varsos and Yahalom (159) distinguished between complications arising in early-stage patients and complications of advanced-stage (nonoperable) cases. The reported incidence of perforation or hemorrhage occurring with nonsurgical treatment of primary gastric lymphoma, including advanced stages was 9.7% (15/158). Yet, the incidence of gastric perforation or hemorrhage in nonsurgically treated cases of primary gastric lymphoma limited to the stomach and first echelon lymph nodes was only 3.5% (3/86) (159). The risk of clinically significant hypertension or renal dysfunction attributable to primary radiation therapy of gastric lymphoma patients is rare (160). Typically, only the left kidney needs to be in a high-dose region. Should part or the entire right kidney receive a significant dose of radiation, the risk of hypertension may increase (161). The possibility exists for development of a second malignancy, such as adenocarcinoma, years after radiation therapy treatment; its incidence, however, is rare (162, 163). Patients with gastric lymphoma tend to be at increased risk for gastric adenocarcinoma, irrespective of the treatment modality, be it surgery, radiation therapy, chemotherapy, or some combination thereof (164, 165). This may be due to a common pathogenesis of gastric lymphoma and gastric adenocarcinoma, as recent data have accumulated linking adenocarcinoma of the stomach with H. pylori infection (166 – 168).

Volume 46, Number 5, 2000

Chemotherapy There is only limited information on the use of chemotherapy as primary or adjuvant therapy in the treatment of lowgrade gastric MALT lymphoma. Hammel and colleagues (128) treated 24 consecutive patients with low-grade MALT lymphoma with 12–24 months of an oral alkylating agent (cyclophosphamide or chlorambucil) alone. Only 18 of the patients (75%) completely responded, and 5 of them relapsed. Median follow-up was 45 months (128). In another series, the 5-year survival of patients with low-grade MALT lymphoma treated with chemotherapy alone was only 34% (169). Ruskone-Fourmestraux and colleagues (129) reported the outcome of seven patients with primary low-grade gastric NHL treated with postoperative COP (cyclophosphamide, vincristine, prednisolone) chemotherapy. The small number of patients in this study with low-grade gastrointestinal tract lymphoma (n ⫽ 28) and the insufficient follow-up did not allow any definite conclusion to be drawn about the role of postoperative chemotherapy (129). Nakamura and colleagues (130) reported an estimated 96% 5-year and 89% 10-year survival for patients with MLS treated with surgery alone or surgery followed by chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Unfortunately, the potential effect of the adjuvant chemotherapy to the low-grade subset of patients was not reported. Montalban and colleagues (50) have reported an estimated 5-year survival of 100% for MLS treated with surgery alone, 34% for those treated with chemotherapy alone, and 100% for those treated with surgery plus chemotherapy (n ⫽ 79; median follow-up of 36 months; multicenter study). Of the 28 patients who were treated with chemotherapy alone, the incidence of hemorrhage was 6.6% (one patient with lowgrade disease and one patient with high-grade disease); and the incidence of perforation was 3.3% (one patient with low-grade disease) (50). CONCLUSION The special characteristics of low-grade B-cell gastric MALT lymphoma have recently been established. Strong evidence exists for its association with H. pylori infection and for the efficacy of antibiotic therapy in achieving lymphoma regression when the bacteria is present. Long-term control of the malignant process with antibiotic therapy is uncertain, and treatment for patients with no evidence of H. pylori or who fail antibiotic therapy has not been determined. With increased use of a uniform staging system and better distinction between low-grade MALT and aggressive lymphomas, studies on the treatment of this disease will be easier to interpret and the best treatment modality more obvious. Recent advances in endoscopy, radiology, and immunology, as well as genetics, have reduced the prior dependence on surgery for diagnosis and staging purposes. Chemotherapy has not been proven as a successful treatment for low-grade B-cell gastric MALT lymphoma. Radiation therapy appears to be a safe and effective alternative that offers the patient the significant advantage of gastric organ preservation.

MALT lymphoma of the stomach

●

N. R. SCHECHTER

AND

J. YAHALOM

1099

REFERENCES 1. Hayes J, Dunn E. Has the incidence of primary gastric lymphoma increased? Cancer 1989;63:2073–2076. 2. Severson RK, Davis S. Increasing incidence of primary gastric lymphoma. Cancer 1990;66:1283–1287. 3. Doglioni C, Wotherspoon AC, Moschini A, et al. High incidence of primary gastric lymphoma in northeastern Italy. Lancet 1992;339:834 – 835. 4. Stolte M, Eidt S. Lymphoid follicles in antral mucosa: immune response to Campylobacter pylori? J Clin Pathol 1989; 42:1269 –1271. 5. Fox ER, Blanco M, Murphy JC, et al. Local and systemic immune responses in murine Helicobacter felis active chronic gastritis. Infect Immun 1993;61:2309 –2315. 6. Hussell T, Isaacson PG, Crabtree JE, et al. The response of cells from low-grade B-cell gastric lymphomas of mucosaassociated lymphoid tissue to Helicobacter pylori. Lancet 1993;342:571–574. 7. Greiner A, Marx A, Heesemann J, et al. Idiotype identity in a MALT-type lymphoma and B cells in Helicobacter pylori associated chronic gastritis. Lab Investig 1994;70: 572–578. 8. Eidt S, Stolte M, Fischer R. Helicobacter pylori gastritis and primary gastric non-Hodgkin’s lymphomas. J Clin Pathol 1994;47:436 – 439. 9. Isaacson PG. Gastrointestinal lymphoma. Hum Pathol 1994; 25:1020 –1029. 10. Du M, Diss TC, Xu C, et al. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 1996; 10:1190 –1197. 11. Hsi ED, Greenson JK, Singleton TP, et al. Detection of immunoglobulin heavy chain gene rearrangement by polymerase chain reaction in chronic active gastritis associated with Helicobacter pylori. Hum Pathol 1996;27:290 –296. 12. Calvert R, Randerson J, Evans P, et al. Genetic abnormalities during transition from Helicobacter pylori gastritis to lowgrade MALToma. Lancet 1995;345:26 –27. 13. Hussell T, Isaacson PG, Crabtree JE, et al. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in lowgrade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 1996;178:122–127. 14. Isaacson PG. Recent developments in our understanding of gastric lymphomas. Am J Surg Pathol 1996;20(Suppl. 1):S1– S7. 15. Cammarota G, Tursi A, Papa A, et al. The growth of primary low-grade B-cell gastric lymphoma is sustained by Helicobacter pylori. Scand J Gastroenterol 1997;32:285–287. 16. Dogan A, Du M, Koulis A, et al. Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue. Am J Pathol 1997;151:1361–1369. 17. Eck M, Schmausser B, Haas R, et al. MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein. Gastroenterol 1997;112:1482– 1486. 18. Isaacson PG, Spencer J, Finn T. Primary B-cell gastric lymphoma. Hum Pathol 1986;17:72– 82. 19. Isaacson P, Wright DH. Malignant lymphoma of mucosaassociated lymphoid tissue. A distinctive type of B cell lymphoma. Cancer 1983;52:1410 –1416. 20. Isaacson P, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984;53:2512–2524. 21. Isaacson PG, Spencer J. Malignant lymphoma of mucosaassociated lymphoid tissue. Histopathol 1987;11:445– 462.

22. Kojima M, Nakamura S, Kurabayashi Y, et al. Primary malignant lymphoma of the intestine: clinicopathologic immunohistochemical studies of 39 cases. Pathol Int 1995;45: 123–130. 23. Moore I, Wright DH. Primary gastric lymphoma–a tumour of mucosa-associated lymphoid tissue. A histological and immunohistochemical study of 36 cases. Histopathol 1984;8: 1025–1039. 24. Schmid C, Vazquez JJ, Diss TC, et al. Primary B-cell mucosa-associated lymphoid tissue lymphoma presenting as solitary colorectal polyp. Histopathol 1994;24:357– 362. 25. Kawai T, Tada T, Yokoyama Y, et al. Lymphoma arising in mucosa-associated lymphoid tissue of the duodenal bulb. J Gastroenterol 1998;33:97–101. 26. Hyjek E, Smith WJ, Isaacson PG. Primary B cell lymphoma of salivary gland and its relationship to myoepithelial sialadenitis. Hum Pathol 1988;19:766 –776. 27. Di LC, Mariuzzi L, De GA, et al. B cell lymphoma of the thymus and salivary gland. J Clin Pathol 1996;49:595– 597. 28. Stewart A, Blenkinsopp PT, Henry K. Bilateral parotid MALT lymphoma and Sjogren’s syndrome. Br J Oral Maxillofacial Surg 1994;32:318 –322. 29. Cha I, Long SR, Ljung BM, et al. Low-grade lymphoma of mucosa-associated tissue in the parotid gland: a case report of fine-needle aspiration cytology diagnosis using flow cytometric immunophenotyping. Diagnostic Cytopathol 1997; 16:345–349. 30. Poletti V, Romagna M, Gasponi A, et al. Bronchoalveolar lavage in the diagnosis of low-grade, MALT type lymphoma in the lung. Monaldi Arch Chest Dis 1995;50:191–194. 31. Fiche M, Caprons F, Berger F, et al. Primary pulmonary non-Hodgkin’s lymphomas. Histopathol 1995;26:529 –537. 32. Liaw YS, Yang PC, Su IJ, et al. Mucosa-associated lymphoid tissue lymphoma of the lung with cold-reactive autoantibody-mediated hemolytic anemia. Chest 1994;105:288 –290. 33. Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol 1988;19:1315–1326. 34. Laing RW, Hoskin P, Hudson BV, et al. The significance of MALT histology in thyroid lymphoma: a review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol 1994;6:300 –304. 35. Sasai K, Yamabe H, Haga H, et al. Non-Hodgkin’s lymphoma of the thyroid. A clinical study of twenty-two cases. Acta Oncol 1996;35:457– 462. 36. Lovchik J, Lane MA, Clark DP. Polymerase chain reactionbased detection of B-cell clonality in the fine needle aspiration biopsy of a thyroid mucosa-associated lymphoid tissue (MALT) lymphoma. Hum Pathol 1997;28:989 –992. 37. Menarguez J, Mollejo M, Carrion R, et al. Waldeyer ring lymphomas. A clinicopathological study of 79 cases. Histopathol 1994;24:13–22. 38. Horny HP, Ferlito A, Carbone A. Laryngeal lymphoma derived from mucosa-associated lymphoid tissue. Ann Otol Rhinol Laryngol 1996;105:577–583. 39. Kato S, Sakura M, Takooda S, et al. Primary non-Hodgkin’s lymphoma of the larynx. J Laryngol Otol 1997;111:571–574. 40. Kracke A, Hiller AS, Tschernig T, et al. Larynx-associated lymphoid tissue (LALT) in young children. Anatom Record 1997;248:413– 420. 41. Isaacson PG, Banks PM, Best PV, et al. Primary low-grade

1100

42. 43.

44. 45. 46. 47.

48.

49. 50.

51. 52. 53. 54. 55.

56.

57. 58.

59.

60. 61.

I. J. Radiation Oncology

●

Biology

●

Physics

hepatic B-cell lymphoma of mucosa-associate tissue (MALT)-type. Am J Surg Pathol 1995;19:571–575. Maes M, Depardieu C, Dargent JL, et al. Primary low-grade B-cell lymphoma of MALT-type occurring in the liver: a study of two cases. J Hepatol 1997;27:922–927. Parveen T, Navarro-Roman L, Medeiros LJ, et al. Lowgrade B-cell lymphoma of mucosa-associated lymphoid tissue arising the kidney. Arch Pathol Lab Med 1993;117: 780 –783. Cahill MT, Moriarty PA, Kennedy SM. Conjunctival ‘MALToma’ with systemic recurrence. Arch Ophthalmol 1998; 116:97–99. Calvo R, Ribera JM, Vaquero M, et al. Low-grade, malttype, primary B-cell lymphoma of the conjunctiva. Leuk Lymph 1997;28:203–207. Kurz-Levin MM, Flury R, Bernauer W. Diagnosis of MALT lymphoma by conjunctival biopsy: a case report. Graefes Arch Clin Exp Ophthalmol 1997;235:606 – 609. Kempton CL, Kurtin PJ, Inwards DJ, et al. Malignant lymphoma of the bladder: evidence from 36 cases that low-grade lymphoma of the MALT-type is the most common primary bladder lymphoma. Am J Surg Pathol 1997; 21:1324 –1333. Kumar S, Kumar D, Kaldjian EP, et al. Primary low-grade B-cell lymphoma of the dura: a mucosa associated lymphoid tissue-type lymphoma. Am J Surg Pathol 1997;21: 81– 87. Cogliatti SB, Schmid U, Schumacher U, et al. Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterol 1991;101:1159 –1170. Montalban C, Castrillo JM, Abraira V, et al. Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma: clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 1995;6:355–362. Fung C, Grossbard M, Linggood R, et al. Mucosa-associated lymphoid tissue lymphoma of the stomach: Long term outcome after local treatment. Cancer 1999;85:9 –17. Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998;16:1916 –1921. Yahalom J, Schechter NR, Gonzales M, et al. Effective treatment of MALT lymphoma of the stomach with radiation alone. (abstr.) Ann Oncol 1999;10(Suppl. 3):135. Isaacson PG. Gastric MALT lymphoma: from concept to cure. Ann Oncol 1999;10:637– 645. Harris NL, Jaffe ES, Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International lymphoma study group. Blood 1994;84:1361– 1392. Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterol 1992;102: 1628 –1638. Musshoff K. Stadieneinteilung der nicht-Hodgkin lymphome. Strahlentherapie 1977;153:218 –221. de Jong D, Aleman B, Taal B, et al. Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: an international survey. Ann Oncol 1999;10:275– 280. Rohatiner A, d’Amore B, Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphomas. Ann Oncol 1994;5:397– 400. Maor MH, Maddux B, Osborne BM, et al. Stages IE and IIE non-Hodgkin’s lymphomas of the stomach: comparison of treatment modalities. Cancer 1984;54:2330 –2337. Arista-Nasr J, Jimenez A, Keirns C, et al. The role of the endoscopic biopsy in the diagnosis of gastric lymphoma: a

Volume 46, Number 5, 2000

62.

63.

64.

65.

66.

67. 68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

morphologic and immunohistochemical reappraisal. Hum Pathol 1991;22:339 –348. Vartanian RK, Leung JK, Davis JE, et al. A novel Alcian yellow-toluidine blue (Leung) stain for Helicobacter species: comparison with standard stains, a cost-effectiveness analysis, and supplemental utilities. Mod Pathol 1998;11: 72–78. Seifert E, Schulte F, Weismuller J, et al. Endoscopic and bioptic diagnosis of malignant non-Hodgkin’s lymph the stomach. Endoscopy 1993;25:497–501. Swaroop VS, Mohandas KM, Swaroop VD, et al. Comparative endoscopic study of primary gastric lymphoma vs. carcinoma. J Surg Oncol 1994;56:94 –97. Ashton-Key M, Diss TC, Isaacson PG. Detection of Helicobacter pylori in gastric biopsy and resection. J Clin Pathol 1996;49:107–111. Lerman-Sagie T, Ziv Y, Rubin M, et al. Gastric lymphoma versus pseudolymphoma: the importance of immunological differentiation. [published erratum appears in Am J Gastroenterol 1986 81(3):223] Am J Gastroenterol 1985;80:763– 766. Fend F, Schwaiger A, Weyrer K, et al. Early diagnosis of gastric lymphoma: gene rearrangement analysis of endoscopic biopsy samples. Leukemia 1994;8:35–39. Savio A, Franzin G, Wotherspoon AC, et al. Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: histology, polymerase chain reaction, or both? Blood 1996;87: 1255–1260. Rudolph B, Bayerdorffer E, Ritter M, et al. Is the polymerase chain reaction or cure of Helicobacter pylori infection of help in the differential diagnosis of early gastric mucosaassociated lymphatic tissue lymphoma? J Clin Oncol 1997; 15:1104 –1109. 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. Nakamura S, Aoyagi K, Furuse M, et al. B-cell monoclonality precedes the development of gastric MALT lymphoma in Helicobacter pylori-associated chronic gastritis. Am J Pathol 1998;152:1271–1279. Rudolph B, Bayerdorffer E, Ritter M, et al. Is the polymerase chain reaction or cure of Helicobacter pylori infection of help in the differential diagnosis of early gastric mucosaassociated lymphatic tissue lymphoma? J Clin Oncol 1997; 15:1104 –1109. Thiede C, Alpen B, Margner A, et al. Ongoing somatic mutations and clonal expansions after cure of Helicobacter pylori infection in gastric-mucosa-associated lymphoid tissue B-cell lymphoma. J Clin Oncol 1998;16:3822–3831. Weston AP, Banerjee SK, Horvat RT, et al. Specificity of polymerase chain reaction monoclonality for diagnosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma: direct comparison to Southern blot gene rearrangement. Digest Dis Sci 1998;43:290 –299. Aiello A, Giardini R, Tondini C, et al. PCR-based clonality analysis: a reliable method for the diagnosis and follow-up monitoring of conservatively treated gastric B-cell MALT lymphomas? Histopathol 1999;34:326 –330. Umemura S, Tang X, Aihara H, et al. Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach progressing to overt B cell malignancy. Pathol Int 1994;44:808 – 814. Kumar S, Krenacs L, Otsuki T, et al. Bc1-1 rearrangement and cyclin D1 protein expression in multiple lymphomatous polyposis. Am J Clin Pathol 1996;105:737–743.

MALT lymphoma of the stomach

78. Zukerberg LR, Benedict WF, Arnold A, et al. Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1. Blood 1996;88:268 – 276. 79. Fraga M, Lloret E, Sanchez-Verde L, et al. Mucosal mantle cell (centrocytic) lymphomas. Histopathol 1995;26:413– 422. 80. Ferry JA, Yang WI, Zukerberg LR, et al. CD5⫹ extranodal marginal zone B-cell (MALT) lymphoma: a low neoplasm with a propensity for bone marrow involvement and rela. Am J Clin Pathol 1996;105:31–37. 81. Wotherspoon AC, Finn TM, Isaacson PG. Trisomy 3 in low-grade B-cell lymphomas of mucosa-associated ly tissue. Blood 1995;85:2000 –2004. 82. Auer IA, Gascoyne RD, Connors JM, et al. T(11;18)(q21; q21) is the most common translocation in Malt lymphomas. Ann Oncol 1997;8:979 –985. 83. Yumoto N, Furukawa M, Kurosu K, et al. A particular characteristic of IgH complementarity-determining region 3 suggests autoreactive B-cell origin of primary gastric B-cell lymphomas. Lab Invest 1998;78:261–268. 84. Banerjee SK, Weston AP, Persons DL, et al. Non-random loss of chromosome 3 during transition of Helicobacter pylori-associated gastric MALT to B-cell MALT lymphoma revealed by fluorescence in situ hybridization. Cancer Lett 1997;121:83–90. 85. Nakamura S, Akazawa K, Kinukawa N, et al. Inverse correlation between the expression of bcl-2 and p53 proteins in primary gastric lymphoma. Hum Pathol 1996;27: 225–233. 86. Du MQ, Peng H, Singh N, et al. The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma. Blood 1995;86:4587– 4593. 87. Chetty R, O’Leary JJ, Biddolph SC, et al. Immunohistochemical detection of p53 and Bcl-2 proteins in Hash thyroiditis and primary thyroid lymphomas. J Clin Pathol 1995; 48:239 –241. 88. Zhang Q, Siebert R, Yan M, et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domaincontaining gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999;22:63– 68. 89. Willis T, Jadayel D, Du M, et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 1999;96:35– 45. 90. Gaidano G, Volpe G, Pastore C, et al. Detection of BCL-6 rearrangements and p53 mutations in Malt-lymphomas. Am Hematol 1997;56:206 –213. 91. Omonishi K, Yoshino T, Sakuma I, et al. Bcl-6 protein is identified in high-grade but not low-grade mucosa-associated lymphoid tissue lymphomas of the stomach. Mod Pathol 1998;11:181–185. 92. Menuck LS. Gastric lymphoma, a radiologic diagnosis. Gastrointestinal Radiol 1976;1:157–161. 93. Gollub MJ, Latrenta L, Yahalom J, et al. Utility of abdominal CT in gastric MALT lymphoma. Am J Radiol 1999; 172(Suppl. 3):57–58. 94. Kessar P, Norton A, Rohatiner A, et al. CT appearances of mucosa-associated lymphoid tissue (MALT) lymphoma. Eur Radiol 1999;9:693– 696. 95. Taal BG, Den Hartog Jager FCA, Burgers JMV, et al. Primary non-Hodgkin’s lymphoma of the stomach: changing aspects and therapeutic choices. Eur J Cancer Clin Oncol 1989;25:439 – 450. 96. Angelelli G, Macarini L, Favia G. The CT aspects and pathological correlations in gastric adenoca and lymphoma. [in Italian] Radiologia Medica 1990;79:191–196. 97. Songur Y, Okai T, Watanabe H, et al. Endosonographic

●

N. R. SCHECHTER

98. 99.

100.

101.

102. 103. 104. 105. 106. 107.

108. 109. 110.

111.

112.

113.

114.

115. 116.

AND

J. YAHALOM

1101

evaluation of giant gastric folds. Gastrointest Endosc 1995; 41:468 – 474. Caletti G, Barbara L. Gastric lymphoma: difficult to diagnose, difficult to stage? [editorial] Endoscopy 1993;25:528 – 530. Levy M, Hammel P, Lamarque D, et al. Endoscopic ultrasonography for the initial staging and follow-up in patients with low-grade gastric lymphoma of mucosa-associated lymphoid tissue treated medically. Gastrointest Endosc 1997;46: 328 –333. Pavlick AC, Gerdes H, Portlock CS. Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors. J Clin Oncol 1997;15: 1761–1766. Sackmann M, Morgner A, Rudolph B, et al. Regression of gastric MALT lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. MALT Lymphoma Study Group. Gastroenterol 1997;113:1087– 1090. Fleming ID, Mitchell S, Dilawari RA. The role of surgery in the management of gastric lymphoma. Cancer 1982;49:1135–1141. Rosen CB, van HJA, Martin JK, Jr., et al. Is an aggressive surgical approach to the patient with gastric warranted? Ann Surg 1987;205:634 – 640. Ichiyoshi Y, Toda T, Nagasaki S, et al. Surgical approaches in primary gastric lymphoma and carcinoma. Int Surg 1993; 78:103–106. Bartlett DL, Karpeh MS, Jr., Filippa DA, et al. Long-term follow-up after curative surgery for early gastric lymphoma. Ann Surg 1996;223:53– 62. Durr ED, Bonner JA, Strickler JG, et al. Management of stage IE primary gastric lymphoma. Acta Haematol 1995;94: 59 – 68. Rigacci L, Bellesi G, Alterini R, et al. Combined surgery and chemotherapy in primary gastric non-H lymphoma: a retrospective study in sixty-six patients. Leuk Lymph 1994;14: 483– 489. Roukos DH, Hottenrott C, Encke A, et al. Primary gastric lymphomas: a clinicopathologic study with literature review. Surg Oncol 1994;3:115–125. Speranza V, Lomanto D, Meli EZ, et al. Primary gastric lymphoma: a 15-year review. Hepatol Gastroenterol 1995; 42:371–376. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993;342:575–577. Weber DM, Dimopoulos MA, Anandu DP, et al. Regression of gastric lymphoma of mucosa-associated lymphoid tissue with antibiotic therapy for Helicobacter pylori. Gastroenterol 1994;107:1835–1838. Cammarota G, Tursi A, Montalto M, et al. Prevention and treatment of low-grade B-cell primary gastric lymphoma by anti-H. pylori therapy. J Clin Gastroenterol 1995;21:118 – 122. 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: 1591–1594. Roggero E, Zucca E, Pinotti G, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Int Med 1995;122:767–769. Surawicz CM. Helicobacter pylori brews ferment in MALT lymphoma. Am J Gastroenterol 1995;90:160. Montalban C, Manzanal A, Boixeda D, et al. Helicobacter pylori eradication for the treatment of low-grade gastric

1102

117. 118. 119. 120. 121. 122.

123. 124. 125. 126. 127. 128.

129. 130.

131. 132. 133.

134.

135. 136. 137. 138.

I. J. Radiation Oncology

●

Biology

●

Physics

MALT lymphoma: follow-up together with sequential molecular studies. Ann Oncol 1997;8(Suppl. 2):37–39. Mittal B, Wasserman TH, Griffith RC. Non-Hodgkin’s lymphoma of the stomach. Am J Gastroenterol 1983;78:780 – 787. Shimm DS, Dosoretz DE, Anderson T, et al. Primary gastric lymphoma. An analysis with emphasis on prognos factors and radiation therapy. Cancer 1983;52:2044 –2048. Burgers JM, Taal BG, van HP, et al. Treatment results of primary stage I and II non-Hodgkin’s lymphoma of the stomach. Radiother Oncol 1988;11:319 –326. Maor MH, Velasquez WS, Fuller LM, et al. Stomach conservation in stages IE and IIE gastric non-Hodgkin’s lymphoma. J Clin Oncol 1990;8:266 –271. Johnsson A, Brun E, Akerman M, et al. Primary gastric non-Hodgkin’s lymphoma. A retrospective clinico-pathological study. Acta Oncologica 1992;31:525–531. Valicenti RK, Wasserman TH, Kucik NA. Analysis of prognostic factors in localized gastric lymphoma: importance of bulk of disease. Int J Radiat Oncol Biol Phys 1993;27:591– 598. Thirlby RC. Gastrointestinal lymphoma: a surgical perspective. Oncol 1993;7:29 –32. [discussion 7:34, and 37–38] Ben-Yosef R, Hoppe RT. Treatment of early-stage gastric lymphoma. J Surg Oncol 1994;57:78 – 86. Zinzani PL, Frezza G, Bendandi M, et al. Primary gastric lymphoma: a clinical and therapeutic evaluation of 82 patients. Leuk Lymph 1995;19:461– 466. McNeer G, Berg JW. The clinical behavior and management of primary malignant lymphoma of the stomach. Surgery 1959;46:829 – 840. Shiu MH, Karas M, Nisce L, et al. Management of primary gastric lymphoma. Ann Surg 1982;195:196 –202. Hammel P, Haioun C, Chaumette MT, et al. Efficacy of single-agent chemotherapy in low-grade B-cell mucosa lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol 1995;13:2524 –2529. Ruskone-Fourmestraux A, Aegerter P, Delmer A, et al. Primary digestive tract lymphoma: a prospective multicentric study of 91 patients. Gastroenterol 1993;105:1662–1671. Nakamura S, Akazawa K, Yao T, et al. Primary gastric lymphoma: a clinicopathologic study of 233 cases with special reference to evaluation with the MIB-1 index. Cancer 1995;76:1313–1324. Schwartz S, ed. Principles of surgery, 4th ed. New York: McGraw-Hill Book Company, 1984. Zucca E, Bertoni F, Roggero E, et al. Autoreactive B cell clones in marginal-zone B cell lymphoma. Leukemia 1998; 12:247–249. Greiner A, Knorr C, Qin Y, et al. Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. Am J Pathol 1997;150: 1583–1593. Eck M, Schmausser B, Haas R, et al. MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein. Gastroenterol 1997;112:1482– 1486. Bouzourene H, Haefliger T, Delacretaz F, et al. The role of Helicobacter pylori in primary gastric MALT lymphoma. Histopathol 1999;34:118 –123. Peng H, Ranaldi R, Diss T, et al. High frequency of CagA⫹ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas. J Pathol 1998;185:409 – 412. Luppi M, Longo G, Ferrari MG, et al. Additional neoplasms and HCV infection in low-grade lymphoma type. Br J Haematol 1996;94:373–375. Shibata K, Shimamoto Y, Nakano S, et al. Mantle cell

Volume 46, Number 5, 2000

139. 140. 141. 142.

143. 144. 145.

146. 147. 148. 149. 150. 151. 152. 153.

154. 155.

156. 157. 158. 159. 160.

lymphoma with the features of mucosa-associated l tissue (MALT) lymphoma in an HTLV-I-seropositive patient. Ann Hematol 1995;70:47–51. Liu Q, Ohshima K, Masuda Y, et al. Detection of the Epstein-Barr virus in primary gastric lymphoma with in situ hybridization. Pathol Int 1995;45:131–136. Long BW, Johnston JH, Wetzel W, et al. Gastric syphilis: endoscopic and histological features mimic lymphoma. Am J Gastroenterol 1995;90:1504 –1507. Steinbach G, Ford R, Glober G, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1999;131:88 –95. Genta RM, Hamner HW, Graham DY. Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy. Hum Pathol 1993;24: 577–583. Kosunen TU, Seppala K, Sarna S, et al. Diagnostic value of decreasing IgG, IgA, and IgM antibody titres after eradication of Helicobacter pylori. Lancet 1992;339:893– 895. Nakamura S, Yao T, Aoyagi K, et al. Helicobacter pylori and primary gastric lymphoma. Cancer 1997;79:3–11. Neubauer A, Thiede C, Morgner A, et al. Cure of Helicobacter pylori infection and duration of remission of lowgrade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst 1997;89:1350 –1355. Dworkin B, Lightdale CJ, Weingrad DN, et al. Primary gastric lymphoma. A review of 50 cases. Digest Dis Sciences 1982;27:986 –992. Orlando Rd, Pastuszak W, Preissler PL, et al. Gastric lymphoma: a clinicopathologic reappraisal. Am J Surg 1982;143: 450 – 455. Thorling K. Gastric lymphomas: clinical features, treatment and prognosis. Acta Radiologica Oncol 1984;23:193–197. Ravaioli A, Amadori M, Faedi M, et al. Primary gastric lymphoma: a review of 45 cases. Eur J Cancer Clin Oncol 1986;22:1461–1465. Shiu MH, Nisce LZ, Pinna A, et al. Recent results of multimodal therapy of gastric lymphoma. Cancer 1986;58:1389 –1399. Hockey MS, Powell J, Crocker J, et al. Primary gastric lymphoma. Br J Surg 1987;74:483– 487. Jones RE, Willis S, Innes DJ, et al. Primary gastric lymphoma: problems in staging and management. Am J Surg 1988;155:118 –123. Chung HC, Roh JK, Koh EH, et al. Comparison of adjuvant radiotherapy and chemoradiotherapy followin in stage IE and IIE primary gastrointestinal tract non-Hodgkin’s lymphoma. Yonsei Med J 1990;31:144 –155. Tsukada K, Arima K, Ohosone Y, et al. Successful treatment of primary gastric non-Hodgkin’s lymphoma chemotherapy and radiotherapy. Int Med 1992;31:368 –372. Brincker H, D’Amore F. A retrospective analysis of treatment outcome in 106 cases of localized gastric non-Hodgkin lymphomas: Danish lymphoma study group, LYFO. Leuk Lymph 1995;18:281–288. Sutherland AG, Kennedy M, Anderson DN, et al. Gastric lymphoma in Grampian Region: presentation, treatment and outcome. J Royal College Surg 1996;41:143–147. Contreary K, Nance FC, Becker WF. Primary lymphoma of the gastrointestinal tract. Ann Surg 1980;191:593–598. Talamonti MS, Dawes LG, Joehl RJ, Nahrwold DL. Gastrointestinal lymphoma: a case for primary surgical resection. Arch Surg 1990;125:972–977. Varsos G, Yahalom J. Alternatives in the management of gastric lymphoma. Leuk Lymph 1991;4:1– 8. Maor M, North L, Cabanillas F, et al. Outcomes of highdose unilateral kidney irradiation in patients with gastric lymphoma. Int J Radiat Oncol Biol Phys 1998;41:647– 650.

MALT lymphoma of the stomach

161. Verheij M, Dewit L, Valdes Olmos R, et al. Evidence for a renovascular component in hypertensive patients with late radiation nephropathy. Int J Radiat Oncol Biol Phys 1994; 30:677– 683. 162. Ettinger DS, Carter D. Gastric carcinoma 16 years after gastric lymphoma irradiation. Am J Gastroenterol 1977;68: 485– 488. 163. 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. 164. Baron BW, Bitter MA, Baron JM, et al. Gastric adenocarcinoma after gastric lymphoma. Cancer 1987;60:1876 –1882. 165. Ghahremani GG, Fisher MR. Lymphoma of the stomach

●

N. R. SCHECHTER

166. 167. 168. 169.

AND

J. YAHALOM

1103

following gastric surgery for benign p ulcers. Gastrointest Radiol 1983;8:213–217. Griffiths AP, Wyatt J, Jack AS, et al. Lymphocytic gastritis, gastric adenocarcinoma, and primary lymphoma. J Clin Pathol 1994;47:1123–1124. De Koster E, Buset M, Fernandes E, et al. Helicobacter pylori: the link with gastric cancer. [Review] Eur J Cancer Prev 1994;3:247–257. Eidt S, Stolte M. The significance of Helicobacter pylori in relation to gastric lymphoma. Eur J Gastroenterol Hepatol 1995;7:318 –321. Montalban C, Manzanal A, Boixeda D, et al. Treatment of low-grade gastric MALT lymphoma with Helicobacter pylori eradication. Lancet 1995;345:798 –799.