It is tempting to hypothesize that H pylori is a common etiological agent for synchronous occurrence of gastric adenocarcinoma and primary gastric lymphoma. Since 1994, the existence of H pylori has been investigated in almost every report. In the present analysis, in areas with high prevalence (Eastern) and low prevalence (Western) of H pylori, synchronous tumors are associated with H pylori infection rates of 86% and 72%, respectively, and are similar to or higher than the reported infection rates of isolated gastric adenocarcinoma and isolated MALT lymphoma or other primary gastric non-hodgkin lymphoma[20,58-60]. Therefore, H pylori may have an important etiological role for synchronous tumors in both high and low prevalence areas.

H pylori plays a key role in the natural history of gastric MALT lymphoma, representing an example of antigen-mediated tissue stimulation and lymphoproliferation, with possible subsequent lymphomagenesis[58,61]. Antigenic mimicry between H pylori and the host mucosa was held responsible for inducing autoimmune responses which lead to development of the disease[62,63]. Kawahara et al[64] found that the increase of antibody titers to HCG-27 cells in

H pylori-positive patients with MALT lymphoma compared to titers in patients with other gastroduodenal diseases and in healthy subjects. Lymphoid follicles which are not present in the normal stomach show development in the setting of chronic gastritis. Genta et al[65] have observed a strong correlation between follicular gastritis and H pylori infection. Wotherspoon et al[58] suggested that H pylori might trigger the acquisition of MALT in the gastric mucosa, and this lymphoid tissue is thought to harbor the precursor cells in MALT-NHL. These precursor cells change gradually into malignant lymphoma cells with autonomous and uncontrolled growth by accumulation of genetic alterations such as mutations, deletions, and amplifications. In vitro experiments have demonstrated that in the earlier phases of development, the growth of genetically altered lymphoid cell is not yet fully autonomous, and proliferation partly depends on H pylori-related proteins and T cells[66-69]. On the other hand, H pylori infection has been linked to the intestinal-type gastric adenocarcinoma through a chain of events that starts as acute gastritis and progresses to chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and eventually, adenocarcinoma formation[70,71]. A recent meta-analysis has revealed that H pylori infection is associated with a 2-fold increase in developing gastric adenocarcinoma[72]. These epidemiologic and pathologic data about the relation of H pylori infection with gastric adenocarcinoma and primary gastric lymphoma are supported by a recent genetic study[73]. H pylori genotyping on archived gastric tissue revealed that H pylori strains with certain combinations of virulence subtypes are associated with gastric carcinoma or MALT lymphoma. Thus, the virulence subtype composition vacA s1a and iceA1 occurs mainly in gastric carcinoma, whereas the vacA s1t/m2 iceA1 combination is found in MALT lymphoma[73]. Therefore, in the future studies, the composition of virulence subtypes might be taken into account during the evaluation of possible sequelae of gastric mucosal damage caused by H pylori infection.

Studies of Epstein-Barr virus (EBV) suggest that an aberrant antibody response to infection may occur years before the appearance of a tumor[74]. The frequency of EBV detection has been reported to be 6%-18% in gastric lymphomas[75-77] and 7%-16% in ordinary gastric adenocarcinomas without lymphoid stroma[78-80]. Whether EBV plays a pathogenic role in either of these tumors is still unclear[81]. Although any mechanism related to EBV in tumorigenesis of gastric malignancies remains highly speculative, it has been demonstrated that there is a delay in apoptosis in EBV-positive gastric carcinomas (associated with up-regulation of BCL-2 and p53) and a decrease in cellular differentiation (associated with decreased E-cadherin expression)[82]. Nakamura et al[10] found no specific association between EBV infection and these double malignancies.

It is controversial whether the incidence of gastric carcinoma is higher in persons exposed to an atomic blast in comparison to non-exposed subjects[83-85], but Suehiro et al[83] suggested that the incidence is the highest in persons exposed within a 2.0-Km radius ground zero. The relation of primary gastric lymphoma and atomic bomb exposure is under debate. Recently, t (11; 18) (q21; q21) and t (1;14) (p22; q32) translocations have been reported to be associated with MALT-type lymphoma. The former translocation results in the formation of fusion protein API2-MALT1, and the latter in the fusion protein pf BCL10 and IgH. These fusion transcripts are thought to be molecular markers for MALT-type lymphoma not responding to H pylori eradication and highly correlated with aberrant nuclear BCL10 expression, which may serve as a screening tool for fusion[86-88]. These investigations support the etiologic role of atomic bomb blast on the formation of MALT-type lymphoma.

Previous gastric surgery is a well known precancerous condition[90,91]. Gastroesophageal reflux and gastritis, formation of nitrosamines due to gastric pH decrease and untreated H pylori infection may play a role in carcinogenesis of the gastric remnant[92]. So-called “stump carcinoma” develops between 13-27 years after resection in patients treated with gastrectomy for benign conditions[91].

Though the stomach is considered relatively radio-resistant compared to other parts of the gastrointestinal tract, side effects and complications progressively increased when the total dosage delivered was above 4500 cGy[93,94]. The effects of radiotherapy on the risk of carcinogenesis are well known[95]. Hirose et al[96] demonstrated that localized radiation induced gastric adenocarcinoma development in an experimental model. Brown et al[97] reported a slight increase in the incidence of gastric adenocarcinoma in patients with ankylosing spondylitis under radiation therapy. In contrast, when the relatively low dose (less than 3400 cGy) radiotherapy was used to decrease acid production in 2049 peptic ulcer patients, only two cases of leiomyosarcoma were reported. The elapsed time between radiotherapy and the diagnosis of these cases were reported as 14 and 26 years[98].

Both series reported by Stanford and Milan concluded that combined administration of chemotherapy and radiotherapy increases the occurrence rate of secondary malignancies[1,2]. In these series, the most common secondary malignancy was especially acute myelogenous leukemia. Its occurrence was associated with the administration of alkylating agents (nitrogen mustard, vincristine, prednisone, and procarbazine in Milan series)[2]. Solid tumors were commonly associated with radiation therapy[1,2]. Brumback et al[40] concluded that secondary gastric adenocarcinoma occurred in one of these cases probably due to oral administration of procarbazine for Hodgkin’s disease. In addition to these factors, H pylori infection was also held accountable for metachronous occurrence of both tumors, as discussed above.

Treatment of synchronous cases is generally applied according to the presence of adenocarcinoma. Distal or total gastrectomy is performed depending on the tumor localization. Preoperative chemotherapy was preferred only in two cases. Cammarota et al[27] decided to administer etoposide, epirubicin, cisplatin chemotherapy according to the presence of locally advanced tumor stage (T3 N1) in laparoscopic exploration. Older patients in the series by Ishihama et al[23] were exposed to 10 courses of vincristine, endoxan, predonisdone, adriamicin chemotherapy and endoscopic resection of the tumor. Postoperative chemotherapy was administered only to 6 (10.7%) patients.

Eight of thirty patients underwent subtotal gastrectomy and radiotherapy against lymphoma. Chemotherapy was administered in different combinations with other treatment modalities in 7 patients. Two patients were treated by only chemotherapy. Radiotherapy was performed solely in 2 patients. Overall, 10 cases with lymphoma were treated without surgical treatment. All patients with MALToma were treated with antibiotic regimen against H pylori, except cases reported by Nakamura et al[10] and Montalban et al[26], the authors of both did not mention anything about the treatment of H pylori infection in their reports. Every patient with H pylori infection was eradicated and no one was re-infected or re-colonized during the follow-up period. Except cases with widespread metastasis, total gastrectomy or palliative resections were performed in patients with AGC. Patients with EGC were exposed to more conservative surgery, such as endoscopic mucosal resection[10,45].

Clear guidelines for management have not been designed for synchronous adenocarcinoma and primary gastric lymphoma. Traditionally, aggressive surgical resection has been the mainstay of gastric lymphoma treatment because by this treatment modality it would be possible to collect definitive tissues for pathologic examination, allow exploration of the abdomen, reduce the tumor burden and obviate the concern that gastric hemorrhage or perforation would complicate medical treatment of lymphomas. Recently, radical gastrectomy is disputed and considered unnecessary for gastric lymphomas. Lesser procedures are now accepted where resection of the gross disease and involved lymph nodes will provide adequate results[99-102]. Some authors advocate wide resection and extensive lymph node dissection alone for adequate treatment of stage 1E or pure MALT lymphomas with a survival rate of > 95%[103,104]. In a retrospective study from Italy patients in different stages of gastric lymphoma who underwent surgical resection when feasible, the ten-year actuarial survival rates were markedly higher (100% and 80%, respectively) for stage IE and IIE as compared with stage IIIE and IVE (21% and 0%, respectively)[105]. Surgical resection with clear margins for lymphoma is advised in order to maximize the chance of cure[100,106]. However, others have found no difference in survival, whether the margin of resection was clear or not, as long as post-operative chemotherapy was given[107]. Operative mortality rates for gastric lymphoma reached 25% in cases with advanced tumor stage[108]. Therefore, aggressive surgery for gastric lymphoma is not indicated due to increased morbidity which outweighs the benefit gained in terms of survival[107]. Surgery for gastric lymphoma is now often reserved for patients with localized disease, residual disease after non-surgical therapy or for rare patients with complications[109]. If the coexisting adenocarcinoma is diagnosed correctly, surgical treatment, a first-line therapy, is preferred according to adenocarcinoma treatment principles. Total or subtotal gastrectomy with D1 or D2 dissection must be performed.

In metachronous cases, generally, the occurrence of primary gastric lymphoma precedes gastric adenocarcinoma, resection of the remnant stomach must be done with or without a combination of other treatment modalities. However, a close follow-up of the patients undergoing gastric lymphoma treatment allows early detection of carcinogenesis. Limited endoscopic resections might be an alternative treatment for these cases. Similar to gastric lymphoma as a previous malignancy, patients in whom limited resection is performed for gastric adenocarcinoma should undergo a close endoscopic follow-up. The H pylori status with histopathologic alterations in the resected stomach and in the remnant stomach must be detected and followed up for early detection of metachronous occurrence of gastric lymphoma.

The effect of chemotherapy as a sole treatment for gastric lymphomas is still under debate. The needs behind trying chemotherapy were the considerable morbidity and mortality associated with resection[108]. Some authors reported better survival rates in patients with primary gastric lymphoma treated by chemotherapy alone or combination with radiotherapy when compared to surgical treatment alone[110,111]. Other reports showed no apparent difference in survival between patients treated by chemotherapy or surgery and chemotherapy with survival rates of 67% and 60%, respectively. The fear of chemotherapy-related complications, for instance, bleeding and perforation, has been disputed, and less significant compared with surgical resection[111,112]. Therefore, chemotherapy has been suggested and adopted as a primary mode of treatment for primary gastric lymphomas. Whereas cyclophoshamide, vincristine and prednisolone were adopted for low grade lymphomas, high grade tumors were treated with doxurubicin, teniposide, cyclophosphamide and prednisolone. The combination of both regimens with surgical resection has increased the survival rates up to 80% and 100%, respectively[113]. In contrast to primary gastric lymphomas, chemotherapy regimens have not been used as a sole therapy in the treatment of gastric adenocarcinoma, except in cases with metastatic disease. Systemic chemotherapy for metastatic disease has a marginal survival benefit when compared with best supportive care, while no standard worldwide regimen has been established yet. In Japan, especially the number of patients treated with endoscopic mucosal resection for early gastric adenocarcinoma is increasing year by year. Chemotherapy may be a more important part of treatment protocols in these patients in near future, because of the increasing survival rates. Cisplatin, 5-fluorouracil and mitomycin C were commonly used in various combinations for patients with gastric adenocarcinoma[114].

In most instances, radiotherapy is used as an adjuvant to surgery, chemotherapy or both for primary gastric lymphoma. It has rarely been tried as a single mode of therapy[115,116]. However, limited trials have suggested that radiotherapy can be utilized as a primary mode of treatment with a reasonable outcome[116,117]. Radiotherapy has been studied in comparison with other treatment modalities for stage IE and IIE of primary gastric lymphomas with a comparable outcome of 80%-89% survival[115,118,119]. Radiation was used post-operatively in high- and low-grade lymphomas, for residual tumors in stages I and II to improve the disease-free survival[120]. Combination of radiotherapy with chemotherapy might improve the chance of stomach conservation of these patients which may approach 100%[121]. Contradictory studies have found combined radiotherapy with either resection or chemotherapy no significant difference in both modalities, with a survival rate of 82%-88%[116,119]. Radiation therapy has a limited but well established role in the care of those afflicted with gastric adenocarcinoma. Radiation therapy can provide considerable relief of local gastric cancer symptoms. Approximately 50% to 75% of patients have had symptomatic improvement of problems, such as obstruction, bleeding and pain in a variety of trials[122,123].

Because gastric MALT lymphomas have a high association with H pylori infection, eradication of H pylori with antibiotics is very important[58,60,124,125]. Isaacson et al[125] suggested that antibiotic eradication of H pylori removes the growth stimulus from gastric MALT lymphoma without necessarily eradicating the neoplastic B-cell clone. This clone may re-expand, but in the absence of concomitant re-infection with H pylori, this is likely to be a self-limiting event. Short and long-term follow-up results of medical eradication of H pylori in patients with gastric MALT lymphoma have been published in the literature[124,125]. However, patients still require periodic surveillance endoscopies and may require more traditional treatment of their lymphoma. Antibiotic therapy may fail to cure gastric lymphomas when there is a bulky tumor with a high-grade component or when the gastric lymphoma is associated with carcinoma. A combination of partial gastrectomy and antibiotic therapy might be an alternative treatment for primary gastric lymphomas. However, periodic surveillance endoscopies are required after partial gastrectomy and antibiotic therapy. There has been no defined role of antibiotic therapy against H pylori in the treatment of gastric adenocarcinoma. Eradication of H pylori infection can be placed in preventive measures of gastric adenocarcinoma. If H pylori infection is detected in the partially resected stomach secondary to adenocarcinoma, the postoperative antibiotic treatment against H pylori may be administered for hindering metachronous occurrence of primary gastric lymphoma.