Expression of oncoproteins and the amount of eosinophilic and lymphocytic infiltrates can be used as prognostic factors in gastric cancer

Abstract

Summary Preoperative staging of gastric cancer is difficult. Several molecular markers associated with initiation and progression of cancer seem promising for obtaining preoperative prognostic information. To investigate whether these markers are indicative especially for the presence of lymph node metastases in patients with gastric cancer, we have examined primary tumour specimens from 105 patients with primary adenocarcinoma of the stomach entered in a surgical trial. In this trial, lymph node status was determined by strictly quality-controlled lymph node dissection and examination. The selected markers were growth regulators (p53, Rb and myc), metastasis-suppressor gene product (nm23), adhesion molecules (Ep-CAM, E-cadherin, CD44v5 and CD44v6) and urokinase-type plasminogen activator (u-PA). Also, the amount of eosinophilic and lymphocytic infiltrates available post-operatively was analysed with respect to its prognostic value for lymph node status. Moreover, the association of these parameters with survival and disease-free period (DFP) was evaluated. Of all molecular markers investigated, only Rb expression had a significant association with the presence of lymph node metastasis in both univariate and multivariate analysis. For curative resectability, a significant association was found with Rb and E-cadherin expression, while in multivariate analysis Rb and myc were selected as the combination with additional independent prognostic value, and E-cadherin had no additional independent value. For overall survival in univariate analysis, the amount of both eosinophilic and lymphocytic infiltrates and Rb and myc expression were of significant prognostic value. Only the amount of lymphocytic infiltrate had a prognostic significance for DFP. In stepwise multivariate analysis, TNM stage (I+II) and marked lymphocytic infiltrate were associated with better overall survival and longer DFP. We conclude that, if these results are confirmed in a larger series of patients, molecular markers can provide useful prognostic information.Keywords: gastric cancer; metastasis; prognosis; molecular marker Despite declining incidence, gastric cancer remains a major clinical management problem with poor prognosis: overall 5 year survival rates vary between 5% and 11%. Only a curative resection (complete tumour removal) offers hope of a cure, but the majority of the patients are diagnosed at an advanced disease stage (Allum et al., 1989). At diagnosis, the first decision to be made is whether or not to attempt a curative resection. This decision is based on stage of disease, which is assessed by radiograph of the stomach, chest and ultrasound of the liver or computerised tomography (CT) scan of the abdomen. Palliative resections offer no survival advantage and are associated with higher operative mortality rates compared with curative resections (Allum et al., 1989;Akoh et al., 1991; Wanebo et al., 1993). Laparoscopy and cytological examination of abdominal washings increase the accuracy of preoperative staging, but are not used r...

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

“…In this study, the human surface antigen EpCAM was found to be such a target, being predominantly expressed on ( pre )malignant lesions of the stomach and esophagus and allowing specific gene transfer to gastric and esophageal cancer cells in vitro. In agreement with the study of Songun et al, 26 we observed no significant association between EpCAM expression and clinicopathological features of the tumors. Most likely, this is due to the high prevalence of high EpCAM expression in the gastric adenocarcinomas.…”

Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer

“…In gastric epithelium the expression of Ep-CAM is low, and its increase is associated with very early stages of development of intestinal metaplasia (unpublished data). However, Ep-CAM loss associated with poor prognosis, as demonstrated in our earlier (Songun et al, 1996) and the present study, differs from previous observations of increased Ep-CAM expression associated with poor prognosis in breast cancer (Mirecka et al, 1995). Although not very strong, Ep-CAM mediated adhesions were able to suppress the scattering of cells embedded into matrigel (Litvinov, 1995).…”

Influence of pathological tumour variables on long-term survival in resectable gastric cancer

“…In the present study based on the MRC trial, as well as those described by Yu et al (1995) and Songun et al (1996), eosinophil infiltration has been graded into three groups: none or few, moderate or scanty, marked or numerous. Only Iwasaki et al (1986) described a more objective index: none, 5100 cells, 4100 cells.…”

“…The improved prognosis associated with the presence of marked tumour-associated tissue eosinophilia (TATE) in two cancers at either end of the gut is interesting and merits further investigation even if this is only found in a small percentage (8% in the present study) of these gastrointestinal cancers. Abnormal recruitment of tissue eosinophils is encountered in a variety of medical conditions including specific malignancies e.g., Hodgkin's disease certain types of leukaemia (Ogata et al, 1998) and some solid tumours (Pretlow et al, 1983;Iwasaki et al, 1986;Bethwaite et al, 1993;Caruso et al, 1993;Yu et al, 1995;Leighton et al, 1996;Songun et al, 1996;Ono et al, 1997;Geisinger et al, 1998;Tajima et al, 1998;Hong et al, 1999;Nielsen et al, 1999;Moezzi et al, 2000). TATE may simply be a surrogate marker of a distinctive cytokine response to an infiltrative tumour.…”

“…As well as determining tumour stage and nodal status, tumours were assessed using the WHO, Lauren, Mulligan and Ming classifications, in addition to grading based on the degree of differentiation. Extent of infiltration of the tumour stroma by lymphocytes and eosinophils was also assessed as some studies had suggested a potential survival benefit for patients with marked stromal infiltrates (Yu et al, 1995;Songun et al, 1996). The effect of these pathological and staging criteria on patient survival is examined in this study.…”