Review of the molecular profile and modern prognostic markers for gastric lymphoma: How do they affect clinical practice?
=========================================================================================================================

* Leonidas Alevizos
* Ilias P. Gomatos
* Spyridon Smparounis
* Manousos M. Konstadoulakis
* Georgios Zografos

## Abstract

Primary gastric lymphoma is a rare cancer of the stomach with an indeterminate prognosis. Recently, a series of molecular prognostic markers has been introduced to better describe this clinical entity. This review describes the clinical importance of several oncogenes, apoptotic genes and chromosomal mutations in the initiation and progress of primary non-Hodgkin gastric lymphoma and their effect on patient survival. We also outline the prognostic clinical importance of certain cellular adhesion molecules, such as ICAM and PECAM-1, in patients with gastric lymphoma, and we analyze the correlation of these molecules with apoptosis, angiogenesis, tumour growth and metastatic potential. We also focus on the host–immune response and the impact of *Helicobacter pylori* infection on gastric lymphoma development and progression. Finally, we explore the therapeutic methods currently available for gastric lymphoma, comparing the traditional invasive approach with more recent conservative options, and we stress the importance of the application of novel molecular markers in clinical practice.

Gastric lymphoma (GL) is a member of the family of neoplasms derived from mucosa-associated lymphoid tissue and is the most common type of extranodal non-Hodgkin lymphoma (NHL).1 Although its incidence is increasing, NHL is a rare disease, accounting for 2%–8% of all primary gastric cancers. It can present in any patient group, but it is most common in men (male:female ratio 2:1) aged 50 years or older.2

## Classic prognostic markers

Gastric lymphoma has a better prognosis than gastrointestinal lymphoma and gastric carcinoma, perhaps reflecting the tendency of GLs to remain localized in the stomach for a long time.3 The stage and histologic grade of the disease are the most clinically important independent prognostic factors.4 Stage I and II GLs have 5-year survival rates of 87% and 61%, respectively (Ann Arbor staging system, modified by Musshoff,5 Table 1), whereas high- and low-grade lymphomas account for 5-year survival rates of 56% and 91%, respectively.6 Younger patients have better survival rates than older patients with the same tumour stage.7 Small lymphomatic lymphoma has a better prognosis than other histolytic types.7,8

View this table:
[Table 1](http://canjsurg.ca/content/55/2/117/T1)

Table 1 
Ann Arbor lymphoma staging, modified by Musshoff, for extranodal lymphomas5

Until recently, the prognosis of GL has been based largely on clinical factors. These factors do not explain why patients at the same stage of disease and with similar clinical characteristics have different prognoses; they also cannot be used to safely determine which patients could benefit from adjuvant chemotherapy.1

## Mutations and oncogenes

Recent progress in molecular biology has contributed to the discovery of several oncogenes that contribute to carcinogenesis by disrupting the cellular cycle. For instance, oncogenes of the *ras* family underlie the development of several neoplasias. Specifically, N-*ras* has been associated with malignant transformation of blood cells, Ki-*ras* with tumours of epithelial tissues, and Ha-*ras* with cancer of the urinary bladder.9 Similarly, the *ERBB2* oncogene (formerly *HER2/neu*) plays a clinically important role in the pathogenesis of cancer of the cervix, endometrium, ovaries and breast, and has been linked to a worse prognosis in patients with these cancers.10

The Ki-*ras*, c-Ha-*ras* and *ERBB2* oncogenes are among those that initiate neoplasias of the gastrointestinal (GI) tract and are likely important to GL.9,11 Mutations to the Ki-*ras* proto-oncogene have been shown to occur early in colorectal tumorigenesis, with the resulting small GTPase protein driving the development of colorectal cancer.12–14 Ki-*ras* mutations are associated with significantly worse prognosis for the patient.14–16 Likewise, c-Ha-*ras* encodes the p21c-Ha-ras protein, which induces G1 cell cycle phase arrest,17 and c-Ha-ras hypomethylation is detected in gastric carcinomas, though without affecting the histopathologic appearance of the cancers.18 Finally, increased serum levels of the ERBB2 protein, which is involved in the signal transduction pathways leading to cell growth and differentiation, are common in patients with gastric carcinomas.19–21 The prognostic value of the oncogenes mentioned, however, has not been verified in patients with GL.22

Ferreri and colleagues23 have pointed out that cyclin E and the p27 gene products are independent prognostic factors for GL and that the p27−/cyclin-E+ phenotype is associated with worse prognosis. Cyclin-E forms complexes with CDK2, stimulating progression from the G1 to S phase of the cell cycle, whereas p27 inhibits the formation of the cyclin-E/CDK2 complex, thus regulating the cell cycle. The synergistic effect of low p27 and high cyclin-E expression accounts for the poor prognosis of the patients presenting this phenotype. The same research group has also reported a correlation between the lack of the expression of p16 and high-grade GLs.

The p16 tumour-suppressor gene may also play a clinically important role in GL. It encodes the cyclin-dependent kinase inhibitor 2A protein (CDKN2A), which plays an important role in regulating the cell cycle G1 progression by inhibiting the CDK4 kinase and, indirectly, p53. Min and colleagues24 found that p16 methylation is more frequent in patients with higher-grade GLs. The role of p16 in the pathogenesis of other gastrointestinal neoplasias, as well as its prognostic value, has been the focus of rigorous investigation. Several researchers have reported that p16 can be used as a prognostic factor for GI stromal tumours, especially for those that range between benign and borderline.25–28 Li and colleagues29 have reported that overexpression of p16 is correlated to endocrine (carcinoid) tumours of the GI tract. It has been noted that acid-induced hypermethylation of p16 is a common pattern in patients with upper GI adenocarcinomas (both esophageal and gastric).30 More recently, Ajani and colleagues31 reported high p16 expression in patients with anal canal carcinoma; however, this observation had no impact on the disease-free survival of the patients.

The pathogenesis of GL is affected by various mutations, such as trisomy 3,32 t(11;18)(q21;q21) translocation,33 (8)(q13q22) deletion11 and t(1q14)(p22;q32) translocation. The latter has been associated with autonomous growth of the lymphoma and its expansion into adjacent gastric lymph nodes.34 Moreover, patients with GL with aneuploid cells have worse survival rates and relapse more often than those with tumours composed of diploid cancer cells.35 Finally, it has been shown with DNA flow cytometry that the median fraction of cells in the S phase (SPF) can be a clinically important prognostic index for GL.36

## Apoptosis

The balance between cancer cell proliferation and death determines the tumour cell population, thus the size of the tumour. Apoptosis (i.e., programmed cell death) is an active process that requires the contribution of many gene products, including p53, the members of the *bcl* family and cellular caspases.37

Commonly, p53 mutations are found in many neoplasms and interfere with the natural oncosuppresor function of the protein, leading to accelerated tumour growth. Immunohistochemical studies have shown that increased expression of p53 is present in high-malignancy GLs. Mutations in p53 appear during the last stages of carcinogenesis,38 possibly playing a role in the transition from smaller to larger and more malignant lymphomas.37 However, the expression of p53 presents no statistically significant effect on patients’ survival and thus is used only as an index of cellular dedifferentiation.38

The Bcl protein family plays a major role in the regulation of the apoptotic cascade, with individual members contributing either pro- or antiapoptotic signals. The Bcl-2-associated protein (Bax) promotes apoptosis and delays disease progression, whereas bcl-6 and bcl-10 are both proto-oncogenes; none of the 3 has any particular prognostic value in GL. Bax, however, has been associated with better patient prognosis and longer disease-free survival in patients with a number of gastrointestinal cancers, such as cancer of the esophagus, the stomach, the small intestine and the colon,39–44 and high bcl-6 expression is correlated with worse prognosis in patients with other tumours of the GI tract, such as esophageal adenocarcinoma.45 Bcl-6 mutations have been detected in many patients with GL and may play an important role in disease pathogenesis,46,47 whereas irregular expression of bcl-10 is correlated with advanced stages of the disease as well as lymph node and remote metastases.48 Bcl-2, a transmembrane member of the family with antiapoptotic qualities, has a significantly greater expression in highly differentiated GLs and GLs consisting of smaller lymphocytes.38,49

Many members of the Bcl family interact with intracellular caspases, enzymes that are activated during the late phases of the apoptotic process, cleaving a number of structural and cellular proteins.50,51 Patients with GL exhibit increased caspase-3 activity in peripheral T lymphocytes.52 However, there is no bibliographic evidence for any prognostic value of caspases in patients with GL.

Individually, most of the genes described above have no prognostic significance in patients with GL; however, on multivariate analysis, several combinations of these genes can be useful as prognostic phenotypes. For example, *bcl-2*−*/bax**+* carriers with GL have better rates of survival than *bcl-2*−*/bax*− carriers with GL. One interpretation is that the simultaneous loss of Bax and Bcl-2 proteins leads to loss of apoptotic control, resulting in aggressive tumour behaviour.38 In addition, Go and Yang53 have demonstrated that *p53**+**/p21*− carriers are less likely to achieve complete remission.

## Cellular adhesion molecules

Cellular adhesion molecules (CAMs) are glycoproteins of the cellular membrane that belong to the families of integrins, cadherins, selectins and immunoglobulins and control the relay of transcellular signals and the migration of cancer cells.54,55 The prognostic value of intracellular adhesion molecules (ICAMs) and of PECAM-1 for several forms of cancer has been investigated recently.

Intracellular adhesion molecules are part of the immuno-globulin superfamily CAMs. They participate in the interaction between the endothelium and lymphocytes and mediate the transmigration and extravasation of the latter. They also participate in signal transduction and inflammatory pathways, in part by recruiting macrophages and other immune-competent cells. ICAM-1 in particular plays an important role in determining the host’s response to malignant tumours and is related to the degree of differentiation and lymphoma stage in patients with NHL. ICAM-1 expression is known to increase in human gastric carcinoma cells as well, being a predictive factor for patients with gastric carcinoma.56 Since non-neoplastic cells of the GI tract do not express ICAM-1, it presents an attractive target for therapeutic interventions.57 The role of ICAM-1 in colonic neoplasms is still under research.58 Terol and colleagues59 reported that ICAM-1− carriers with NHL were characterized by more severe clinical syndromes, numerous extranodular metastases, infiltration of bone marrow and worse prognosis. Although there is no concrete supporting evidence, there is speculation that the absence of ICAM-1 expression may be related to shorter life expectancy for patients with GL.

PECAM-1 is expressed on the surface of endothelial and blood cells and plays an important role in vascularization and cellular translocation. PECAM-1 is related to a worse prognosis in a large range of neoplasms, and previous studies have suggested that its prognostic value in patients with GL is limited to those with nodular infiltrations.60,61 However, we recently reported that PECAM-1-positive GL cells were an independent prognostic factor associated with unfavourable disease outcome in patients with GL.62 One possible explanation is that PECAM-1 leads to the extravasation of leukocytes via its involvement in the cellular adhesion process, thus facilitating the metastasis of lymphogenic neoplasms. We also found that the PECAM-1+/ICAM-3− phenotype was associated with decreased 5-year survival compared with the PECAM-1−/ICAM-3+ phenotype.

Concerning the other CAMs, it is remarkable that low-malignancy GL cells generally have an α4β7 integrin+/L-selectin+ phenotype, whereas high-malignancy GLs do not express these 2 molecules.63 The percentage of ELAM-1+/VCAM-1+ venules in the tumour is increased in high-malignancy primary GLs compared with low-malignancy primary GLs or secondary GLs. The pattern of CAM expression may also be important. In most primary high-grade GLs, the stromal cells of the germinal centre are positive for ICAM-1, ELAM-1 and VCAM-1 (germinal centre pattern), whereas in low-grade and secondary high-grade GLs, the stromal cells of the marginal zone are positive only for ICAM-1 (marginal zone pattern).64 The observation that low-grade and secondary high-grade GLs present the marginal zone pattern, while most primary high-grade gastric GLs present the germinal centre pattern, is of exceptional significance, since it suggests that low-grade and secondary high-grade lymphomas are of marginal zone cell lineage, whereas most of the high-grade primary lymphomas are of germinal centre cell lineage.64

## Neoangiogenesis

In addition to cellular adhesion, several of the CAMs, in particular ICAM-3 and PECAM-1, contribute to neoangiogenesis by participating in the transcellular relay of signals necessary for the recruitment and organization of endothelial cells into vascular canals. Neoangiogenesis is a prerequisite for tumour development beyond a critical size; it also allows the entrance of tumour cells into the bloodstream,65 leading to metastasis. The link to the metastatic tumour potential helps to explain the correlation between the degree of neoangiogenesis (microvessel density [MVD]) and the aggressiveness and prognosis of many types of cancer.66

Cycloxygenase (COX), an intracellular enzyme belonging to the prostaglandin synthase family, participates in the process of neoangiogenesis in patients with GL. COX converts arachidonic acid to prostaglandin H2, which is the rate-limiting step in the formation of prostaglandins. Recent evidence strongly implicates the COX-2 isoform in the tumorigenesis process, being influenced by mutation of genes such as *ras*, several cytokines and *Helicobacter pylori* infection. The latter observation explains the return of COX-2 expression to normal levels after treatment with amoxicillin.67

The effect of COX-2 is exerted by the release of the PGE-2 prostaglandin and contributes to the development of GL by enhancing cancer cell division and neoangiogenesis and by suppressing the host’s immune reaction. Tumour cells overexpressing COX-2 stave off apoptosis and exhibit irregular interaction with neighbouring cells. It has also been suggested that COX-2 promotes the production of angiogenic factors in perineoplastic cells.67,68 Both COX-1 and COX-2 inhibitors, which are expressed in tumour endothelial cells, inhibit angiogenesis and endothelial migration of cancer cells.68

## Immune properties of gastric lymphoma

Gastric lymphoma — like all extranodular lymphomas —has immune-like properties. B-cell lymphomas have the common trait of proliferating under the influence of T cells.69 Most of the T cells contributing to this process are of T helper (Th) type, possess HLA-DR antigens, and lack interleukin-2 (IL-2) receptors and the cytotoxic mechanisms necessary to control B cell growth. However, increased levels of activated Th lymphocytes in large cell B lymphomas are associated with better prognosis.70 In patients with high-malignancy GLs, the cytotoxic activity of cytotoxic T lymphocytes (CTLs) is more intense, which may in part account for the increased rate of apoptosis observed in patients with these tumours; the response of these CTLs is possibly related to better prognosis, since it is part of the host’s immune reaction.71

Survival of patients with GL is substantially affected by changes in the expression of major histocompatibility complex (MHC) antigens as well. Reduced MHC I expression is often observed in patients with malignant tumours and lymphomas and is related to worse prognosis and aggressive tumour behaviour.72 Patients with NHL present elevated serum levels of sHLA, the soluble form of HLA secreted by B and T cells when activated.73

The HLA-DR antigen is an MHC II-class glycoprotein located on the surface of cells of the immune system and certain tissues and is an index of the host’s immune response to the tumour. Although this particular antigen is expressed in the healthy gastric epithelium, a small percentage of patients with gastric cancer express HLA-DR in cancer cells.74 We have reported that HLA-DR expression in cancer cells of patients with GL is an independent factor associated with better prognosis, possibly because it induces the presentation of cancer cell antigens to Th lympocytes, thereby improving the immune response against them.62 Patients with the HLA-DR−/ICAM-3− phenotype have reduced 5-year survival odds compared with HLA-DR+/ICAM-3+ carriers, whereas all HLA-DR+/ICAM-3+/PECAM-1− carriers have 100% 5-year survival compared with 54.2% for the rest of the population. It appears that ICAM-3, PECAM-1 and HLA-DR represent complementary molecular pathways that connect the host’s immune reaction to nonspecific transcellular communication and cellular migration.62

### Helicobacter pylori

*H. pylori* has been detected in 86% of patients with low-malignancy GL and in 74% with high-malignancy GL, a percentage higher than that of the general population. The infection leads to chronic inflammation of the gastric epithelium and stimulation of the immune system via activation of Th lymphocytes. These in turn induce B lymphocyte proliferation in the gastric mucosa until a clone is mutated and eventually leads to lymphoma.75

Recent research has focused on the effect of *H. pylori* on certain oncogenes. The activation of these genes is an important step in the initiation of neoplasia. Exposure of gastric mucosa to *H. pylori* activates the transcription factor activator protein 1 (TFA-1), ultimately leading to the activation of the proto-oncogenes *c-fos* and *c-jun. H. pylori* infection also activates the ERK/MAP kinase, which phosphorylates the transcription factor Elk-1 and increases the transcription of *c-fos*. Strains of *H. pylori* that do not express the CagA surface antigen (cytotoxin-associated antigen A) or carry mutations of the *cag* family of genes do not activate TFA-1, *c-fos* and *c-jun*.76

Radical antibiotic treatment of *H. pylori* is effective for localized low-malignancy GL, even though disease recurs quite often.77 It has been recently reported that increased levels of paraprotein were inversely related to tumour response to radical treatment for *H. pylori*, whereas reduction of paraprotein levels were observed in patients who responded to radiation or chemotherapy. As a result, paraprotein levels could be used as a prognostic marker of response to *H. pylori* treatment and during patient follow-up.78

## Surgical treatment and molecular prognostic markers

The tumour–nodes–metastasis (TNM) system has not been widely used for staging of GI lymphomas. The most popular staging systems for such tumours are the Ann Arbor system, as modified by Musshoff for extranodal lymphomas in 19775 (Table 1), the Lugano system established by Rohatiner and colleagues in 199479 (Table 2) and the more recent Paris staging system, suggested in 2003 by the European Gastro-Intestinal Lymphoma Study Group80 (Table 3). Treatment decisions are made according to these staging systems.

View this table:
[Table 2](http://canjsurg.ca/content/55/2/117/T2)

Table 2 
Lugano system for staging of lymphomas79

View this table:
[Table 3](http://canjsurg.ca/content/55/2/117/T3)

Table 3 
Paris staging system (TNMB) for primary gastrointestinal tract lymphomas80

Gastric lymphomas can be treated in a variety of ways: antimicrobial treatment seems to be the first-line therapy for patients with *H. pylori* infection, yielding high disease remission rates for all T1/stage I and most T2/stage I tumours (staging mentioned refers to both TMNB-Paris and Ann Arbor staging systems, respectively).81 Stage I tumours extending beyond the submucosa are better treated with chemotherapy, radiation or a combination of both, yielding remission rates of up to 90%.82 Stage II or higher GL tumours can be treated with subtotal gastrectomy (open or laparoscopic) combined with removal of any nodular metastases.83 Careful and periodic follow-up of patients is highly encouraged: endoscopic ultrasonography and gastric biopsies can detect any relapses early on, allowing these patients to switch to an alternative therapy.84,85 However, it has been suggested that organ-preserving treatments present the same survival rates as surgical treatment, indicating that primary stomach resection should be questioned.83

To achieve the best therapeutic result, the surgeon must be aware of the factors that influence the effectiveness of therapeutic interventions. Thus, determining new prognostic markers is imperative; the analysis of these indices offers the surgeon the opportunity to predict the biological behaviour of the GL and choose an appropriate treating regimen according to tumour aggressiveness.2 Molecular prognostic markers predict the aggressiveness and prognosis for each patient’s particular disease better than the classic markers. The correlation of these modern markers with tumour relapse and overall survival makes possible the more specific and personalized choice of treatment for patients with GL. For example, the HLA-DR+/ICAM-3+/PECAM-1− phenotype has been associated with a 100% 5-year survival rate compared with other phenotypes. Patients with this phenotype could be considered eligible for treatment with chemotherapy and radiation instead of more invasive methods, even when the tumour is not at stage I. The same strategy can be applied for patients with GL who have the bcl2−/bax+ and the α4β7 integrin+/L-selectin+ phenotypes. On the contrary, lower remission rates for these tumours have been reported in patients with the p53+/p21- phenotypes. These patients could be treated in a more radical and efficient manner to prevent disease recurrence; at the very least, the surgeon should consider these patients as high-risk individuals and pursue their follow-up meticulously.

## Conclusion

Recent work in the molecular biology of GL offers a much better appreciation of an individual patient’s prognosis. The p27−/cyclin E+ phenotype is associated with worse prognosis. The expression of p53 increases with the degree of malignancy and is indicative of cellular dedifferentiation. Bcl-2 expression is greater in patients with highly differentiated lymphoma, and irregular bcl-10 expression is related to advanced stages of disease. Moreover, bcl-2−/bax+ phenotypes are associated with better prognosis, whereas the p53+/p21− phenotypes are associated with lower rates of complete remission. On the CAM level, PECAM-1 is an independent prognostic factor associated with unfavourable disease outcome, whereas increased ELAM-1 and VCAM-1 expression are associated with high-malignancy lymphomas. Conversely, absence of ICAM-1 expression is predictive of advanced disease stage, worse survival prognosis and both extra-nodal and marrow infiltration; lack of the adhesion molecule could relate to aggressive dissemination of the disease. The PECAM-1+/ICAM-3− phenotype is associated with a reduced 5-year survival rate. The ICAM-3 and PECAM-1 molecules play a major role along with the COX enzyme in neoangiogenesis, whose increased rate leads to worse prognosis. Intense T cell reactions may translate to longer life expectancy, whereas increased HLA-DR expression is an independent prognostic factor associated with increased survival. There is a correlation with the HLA-DR−/ICAM-3− phenotype and reduced 5-year survival rate in contrast to the HLA-DR+/ICAM+/PECAM− phenotype, which has been correlated with increased 5-year survival rates. Proliferation of gastric mucosa B cells and *H. pylori*–induced activation of *c-fos* and *c-jun* contributes to the pathogenesis of GL; serum paraprotein levels may be used as an index of patient response to *H. pylori* eradication treatment.

The proper treatment for a patient with GL is influenced by the presence of *H. pylori* and by the size and the stage of the disease. Patients infected with *H. pylori* who exhibit T1/2 tumours (Paris staging system; Table 3) or stage I tumours (Lugano staging system; Table 2) are best treated with antibiotics, whereas patients with larger tumours can be subjected to radiation and chemotherapy. Disease at stage II or higher (Ann Arbor staging; Table 1) is a clear indication for surgical treatment, although recent research debates the necessity of invasive compared with conservative treatment.

The new generation of molecular markers summarized in Table 4 enables personalized prognosis and allows the surgeon to select the optimal therapeutic modality when treating primary GL. To maintain low recurrence rates and greater disease-free survival, patients with tumours of stage II or higher by Ann Arbor staging and/or phenotypes indicating more aggressive or more persistent disease behaviour (ELAM-1+/VCAM-1+, p53+/p21−, PECAM-1+/ICAM-3−) could be treated using more conventional and proven surgical methods. Conversely, patients with GLs whose genetic profile is indicative of favourable disease outcome and lower malignancy potential (HLA-DR+/ICAM-3+/PECAM-1−, bcl2−/bax+, α4β7 integrin+/L-selectin+) are candidates for less invasive treatment, such as chemotherapy and radiation. The specific guidelines for this modern concept of treating patients with GL merits further research before becoming mainstream clinical practice. Whatever the treatment modality, careful patient follow-up via ultrasonography and endoscopic biopsies is paramount in preventing GL relapses and ensuring maximum disease-free survival for the patient.

View this table:
[Table 4](http://canjsurg.ca/content/55/2/117/T4)

Table 4 
Molecular markers and their prognostic value for gastric lymphoma

## Footnotes

*   **Competing interests:** None declared.

*   **Contributors:** L. Alevizos and M.M. Konstadoulakis designed the study. I.P. Gomatos acquired the data, which S.A. Smparounis and G. Zografos analyzed. L. Alevizos and S.A. Smparounis wrote the article, which all other authors reviewed. Each author approved the article submitted for publication.

*   Accepted September 6, 2011.

## References

1.  Bailey RL, Laws HL.Lymphoma of the stomach.Am Surg 1989;55:665–8.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=2817620&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

2.  Brands F, Monig SP, Raab M.Treatment and prognosis of gastric lymphoma.Eur J Surg 1997;163:803–13.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9414040&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1997YF46400001&link_type=ISI) 

3.  Isaacson PG, Spencer J.Malignant lymphoma of mucosa-associated lymphoid tissue.Histopathology 1987;11:445–62.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1111/j.1365-2559.1987.tb02654.x&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=3497084&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1987H275400001&link_type=ISI) 

4.  Azab MB, Henry-Amar M, Rougier P.Prognostic factors in primary gastrointestinal non-Hodgkin’s lymphoma. A multivariate analysis, report of 106 cases, and review of the literature.Cancer 1989;64:1208–17.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/1097-0142(19890915)64:6<1208::AID-CNCR2820640608>3.0.CO;2-Z&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=2670184&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1989AM58900007&link_type=ISI) 

5.  Musshoff K.Klinische Stadieneinteilung der Nicht-Hodgkin lymphome. [Article in German].Strahlentherapie 1977;153:218–21.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=857349&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1977DC36900003&link_type=ISI) 

6.  Cogliatti SB, Schmid U, Schumacher U, et al.Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients.Gastroenterology 1991;101:1159–70.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=1936785&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1991GM00800002&link_type=ISI) 

7.  Talamonti MS, Dawes LG, Joehl RJ, et al.Gastrointestinal lymphoma: a case for primary surgical resection.Arch Surg 1990;125:972–6.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1001/archsurg.1990.01410200030003&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=2378562&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

8.  Lim FE, Hartman AS, Tan EG, et al.Factors in the prognosis of gastric lymphoma.Cancer 1977;39:1715–20.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/1097-0142(197704)39:4<1715::AID-CNCR2820390449>3.0.CO;2-M&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=322839&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1977DD64500048&link_type=ISI) 

9.  Rodenhuis S.ras and human tumors.Semin Cancer Biol 1992;3:241–7.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=1421168&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

10. Cirisano FD, Karlan BY.The role of the HER-2/neu oncogene in gynecologic cancers.J Soc Gynecol Investig 1996;3:99–105.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1016/1071-5576(96)00001-9&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=8796816&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

11. Hiyama T, Haruma K, Kitadai Y, et al.K-ras mutation in helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer.Int J Cancer 2002;97:562–6.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/ijc.1644&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11807778&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000173364500002&link_type=ISI) 

12. Einspahr JG, Martinez ME, Ruiyun J, et al.Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics.Cancer Epidemiol Biomarkers Prev 2006;15:1443–50.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo5OiIxNS84LzE0NDMiO3M6NDoiYXRvbSI7czoxODoiL2Nqcy81NS8yLzExNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

13. Catalano T, Curia MC, Aceto G, et al.Mutations in the p53 and Ki-ras genes, microsatellite instability and site of tumor origin in colorectal cancer.Oncol Rep 2005;14:625–31.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16077965&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

14. Seiden-Long IM, Brown KR, Shih W, et al.Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer.Oncogene 2006;25:91–102.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16158056&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000234406400010&link_type=ISI) 

15. Lin JK, Shih-Ching C, Huann-Sheng W, et al.Distinctive clinicopathological features of Ki-ras mutated colorectal cancers.J Surg Oncol 2006;94:234–41.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16900509&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

16. Bazan V, Bruno L, Augello C, et al.Molecular detection of TP53, Ki-Ras and p16INK4A promoter methylation in plasma of patients with colorectal cancer and its association with prognosis. Results of a 3-year GOIM (Gruppo Oncologico dell’Italia Meridionale) prospective study.Ann Oncol 2006;17Suppl 7vii84–90.
    
    

17. Olson MF, Paterson HF, Marshall CJ.Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1.Nature 1998;394:295–9.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1038/28425&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9685162&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000074851900053&link_type=ISI) 

18. Fang JY, Zhu SS, Xiao SD, et al.Studies on the hypomethylation of c-myc, c-Ha-ras oncogenes and histopathological changes in human gastric carcinoma.J Gastroenterol Hepatol 1996;11:1079–82.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=8985834&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

19. Li JW, Chuang TC, Yang AH, et al.Clinicopathological relevance of HER2/neu and a related gene-protein cubic regression correlation in colorectal adenocarcinomas in Taiwan.Int J Oncol 2005;26:933–43.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=15753987&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

20. Zhang XL, Yang YS, Xu DP, et al.Comparative study on overexpression of HER2/neu and HER3 in gastric cancer.World J Surg 2009;33:2112–8.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/s00268-009-0142-z&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=19636613&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

21. Ochs AM, Wong L, Kakani V, et al.Expression of vascular endothelial growth factor and HER2/neu in stage II colon cancer and correlation with survival.Clin Col Cancer 2004;4:262–7.
    
    

22. Ross JS, McKenna BJ.The HER-2/neu oncogene in tumors of the gastrointestinal tract.Cancer Invest 2001;19:554–68.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1081/CNV-100103852&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11458821&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000169919200010&link_type=ISI) 

23. Ferreri AJ, Ponzoni M, Pruneri G, et al.Immunoreactivity for p27(KIP1) and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin’s lymphoma.Int J Cancer 2001;94:599–604.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/ijc.1509&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11745451&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

24. Min KO, Seo EJ, Kwon HJ, et al.Methylation of p16(INK4A) and p57(KIP2) are involved in the development and progression of gastric MALT lymphomas.Mod Pathol 2006;19:141–8.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16357845&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

25. Ricci R, Arena V, Castri F, et al.Role of p16/INK4a in gastrointestinal stromal tumor progression.Am J Clin Pathol 2004;122:35–43.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1309/MJ4XN2M57HNC8X5H&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=15272528&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

26. Schneider-Stock R, Boltze C, Lasota J, et al.High prognostic value of p16INK4 Alterations in gastrointestinal stromal tumors.J Clin Oncol 2003;21:1688–97.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjk6IjIxLzkvMTY4OCI7czo0OiJhdG9tIjtzOjE4OiIvY2pzLzU1LzIvMTE3LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

27. Sarbia M, Geddert H, Klump B, et al.Hypermethylation of tumor suppressor genes (p16INK4A, p14ARF, and APC) in adenocarcinomas of the upper gastrointestinal tract.Int J Cancer 2004;111:224–8.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/ijc.20212&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=15197775&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

28. Schmieder M, Wolf S, Danner B, et al.p16 expression differentiates high-risk gastrointestinal stromal tumor and predicts poor outcome.Neoplasia 2008;10:1154–62.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=18813351&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

29. Li AF, Li A, Tsay SH, et al.Alterations in the p16INK4a/Cyclin D1/RB pathway in gastrointestinal tract endocrine tumors.Am J Clin Pathol 2008;130:535–42.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1309/TLLVXK9HVA89CHPE&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=18794045&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

30. Hong J, Resnick M, Behar J, et al.Acid-induced P16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S.Am J Physiol Gastrointest Liver Physiol 2010;299:G697–706.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1152/ajpgi.00186.2010&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=20576920&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000281382600016&link_type=ISI) 

31. Ajani JA, Wang X, Izzo JG, et al.Molecular biomarkers correlate with disease-free survival in patients with anal canal carcinoma treated with chemoradiation.Dig Dis Sci 2010;55:1098–105.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/s10620-009-0812-6&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=19399614&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

32. Yasui W, Oue N, Kuniyasu H, et al.Molecular diagnosis of gastric cancer: present and future.Gastric Cancer 2001;4:113–21.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/PL00011733&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11760076&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

33. Liu H, Ye H, Dogan A, et al.t(11,18)(q21,q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10.Blood 2001;98:1182–7.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czo5OiI5OC80LzExODIiO3M6NDoiYXRvbSI7czoxODoiL2Nqcy81NS8yLzExNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

34. Fan YS, Rizkalla K, Engel J.Interstitial deletion of 8(q13q22) in diffuse large B-cell gastric lymphoma.Cancer Genet Cytogenet 1999;115:28–31.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1016/S0165-4608(99)00078-3&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10565296&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

35. Joensuu H, Soderstrom KO, Klemi PJ, et al.Nuclear DNA content and its prognostic value in lymphoma of the stomach.Cancer 1987;60:3042–8.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/1097-0142(19871215)60:12<3042::AID-CNCR2820601231>3.0.CO;2-9&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=3677026&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1987L076700030&link_type=ISI) 

36. Aydin ZD, Barista I, Canpinar H, et al.Gastric lymphomas in Turkey. Analysis of prognostic factors with special emphasis on flow cytometric DNA content.Cancer 2000;89:12–20.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1002/1097-0142(20000701)89:1<12::AID-CNCR3>3.0.CO;2-Y&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10896995&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000088017800004&link_type=ISI) 

37. Gisbertz IA, Schouten HC, Bot FJ, et al.Proliferation and apoptosis in primary gastric B-cell non-Hodgkin’s lymphoma.Histopathology 1997;30:152–9.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1046/j.1365-2559.1997.d01-573.x&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9067740&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

38. Gisbertz IA, Schouten HC, Bot FJ.Cell turnover parameters in small and large cell varieties of primary intestinal non-Hodgkin’s lymphoma.Cancer 1998;83:158–65.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9655306&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

39. Koda M, Reszec J, Sulkowska M, et al.Expression of the insulin-like growth factor-I receptor and proapoptotic Bax and Bak proteins in human colorectal cancer.Ann N Y Acad Sci 2004;1030:377–83.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1196/annals.1329.047&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=15659820&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

40. Tahara M, Ochiai A, Fujimoto J, et al.Expression of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, E2F-1, Bak, Bcl-X, and Bcl-2, and clinical outcomes for gastric cancer patients treated with bolus 5-fluorouracil.Oncol Rep 2004;11:9–15.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=14654896&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000187391300002&link_type=ISI) 

41. Gao C, Wang AY.Significance of increased apoptosis and Bax expression in human small intestinal adenocarcinoma.J Histochem Cytochem 2009;57:1139–48.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1369/jhc.2009.954446&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=19729672&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

42. Nehls O, Hass HG, Okech T, et al.Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone.Int J Colorectal Dis 2009;24:655–63.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/s00384-009-0635-0&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=19221769&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

43. Aggarwal S, Taneja N, Lin L, et al.Indomethacin-induced apoptosis in esophageal adenocarcinoma cells involves upregulation of Bax and translocation of mitochondrial cytochrome C independent of COX-2 expression.Neoplasia 2000;2:346–56.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1038/sj.neo.7900097&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11005569&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000089343300007&link_type=ISI) 

44. Nehls O, Okech T, Hsieh C-J, et al.Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX.Br J Cancer 2007;96:1409–18.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=17426704&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000246162600015&link_type=ISI) 

45. Saadi A, Shannon NB, Lao-Sirieix P, et al.Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers.Proc Natl Acad Sci U S A 2010;107:2177–82.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMDoiMTA3LzUvMjE3NyI7czo0OiJhdG9tIjtzOjE4OiIvY2pzLzU1LzIvMTE3LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

46. Liang R, Chan WP, Kwong YL, et al.Bcl-6 gene hypermutations in diffuse large B-cell lymphoma of primary gastric origin.Br J Haematol 1997;99:668–70.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9401082&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1997YK46200030&link_type=ISI) 

47. Charalambous GK, Gomatos IP, Konstadoulakis MM, et al.Protein expression of bax, bcl-2, and p53 in patients with non-Hodgkin’s gastric lymphoma: prognostic significance.World J Surg 2000;24:608–14.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/s002689910098&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10787085&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

48. Isaacson PG.Gastric MALT lymphoma: from concept to cure.Ann Oncol 1999;10:637–45.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1023/A:1008396618983&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10442184&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000081265100008&link_type=ISI) 

49. Liang R, Chan WP, Kwong YL, et al.High incidence of bcl-6 gene rearrangement in diffuse large B-cell lymphoma of primary gastric origin.Cancer Genet Cytogenet 1997;97:114–8.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9283593&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

50. Sadowski-Debbing K, Coy JF, Mier W, et al.Caspases: their role in apoptosis and other physiological processes as revealed by knock-out studies.Arch Immunol Ther Exp (Warsz) 2002;50:19–34.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11916306&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

51. Voutsadakis IA.Apoptosis and the pathogenesis of lymphoma.Acta Oncol 2000;39:151–6.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1080/028418600430707&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10859004&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000087123100005&link_type=ISI) 

52. Takahashi A, Kono K, Amemiya H, et al.Elevated caspase-3 activity in peripheral blood T cells coexists with increased degree of T-cell apoptosis and down-regulation of TCR zeta molecules in patients with gastric cancer.Clin Cancer Res 2001;7:74–80.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNsaW5jYW5yZXMiO3M6NToicmVzaWQiO3M6NjoiNy8xLzc0IjtzOjQ6ImF0b20iO3M6MTg6Ii9janMvNTUvMi8xMTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

53. Go JH, Yang WI.Expressions of p53 and p21 in primary gastric lymphomas.J Korean Med Sci 2001;16:731–5.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11748353&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

54. Tang DG, Honn KV.Adhesion molecules and tumor metastasis: an update.Invasion Metastasis 1994–1995;14:109–22.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=7657506&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

55. Roos E.Adhesion molecules in lymphoma metastasis.Cancer Metastasis Rev 1991;10:33–48.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1007/BF00046842&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=1680576&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

56. Ke JJ, Shao QS, Ling ZQ.Expression of E-selectin, integrin β1 and immunoglobulin superfamily member in human gastric carcinoma cells and its clinicopathologic significance.World J Gastroenterol 2006;12:3609–11.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16773720&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

57. Hayes SHH, Seigel GM.Immunoreactivity of ICAM-1 in human tumors, metastases and normal tissues.Int J Clin Exp Pathol 2009;2:553–60.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=19636402&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

58. Vainer B, Horn T, Nielsen OH.Colonic epithelial cell expression of ICAM-1 relates to loss of surface continuity: a comparative study of inflammatory bowel disease and colonic neoplasms.Scand J Gastroenterol 2006;41:318–25.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1080/00365520510024241&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16497620&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

59. Terol M-J, Lopez-Guillermo A, Bosch F, et al.Expression of the adhesion molecule icam-1 in non-Hodgkin’s lymphoma: relationship with tumor dissemination and prognostic importance.J Clin Oncol 1998;16:35–40.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjc6IjE2LzEvMzUiO3M6NDoiYXRvbSI7czoxODoiL2Nqcy81NS8yLzExNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

60. Charpin C, Devictor B, Bergeret D, et al.CD31 quantitative im-munocytochemical assays in breast carcinomas. Correlation with current prognostic factors.Am J Clin Pathol 1995;103:443–8.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1093/ajcp/103.4.443&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=7726141&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

61. Charpin C, Garcia S, Bouvier C, et al.CD31/PECAM automated and quantitative immunocytochemical assays in breast carcinomas: correlation with patient follow-up.Am J Clin Pathol 1997;107:534–41.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1093/ajcp/107.5.534&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9128265&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

62. Darom A, Gomatos IP, Leandros E, et al.Molecular markers (PECAM-1, ICAM-3, HLA-DR) determine prognosis in primary non-Hodgkin’s gastric lymphoma patients.World J Gastroenterol 2006;12:1924–32.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=16610000&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

63. Liu YX, Yoshino T, Ohara N, et al.Loss of expression of alpha4beta7 integrin and L-selectin is associated with high-grade progression of low-grade MALT lymphoma.Mod Pathol 2001;14:798–805.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1038/modpathol.3880393&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11504840&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000170460100009&link_type=ISI) 

64. Sato Y, Ito M, Morise K, et al.Expression of adhesion molecules in primary B-cell gastric lymphoma and lymphoid follicles.Virchows Arch 1996;429:377–82.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=8982383&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1996VZ67400009&link_type=ISI) 

65. Saito H, Tsujitani S.Angiogenesis, angiogenic factor expression and prognosis of gastric carcinoma.Anticancer Res 2001;21:4365–72.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11908692&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

66. Schaerer L, Schmid MH, Mueller B, et al.Angiogenesis in cutaneous lymphoproliferative disorders: microvessel density discriminates between cutaneous B-cell lymphomas and B-cell pseudolymphomas.Am J Dermatopathol 2000;22:140–3.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10770434&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

67. Konturek SJ, Konturek PC, Hartwich A, et al.Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies.Regul Pept 2000;93:13–9.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1016/S0167-0115(00)00173-7&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11033048&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

68. Tsuji S, Tsujii M, Kawano S, et al.Cyclooxygenase-2 upregulation as a perigenetic change in carcinogenesis.J Exp Clin Cancer Res 2001;20:117–29.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11370818&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

69. Guindi M.Role of activated host T cells in the promotion of MALT lymphoma growth.Semin Cancer Biol 2000;10:341–4.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1006/scbi.2000.0351&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11100881&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

70. Ansell SM, Stenson M, Habermann TM, et al.CD4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome.J Clin Oncol 2001;19:720–6.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjg6IjE5LzMvNzIwIjtzOjQ6ImF0b20iO3M6MTg6Ii9janMvNTUvMi8xMTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

71. Guidoboni M, Doglioni C, Laurino L, et al.Activation of infiltrating cytotoxic T lymphocytes and lymphoma cell apoptotic rates in gastric MALT lymphomas. Differences between high-grade and low-grade cases.Am J Pathol 1999;155:823–9.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=10487840&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

72. Amiot L, Onno M, Lamy T, et al.Loss of HLA molecules in B lymphomas is associated with an aggressive clinical course.Br J Haematol 1998;100:655–63.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1046/j.1365-2141.1998.00631.x&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9531330&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

73. Nocito M, Montalban C, González-Porque P, et al.Increased soluble serum HLA class I antigens in patients with lymphoma.Hum Immunol 1997;58:106–11.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1016/S0198-8859(97)00227-9&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9475339&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000071674300005&link_type=ISI) 

74. Cabrera T, Ruiz-Cabbelo F, Garrido F.Biological implications of HLA-DR expression in tumors.Scand J Immunol 1995;41:398–406.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1111/j.1365-3083.1995.tb03584.x&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=7899828&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1995QP15700012&link_type=ISI) 

75. Greiner A, Qin Y, Knorr C, et al.Autoantigen receptors in extranodal non-Hodgkin B-cell lymphomas.Verh Dtsch Ges Pathol 1996;80:160–8.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9020571&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

76. Meyer-ter-Vehn T, Covacci A, Kist M, et al.Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c-fos and c-jun.J Biol Chem 2000;275:16064–72.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamJjIjtzOjU6InJlc2lkIjtzOjEyOiIyNzUvMjEvMTYwNjQiO3M6NDoiYXRvbSI7czoxODoiL2Nqcy81NS8yLzExNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

77. Yoshino T, Akagi T.Gastric low-grade mucosa-associated lymphoid tissue lymphomas: their histogenesis and high-grade transformation.Pathol Int 1998;48:323–31.
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=9704338&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

78. Wöhrer S, Streubel B, Bartsch R, et al.Monoclonal immunoglobulin production is a frequent event in patients with mucosa-associated lymphoid tissue lymphoma.Clin Cancer Res 2004;10:7179–81.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNsaW5jYW5yZXMiO3M6NToicmVzaWQiO3M6MTA6IjEwLzIxLzcxNzkiO3M6NDoiYXRvbSI7czoxODoiL2Nqcy81NS8yLzExNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

79. Rohatiner A, D’Amore F, Coiffier B, et al.Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma.Ann Oncol 1994;5:397–400.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1093/oxfordjournals.annonc.a058869&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=8075046&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=A1994NT92800005&link_type=ISI) 

80. Ruskoné-Fourmestraux A, Dragosics B, Morgner A, et al.Paris staging system for primary gastrointestinal lymphomas.Gut 2003;52:912–3.
    
    [FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjg6IjUyLzYvOTEyIjtzOjQ6ImF0b20iO3M6MTg6Ii9janMvNTUvMi8xMTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

81. Andriani A, Miedico A, Tedeschi L, et al.Management and long-term follow-up of early stage H. pylori-associated gastric MALT-lymphoma in clinical practice: an Italian, multicentre study.Dig Liver Dis 2009;41:467–73.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1016/j.dld.2008.09.009&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=18945654&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 

82. McLaughlin P, Seymour J, Fuller L, et al.Combined modality therapy for stage I–II MALT lymphoma and mantle cell lymphoma.Ann Oncol 1996;7:211–3.
    
    

83. Fischbach W, Dragosics B, Kolve-Gobeler ME, et al.Primary gastric B-cell-lymphoma: results of a prospective multicenter study.Gastroenterology 2000;119:1191–202.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1053/gast.2000.19579&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=11054376&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000090060900005&link_type=ISI) 

84. Nakamura S, Matumoto T, Suekane H, et al.Predictive value of endoscopic ultrasonography for regression of gastric low-grade and high-grade MALT lymphomas after eradication of Helicobacter pylori.Gut 2001;48:454–60.
    
    [Abstract/FREE Full Text](http://canjsurg.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjg6IjQ4LzQvNDU0IjtzOjQ6ImF0b20iO3M6MTg6Ii9janMvNTUvMi8xMTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

85. Caletti G, Zinzani PL, Fusaroli P, et al.The importance of endoscopic ultrasonography in the management of low-grade gastric mucosa-associated lymphoid tissue lymphoma.Aliment Pharmacol Ther 2002;16:1715–22.
    
    [CrossRef](http://canjsurg.ca/lookup/external-ref?access_num=10.1046/j.1365-2036.2002.01334.x&link_type=DOI) 
    
    [PubMed](http://canjsurg.ca/lookup/external-ref?access_num=12269963&link_type=MED&atom=%2Fcjs%2F55%2F2%2F117.atom) 
    
    [Web of Science](http://canjsurg.ca/lookup/external-ref?access_num=000178110000004&link_type=ISI)