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The primary gastric lymphoma: therapeutic strategies.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

October 2001.     Review Article.

JC Vaillant and colleagues underline the advantages for first-line surgery in GL, that include more reliable grading and staging, prevention of complications of chemotherapy or radiotherapy and, finally, improvement of local control and survival by tumor reduction.
They conclude that complete resection is a major determinant of prolonged complete remission.

Nowadays the histologic diagnosis and typing is correctly assessed on adequate histologic biopsies specimens examined by experienced pathologist in more than 90% of the cases ( 1 ).
But given the high incidence of coexistence for low grade and high grade components in a single lesion, it is important to bear in mind that the diagnosis of histopathologic grade based on the endoscopic biopsy specimens alone could be misleading. In fact the HG components may be deeper in the gastric wall. For this reason Kodera and colleagues agree with the above authors summing up that there are no sufficient hard data to deny the place of surgery in the treatment of early stage gastric lymphoma, although primary chemotherapy is an alternative worthy of consideration. In particular they advocate treatment by surgery alone for patients diagnosed with stage I E or pure MALT lymphoma and although no statistically significant difference are identified,because the prognosis of stage II E appear worse than that of stage I E they administer adjuvant chemotherapy for stage II E patients even after a potentially curative resection ( 7, 8, 9 ).

Moreover while disseminated lesions are usually disclosed by the staging work up, non-invasive techniques are not reliable enough to predict the locoregional extension of the gastric lymphoma.
In spite of endoscopic ultrasonography (EUS), distant lymph node involvement and serosal infiltration , which are the main prognostic factors to guide complementary treatment, are indeed more accurately evaluated during laparotomy and on the resection specimen.

Gastric resection is questionable since low-grade gastric lymphoma in its later stages seems to disseminate in the same way as nodal lymphomas. In cases of localized low grade GL, as long as it is carefully staged with an exhaustive work-up, complete resection seems the best therapeutic approach to achieve long term cure.
Total gastrectomy seems advisable to achieve complete resection since low grade GL are often surface spreading and patchy and frequently develop above the incisura. Furthermore EUS underestimates the surface spread of GL and is unable to guide accurately the proximal extent of gastric resection, and peroperative frozen sections are neither unreliable to detect involved margins.
In stage II 2E GL, where involved nodes are often bulky and close to major structures, lymphadenectomy would be mandatory to achieve complete tumour clearance; if the operative risk of this procedure is excessive radiation therapy could be then proposed as a complementary treatment to partial resection.
An alternative approach to resection could be radiation therapy; it can be effective after incomplete resection or as a second-line treatment ( 1 ).
Also a study of Fung and colleagues confirms that a high probability of long term remission can be achieved with only local treatment of patients with stage I gastric MALT lymphoma. Preliminary results suggest that radiation therapy is well tolerated and effective and may be the optimal nonantibiotic treatment for patients with localized gastric MALT lymphoma ( 11 ).

In high grade gastric lymphoma resection and chemotherapy result in better 5 year survival rates than chemotherapy alone. Moreover some authors argue that resection is not essential since favourable results may be obtained after chemotherapy alone or combined with radiation.
First line resection seems advisable in high grade gastric lymphoma with full-tickness involvement of the gastric wall assessed by EUS.
In high grade gastric lymphoma, a randomized trial comparing resection plus chemotherapy and chemotherapy alone would be advisable ( 1 ).
But randomized trials to compare these approaches are not likely to be feasible because the absolute number of patients is low and the range of stage migration is wide. The disease range has been further widened by the recent introduction of the concept of mucosa associated lymphoid tissue lymphoma and the evidence of the involvement of Helicobacter pylori infection ( 9 ).
Raderer and colleagues affirm that polychemotherapy with the CHOP regimen (cyclo-phosphamide, doxorubicin, vincristine and prednisone) is safe as well as highly effective for the management of localized high grade gastric B cell lymphoma ( Ann Arbor I E and II E disease ), irrespective of age. Similar to the lymph node lymphoma, treatment is scheduled to continue for an additional theree cycles after patients achieve a CR.
In their study results suggest high grade lymphoma of the stomach to be a highly chemosensitive disease compared with diffuse large cell lymphoma of lymph node origin. They include in their series only patients ( 25 consecutive patients studied prospectively) without evidence of lymphoma outside the stomach or local lymph nodes as judged by extensive staging.
Nevertheless these authors recommend that the optimal management of patients with localized high grade disease remains to be determined in a randomized study also designed to answer the question of whether shorter chemotherapy comprised of the CHOP regimen is as effective as an approach using at least six cycles ( 2 ).

Hsu and colleagues affirm that gastric lymphoma has a histologic spectrum, that ranges from pure low grade MALT lymphoma to pure diffuse large cell lymphoma. Patients who have a low grade component admixed in large cell lymphoma appear to have an intermediate prognosis between the two extremes.
They suggest that systemic chemotherapy as primary treatment can be as effective as surgery followed by adjuvant chemotherapy for patients with stage I / II large cell lymphoma ( 4 ).
Moreover in patients with large cell lymphoma of the stomach, the presence of histologic evidence of MALT origin may be associated with a better response to systemic chemotherapy and a better prognosis ( 5 ).

The debate about the therapeutic strategy in low-grade gastric lymphoma becomes more crucial since several studies have now confirmed that eradication of H Pylori may induce remission in some low grade gastric lymphoma. This eradication has nowadays to be proposed in any case as the first line approach before conventional treatment, especially gastrectomy. However the duration of response remains unknown and prolonged follow up of treated cases is needed ( 1 ).
Over 10% of responders may develop a recurrence of lymphoma, and even among patients who were in histologic remission, 70% have persistence of monoclonal B cells detectable by polymerase chain reaction assays ( 11 ).
Not all cases of gastric MALT Lymphoma are clearly H pylori associated, since this organism is found in only about 92% of cases. It is possible that low bacterial count may escape detection by the currently available tests, although the combination of urease test, serology, and histologic evaluation is highly sensitive. Another explanation is that a yet unknown bacterium is similarly associated with lympho-proliferation. Because antibiotic treatment is simple, inexpensive, and harmless it may be worthwhile to employ this therapeutic option first, before turning to oncologic or surgical modalities. In such cases, the indolent course of gastric MALT lymphoma makes this approach safe should there be no response. Or the Helicobacter pilory negative cases, as the presence of gastric adenocarcinoma coexistent with MALT lymphoma and the MALT lymphomas resistant to antibiotic treatment are indications for oncologic or surgical treatment ( 6 ).
Gretschel and colleagues (case report) assert the evidence that Helicobacter Pylori may be a key factor in the development of high grade MALT lymphomas and that Helicobacter Pylori eradication can play a role in regression of high grade MALT lymphomas. The authors suggest that the high grade MALT-NHL may progress from low grade MALT-NHL and that both components may then represent a specific tumor entity. Generally antibacterial treatment cannot be considered as a standard treatment for high grade MALT-NHL. Cases of rapidly growing primary gastric B cell lymphoma after eradication of H pylori have been reported. However eradication of H Pylori may be suited for therapy of synchronous early high-grade and low-grade lymphoma when the low grade component is predominant ( 3 ).
In fact Hsu and colleagues underline that the presence of a low grade components in a large cell lymphoma may indicate that some of the biologic characteristic of low grade MALToma are preserved in the high grade tumors. Although many experts consider anti-Helicobacter therapy ineffective for patients who have documented high grade transformation, they recently have observed complete remission of primary high grade gastric MALToma after antibiotic treatment against Helicobacter pylori ( 5 ).
Moreover an Helicobacter pylori infection is considered to be associated with the development of synchronus and metachronus primary gastric lymphoma and adenocarcinoma. In many such synchrounously observed cases, lymphoma may precede carcinogenesis, while the prognosis appears to be more closely associated with the adenocarcinoma than the lymphoma ( 10 ).


1) Jean-Christophe Vaillant et al. Management and long-term results of Surgery for localized gastric lymphomas. The American Journal of Surgery. 2000; 179: 216-222.

2) M Raderer et al. Chemotherapy for the treatment of patients with primary high grade gastric B-Cell lymphoma of modified Ann Arbor Stages I E and II E. Cancer 2000; 88: 1979-85.

3) S Gretschel et al. Regression of high grade gastric B cell lymphoma after eradication of Helicobacter pylori. Endoscopy 2001; 33 (9): 805-807.

4) Liu HT, Hsu C and colleagues. Chemotherapy alone versus surgery followed by chemotherapy for stage I / II large cell lymphoma of the stomach. Am J Hematol 2000; 64:175-9.

5) Chiun Hsu et al. Comparison of MALT and non-MALT primary large cell lymphoma of the stomach. Cancer 2001; 91: 49-56.

6) Danny Rosin et al. Gastric MALT lymphoma in a Helicobacter pylori-negative patient: a case report and review of the literature. J Am Coll Surg 2001; 192: 652-657.

7) Y Kodera et al. Primary gastric B cell lymphoma : audit of 82 cases treated with surgery and classified according to the concept of mucosa-associated lymphoid tissue lymphoma. World J Surg. 24, 857-862, 2000.

8) Y Kodera et al. The role of radical gastrectomy with systematic lymphadenectomy for the diagnosis and treatment of primary gastric lymphoma. Annals of Surgery, 1998, vol 227, n1, 45-50.

9) T Sano, M Sasako et al. Total gastrectomy for primary gastric lymphoma at stages I E and II E: a prospective study of fifty cases. Surgery 1997; 121: 501-5.

10) S Nakamura et al. Synchronus and metachronus primary gastric lymphoma and adenocarcinoma. Cancer 1997; 79: 1077-85.

11) C Y Fung et al. Mucosa-associated lymphoid tissue lymphoma of the stomach. Cancer 1999; 85: 9-17.

12) K Kume et al. Disappearance of both MALT lymphoma and hyperplastic polyps in the stomach after eradication of Helicobacter pylori. AJG vol 96, n 9, 2001: 2796-7.

13) N Lugering et al. Impact of miniprobes compared to conventional endosonography in the staging of low grade gastric MALT lymphoma. Endoscopy 2001; 33: 832-7.

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