Plasma membrane expression of ZNF185 is a prognostic factor in pancreatic ductal carcinoma.

Pancreatic ductal carcinoma (PDC) is one of the major causes of cancer-associated mortality globally due to its high potential for distant metastasis. To understand hematogenous metastasis, the molecular expression profiles of weak metastatic PDC cell subline BxPC-3 and highly liver-metastatic cell subline LM-BxPC-3 were compared, and zinc finger protein 185 (ZNF185) was identified as a molecule that is upregulated in LM-BxPC-3 cells. The aim of the present study was to evaluate the clinicopathological significance of ZNF185 in PDC. Using immunohistochemistry, ZNF185 expression was investigated in 182 patients with PDC, in association with numerous clinicopathological variables. The expression profile of ZNF185 was also characterized using xenograft models. In contrast to parent BxPC-3 cells in subcutaneous transplanted tumor foci, which only expressed ZNF185 on their plasma membrane (m)ZNF185, LM-BxPC-3 cells in liver-metastatic foci that were formed subsequent to transplantation all expressed cytoplasmic (c)ZNF185. Additionally, 51% of the cells at the periphery of the tumor foci expressed mZNF185. Expression of cZNF185, and of mZNF185 and cZNF185 combined was identified in 93 and 39% of clinical patients with PDC, respectively. Patients with mZNF185-negative and -positive PDC exhibited a median survival time of 30.2 months and 21.3 months, respectively. Multivariate analysis indicated that the expression of mZNF185 is closely associated with a shorter overall survival time. Increased marked venous invasion was more prevalent in patients who were mZNF185-positive, as compared with patients who were mZNF185-negative. These data suggest that the expression of mZNF185 is an independent and unfavorable prognosticator in patients with PDC. The results suggested that the amount and subcellular location of ZNF185 are correlated with the position of the cancer cells expressing it within the nests. Additionally, the subcellular location of ZNF185 may be important to its biological function.

Zinc finger protein 185 is a liver metastasis-associated factor in colon cancer patients.

LIM domain proteins are involved in several fundamental biological processes, including cell lineage specification, cytoskeleton organization and organ development. Zinc finger protein 185 (ZNF185) is one of the LIM domain proteins considered to be involved in the regulation of cellular differentiation and/or proliferation. However, the detailed functions and properties of ZNF185 in the multistep process of cancer biology have not yet been elucidated. In this study, we analyzed the association between ZNF185 and the clinicopathological characteristics of colon cancer, such as patient age and gender, histological type, lymphatic and venous involvement, T and N status, liver metastasis and stage. ZNF185 protein expression was immunohistochemically analyzed and ZNF185 was detected in the cancer cells of 78 of the 87 colon cancer patients. The correlation between ZNF185 and histological type was significant (P=0.010, G-test). ZNF185 expression was also significantly correlated with liver metastasis (P=0.030, G-test). A multivariate analysis using the Cox proportional hazards model was performed among cause-specific survival rate, ZNF185 expression and clinicopathological characteristics. Histological type, liver metastasis and ZNF185 expression were found to be independent prognostic indicators (P=0.028, P<0.0001 and P=0.036, respectively). Therefore, ZNF185 expression was found to be an independent indicator of liver metastasis and prognosis in patients with colon cancer.

Clinical significance of wall invasion pattern of subserosa-invasive gallbladder carcinoma.

We have previously classified wall invasion patterns of gallbladder carcinoma (GBC) cases into two groups, i.e., the infiltrative growth type (IG type) and destructive growth type (DG type). The DG type was significantly associated with poor differentiation, aggressive infiltration and decreased postoperative survival in terms of its histological differentiation, lymphatic invasion, venous invasion, lymph node status, neural invasion and mode of subserosal infiltration. In the present study, we analyzed 42 surgically-resected subserosal invasive gallbladder adenocarcinomas, invading the perimuscular connective tissue (pT2). The cumulative 5-year survival rate in the series was 48.7%. Lymphatic invasion (p=0.021), venous invasion (p=0.020), mode of subserosal infiltration (p<0.001), histological differentiation (p=0.030) and biliary infiltration (p=0.007) were noted, respectively, at a significantly higher incidence in more aggressive infiltration or poor differentiation in the DG type. The cumulative 5-year survival rate of curative resection cases was lower in patients with the DG type than in those with the IG type (68.9 versus 20.2%, respectively, p=0.006, log-rank test). On Cox's proportional hazard regression modeling, the low degree of venous/perineural invasion and IG type of wall invasion pattern were associated with a significant improvement in overall survival. Our data suggest that the wall invasion pattern is an independent predictor of survival in subserosal invasive GBC. Regarding the clinical application of our concept, on the classification of patients with subserosal invasive GBC based on a combination of the wall invasion pattern and lymph node status, the overall survival rate in patients with the DG type and/or N2 metastasis (n=21) was lower than in patients with the IG type and N0, 1 metastasis (n=21) (p=0.0023, log-rank test). The wall invasion pattern could contribute to decision-making concerning curative resection for subserosal invasive GBC.

An annular pancreas associated with carcinoma of the papilla of Vater: report of a case.

An annular pancreas is an uncommon congenital anomaly that usually presents early in childhood. Malignancy in the setting of an annular pancreas is unusual. We herein report a case of annular pancreas with carcinoma of the papilla of Vater. A 59-year-old man presented with epigastric discomfort and was referred to us after gastroduodenal endoscopy showed a tumor of the papilla of Vater. Preoperative imaging showed the pancreatic parenchyma encircling the descending duodenum and a tumor at the papilla of Vater. A pancreaticoduodenectomy was performed for the annular pancreas and the ampullary tumor. Histological examination confirmed a complete annular pancreas and carcinoma in situ of the papilla of Vater. We also provide a review of the reported cases of an annular pancreas with periampullary neoplasms and discuss the clinical characteristics of this anomaly.

Leiomyosarcoma of the pancreas: report of a case.

Leiomyosarcoma of the pancreas is a rare neoplasm, with only 34 reported cases in the literature. We encountered a rare case of leiomyosarcoma of the pancreas, treated successfully by surgery. A 41-year-old woman was referred to our hospital for further examinations of a pancreatic tumor. Imaging studies demonstrated a solid and lobular mass, about 4 cm in diameter, in the body of pancreas. This mass had a nonuniform content and was encapsulated. We performed distal pancreatectomy and splenectomy for an assumed diagnosis of invasive ductal carcinoma. Macroscopically, a sagittal section of the operative specimen showed a well-circumscribed yellowish-white mass without any cystic changes. Immunohistological examination revealed that α-smooth muscle actin, desmin, and vimentin were positive, and the labeling index of MIB-1 was 50% or more. Based on these findings, we confirmed a diagnosis of leiomyosarcoma originating from the pancreas. During 14 months of follow-up to date, there has not been any evidence of local recurrence or distant metastasis.

Nonfunctioning pancreatic endocrine tumor with extension into the main pancreatic duct: report of a case.

Pancreatic endocrine tumors (PETs) rarely involve the main pancreatic duct. We report a case of malignant nonfunctioning pancreatic endocrine tumor (NFPET) with prevalent intraductal growth. A 47-year-old woman was referred to us after ultrasonography at a routine health check showed diffuse swelling of the pancreas. Preoperative imaging showed a solid mass in the tail of the pancreas and a bulging intraductal mass in the main pancreatic duct. We performed total pancreatectomy because the tumor occupied almost the entire lumen of the main pancreatic duct. Histological examination confirmed well-differentiated endocrine carcinoma. We review reported cases of the intraductal growth of NFPETs and discuss the pathogenesis of these unusual tumors.

[Retroperitoneal liposarcoma: a case report].

A 35-year-old woman who had visited an other hospital because of epigastralgia and anorexia was found to have a giant abdominal tumor, and was referred to our hospital. On admission, the abdomen was markedly distended. Abdominal CT scan and MRI showed the presence of a retroperitoneal tumor which occupied almost the entire abdominal cavity. She was operated a under a diagnosis of retroperitoneal liposarcoma. The tumor was located between the subphrenic space and the pelvic cavity, and was compressing the stomach, duodenum, pancreas and colon. Removal of the retroperitoneal tumor, including the right kidney, was performed. The resected tumor was 34 × 28 × 20 cm, weighed 5.5 kg and showed a variety of finding. The pathological diagnosis was a mixed type of retroperitoneal liposarcoma, consisting of well-differentiated type and myxoid type. We reported a case of giant retroperitoneal liposarcoma, with a review of the literature.

The distance of tumor spread in the main pancreatic duct of an intraductal papillary-mucinous neoplasm: where to resect and how to predict it.

BACKGROUND: The surgical decision regarding where to resect the pancreas is an important judgement that is directly linked to the surgical procedure. An appropriate surgical margin to resect intraductal papillary-mucinous neoplasm (IPMN) of the pancreas based on the distance of tumor spread (DTS) in the main pancreatic duct has not been adequately documented. We analyzed the appropriate surgical margin based on the DTS in the main pancreatic duct of IPMN and the positive rate at the pancreatic cut end margin. METHODS: Forty patients with main duct- or mixed-type IPMN diagnosed histopathologically who underwent surgery at Tokai University Hospital between 1991 and 2008 were retrospectively analyzed. The resection line was determined to achieve a 2-cm surgical margin in patients with main duct- or mixed-type IPMN and as limited a resection as possible to remove the dilated branch duct in patients with branch duct-type IPMN according to macroscopic type. The dysplastic state of the epithelium was judged as positive for carcinoma in situ (high-grade dysplasia) or adenoma (very low to moderate dysplasia) and judged as negative for hyperplasia or normal. RESULTS: The mean DTS in the main pancreatic duct was 41.6 +/- 30.0 mm, and that of the distance of tumor absence was 13.6 +/- 12.4 mm. The positive rate at the pancreatic cut end margin in frozen sections was 29.7%. The final positive rate at the pancreatic cut end margin was 26.2%. There has been no evidence of local recurrence in the remnant pancreas. DTS in the main pancreatic duct of IPMN was correlated with the maximum diameter of the duct (R = 0.678). CONCLUSION: Distance of tumor spread offered important insights about the appropriate site to resect the pancreas and the positive rate at the cut end margin in IPMN.

Stromal thrombospondin-1 expression is a prognostic indicator and a new marker of invasiveness in intraductal papillary-mucinous neoplasm of the pancreas.

The invasion of intraductal papillary-mucinous neoplasm (IPMN) is sometimes difficult to diagnose using only ordinary hematoxylin-eosin sections. The aim of this study was to evaluate the invasion of IPMN more precisely using thrombospondin-1 (TSP1) immunohistochemistry as a useful adjunct to morphological examination. Eighty patients that underwent primary resection for pancreatic IPMNs were retrospectively analyzed. The 80 IPMNs were studied for the expression of TSP1, MUC1-CORE, MUC2, and MUC5AC. The cases were evaluated for dysplasia, the presence of invasion, hisological subtypes, and survival. The 80 IPMNs were classified into 29 intraductal papillary-mucinous adenomas (IPMAs), 10 borderline IPMNs, 18 noninvasive intraductal papillary-mucinous carcinomas (IPMCs), and 23 invasive IPMCs according to the WHO classification. Invasive IPMCs were further divided into 12 minimally invasive IPMCs (MI-IPMCs) and 11 invasive carcinomas originating from IPMCs (IC-IPMCs) according to the Japan Pancreatic Society classification. The rate of strongly positive cases with more than 30% of the cancer stroma area expressing TSP1 was significantly higher in MI-IPMC and IC-IPMC than in noninvasive IPMC (P = 0.035, 0.005). Furthermore, patients in the strongly positive group had a significantly poorer prognosis compared to patients in the negative-weakly positive group (P = 0.008, log-rank test). Of the 80 tumors, 22 were classified into gastric-, 45 into intestinal-, 7 into pancreatobiliary-, and 6 into oncocytic-type IPMNs according to criteria described previously. The cases with a strongly positive expression of TSP1 were frequently detected in the pancreatobiliary and oncocytic types (P = 0.001). In conclusion, stromal TSP1 expression is a prognostic indicator and a new marker of invasiveness in IPMN.

Reduced CD73 expression and its association with altered purine nucleotide metabolism in colorectal cancer cells robustly causing liver metastases.

Liver metastases of colorectal cancers significantly affect the prognoses of patients. To further understand the biological aspects of the metastatic phenotypes, we established the highly liver-metastatic human colorectal cancer cell subline SW48LM2. The subline was established through the serial intrasplenic transfer of cells derived from poor but visible hepatic tumor foci formed by parental SW48 cells and transferred to NOD/SCID/IL-2Rγc(null) mice. The growth, both under monolayer culture conditions and during the formation of subcutaneous tumors, was similar between the two cell lines, although there were morphological differences in the in vitro spheroid formation. Of 41 molecules reportedly associated positively or negatively with tumor progression, four were overexpressed and four were underexpressed in SW48LM2 cells. Notably, this liver-metastatic cell subline exhibited a strongly reduced expression of the ecto-5'-nucleotidase CD73 as well as an altered metabolism of purine nucleotides. Previous studies showed a positive correlation between CD73 expression and metastatic cancer phenotypes. A reduced CD73 expression in tumor cells, however, may contribute to obtaining insight into the mechanisms of liver metastases.

Alternative splicing variant of vascular endothelial growth factor-A is a critical prognostic factor in non-small cell lung cancer.

Lung cancer is one of the most common malignant diseases in the world, and its prognosis is generally poor. Cancer and metastasis involve numerous biological steps, including angiogenesis in both the primary and metastatic sites. Although various molecules that are involved in both tumor neovascularization (angiogenesis) and invasion have been identified, little is known about how these molecules interact in cancerous microenvironments. We previously reported that the gene expressions of some factors associated with vascularization correlated with the prognosis of non-small cell lung cancer (NSCLC). In this study, we performed multivariate analysis of the mRNA levels of 10 selected genes [VEGF-A, VEGF121, VEGF165, VEGF189, S100A4, E-cadherin, Thrombospondin (TSP)-1, TSP-2, matrix metalloproteinase (MMP)-2, and MMP-9] in 130 NSCLC specimens using the real-time quantitative reverse transcription-polymerase chain reaction. Spearman's rank correlation test was used to determine the co-expression patterns. The analysis demonstrated highly significant co-expressions (P<0.0001) among the VEGF isoforms (VEGF-A, VEGF121, VEGF165, and VEGF189). We also analyzed the correlations among the prognosis, gene expressions, clinical factors (age and gender), and pathological features (histological types, TNM status, stages, lymphatic involvement, and venous involvement) using the Cox proportional hazards model. Multivariate analyses showed that only VEGF189 expression was an independent prognostic indicator (P=0.0252). The alternative splicing variant VEGF189, the cell binding isoform, plays a leading role in the progression of NSCLC.

Cancerous, but not stromal, thrombospondin-2 contributes prognosis in pulmonary adenocarcinoma.

Thrombospondin (TSP)-2 is known to be an endogenous negative regulator of vascularization in human cancer. However, it is unclear whether TSP-2 expression is related to neovascularization and prognosis in non-small cell lung cancer. In this study, we quantitatively examined the expression of TSP-2 mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) in 102 pulmonary adenocarcinomas. All 102 carcinoma specimens expressed TSP-2 mRNA. The expression of TSP-2 mRNA in carcinoma was significantly higher than normal lung tissues (p<0.0001, Kruskal-Wallis test). Sizes of tumors were significantly correlated with TSP-2 gene expression (p=0.0179, Kruskal-Wallis test). The TSP-2 expression levels of the stage II/III pulmonary carcinomas were significantly increased as compared to those of stage I (p=0.0136, Kruskal-Wallis test). Thirty-five patients with high TSP-2 mRNA expression showed poor prognosis in survival (p=0.0139, log-rank test). We examined TSP-2 protein localizations in the pulmonary adenocarcinoma overexpressing TSP-2 mRNA. The TSP-2 localizations were categorized in two patterns: cancerous TSP-2 expression pattern (TSP-2 expression in the cancerous cells) and non-cancerous TSP-2 expression pattern (TSP-2 expression in the stromal lymphoid cells). Pulmonary adenocarcinoma patients with cancerous TSP-2 expression pattern showed good prognosis (p=0.0322; Fisher's probability exact test). Pulmonary adenocarcinoma patients with non-cancerous TSP-2 expression pattern showed poor prognosis (p=0.0220; Fisher's probability exact test). Non-cancerous TSP-2 expressions may reflect secondary reactions in the cancerous stroma. The stromal TSP-2 expression is not enough to suppress growth of pulmonary adenocarcinoma, while the cancerous TSP-2 expression directly inhibits growth of the carcinoma.

Wall-invasion pattern correlates with survival of patients with gallbladder adenocarcinoma.

Gallbladder carcinomas (GBC) frequently show vascular invasion and metastasis when the carcinoma cells invade the perimuscular connective tissue (pT2 according to the TNM classification) through the muscular layer. In this study, two intramural invasion patterns were defined as (i) infiltrative growth (IG) type, infiltrative growth in the muscle layer without destruction and (ii) destructive growth (DG) type, massive growth with destruction of the muscle layer. Sixty-six surgically resected gallbladder adenocarcinomas invading the perimuscular connective tissue (pT2) and beyond the gallbladder wall, including the visceral serosa, (pT3/pT4) were examined. The overall survival rate of the patients with the DG type was significantly lower than that of the patients with the IG type (p = 0.018). Lymphatic invasion (37.5% of IG and 62.5% of DG, p = 0.014), venous invasion (41.9%, 58.1%, p = 0.089), nodal status (30.4%, 69.6%, p = 0.015) and scirrhous growth (INFgamma) (31.0%, 69.0%, p = 0.0035) were more frequently detected in DG cases than in IG cases. In addition, median survival and survival rates were statistically analyzed. The patients with a high grade of lymphatic and venous invasion had lower survival rates (p < 0.0001 and p < 0.05, respectively). The patients with the DG type and scirrhous growth (INFgamma) also had lower survival rates (p < 0.05 and p < 0.0001, respectively) than did patients with the IG type and expansive/intermediate growth (INFalpha,beta). On multivariate analysis, neural invasion (odds ratio, 0.157; 95% confidence interval, 0.039-0.629) was an independent predictor of mortality. In conclusion, the DG invasion pattern is an indicator of high malignant potential and indirectly worsens the prognosis of patients with gallbladder adenocarcinoma.

Stromal laminin-5gamma2 chain expression is associated with the wall-invasion pattern of gallbladder adenocarcinoma.

Our previous study demonstrated that the pT2 and pT3-4 gallbladder carcinomas can be classified into two groups, i.e. infiltrative growth type (IG type) and destructive growth type (DG type) and that the DG type is associated with poor differentiation, aggressive infiltration, and decreased postoperative survival. The present study focused on the clinicopathologic significance of laminin-5gamma2 chain expression as an indicator of local aggressiveness and Ki-67 labeling index (Ki-67 LI) as an indicator of the cell proliferation activity of gallbladder carcinoma. Ki-67 LI was higher in the DG type (26.3%) than in the IG type (21.4%), and the rate of high-grade cell proliferation cases (Ki-67 LI > or = 30%) was high in the DG type (P = 0.012). Gallbladder carcinoma cases with high Ki-67 LI were significantly associated with poorly differentiation (P = 0.089) and distant lymph node metastasis (P = 0.079). Laminin-5gamma2 expression patterns of gallbladder carcinoma were divided into two distinct types, extracellular staining and cytoplasmic staining. The extracellular staining was subclassified into two groups, basement membrane staining and stromal staining. In the basement membrane staining, laminin-5gamma2 was present in the basement membranes surrounding neoplastic glandular structures. The basement membrane staining of laminin-5gamma2 was more frequent in the IG type (40%) than in the DG type (12.9%) (P = 0.025). The stromal staining was more frequent in the DG type. Furthermore, the stroma-positive group was more closely associated with decreased overall survival than the stroma-negative group (P = 0.028). The cytoplasmic staining was not significantly correlated with invasion pattern in gallbladder carcinoma (P = 0.545). Univariate analysis demonstrated that laminin-5gamma2 stromal staining is a predictor of lymphatic invasion, venous invasion, neural invasion, the mode of subserosal infiltration, and lymph nodal status. Multivariate analysis revealed the mode of subserosal infiltration is the strongest predictor of stromal invasion (P = 0.068). In conclusion, high-grade cell proliferation and stromal laminin-5gamma2 staining were significantly correlated with a wall-invasion pattern of aggressive gallbladder carcinoma indicating destructive growth (DG type).

Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/gammaCnull (NOG) mice.

Thrombospondin (TSP) 2 interacts with matrix metalloproteinases (MMPs) and matrix serine proteases such as plasminogen activator (PA). Malignant melanoma is an aggressive human neoplasm showing aggressive metastatic features. We examined the effects of TSP2 gene introduction in the human malignant melanoma cell line A375. We established three clones transfected with human TSP2 (A375/TSP2). The in vitro invasiveness was remarkably suppressed (42-61%) in the TSP2-transfectants, while growth properties were preserved. The A375/TSP2 showed significantly decreased liver metastatic potential (liver weight: 3.88+/-0.30 g in A375/TSP2, 7.07+/-0.67 g in vector-transfectant (A375/V), p<0.01, Mann-Whitney U test) in super immuno-deficient mice (NOD/SCID/gammacnull, NOG). The PA inhibitor-1 (PAI-1) and PAI-2 mRNAs were significantly overexpressed in A375/TSP2. The increased activities of PAI-1 and PAI-2 were confirmed by reverse zymography. The vascularity of metastatic lesions was significantly decreased in A375/TSP2 (vascular density: 0.62+/-0.15% in A375/TSP2, 4.96+/-0.61% in A375/V, p<0.01, Welch test). These results suggest that TSP2 suppresses hematogenous metastasis through microenvironment-modification including PAI up-regulation and anti-vascularization in human malignant melanoma.

Curative surgical treatment after preoperative chemotherapy for primarily inoperable locally advanced pancreatic carcinoma: report of a case.

Pancreatic cancer is considered resectable only when there are no distant metastases or infiltration of surrounding organs or arteries. We describe a patient with primarily inoperable locally advanced pancreatic adenocarcinoma who underwent curative surgical treatment after preoperative chemotherapy. A 61-year-old woman was admitted for further evaluation of a pancreatic head mass discovered fortuitously on a health screening. Examination revealed locally advanced pancreatic cancer with infiltration of the superior mesenteric artery. After a partial response was obtained by chemotherapy with gemcitabine (GEM) and S-1, we performed pancreaticoduodenectomy. Microscopically, the main tumor was replaced with fibrotic tissue, and there were only a few residual adenocarcinoma cells in the pancreatic head. The radicality of the surgery was R0, according to the TNM classification. Our results suggest that neoadjuvant treatment with GEM/S-1 on a sustainable regimen offers the possibility of a multimodal treatment concept for all patients and a higher radical-resection rate in patients with otherwise unresectable pancreatic cancers.

Thrombospondin-2 inhibits tumor cell invasion through the modulation of MMP-9 and uPA in pancreatic cancer cells.

The extracellular matrix protein thrombospondin (TSP) plays an important role in a variety of biological processes, including cell-cell and cell-matrix interactions. The biological role of TSP-2 in invasion and metastasis is poorly understood, while it is known that TSP-1 regulates a proteolytic cascade that allows tumor cells to invade and metastasize. In this study, we examined the role of TSP-2 in tumor cell invasion and its association with proteolytic proteins, matrix metalloproteinase (MMP) and the plasminogen/plasmin system, including urokinase-type plasminogen activator (uPA), in the human pancreatic cancer cell line PANC-1. PANC-1 cells expressed a low level of TSP-2, but significant levels of TSP-1. We isolated three clones of PANC-1 transformants stably overexpressing human TSP-2 (PANC-T). PANC-T highly expressed the TSP-2 gene and protein, while TSP-1 expression was not altered. In vitro invasion assays demonstrated that the invasiveness of PANC-T clones was significantly suppressed (p<0.05; Welch test). Zymography revealed that restoration of TSP-2 synthesis in the PANC-T clones significantly inhibited MMP-9 activity (p<0.05; Welch test). uPA activity in the PANC-T clones was significantly suppressed (p<0.05; Welch test). We concluded that restoration of TSP-2 can inhibit cell invasion through the down-regulation of MMP-9 and uPA activity in pancreatic cancer cell lines. Thus, TSP-2 may be a potent inhibitor of metastasis in pancreatic cancer.

Multiple gastric carcinoids associated with hypergastrinemia. A review of five cases with clinicopathological analysis and surgical strategies.

Previously, total gastrectomy was regarded as the treatment for multiple gastric carcinoids because of the unknown biological characteristics of this disease. Recent studies, however, have revealed that type 1 gastric carcinoids have a low potential for malignancy. In this study, five patients with hypergastrinemia and multiple gastric carcinoids, who underwent gastrectomy with regional node dissection, were analyzed. On serum chemistry examinations, the serum gastrin level was found to be high (515.5-over 3000 pg/ml) in all patients pre-operatively, but returned to a normal range (40-50 pg/ml) in all three cases examined post-operatively. Histopathological examination of our five cases revealed multiple gastric tumors, i.e. three to five tumors in Cases 1-4 and numerous tumors in Case 5. The multiple tumors were histologically carcinoid tumors up to 15 mm in size, limited to the submucosa, and no lymph node metastasis was identified in any of the cases. The patients were followed-up at outpatient clinics with no additional adjuvant therapy, and there was no evidence of recurrence during follow-up. Recently, minor invasive surgery such as endoscopic mucosal resection or laparoscopic antrectomy has been performed to treat type 1 gastric carcinoids. Our data provide important insights into understanding the biological behavior of multiple gastric carcinoids.