April 2000

present patients had imaging studies every 3 to 6 months. All livermetastases were confirmed by histological examination. Primary tumorlocation was established in 56 (81%) patients by surgical exploration(n=50) or autopsy (n=6)] and the remaining 13 (19%) patients by imagingstudies. Pancreatic tail (PT) gastrinomas were present in 36 patients in­cluding 3 patients with both tail and body gastrinomas. 33 patients hadpancreatic head (PH) gastrinomas including 4 patients with a gastrinoma atthe head and body junction. Patients with PT or PH gastrinomas did notdiffer in age, gender, percentage with MEN-I, duration of disease fromonset, basal acid output, mean size of gastrinoma, percentage that under­went surgery or autopsy and the rate of lymph node metastases. Patientswith PH gastrinoma more frequently had gastrinomas that could not beeasily resected or enucleated (8/33 = 24% vs 2/36 = 6%; p=0.034), lessfrequently had liver metastases (15/33 = 45% vs 26/36 = 72%; p=0.016),less frequently developed liver metastases post primary resection (1Il3 =7% vs 9118 = 50%; p=0.015). These results demonstrate that pancreatichead and tail gastrinomas differ in biologic behavior. Previous studiesshow that the rate of development of liver metastases from pancreaticgastrinomas is size-dependent and the current study shows it is alsolocation-dependent with pancreatic tail gastrinomas more likely to developliver metastases. These results support the conclusion that patients withpancreatic tail gastrinomas should be aggressively treated and need to befollowed carefully because they are at increased risk of developing livermetastases.

2729

PREDICTIVE VALUE OF CATHEPSIN D AND KI-67 EXPRES­SION AT THE DEEPEST PENETRATION SITE FOR LYMPHNODE METASTASES INGASTRIC CANCER.Hirokazu Goishi, Shinji Tanaka, Ken Haruma, Toru Amioka, YasuhikoKitadai, Masaharu Yoshihara, Koji Sumii, Goro Kajiyama, Fumio Shi­mamoto, Hiroshima Univ Sch of Med, Hiroshima, Japan.

Treatment methods for gastric cancers have become increasingly minimalby the appearance of endoscopic mucosal resection (EMR) and laparo­scopic gastrectomy. However, curative resection by EMR or laparoscopicgastrectomy can be performed in only differentiated type intramucosal orscanty invasive submucosal adenocarcinoma that is considered to have nometastasis, because there are no reliable predictors for lymph node metas­tasis except those lesions. The AIM of this study is to search the relation­ship between cathepsin D expression, Ki-67 expression at the deepestpenetration site of the tumor and lymph node metastasis in 136 cases withsurgically resected gastric cancer showing invasion from submucosa (sm)to muscularis propria (mp). They were divided into two groups by depth(sml and sm2 group for EMR, sm3 and mp group for laparoscopicgastrectomy). Immunohistochemical staining was performed by the labeledstreptavidin-biotin method using the monoclonal antibody to human Ki-67(MIB-I, IMMUNOTECH, Marseille, France) and the monoclonal antibodyto cathepsin D (NCL-CDm, NOVOCASTRA, Newcastle, UK). RE­SULTS: In smI and sm2 group, the incidence of lymph node metastases intumors with a higher Ki-67 LI (labeling index) (>39.0) (44%) was signif­icantly (p<O.OI) higher than that in those with a lower Ki-67 LI «39.0)(0%). In sm3 and mp group, the incidence of lymph node metastases incathepsin Dvpositive (56%) and higher Ki-67 LI tumors (64%) was signif­icantly higher than that in cathepsin D-negative (33%) and lower Ki-67 LI(33%), respectively. Furthermore, combined analysis of cathepsin D ex­pression and Ki-67 LI correlated all the more strongly with lymph nodemetastases, showing that no tumors with both cathepsin D-negative ex­pression and lower Ki-67 LI had lymph node metastases in both groups.CONCLUSION: These results indicated that cathepsin D and Ki-67 ex­pression may be useful predictors for lymph node metastases in gastriccancer with invasion of sm and mp. The combined analysis of them canpick up the tumors that have no lymph node metastases and clarify whatlesion needs no additional treatments after EMR or laparoscopic gastrec­tomy.

2730NEUROENDOCRINE DIFFERENTIATION IN STAGE III-IVCOLORECTAL CANCER.Isabell Schindler, Patricia Grabowski, Iannis Anagnostopoulos, Hans-Di­eter Foss, Gerd Berger, Julia Schoenfelder, Ernst-Otto Riecken, HansScheruebl, Benjamin Franklin Clinics, Free Univ of Berlin, Berlin, Ger­many.

Background: -The prognostic relevance of neuroendocrine differentiationin colorectal cancer remains controversial. Methods:-The survival of 116patients with colorectal cancer of either stage III (n=59) or stage IV(n=57) was correlated with the extent of neuroendocrine differentiation.Chromogranin A and synaptophysin were used as neuroendocrine markers.Based on the extent of neuroendocrine immunoreactivity the tumors weredivided into group 0 (no immunoreactivity), group I «2% positiveimmunoreactivity) and group 2 (> 2% positive immunoreactivity for eitherchromogranin A or synaptophysin). Patients were followed-up for morethan 5 years or till death. Results:-7 of 59 (11.8 %) stage III cancers and l3of 57 (22.8 %) stage IV cancers belonged to group 2. The 96 patients ofgroups 0 and I lived for 48,9 months, whereas tbe 20 patients of group 2only survived for 18,6 months (Kaplan- Meier survival curves, p< 0,05).The difference was most striking in stage III disease with a 79,4 month ssurvival for group 0 and I and a 38,9 month s survival in group 2 (P<O.OI).Using the multivariate Cox regression test, neuroendocrine differentiation

AGAA511

was found to be an independent prognostic marker both for stage III andstage IV disease. No correlation was observed between neuroendocrineimmunoreactivity and tumor location, grade, depth of invasion, or stage.Conclusioni- Neuroendocrine differentiation is seen commonly in colorec­tal cancer. It is an independent prognostic factor in stage III-IV colorectalcancer.

2731PROGNOSTIC RELEVANCE OF SIALYL-LEx ANTIGEN EX­PRESSION IN COLORECTAL CANCER.Patricia Grabowski, Benno Mann, Christoph Hanski, Hans-Dieter Foss,Iannis Anagnostopoulos, Ernst-Otto Riecken, Heinz 1. Buhr, HansScheruebl, Benjamin Franklin Clinics, Free Univ of Berlin, Berlin, Ger­many; UK Benjamin Franklin, FU Berlin, Berlin, Germany.

Background:- Sialyl-Le" is a carbohydrate antigen expressed in about 90%of colorectal carcinomas but not in normal colonic tissue. We tested theprognostic relevance of sialyl-Le" expression in colorectal carcinomas atdifferent stages of disease. Methods:- 178 patients (62 patients in UICCstage II, 59 patients in VICC stage III and 57 patients in VICC stage IV),who had undergone surgery for colorectal cancer at our institution werefollowed up for five years. Paraffin-embedded sections of all tumors wereinvestigated by immunohistochemistry using mAb AM-3, which detectsmonomeric sialyl-Le" on colonic mucins. Using a scoring system compris­ing staining intensity and the percentage of positive cells sections wereclassified as either weakly (score 0-6) or strongly (score 7-12) expressing.Kaplan-Meier-curves were calculated for detecting differences in the cu­mulative survival. Results:- 100 of the 178 tumors (56%) showed a strongsialyl-Le" expression. Patients whose tumors expressed sialyl-Le" stronglyhad a significantly worse prognosis than those with weakly expressingtumors. The difference was most striking in tumors at stage II with acumulative 5 year survival of 85% for strongly versus 55 % for weaklyexpressing tumors (p=0,013) and at stage III with 94% versus 51%,respectively,(p=0,OOO8). In stage IV disease the differerence did not reachstatistical significance (p=0,27). Using the multivariate Cox-regressiontest, sialyl-Le" was found to be an independent prognostic marker incolorectal cancer at stage II-IV. No correlation was found between sialyl­LeX-expression and tumor location, grade or depth of invasion. Conclu­sion:- These results show that sialyl-Le" expression is an independentunfavorable prognostic factor in colorectal cancer. Thus, sialyl-Le" expres­sion may be helpful to define patients at risk for recurrent disease (at stageII-III), and should be evaluated in future clinical trials.

2732THE PROGNOSTIC IMPACT OF UROKINASE TYPE PLASMIN­OGEN ACTIVATOR RECEPTOR IN COLORECTAL CANCER.L. Herszenyi, F. Farinati, M. Plebani, G. Istvan, P. Carraro, M. De Paoli,Z. Sapi, R. Cardin, R. Naccarato, Z. Tulassay, 2nd Dept of Medicine,Budapest, Hungary; Dept Gastroenterology, Padova, Italy; Dept Lab,Padova, Italy; 2nd Dept of Surg, Budapest, Hungary; Dept of Pathology,Szt Janos, Budapest, Hungary.

Background: We have previously demonstrated that urokinase type plas­minogen activator (UPA) and its inhibitor PAI-I are strong prognosticfactors for survival in colorectal cancer (CRC) and urokinase type plas­minogen activator receptor (UPA-R) may playa role in CRC invasion andmetastasis. Little is known on the prognostic relevance of UPA-R in CRC.Aim: to determine the prognostic role ofUPA-R in CRC. Methods: UPA-Rwas determined by ELISA in the colorectal mucosa of 35 patients (pts)with CRC undergoing surgery. The pts were enrolled in a follow-upprotocol. The follow-up ended in the event of death or, when the pts werestill alive. at the last follow-up date. Fourteen pts (40%) died of tumorrecurrence. Their median survival was 25 months (95% CL, 9-34, range5-39 months). At the end of the follow-up period, 21 pts (60%) were stillalive; their median follow-up was 43 months (95% CL, 38-46, range 32-56months). The median survival time calculated for all pts was 36 months(95% CL, 32-43). Survival was analyzed according to Mantel-Haenszellifetable analysis. Results: (ng/mg protein); (mean ::':: SD): DECEASED(m= 14)* vs ALIVE (m=21): UPA-R 2.94::'::0.89* vs 1.24::'::0.46p<O.OOOOI UPA-R antigen levels were significantly higher in deceased ptsthan in pts still alive. The Mantel-Haenszel survival curves showed asignificant association with survival for the following parameters: UPA-R(p=O.OOOI), Dukes classification (p=O.OOOI) and presence of metastases(p=O.OO4). Conclusion: Our results demonstrate the strong prognosticimpact of UPA-R in eRe.