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Primary diffuse large B-cell lymphoma of the stomach

1. GENERAL INFORMATION

1.1 Definition

Primary non-Hodgkin’s lymphomas of the gastrointestinal tract represent 3-4% of all malignancies arising in the digestive tract. The most commonly involved site is the stomach (60% of cases), followed by small bowel, ileum, caecum, colon, and rectum (Tondini 1993). Primary gastric non-Hodgkin’s lymphoma is a malignancy exclusively localised in the stomach. It can present with or without perigastric and/or abdominal lymph nodal involvement, and is primarily localised to the gastric wall. Any histotype can arise in the stomach, but over 70% of cases are aggressive lymphomas.

1.2 Incidence

Primary gastric lymphoma shows an incidence of 1 per 100.000 of the population in Western countries, but the incidence is progressively increasing. It constitutes 60% of all gastrointestinal lymphomas, and 20% – 30% of all extranodal NHLs.

1.3 Risk factors

No risk factors have been clearly identified in primary gastric diffuse large B-cell lymphomas (PGDLCL). However, there is some evidence that atrophic gastritis, especially if it is associated with some immunodeficiency conditions, may be a risk factor for this malignancy (Freeman 1972). The role of Helicobacter pylori infection in diffuse large cell lymphoma of the stomach is controversial. This bacterium has been linked to the development of low-grade marginal zone MALT-type (mucosa-associated lymphoid tissue) lymphomas of the stomach (Fagiolo 1996), which has been reproduced experimentally (Hussell 1993). Helicobacter pylori antigens elicit a T-cell specific response, that induces a B-cell proliferation, which may evolve into a neoplastic marginal zone B-cell proliferation. In some cases, Helicobacter pylori infection, low-grade MALT component, and diffuse large cell lymphoma are present simultaneously. Regardless of H pylori infection, these malignancies have been termed diffuse large cell lymphoma with concomitant low-grade MALT component (Harris 1999). Gastrointestinal involvement is common in patients undergoing solid-organ transplantation and being treated with cyclosporine, especially renal graft recipients (Thomas 1991). In these patients, lymphoma is aggressive, presenting with obstruction, perforation, bleeding, ulceration and/or palpable masses.

2. PATHOLOGY and BIOLOGY

2.1 Morphology

Primary gastric diffuse large B-cell lymphoma (PGDLCL) is defined as a malignancy composed of large cells (nuclei at least twice the size of a small lymphocyte; usually larger than tissue macrophage nuclei) with vesicular nuclei, prominent nucleoli, basophilic cytoplasm and a moderate to high proliferation fraction. This malignancy constitutes 40% – 70% of all gastric lymphomas. Lesions are characterized by an intense cellular infiltration of the lamina propria. In most cases, the predominant cells resemble either centroblasts (large noncleaved cells) or immunoblasts; the most common appearance is that of a mixture of centroblast-like and immunoblast-like cells. Characteristics reported for other diffuse large B-cell lymphomas can be applied to PGDLCL. In some cases, a concomitant low-grade MALT-component is observed. The definition of these malignancies, previously called high-grade MALT-type lymphomas, has recently been incorporated under the term diffuse large cell lymphomas (Harris 1999). The name has been changed to diffuse large cell lymphoma with concomitant low-grade MALT-component. The clinical relevance of distinguishing two subgroups of diffuse large cell lymphomas of the stomach according to the presence or absence of a low-grade MALT-component is matter of debate.

2.2 Immunophenotype

As with all other diffuse large B-cell lymphomas, the cells of primary gastric lymphoma are SIg+/-, Cig-/+ and express B-cell-associated antigens (CD19, CD20, CD22, and CD79a). They are CD45+/-, CD5-/+, and CD10-/+. Half of cases is bcl-6 positive and 26% are CD10 positive, while CD38 immunoreactivity is observed in 47% of cases (Ponzoni 2003).

2.3 Genetic features

In common with all other diffuse large B-cell lymphomas, the rearrangement of bcl-2 gene is present in about 30% of primary gastric lymphoma (Weiss 1987). c-myc is reported to be rearranged in some cases (Yunis 1989).

3. DIAGNOSIS

3.1 Clinical presentations

Primary diffuse large cell lymphoma of the stomach (PGDLCL) occurs more frequently in males, with a median age range of occurrence of 50-60 years; 25% of patients with PGDLCL are 60 years of age or older (Lewin 1978; Tondini 1993; van Krieken 1989). Clinical presentation is similar to that of gastric carcinoma or of benign ulcer. The majority of patients report epigastric pain (70% of cases) or dyspepsia (30%). The duration of symptoms before diagnosis is variable, ranging between a few weeks to several years. Weight loss is observed in 40% of patients, which is usually a consequence of the dyspepsia; only infrequently is it a systemic symptom. Bleeding and perforation are rare at time of presentation (Tondini 1997; Ferreri 1999a; Ferreri 1999b). An obvious epigastric mass is also extremely uncommon at diagnosis. Previously an exploratory laparotomy was considered necessary for accurate diagnosis (Marshak 1976; Menuck 1976). However, technical advances in flexible gastroscopy have improved the diagnostic accuracy of endoscopic biopsy, which is associated with a remarkably lower morbidity than laparotomy (Maor 1984). Furthermore, a greater awareness of PGDLCL as a possible diagnosis means that patients now rarely present with transmural or bulky disease, with a consequently considerably reduced risk of bleeding or perforation. The combined use of endoscopic ultrasonography and high-resolution computed tomography scanning has significantly improved the reliability of clinico-radiological staging, making exploratory laparotomy redundant (D’Amore 1994; Tio 1995). The efficacy of endoscopic biopsy is very high, with a diagnostic accuracy of 70-90% (Valicenti 1993). However, its efficacy can be lower in cases in which there is deep infiltration and preservation of the mucosa. Endoscopic ultrasonography can improve the diagnostic efficacy of endoscopic biopsies by clearly delineating the areas of involvement in the submucosa (Solbiati 1986).

3.2 Diagnostic criteria

Primary gastric diffuse large cell lymphoma (PGDLCL) presents more frequently in males, with a median age range of 50-60 years (Lewin 1978; Tondini 1993; van Krieken 1989). Clinical presentation is similar to that of gastric carcinoma or of benign ulcer. The majority of patients report epigastric pain (70% of cases) or dyspepsia (30%). The duration of symptoms before diagnosis is variable, ranging from a few weeks to several years. Weight loss is observed in 40% of patients. Usually, it is a consequence of dyspepsia; only infrequently is it a systemic symptom. Bleeding and perforation are rare at presentation (Ferreri 1999a; Ferreri 1999b; Tondini 1997). An obvious epigastric mass is also extremely uncommon at diagnosis. Previously, an exploratory laparotomy was considered necessary for accurate diagnosis (Marshak 1976; Menuck 1976). However, technical advances in flexible gastroscopy have improved the diagnostic accuracy of endoscopic biopsy which is associated with a remarkably lower risk than laparotomy (Maor 1984). Furthermore, a greater awareness of PGDLCL as a possible diagnosis means that patients now rarely present with transmural or bulky disease, with a consequently considerably reduced risk of bleeding or perforation. The combined use of endoscopic ultrasonography and high-resolution computed tomography scanning has significantly improved the reliability of clinico-radiological staging, making exploratory laparotomy redundant (D’Amore 1994;Tio 1995). The efficacy of endoscopic biopsy is very high, with diagnostic accuracy of 70-90% (Valicenti 1993). However, its efficacy can be lower in cases in which there is deep infiltration and preservation of the mucosa. Endoscopic ultrasonography can improve the diagnostic efficacy of endoscopic biopsies by clearly delineating the areas of involvement in the submucosa (Solbiati 1986). Morphologically, PGDLCL is composed of large cells (nuclei at least twice the size of a small lymphocyte; usually larger than tissue macrophage nuclei), with vesicular nuclei, prominent nucleoli, basophilic cytoplasm and a moderate to high proliferation fraction. Lesions are characterized by an intense cellular infiltration of the lamina propria. In most cases, the predominant cells resemble either centroblasts (large noncleaved cells) or immunoblasts; the most common appearance is that of a mixture of centroblast-like and immunoblast-like cells. Characteristics reported for other diffuse large B-cell lymphomas can be applied to PGDLCL. In some cases, a concomitant low-grade MALT-component is observed. The definition of these malignancies, previously called high-grade MALT-type lymphomas, has recently been incorporated under the term diffuse large cell lymphomas (Harris 1999). The name has been changed to diffuse large cell lymphoma with concomitant low-grade MALT-component. The clinical relevance of distinguishing two subgroups of diffuse large cell lymphomas of the stomach according to the presence or absence of a low-grade MALT-component is matter of debate. The cells of diffuse large B-cell lymphoma of the stomach are SIg+/-, CIg-/+ and express B-cell-associated antigens (CD19, CD20, CD22, and CD79a). They are CD45+/-, CD5-/+, and CD10-/+. Genetic features rarely constitute diagnostic criteria in PGDLCL.

3.3 Additional useful tests

No reliable molecular markers are available for monitoring of minimal residual disease in diffuse large cell lymphoma of the stomach.

4. STAGING

4.1 Staging procedures

Complete staging work-up for primary diffuse large B-cell lymphoma of the stomach (PGDLCL) includes an accurate physical examination (Waldeyer’s ring involvement should be excluded) complete haematological and biochemical exams, total-body computerized tomography, gastrointestinal tract examination, and bone marrow aspiration and biopsy. In the past, abdominal staging was performed by exploratory laparotomy, and gastrectomy was considered as relevant in primary treatment. In the last few decades, however, a surgical approach has increasingly been replaced by conservative management. This approach requires an accurate endoscopic evaluation as part of the staging procedure. The evaluation of perigastric lymph nodes in order to distinguish between stage I- to stage III-disease, is a very relevant issue given the low sensitivity of computed tomography scans to visualize these lymph nodes (Ferreri 1998). These difficulties can be circumvented by using endoscopic ultrasonography. The combined use of endoscopic ultrasonography and high-resolution computed tomography scans significantly improves the reliability of clinico-radiological staging, making exploratory laparotomy unnecessary (D’Amore 1994; Tio 1995). Bone marrow assessment in PGDLCL should follow the general guidelines for all NHLs.

4.2 Staging system

The Ann Arbor staging system (Carbone 1971), currently used for the majority of non-Hodgkin’s lymphomas, has been considered unsatisfactory for primary gastric lymphomas (PGDLCL). Several alternative staging systems have been used for this malignancy (Blackledge 1979; Musshoff 1977;Rohatiner 1994). An International Workshop in 1994 recommended the following classification (Rohatiner 1994):
Stage I: lymphoma confined to the stomach. Single primary site or multiple noncontiguous lesions.
Stage I1: lymphoma confined to the mucosa.
Stage I2: lymphoma infiltrating the gastric wall up to the serosa.
Stage II: lymphoma extending to abdominal lymph nodes,
Stage II1: involvement of local (paragastric) lymph nodes
Stage II2: involvement of distant (mesenteric, para-aortic, paracaval, pelvic, inguinal) lymph nodes
Stage IIE: infiltration of adjacent organs or tissues by direct infiltration.
Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs, or a gastrointestinal tract lesion with supradiaphragmatic nodal involvement.
Patients should be divided in two subsets according to the presence (A) or absence (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. These symptoms must be meticulously evaluated because they are frequently due to causes other than PGDLCL. The presence of a bulky mass, such as a lesion of 10 cm or more in the longest diameter, is signaled as “X”.

4.3 Molecular analysis of minimal residual disease

No reliable molecular markers are available for the monitoring of minimal residual disease in diffuse large cell lymphoma of the stomach.

4.4 Restaging procedures

Restaging should include all the diagnostic procedures which were positive at time of diagnosis and initial staging.

5. PROGNOSIS

5.1 Natural history

Diffuse large cell lymphoma of the stomach (PGDLCL) is an aggressive malignancy characterized by rapid growth. However, in contrast to intestinal lymphomas, the prognosis of PGDLCL is good, with a 5-year survival higher than 80%. In patients with PGDLCL bleeding, perforation or obstruction are significantly less common than in patients with intestinal lymphomas, consequently the clinical performance status of PGDLCL patients is usually excellent. Significant weight loss and compromise of immunological or nutritional status are uncommon conditions. Thus, these patients can be treated with more aggressive and opportune therapeutic modalities by comparison with patients with intestinal lymphomas. Currently, data support the safety and efficacy of conservative treatment of stage I/II PGDLCL, with primary chemotherapy either given alone or followed by radiation therapy. The incidence of severe complications during chemotherapy is lower than 5%, and only a few of these patients require urgent gastrectomy for bleeding (Ferreri 1999b). To date, patients with gastric bleeding can be treated with surgical devascularization, reducing the number of unnecessary gastrectomies (Aviles 1998; Haim 1995; Schein 1994). In patients treated with a conservative approach, gastrectomy has been reported to be indicated in 3% of survivors (Aviles 1991; Tondini 1997; Haim 1995; Ferreri 1999b; Maor 1990; Burgers 1988). The main reasons for this therapeutic choice are local tumour progression or benign obstruction (Ferreri 1999b). Objective response rates with chemotherapy alone or with combined treatment ranges between 76% and 100%. Local recurrences are observed in 20% of patients treated with chemotherapy alone, while the addition of radiotherapy reduces this rate to 9% (Ferreri 1999b). Systemic relapse is observed in up to 12% of cases. The 5-year actuarial survival rate ranges between 73% and 90%.

5.2 Prognostic factors

No reliable prognostic factors in diffuse large cell lymphoma of the stomach (PGDLCL) have been definitively established. This may be due to the fact that studies have involved heterogeneous management and have been retrospective in nature, and the fact that, in several cases, patients with gastric lymphomas have been analyzed together with patients who have intestinal lymphomas. Those series usually included patients with all stages of disease. In the largest series of gastrointestinal lymphoma, bulky lesion, stage, histology, immunophenotype, B symptoms, b2-microglobulin, and LDH ratio have been reported as the main prognostic indicators (Aviles 1998; Tytgat 1998; Godlewski 1997; Yoo 1998; Morton 1993). In a series of 83 patients with stage I/II PGDLCL, age, stage of disease, LDH ratio, and use of chemotherapy have been independently and significantly associated with survival (Ferreri 1999a). The prognostic role of the International Prognostic Index is matter of debate (Ibrahim 1999; Castrillo 1996). A modified Index has been proposed (Cortelazzo 1999) Stage of disease has prognostic value using both the Ann Arbor and Musshoff’s staging systems. When analysis has been limited to only those patients who were treated with gastrectomy, which may or may not have been followed by complementary treatment, the comparison between patients who underwent a complete surgical resection and those with an incomplete resection showed that the extent of surgery did not modify survival (Ferreri 1999a). In a large Arabian series, performance status and stage showed significant prognostic value, and a prognostic index has been constructed (Ibrahim 1999). A more aggressive clinical course has been reported in patients with more extensive disease (tumor mass endoscopic pattern), with lymph nodes dissemination, elevated serum LDH levels, and systemic symptoms (Montalban 1995). Regarding histopathological parameters, an increasing worst prognosis with increasing proportion of high grade cells has been described (De Jong 1997; Nakamura 1995). CD10 immunoreactivity assessment could be a clear, easy-to-interpret and reliable prognostic factor in gastric lymphomas (Ponzoni 2003). In fact, patients with CD10-positive diffuse large B-cell lymphomas of the stomach display a significantly longer survival with respect to patients with CD10-negative lymphomas (Ponzoni 2003). The prognostic and diagnostic roles of some molecular variables, like microsatellite instability, allelic imbalance and chromosome trisomy, are matter of investigation (Skacel 2002).

6. TREATMENT

6.1 Treatment of stage I-II diffuse large-cell lymphoma of the stomach

The standard option for patients with stage I-II primary gastric diffuse large B-cell lymphoma (PGDLCL) is undefined and is currently a matter of debate. Surgery, which until a few years ago was was deemed an essential first-line therapeutic intervention, is now being questioned. In fact, there is a growing consensus that, for patient who do not present with ongoing bleeding or perforation, combined treatment with primary systemic conventional-dose anthracycline-containing chemotherapy which may or may not be followed by radiation therapy is suitable for individual clinical use on a type C basis. There is growing evidence about the safety and efficacy of conservative treatment of stage I/II diffuse large B-cell lymphoma of the stomach (PGDLCL), with primary chemotherapy alone or followed by radiation therapy. Some retrospective and prospective series suggested that conservative non-surgical treatment achieves equal or better results than gastrectomy (Tondini 1997; Haim 1995;Ferreri 1999b; Maor 1990; Burgers 1988; Montalban 1995; Binn 2003; Ibrahim 1999; Aviles 2004;Koch 2001; Koch 2005). A small prospective randomized trial comparing patients with PGDLCL treated by chemotherapy alone or with surgical resection followed by chemotherapy concluded that gastrectomy is unnecessary (Aviles 1991). Objective response rates with chemotherapy alone or with combined treatment ranges between 76% and 100%. CHOP chemotherapy regimen is the standard combination, producing 85-100% of responses and more than 90% overall survival at 5 years (Raderer 2002). CHOP14 regimen achieved similar results (Koch 2005), but with a higher toxicity. The addition of rituximab to CHOP has not improved the results as compared to CHOP alone (Wohrer 2004). Local recurrences were observed in 20% of patients treated with chemotherapy alone, and in 9% of patients treated with chemoradiotherapy. Systemic relapse is observed in 12% of cases. The 5-year survival with conservative treatment ranges between 73% and 90% (Ferreri 1999b). The central role of gastrectomy in the management of PGDLCL is now under discussion. Some authors, mostly surgeons, recommend gastrectomy as the initial treatment to avoid the potential risk of bleeding or perforation attributed to primary chemotherapy, while recent experience suggests that it is possible to avoid surgical resection and its acute and long-term complications. Gastrectomy impairs gastrointestinal functionality with a remarkable deterioration in the quality of life. In fact, rates of 17% of malabsorption syndrome, a 38% of weight loss and a 13% of “dumping syndrome” were reported amongst patients undergoing gastrectomy followed by chemotherapy in comparison with only a 3% weight loss in patients treated with chemotherapy alone (Aviles 1991). Moreover, gastrectomy per se dictates a delay of the chemotherapy onset, a crucial step in treating aggressive lymphomas (Salles 1991). Furthermore, it is accompanied by a relevant nutritional sequel (Bozzetti 1990) that may affect the use of complementary chemotherapy or radiotherapy. The incidence of bleeding or perforation during chemotherapy is lower than 5%, and only few patients who have bleeding require urgent gastrectomy (Ferreri 1999b). To date, patients with gastric bleeding can be treated with surgical devascularization, reducing the number of unnecessary gastrectomies (Aviles 1998; Haim 1995; Schein 1994). In patients treated with a conservative approach, gastrectomy is indicated in 3% of reported survivors (Aviles 1991; Ferreri 1999b; Maor 1990; Burgers 1988 ; Tondini 1997; Haim 1995). The main reasons for this therapeutic choice are local tumour progression or benign obstruction (Ferreri 1999b). Treatment-related mortality is 2.5%, mainly due to myelosuppression-related sepsis. Some open questions relating to the optimal conservative treatment schedule involve the regimen and the number of courses of chemotherapy to be given, and the role of consolidation radiotherapy (Tondini 1997; Haim 1995; Ferreri 1999b; Maor 1990; Burgers 1988). Conservative treatment with 6 – 8 courses of CHOP or CHOP-like regimens as exclusive treatment, or 4 – 6 courses of the same regimens in patients treated with combined chemoradiotherapy produces a response rate of 90% and a 10-year actuarial cause-specific survival of 82% (Ferreri 1999b). More prolonged treatments did not modify response rates or survival (Aviles 1991; Maor 1990). The role of consolidation radiotherapy is debated. In retrospective series, irradiated patients showed a lower local relapse rate compared with patients treated with chemotherapy alone (Ferreri 1999b). This observation, however, should be considered with caution in view of its retrospective nature, and the role of consolidation radiotherapy must be tested in a randomized clinical trial in the future. Nevertheless, there does not seem to be any reason to treat limited-disease PGDLCL differently to an analogous stage I/II intermediate- or high-grade nodal or extranodal lymphoma considering that these malignancies share the same phenotypic, genetic and biological characteristics (Narita 1996). Some technical improvements have allowed to deliver radiotherapy with lower impact on nearby organs, in particular, the addition of intensity-modulated radiation therapy led to further incremental improvements in the left kidney and liver dose in selected patients (Della Biancia 2005). In a prospective, Japanese study, CHOP regimen followed by radiation therapy is safe and highly effective against these malignancies (Ishikura 2005). In the prospective, German study, six courses of CHOP-14 followed by involved-field radiotherapy (40 Gy) has been associate with a survival rate at 42 months of 91% (Koch 2005). In addition to chemotherapy, H. pylori should always be eradicated in localized or extensive high grade gastric lymphoma (Raderer 2002). If not eradicated, although the lymphoma may temporarily respond to a variety of treatments, it may eventually relapse as the H.pylori antigenic drive to the appearance and development of lymphoma is still active. This is especially the case of PGDLCL with concomitant MALT areas which may eventually relapse with a low grade component (Boot 1995) unless H. pylori can be successfully treated.

6.2 Treatment of relapsed or refractory diffuse large-cell lymphoma of the stomach

The standard option for patients with relapsed or refractory primary gastric lymphoma (PGDLCL) reflects current guidelines for the treatment of analogous relapsed or refractory disease in Diffuse large cell lymphomas.

6.3 Experimental approaches

INDEX

Aviles A, Diaz-Maqueo JC, de la Torre A, Rodriguez L, Guzman R, Talavera A, et al. Is surgery necessary in the treatment of primary gastric non-Hodgkin’s lymphoma? Leuk Lymphoma 1991; 5: 365-369 [Medline]

Aviles A, Nambo MJ, Neri N, Huerta-Guzman J, Cuadra I, Alvarado I, et al. The role of surgery in primary gastric lymphoma: results of a controlled clinical trial. Ann Surg 2004; 240: 44-50 [Medline]

Aviles A, Narvaez BR. Beta-2 microglobulin and lactate dehydrogenase levels are useful prognostic markers in early stage primary gastric lymphoma. Clin Lab Haematol 1998; 20: 297-302 [Medline]

Ben-Yosef R, Hoppe RT. Treatment of early-stage gastric lymphoma. J Surg Oncol 1994; 57: 78-86 [Medline]

Binn M, Ruskone-Fourmestraux A, Lepage E, Haioun C, Delmer A, Aegerter P, et al. Surgical resection plus chemotherapy versus chemotherapy alone: comparison of two strategies to treat diffuse large B-cell gastric lymphoma. Ann Oncol 2003; 14: 1751-1757 [Medline]

Blackledge G, Bush H, Dodge OG, Crowther D. A study of gastro-intestinal lymphoma. Clin Oncol 1979; 5: 209-219 [Medline]

Boot H, de Jong D, Aleman BM, Taal BG. Comment on radiotherapy for treatment of localized gastrointestinal non- Hodgkin’s lymphoma. Radiother Oncol 1998; 46: 105 [Medline]

Boot H, de Jong D, van Heerde P, Taal B. Role of Helicobacter pylori eradication in high-grade MALT lymphoma. Lancet 1995; 346: 448-449 [Medline]

Bozzetti F, Ravera E, Cozzaglio L, Dossena G, Agradi E, Bonfanti G, et al. Comparison of nutritional status after total or subtotal gastrectomy. Nutrition 1990; 6: 371-375 [Medline]

Brands F, Monig SP, Raab M. Treatment and prognosis of gastric lymphoma. Eur J Surg 1997; 163: 803-813 [Medline]

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 Lymphoma 1995; 18: 281-288 [Medline]

Burgers JM, Taal BG, van Heerde P, Somers R, den Hartog J, Hart AA. Treatment results of primary stage I and II non-Hodgkin’s lymphoma of the stomach. Radiother Oncol 1988; 11: 319-326 [Medline]

Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]

Caruso ML, Rizzi E. Gastric Malt lymphoma: a clinicopathological study. Anticancer Res 1998; 18: 3781-3783 [Medline]

Castrillo JM, Montalban C, Abraira V, Carrion R, Cruz MA, Larana JG, et al. Evaluation of the international index in the prognosis of high grade gastric malt lymphoma. Leuk Lymphoma 1996; 24: 159-163 [Medline]

Chang KJ. Indications of endoscopic ultrasound in gastric lesions. Endoscopy 1998; 30 Suppl 1: A53-A54 [Medline]

Chen LT, Lin JT, Shyu RY, Jan CM, Chen CL, Chiang IP, et al. Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 2001; 19: 4245-4251 [Medline]

Chen LT, Lin JT, Tai JJ, Chen GH, Yeh HZ, Yang SS, et al. Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 2005; 97: 1345-1353 [Medline]

Chonan A, Mochizuki F, Ando M, Atsumi M, Mishima T. Endoscopic ultrasonography for the diagnosis of gastric malignant lymphoma. Endoscopy 1998; 30 Suppl 1: A76-A77 [Medline]

Colucci G, Naglieri E, Maiello E, Marzullo F, Caruso ML, Leo S, et al. Role of prognostic factors in the therapeutic strategy of primary gastric non Hodgkin’s lymphomas. Clin Ter 1998; 149: 25-30 [Medline]

Cortelazzo S, Rossi A, Roggero F, Oldani E, Zucca E, Tondini C, et al. Stage-modified international prognostic index effectively predicts clinical outcome of localized primary gastric diffuse large B-cell lymphoma. International Extranodal Lymphoma Study Group (IELSG). Ann Oncol 1999; 10: 1433-1440 [Medline]

D’Amore F, Brincker H, Gronbaek K, Thorling K, Pedersen M, Jensen MK, et al. Non-Hodgkin’s lymphoma of the gastrointestinal tract: a population- based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. Danish Lymphoma Study Group. J Clin Oncol 1994; 12: 1673-1684 [Medline]

de Jong D, Boot H, van Heerde P, Hart GA, Taal BG. Histological grading in gastric lymphoma: pretreatment criteria and clinical relevance. Gastroenterology 1997; 112: 1466-1474 [Medline]

Della Biancia C, Hunt M, Furhang E, Wu E, Yahalom J. Radiation treatment planning techniques for lymphoma of the stomach. Int J Radiat Oncol Biol Phys 2005; 62: 745-751 [Medline]

Doglioni C, Dei TA, Barbareschi M. [MALT gastric lymphoma: update]. Pathologica 1998; 90: 313-317 [Medline]

Dragosics B, Bauer P, Radaszkiewicz T. Primary gastrointestinal non-Hodgkin’s lymphomas. A retrospective clinicopathologic study of 150 cases. Cancer 1985; 55: 1060-1073 [Medline]

Economopoulos T, Alexopoulos C, Stathakis N, Styloyannis S, Dervenoulas J, Tsousis S, et al. Primary gastric lymphoma–the experience of a general hospital. Br J Cancer 1985; 52: 391-397 [Medline]

Fagiolo E, Abenante L. Lymphocyte activation and cytokine production in autoimmune hemolytic anaemia (AIHA). Autoimmunity 1996; 24: 147-156 [Medline]

Farthing MJ. Helicobacter pylori infection: an overview. Br Med Bull 1998; 54: 1-6 [Medline]

Ferreri AJ, Cordio S, Paro S, Ponzoni M, Freschi M, Veglia F, et al. Therapeutic management of stage I-II high-grade primary gastric lymphomas. Oncology 1999a; 56: 274-282 [Medline]

Ferreri AJ, Cordio S, Ponzoni M, Villa E. Non-surgical treatment with primary chemotherapy, with or without radiation therapy, of stage I-II high-grade gastric lymphoma. Leuk Lymphoma 1999b; 33: 531-541 [Medline]

Ferreri AJ, Freschi M, Dell’Oro S, Viale E, Villa E, Ponzoni M. Prognostic significance of the histopathologic recognition of low- and high-grade components in stage I-II B-cell gastric lymphomas. Am J Surg Pathol 2001; 25: 95-102 [Medline]

Ferreri AJ, Ponzoni M, Cordio S, Vanzulli A, Garuti E, Viale E, et al. Low sensitivity of computed tomography in the staging of gastric lymphomas of mucosa-associated lymphoid tissue: impact on prospective trials and ordinary clinical practice. Am J Clin Oncol 1998; 21: 614-616 [Medline]

Fischbach W. [Helicobacter and lymphoma]. Chirurg 1998; 69: 249-251 [Medline]

Fleming ID, Mitchell S, Dilawari RA. The role of surgery in the management of gastric lymphoma. Cancer 1982; 49: 1135-1141 [Medline]

Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972; 29: 252-260 [Medline]

Gisbertz IA, Schouten HC, Bot FJ, Arends JW. Proliferation and apoptosis in primary gastric B-cell non-Hodgkin’s lymphoma. Histopathology 1997; 30: 152-159 [Medline]

Godlewski G, Prudhomme M, Pignodel C, Gres P, Rodier M, Copie BC. [Double gastric and thyroid localization of MALT lymphoma with lymphocytic thyroiditis]. J Chir (Paris) 1997; 134: 438-441 [Medline]

Haim N, Leviov M, Ben-Arieh Y, Epelbaum R, Freidin N, Reshef R, et al. Intermediate and high-grade gastric non-Hodgkin’s lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy. Leuk Lymphoma 1995; 17: 321-326 [Medline]

Hansen PB, Vogt KC, Skov RL, Pedersen-Bjergaard U, Jacobsen M, Ralfkiaer E. Primary gastrointestinal non-Hodgkin’s lymphoma in adults: a population- based clinical and histopathologic study. J Intern Med 1998; 244: 71-78 [Medline]

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835-3849 [Medline]

Herman K, Stelmach A, Kalita A, Gruchala A. [Prognostic factors in gastric lymphoma]. Wiad Lek 1997; 50 Su 1 Pt 2:411-6: 411-416 [Medline]

Hsi ED, Eisbruch A, Greenson JK, Singleton TP, Ross CW, Schnitzer B. Classification of primary gastric lymphomas according to histologic features. Am J Surg Pathol 1998; 22: 17-27 [Medline]

Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa- associated lymphoid tissue to Helicobacter pylori. Lancet 1993; 342: 571-574 [Medline]

Ibrahim EM, Ezzat AA, Raja MA, Rahal MM, Ajarim DS, Mann B, et al. Primary gastric non-Hodgkin’s lymphoma: clinical features, management, and prognosis of 185 patients with diffuse large B-cell lymphoma. Ann Oncol 1999; 10: 1441-1449 [Medline]

Ishikura S, Tobinai K, Ohtsu A, Nakamura S, Yoshino T, Oda I, et al. Japanese multicenter phase II study of CHOP followed by radiotherapy in stage I-II, diffuse large B-cell lymphoma of the stomach. Cancer Sci 2005; 96: 349-352 [Medline]

Ishizuka H, Kubota T, Hayashi N, Otani Y, Kumai K, Kitajima M. Management of primary gastric lymphomas from a surgeon’s viewpoint. Oncol Rep 1999; 6: 103-106 [Medline]

Koch P, del Valle F, Berdel WE, Willich NA, Reers B, Hiddemann W, et al. Primary gastrointestinal non-Hodgkin’s lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma–results of the prospective German Multicenter Study GIT NHL 01/92. J Clin Oncol 2001; 19: 3874-3883 [Medline]

Koch P, Grothaus-Pinke B, Hiddemann W, Willich N, Reers B, del Valle F, et al. Primary lymphoma of the stomach: three-year results of a prospective multicenter study. The German Multicenter Study Group on GI-NHL. Ann Oncol 1997; 8 Suppl 1: 85-88 [Medline]

Koch P, Probst A, Berdel WE, Willich NA, Reinartz G, Brockmann J, et al. Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT NHL 02/96). J Clin Oncol 2005; 23: 7050-7059 [Medline]

Kocher M, Muller RP, Ross D, Hoederath A, Sack H. Radiotherapy for treatment of localized gastrointestinal non-Hodgkin’s lymphoma. Radiother Oncol 1997; 42: 37-41 [Medline]

Kodera Y, Yamamura Y, Nakamura S, Shimizu Y, Torii A, Hirai T, et al. The role of radical gastrectomy with systematic lymphadenectomy for the diagnosis and treatment of primary gastric lymphoma. Ann Surg 1998; 227: 45-50 [Medline]

Krol AD, Hermans J, Kramer MH, Kluin PM, Kluin-Nelemans HC, Blok P, et al. Gastric lymphomas compared with lymph node lymphomas in a population- based registry differ in stage distribution and dissemination patterns but not in patient survival. Cancer 1997; 79: 390-397 [Medline]

Lewin KJ, Ranchod M, Dorfman RF. Lymphomas of the gastrointestinal tract: a study of 117 cases presenting with gastrointestinal disease. Cancer 1978; 42: 693-707 [Medline]

Lucandri G, Stipa F, Mingazzini PL, Ferri M, Sapienza P, Stipa S. The role of surgery in the treatment of primary gastric lymphoma. Anticancer Res 1998; 18: 2089-2094 [Medline]

Lybeert ML, De Neve W, Vrints LW, Coen V, Coebergh JW. Primary gastric non-Hodgkin’s lymphoma stage IE and IIE. Eur J Cancer 1996; 32A: 2306-2311 [Medline]

Maor MH, Maddux B, Osborne BM, Fuller LM, Sullivan JA, Nelson RS, et al. Stages IE and IIE non-Hodgkin’s lymphomas of the stomach. Comparison of treatment modalities. Cancer 1984; 54: 2330-2337 [Medline]

Maor MH, North LB, Cabanillas FF, Ames AL, Hess MA, Cox JD. Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma. Int J Radiat Oncol Biol Phys 1998; 41: 647-650 [Medline]

Maor MH, Velasquez WS, Fuller LM, Silvermintz KB. Stomach conservation in stages IE and IIE gastric non-Hodgkin’s lymphoma. J Clin Oncol 1990; 8: 266-271 [Medline]

Marshak RH, Lindner AE, Maklansky D. Lymphosarcoma of the stomach. American Journal of Gastroenterology 1976; 66: 176-184 [Medline]

Menuck LS. Gastric lymphoma, a radiologic diagnosis. Gastrointest Radiol 1976; 1: 157-161 [Medline]

Montalban C, Castrillo JM, Abraira V, Serrano M, Bellas C, Piris MA, 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 [Medline]

Montalban C, Santon A, Boixeda D, Bellas C. Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication. Gut 2001; 49: 584-587 [Medline]

Morgner A, Miehlke S, Fischbach W, Schmitt W, Muller-Hermelink H, Greiner A, et al. Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 2001; 19: 2041-2048 [Medline]

Morton JE, Leyland MJ, Vaughan HG, Vaughan HB, Anderson L, Bennett MH, et al. Primary gastrointestinal non-Hodgkin’s lymphoma: a review of 175 British National Lymphoma Investigation cases. Br J Cancer 1993; 67: 776-782 [Medline]

Musshoff K. [Clinical staging classification of non-Hodgkin’s lymphomas (author’s transl)]. Strahlentherapie 1977; 153: 218-221 [Medline]

Nakamura S, Aoyagi K, Iwanaga S, Yao T, Tsuneyoshi M, Fujishima M. Synchronous and metachronous primary gastric lymphoma and adenocarcinoma: a clinicopathological study of 12 patients. Cancer 1997; 79: 1077-1085 [Medline]

Narita M, Yatabe Y, Asai J, Mori N. Primary gastric lymphomas: morphologic, immunohistochemical and immunogenetic analyses. Pathol Int 1996; 46: 623-629 [Medline]

Negrini R, Savio A, Poiesi C, Appelmelk BJ, Buffoli F, Paterlini A, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 1996; 111: 655-665 [Medline]

Ohashi S, Segawa K, Okamura S, Mitake M, Urano H, Shimodaira M, et al. Aggressive non-Hodgkin’s lymphoma after successful eradication of Helicobacter pylori and regression of gastric lymphoma of mucosa- associated lymphoid tissue. J Gastroenterol 1998; 33: 724-727 [Medline]

Ponzoni M, Ferreri AJ, Pruneri G, Pozzi B, Dell’Oro S, Pigni A, et al. Prognostic value of bcl-6, CD10 and CD38 immunoreactivity in stage I-II gastric lymphomas: identification of a subset of CD10+ large B-cell lymphomas with a favorable outcome. Int J Cancer 2003; 106: 288-291 [Medline]

Raderer M, Chott A, Drach J, Montalban C, Dragosics B, Jager U, et al. Chemotherapy for management of localised high-grade gastric B-cell lymphoma: how much is necessary? Ann Oncol 2002; 13: 1094-1098 [Medline]

Rodriguez M. Computed tomography, magnetic resonance imaging and positron emission tomography in non-Hodgkin’s lymphoma. Acta Radiol Suppl 1998; 417:1-36: 1-36 [Medline]

Rohatiner A, D’Amore F, Coiffier B, Crowther D, Gospodarowicz M, Isaacson P, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994; 5: 397-400 [Medline]

Rosen CB, van Heerden JA, Martin JKJ, Wold LE, Ilstrup DM. Is an aggressive surgical approach to the patient with gastric lymphoma warranted? Ann Surg 1987; 205: 634-640 [Medline]

Rossi A, Lister TA. Primary gastric non-Hodgkin’s lymphoma: a therapeutic challenge. Eur J Cancer 1993; 29A: 1924-1926 [Medline]

Ruskone-Fourmestraux A, Aegerter P, Delmer A, Brousse N, Galian A, Rambaud JC. Primary digestive tract lymphoma: a prospective multicentric study of 91 patients. Groupe d’Etude des Lymphomes Digestifs. Gastroenterology 1993; 105: 1662-1671 [Medline]

Salles G, Herbrecht R, Tilly H, Berger F, Brousse N, Gisselbrecht C, et al. Aggressive primary gastrointestinal lymphomas: review of 91 patients treated with the LNH-84 regimen. A study of the Groupe d’Etude des Lymphomes Agressifs. Am J Med 1991; 90: 77-84 [Medline]

Sanchez-Bueno F, Garcia-Marcilla JA, Alonso JD, Acosta J, Carrasco L, Pinero A, et al. Prognostic factors in primary gastrointestinal non-Hodgkin’s lymphoma: a multivariate analysis of 76 cases. Eur J Surg 1998; 164: 385-392 [Medline]

Sano T, Sasako M, Kinoshita T, Katai H, Maruyama K, Takenaka T, et al. Total gastrectomy for primary gastric lymphoma at stages IE and IIE: a prospective study of fifty cases. Surgery 1997; 121: 501-505 [Medline]

Schein M, Stein M, Haim N. Role of surgery in patients with primary non-Hodgkin’s lymphoma of the stomach: an old problem revisited [letter; comment]. Br J Surg 1994; 81: 778-779 [Medline]

Schwarz RJ, Conners JM, Schmidt N. Diagnosis and management of stage IE and stage IIE gastric lymphomas. Am J Surg 1993; 165: 561-565 [Medline]

Sheridan WP, Medley G, Brodie GN. Non-Hodgkin’s lymphoma of the stomach: a prospective pilot study of surgery plus chemotherapy in early and advanced disease. J Clin Oncol 1985; 3: 495-500 [Medline]

Shiu MH, Nisce LZ, Pinna A, Straus DJ, Tome M, Filippa DA, et al. Recent results of multimodal therapy of gastric lymphoma. Cancer 1986; 58: 1389-1399 [Medline]

Singh DP, Sharma SC, Sandhu AP, Goenka MK, Kochhar R, Nagi B, et al. Primary gastrointestinal lymphoma–disease spectrum and management: a 15-year review from north India. Indian J Gastroenterol 1997; 16: 88-90 [Medline]

Skacel M, Paris PL, Pettay JD, Tsiftsakis EK, Tubbs RR, Casey G, et al. Diffuse large B-cell lymphoma of the stomach: assessment of microsatellite instability, allelic imbalance, and trisomy of chromosomes 3, 12, and 18. Diagn Mol Pathol 2002; 11: 75-82 [Medline]

Solbiati L, Montali G, Croce F, Ravetto C, Livraghi T, Derchi LE, et al. Fine-needle aspiration biopsy of bowel lesions under ultrasound guidance: indications and results. Gastrointest Radiol 1986; 11: 172-176 [Medline]

Solidoro A, Payet C, Sanchez-Lihon J, Montalbetti JA. Gastric lymphomas: chemotherapy as a primary treatment. Semin Surg Oncol 1990; 6: 218-225 [Medline]

Steward WP, Harris M, Wagstaff J, Scarffe JH, Deakin DP, Todd ID, et al. A prospective study of the treatment of high-grade histology non- Hodgkin’s lymphoma involving the gastrointestinal tract. Eur J Cancer Clin Oncol 1985; 21: 1195-1200 [Medline]

Taal BG, Burgers JM, van Heerde P, Hart AA, Somers R. The clinical spectrum and treatment of primary non-Hodgkin’s lymphoma of the stomach. Ann Oncol 1993; 4: 839-846 [Medline]

Takenaka T, Maruyama K, Kinoshita T, Sasako M, Sano T, Katai H, et al. A prospective study of surgery and adjuvant chemotherapy for primary gastric lymphoma stage II. Br J Cancer 1997; 76: 1484-1488 [Medline]

Tanaka Y, Takao T, Watanabe H, Kido T, Ogawa N, Iwase K, et al. Early stage gastric lymphoma: is operation essential?. World J Surg 1994; 18: 896-899 [Medline]

Thomas JA, Allday MJ, Crawford DH. Epstein-Barr virus-associated lymphoproliferative disorders in immunocompromised individuals. Adv Cancer Res 1991; 57:329-80: 329-380 [Medline]

Tio TL. Large gastric folds evaluated by endoscopic ultrasonography. Gastrointest Endosc Clin N Am 1995; 5: 683-691 [Medline]

Tondini C, Balzarotti M, Santoro A, Zanini M, Fornier M, Giardini R, et al. Initial chemotherapy for primary resectable large-cell lymphoma of the stomach. Ann Oncol 1997; 8: 497-499 [Medline]

Tondini C, Giardini R, Bozzetti F, Valagussa P, Santoro A, Bertulli, et al. Combined modality treatment for primary gastrointestinal non-Hodgkin’s lymphoma: the Milan Cancer Institute experience. Ann Oncol 1993; 4: 831-837 [Medline]

Tytgat GN. Helicobacter infection in man: problems to be solved. Dig Dis 1998; 16: 192-197 [Medline]

Valicenti RK, Wasserman TH, Kucik NA. Analysis of prognostic factors in localized gastric lymphoma: the importance of bulk of disease. Int J Radiat Oncol Biol Phys 1993; 27: 591-598 [Medline]

van Krieken JH, Otter R, Hermans J, van Groningen K, Spaander PJ, van, et al. Malignant lymphoma of the gastrointestinal tract and mesentery. A clinico-pathologic study of the significance of histologic classification. NHL Study Group of the Comprehensive Cancer Center West. Am J Pathol 1989; 135: 281-289 [Medline]

Weiss LM, Warnke RA, Sklar J, Cleary ML. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 1987; 317: 1185-1189 [Medline]

Wohrer S, Puspok A, Drach J, Hejna M, Chott A, Raderer M. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for treatment of early-stage gastric diffuse large B-cell lymphoma. Ann Oncol 2004; 15: 1086-1090 [Medline]

Yoo CC, Levine MS, Furth EE, Salhany KE, Rubesin SE, Laufer I, et al. Gastric mucosa-associated lymphoid tissue lymphoma: radiographic findings in six patients. Radiology 1998; 208: 239-243 [Medline]

Yunis JJ, Mayer MG, Arnesen MA, Aeppli DP, Oken MM, Frizzera G. bcl-2 and other genomic alterations in the prognosis of large-cell lymphoma. N Engl J Med 1989; 320: 1047-1054 [Medline]

Zippel K, Agnes A, Zieren HU. [Surgical therapy of non-Hodgkin lymphoma of the stomach]. Zentralbl Chir 1998; 123: 53-57 [Medline]

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Carlos Montalbàn (Author)
Hospital Ramon y Cajal, Universidad de Alcala de Henares – Madrid, Spain
mail: cmontalban.hrc@salud.madrid.org

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
mail: carlo.tondini@ospedaliriuniti.bergamo.it