Intestinal-type Early Gastric Cancer Research Articles

High Expression of Claudin-4 Is Associated with Synchronous Tumors in Patients with Early Gastric Cancer.

Claudin (CLDN) is a tight junction protein found in human epithelial cells and its altered expression is known to be associated with the progression of gastric cancer. We aimed to investigate the differential expression of CLDN-4 in early gastric cancer (EGC) according to its clinicopathological characteristics. We enrolled 53 patients with EGC who underwent surgical gastric resection from January 2007 to December 2018. The staining intensity of the tumor cells was scored as 0–3, and the percentage of staining was scored as 0–5; high expression was defined if the intensity plus percentage score was 7 or 8, and low expression was defined if the score was 0–6. Among the 53 patients, 16 (30.2%) showed low CLDN-4 expression, while 37 (69.8%) had high CLDN-4 expression. High CLDN-4 expression was significantly associated with intestinal-type EGC (low: 12.5% vs. high: 56.8%, p = 0.003), open-type atrophic change (low: 60.0% vs. high: 90.9%, p = 0.011), and the presence of synchronous tumors (0 vs. 32.4%, p = 0.010), and all 12 EGCs with synchronous tumors showed high CLDN-4 expression. However, expression of CLDN-3, a typical intestinal phenotype CLDN, was neither correlated with CLDN-4 expression nor associated with synchronous tumors. Taken together, high CLDN-4 expression may be considered as an auxiliary tool for screening synchronous tumors in patients with EGC.

Propensity score-matched comparison of short- and long-term outcomes between surgery and endoscopic submucosal dissection (ESD) for intestinal type early gastric cancer (EGC) of the middle and lower third of the stomach: a European tertiary referral center experience.

Despite the comparable results between ESD and gastrectomy reported in multiple Asiatic studies, limited data are currently present on the long-term efficacy of ESD for EGC in Western countries. The aim of this study was to compare the short- and long-term outcomes of the endoscopic submucosal dissection and surgery for non-diffuse early gastric cancer treatment in a Western cohort of patients. All patients with a diagnosis of intestinal type EGC located in the middle and lower third of the stomach from 2005 to 2015 were enrolled in the study. All patients completed a 5-year follow-up. Patients were divided according to the procedure performed (ESD/subtotal gastrectomy). The two groups were matched for age, gender, ASA score, tumor dimension, and grade of infiltration (mucosa/submucosa). After matching, 84 patients (42 per group) were included in the analysis. Peri-procedural morbidity rate was 7.1% and no difference was observed between the two groups (4.8% vs 9.5% for ESD and STG groups, respectively; p = 0.3). Similar results in terms of 5-year OS and DFS were observed for ESD and STG (77.7% vs 71.8% ; p = 0.78 and 74.9% vs 72% ; p = 0.7, respectively). At the multivariate analysis, ASA3 score was recognized as the only negative predictor factor for the 5-year OS (OR 6.2; 95% CI 2.2-16.8; p < 0.001). Regarding the DFS, both ASA3 score (OR 4.4; 95% CI 1.7-10.9; p < 0.001) and submucosal infiltration(OR 5.1; 95% CI 1.2-22.4 ; p = 0.02) were identified as independent risk factors for a worse outcome. Our results confirm the safety and feasibility ESD for EGC treatment in a Western setting. In addition, this is one of the few reports showing comparable results both in terms of short- and long-term outcomes between ESD and surgery for intestinal type ECG treatment in Western countries.

Comparable rates of lymph node metastasis and survival between diffuse type and intestinal type early gastric cancer patients: a large population-based study

Limited evidence and contradictory results exist regarding the impact of Lauren type, namely diffuse and intestinal types, of lymph node metastasis (LNM) and prognosis for early gastric cancer (EGC). We aimed to compare LNM and prognosis between diffuse and intestinal type EGCs using comprehensive statistical analysis. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all patients with surgically resected, histologically diagnosed, intestinal or diffuse type EGC. Multivariate logistic regression, multivariate Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the Lauren type and LNM or prognosis. We identified 5593 EGCs from the SEER database, including 4376 intestinal types and 1217 diffuse types. No positive association was found between LNM and Lauren type (odds ratio, .93; 95% confidence interval [CI], .70-1.24; P= .62) after adjustment for other risk factors. Moreover, diffuse-type EGCs showed a similar prognosis to intestinal type EGCs in both multivariate Cox regression (HR [hazard ratio], .95; 95% CI, .77-1.18; P= .66) and the multivariate competing risk model (subdistribution HR [SHR], .99; 95% CI, .80-1.22; P= .926). Propensity score matching was used, and 733 diffuse types were matched with 733 intestinal types. We did not find any association between the Lauren type and LNM (odds ratio, .98; 95% CI, .71-1.37; P= .934) or prognosis in the univariate Cox regression (HR, .98; 95% CI, .76-1.26; P= .893) and univariate competing risk model (SHR, .98; 95% CI, .76-1.26; P= .893). Diffuse-type EGC may have a comparable risk of LNM and prognosis to intestinal-type EGC. Nevertheless, these results should be carefully interpreted with caution when choosing endoscopic resection instead of surgery, because the treatment choice for EGC depends on the risk of lymphovascular invasion rather than LNM rate or prognosis.

Whole genome MBD-seq and RRBS analyses reveal that hypermethylation of gastrointestinal hormone receptors is associated with gastric carcinogenesis

DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human carcinogenesis. To detect critical methylation events associated with gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal metaplasia (IM), and gastric tumor (GT) cells that were microscopically dissected from an intestinal-type early gastric cancer (EGC) using methylated DNA binding domain sequencing (MBD-seq) and reduced representation bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (DMPs) that could be directly associated with gene expression. We detected 2,761 and 677 DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035 DMPs. Then, 514 (17%) of all DMPs were detected in the IM genome, which is a precancer of GC, supporting that some DMPs might represent an early event in gastric carcinogenesis. A pathway analysis of all DMPs demonstrated that 59 G protein-coupled receptor (GPCR) genes linked to the hypermethylated DMPs were significantly enriched in a neuroactive ligand–receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of gastrin or gastric acid were selected and validated as potential biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI) hormone receptors by promoter methylation may lead to gastric carcinogenesis because gastrin and gastric acid have been known to play a role in cell differentiation and carcinogenesis in the GI tract.

Pilot research for the correlation between the expression pattern of E-cadherin-β-catenin complex and lymph node metastasis in early gastric cancer.

Early gastric cancer without lymph node metastasis can be treated with minimally invasive endoscopic surgery. Hence, a better modality for predicting lymph node metastasis should be beneficial to early gastric cancer patients who may only require minimally invasive treatment. In vitro, phosphorylation of β-catenin induces the loss of membranous β-catenin and E-cadherin, subsequently increasing the potential for metastasis. We investigated the behavior of these molecules comparing lymph node metastasis-positive and lymph node metastasis-negative groups, using the specimens from the patients with early gastric cancer. This was a pilot research evaluating the usefulness of combined analysis of these molecules in predicting lymph node metastasis in early gastric cancer. The clinicopathological features and immunohistochemical expression patterns of E-cadherin and β-catenin in the primary lesion were studied retrospectively in 28 patients (lymph node metastasis-positive versus lymph node metastasis-negative: 14 vs 14) selected from 272 patients. These patients underwent radical surgery for the early gastric cancer treatment from April 2000 to March 2004 at our hospital. All patients gave written informed consent to use their tissues for the clinical study. Statistical analyses were performed by the chi-square test and Mann-Whitney test. More loss of membranous E-cadherin was observed in the lymph node metastasis-positive group than in the lymph node metastasis-negative group. Although the finding was slightly more marked in the intestinal than in the diffuse type early gastric cancer, there was no statistical significance. Loss of membranous β-catenin showed a similar trend and no statistical significance. When we evaluated the expression patterns of both molecules, dual loss of membranous E-cadherin and β-catenin significantly correlated with lymph node metastasis [dual loss in lymph node metastasis-positive versus lymph node metastasis-negative patients: 12 (86%) vs 6 (43%), P = 0.046]. Additionally, corresponding proportions in intestinal type early gastric cancer were 5 of 6 (83%) vs 0 of 6 (0%), P = 0.015. Based on our results, the combined analysis of E-cadherin and β-catenin localizations may be helpful to accurately predict lymph node metastasis in intestinal type early gastric cancer.

Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Factors predictive of inaccurate determination of horizontal extent of intestinal‐type early gastric cancers during endoscopic submucosal dissection: A retrospective analysis

Certain tumor characteristics may pose challenges when endoscopically determining the horizontal extent of early gastric cancers (EGC). In the present study, clinicopathological features related to inaccurate endoscopic evaluation of horizontal extent of intestinal-type EGC were analyzed. We analyzed 431 lesions with intestinal-type EGC treated by endoscopic submucosal dissection (ESD) at our hospital. We focused on whether pretreatment demarcation was accurate by comparing positional relationships between marking dots and tumor edges in resected specimens, and factors related to inaccurate evaluation were analyzed. Gender, age, tumor size, location, circumference, depth, ulceration, macroscopic type, presence of a flat (0-IIb) component, predominant histological type, mixture of diffuse-type adenocarcinoma, mixed histology, and use of magnification endoscopy with narrow band imaging were analyzed. Reasons for inaccurate evaluation were also investigated by re-examining endoscopic images and prepared histological slides. Rate of inaccurate evaluation of horizontal extent was 7.4% (32/431 lesions). Multivariate analysis revealed the following significant independent variables contributing to inaccurate endoscopic evaluation: presence of a flat component, large size, and predominant histological findings of moderately differentiated adenocarcinoma. Re-examination of prepared histological slides of inaccurately evaluated cases revealed a marginal flat spreading area in 28 of the 32 lesions (87.5%). In 14 of the 32 lesions (43.8%), tumor margins were composed of moderately differentiated adenocarcinoma. For lesions with a flat component, large lesions, and moderately differentiated adenocarcinoma, determination of the horizontal extent can be challenging in EGC indicated for ESD, even with the best available endoscopic tools.

Pilot Research for the Correlation between the Expression Pattern of E-cadherin-β-Catenin Complex and Lymph Node Metastasis in Early Gastric Cancer

Early gastric cancer without lymph node metastasis can be treated with minimally invasive endoscopic surgery. Hence, a better modality for predicting lymph node metastasis should be beneficial to early gastric cancer patients who may only require minimally invasive treatment. In vitro, phosphorylation of β-catenin induces the loss of membranous β-catenin and E-cadherin, subsequently increasing the potential for metastasis. We investigated the behavior of these molecules comparing lymph node metastasis-positive and lymph node metastasis-negative groups, using the specimens from the patients with early gastric cancer. This was a pilot research evaluating the usefulness of combined analysis of these molecules in predicting lymph node metastasis in early gastric cancer. The clinicopathological features and immunohistochemical expression patterns of E-cadherin and β-catenin in the primary lesion were studied retrospectively in 28 patients (lymph node metastasis-positive versus lymph node metastasis-negative: 14 vs 14) selected from 272 patients. These patients underwent radical surgery for the early gastric cancer treatment from April 2000 to March 2004 at our hospital. All patients gave written informed consent to use their tissues for the clinical study. Statistical analyses were performed by the chi-square test and Mann-Whitney test. More loss of membranous E-cadherin was observed in the lymph node metastasis-positive group than in the lymph node metastasis-negative group. Although the finding was slightly more marked in the intestinal than in the diffuse type early gastric cancer, there was no statistical significance. Loss of membranous β-catenin showed a similar trend and no statistical significance. When we evaluated the expression patterns of both molecules, dual loss of membranous E-cadherin and β-catenin significantly correlated with lymph node metastasis [dual loss in lymph node metastasis-positive versus lymph node metastasis-negative patients: 12 (86%) vs 6 (43%), P = 0.046]. Additionally, corresponding proportions in intestinal type early gastric cancer were 5 of 6 (83%) vs 0 of 6 (0%), P = 0.015. Based on our results, the combined analysis of E-cadherin and β-catenin localizations may be helpful to accurately predict lymph node metastasis in intestinal type early gastric cancer.

Gastric mucin and beta-catenin are useful markers to predict submucosal invasion and lymph node metastasis in intestinal type early gastric cancer

Background and aim: With the increasing therapeutic use of endoscopic resection for intestinal early gastric cancer (EGC), it is very important to predict biological behaviors of intestinal type EGC prior to endoscopic resection. On this background, we tried to elucidate the presumptive clinicopathologic factors and biologic markers to predict submucosal invasion and lymph node metastasis based on mucin expression in EGCs. Methods: One hundred and thirty cases of intestinal EGCs were divided as EGCs with intestinal mucin phenotypes (EGC-IPs) and EGCs with gastric mucin phenotypes (EGC-GPs) based on mucin expression. The expressions of mucins (Muc2, Muc5Ac, Muc6, CD10), other protein markers (p53, CDX2, beta-catenin, E-cadherin, Smad4) by immunohistochemistry were studied. Results: EGC-IPs showed significantly increased p53 expression, CDX2 expression and beta-catenin delocalization than EGC-GPs. Using binary logistic regression analysis, expression of both gastric mucin and nuclear beta-catenin expression could be independent predictive factors of lymph node metastasis and submucosal invasion in intestinal EGCs. Lymphovascular emboli, and size of lesion could be clinicopathological independent predictive factors of lymph node metastasis and submucosal invasion in intestinal EGCs, respectively. Conclusions: Taken together, we suggest that beta-catenin expression based on mucin phenotype might be used to predict biologic behavior prior to endoscopic mucosal resection in intestinal EGC.

Mo1556 Long-Term Follow-up Investigation of the Expanded Indications for Endoscopic Submucosal Dissection of Submucosal Gastric Cancer

The 2010 Japanese Gastric Cancer Association guidelines for curative endoscopic resection of submucosal gastric cancer (SM-GC) are as follows: intestinal-type early gastric cancer ≤3 cm in diameter that has invaded to a depth of <500 μm from the lower margin of the muscularis mucosa (SM1) without vessel involvement. Aim: We conducted a two-part study of long-term outcomes after endoscopic submucosal dissection (ESD) to determine whether the expanded indications for curative ESD of SM-GC are valid.

Topographic differences in gastric micromucosal patterns observed by magnifying endoscopy with narrow band imaging

The distributions and grades of Helicobacter pylori induced gastritis are known to vary among H. pylori-associated diseases. The aim of this study was to investigate the differences in distributions of gastric micromucosal structures observed by magnifying narrow band imaging (NBI) endoscopy among patients with different H. pylori-associated diseases. Ninety-five patients with active duodenal ulcers (n = 24) and diffuse-type (n = 24) and intestinal-type (n = 47) early gastric cancers were enrolled. The magnified NBI findings were evaluated at the lesser and greater curvatures in the upper gastric corpus and were classified according to the modified A-B classification system. Biopsy specimens were also evaluated. In a total of 190 areas observed with magnifying NBI, histological grading (inflammation, activity, atrophy and intestinal metaplasia) showed significant differences among the classified micromucosal patterns (P < 0.001). Types B-1 and B-2, with mild atrophic changes and few areas of intestinal metaplasia, were seen mostly in the duodenal ulcers group. Types B-3 and A-1, with moderate atrophic changes, were seen in the diffuse-type early gastric cancers at the lesser curvature. Types A-1 and A-2, with severe atrophic change and a high frequency of intestinal metaplasia, were seen in the intestinal-type early gastric cancers at the lesser curvature. The prevalence of micromucosal structures differed significantly among the three groups both at the lesser and greater curvatures (P < 0.001). Magnifying NBI endoscopy clearly revealed detailed micromorphological differences corresponding to the histology and endoscopic findings among patients with different H. pylori-associated diseases.

Upper gastrointestinal tumors

Improvements in both endoscopic detection methods and treatment techniques such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been readily applied in the treatment of early gastric cancers (EGC), notably in Asia. The risk of lymph node metastases have been largely based on Japanese series. Proposed extended criteria for ESD in treating intestinal-type EGC include [2] [3]:1) differentiated mucosal cancer of any size without ulcer; 2) differentiated mucosal cancer ≤ 3 cm with ulcer; and 3) submucosal cancer ≤ 3 cm (sm1 < 500 µm), without lymphovascular invasion. This large retrospective Korean cohort described by Kang et al. included 478 patients who were naive to endoscopic therapies and who were undergoing gastrectomy and lymph node dissection for EGC (intramucosal 56 %, submucosal 44 %). Risk factors for lymph node invasion were analyzed and also compared with the extended criteria used for ESD of intestinal-type EGC. Similar to previous reports, the incidence of lymph node metastasis (13 %) was higher for submucosal EGCs than for mucosal EGCs (25 % vs. 3 %; P < 0.001), increased size (P < 0.001), depth of invasion (P < 0.001), and lymphovascular invasion (P < 0.001). In contrast to other reports, an elevated morphology (grouping Paris classification types I, IIa, IIa + IIb, IIa + IIc) was strongly associated with the risk for lymph node metastasis for the entire cohort (P < 0.001) and remained significant on multivariate analysis when restricted to intestinal-type lesions (n = 296) (P < 0.006). When the authors compared their results to the established extended criteria permitting ESD, seven patients with intestinal-type EGCs were found to have lymph node metastasis: 2 / 146 patients (1.4 %) with small (≤ 3 cm) non-ulcerated mucosal cancer; 2 / 126 patients (1.6 %) with cancer ≤ 3 cm with no lymphovascular emboli and irrespective of the presence of ulceration; and 3/20 patients (15.0 %) with intestinal-type submucosal cancer (sm1 ≤ 500 mm) without lymphovascular invasion and measuring ≤ 3 cm in size.

Lymph node metastasis from intestinal-type early gastric cancer: experience in a single institution and reassessment of the extended criteria for endoscopic submucosal dissection

Given the increasing use of endoscopic resection as a therapeutic modality for cases of early gastric cancer (EGC), it is very important to define strict criteria for the use of endoscopic mucosal resection and endoscopic submucosal dissection. To date, the criteria are almost entirely based on Japanese literature evaluating the risk of lymph node (LN) metastasis in patients with EGC. To analyze our own experience with the factors affecting LN metastasis and to reappraise the extended criteria for endoscopic submucosal dissection. Retrospective, single-center study. University teaching hospital. This study involved 478 patients who underwent gastrectomy with LN dissection (n = 270, mucosal [m] EGC; n = 208, submucosal [sm] EGC). Gastrectomy with LN dissection. LN metastasis. Overall, 12.6% (60/478) of patients with EGCs presented with LN metastasis (mEGC, 3.0% [8/270], smEGC, 25.0% [52/208]). Increased size, macroscopic type (elevated), depth of invasion, and lymphovascular invasion were associated with LN metastasis. In 270 cases of mEGC, there was no relationship between clinicopathologic features and LN metastasis. In the smEGC group, size, depth of invasion, and lymphovascular emboli were associated with an increased risk of LN metastasis. Significantly, LN metastasis was noted in EGCs falling within established extended endoscopic submucosal dissection criteria, that is, intestinal-type mucosal cancer of any size without ulcer and no lymphovascular emboli (2/146 [1.4%]) or < or =3 cm with no lymphovascular emboli and irrespective of the presence of ulceration (2/126 [1.6%]) or intestinal-type submucosal cancer (sm1, <500 microm) without lymphovascular invasion and measuring < or =3 cm in size (3/20 [15.0%]). Retrospective review of a single-center study. We recommend that more centers survey their experiences of LN metastasis in cases of EGC to refine the criteria for endoscopic submucosal dissection as a therapeutic modality of intestinal-type EGC.

Autofluorescence videoendoscopy system using the SAFE‐3000 for assessing superficial gastric neoplasia

Autofluorescence (AF) videoendoscopy has an advantage over ordinary videoendoscopy in the diagnosis of gastric neoplasias, and the aim of the present study was to evaluate the effectiveness of using the SAFE-3000 videoendoscopy system to diagnose superficial gastric neoplasias. Ordinary videoendoscopy, AF videoendoscopy, and chromoendoscopy (CE) were used to diagnose the tumor existence and extent in 14 patients with gastric adenoma, 40 patients with intestinal-type early gastric cancer (EGC) (10 protruded, and 30 depressed), and nine patients with diffuse-type EGC. The diagnostic accuracies of the three kinds of images were evaluated by comparison with the results of histopathological assessment of resected specimens. For gastric adenomas the diagnostic accuracy between the AF images and white light (WL) images did not differ significantly, and for protruded intestinal-type EGCs and diffuse-type EGCs the diagnostic accuracy did not differ significantly between any of the types of images. For depressed intestinal-type EGCs, the diagnostic accuracy of AF images tended to be higher than that of the WL images (P < 0.05) and it was not significantly different from that of the CE images. The detection rate of pink or orange color in AF images was significantly higher for protruded intestinal-type EGCs than gastric adenomas (P = 0.005), depressed intestinal-type EGCs (P < 0.001), and diffuse-type EGCs (P = 0.027). Autofluorescence videoendoscopy using the SAFE-3000 system for gastric neoplasias might be useful for diagnosing depressed intestinal-type early gastric cancers. The detection of orange or pink color in AF images may be efficacious in discriminating protruded intestinal-type early gastric cancers from gastric adenomas.

Appropriate indications for endoscopic submucosal dissection of early gastric cancer according to tumor size and histologic type

Endoscopic submucosal dissection (ESD) is increasingly being performed for early gastric cancers (EGCs) that are larger than 2 cm and those that are not intestinal-type (IT) cancers by Lauren's classification. The technical feasibility of ESD for these EGCs has not been fully evaluated. To identify appropriate expanded indications for ESD of EGC. A retrospective analysis of prospectively collected data was performed on consecutive patients who underwent ESD at a single tertiary center. In total, 487 EGCs in 461 patients treated by ESD were classified by size and histologic type: IT EGCs 2 cm or less (257 lesions in 235 patients), IT EGCs larger than 2 cm (172 lesions in 168 patients), and non-IT EGCs (58 lesions in 58 patients). Curative resections were assessed among the 3 groups, and logistic regression analysis was used to analyze factors related to curative resection. The rates of curative resection significantly decreased from IT EGCs 2 cm or less (88.7%) to IT EGCs larger than 2 cm (73.3%) to non-IT EGCs (37.9%). Tumor size (>3 cm), ulceration, histologic type (non-IT), and piecemeal resection were independently unfavorable factors in curative resection. Small sample size and short-term duration of follow-up study. ESD with curative intent is technically most feasible for nonulcerative and IT EGCs smaller than 3 cm.

CDX2 expression in the intestinal-type gastric epithelial neoplasia: frequency and significance

CDX2 is an intestinal transcription factor responsible for regulating the proliferation and differentiation of intestinal epithelial cells. In gastric adenocarcinoma, CDX2 expression is known to be associated with limited invasiveness and intestinal phenotypes. The aims of this study were to analyze CDX2 expression in a series of well-characterized cases of gastric epithelial dysplasia, based on the morphologic and mucin phenotypes, and also to analyze CDX2 expression along the metaplasia–dysplasia–carcinoma sequence. CDX2 expression was evaluated in 69 cases of gastric epithelial dysplasia, 88 cases of intestinal-type early gastric cancers, and 56 cases of advanced gastric cancers. Increased CDX2 expression was more frequently associated with adenomatous-type gastric epithelial dysplasia (27/31, 87%) compared with foveolar (7/15, 47%) or hybrid (10/23, 44%) types of gastric epithelial dysplasia (P=0.001). CDX2 expression correlated with an increase in CD10 expression (P=0.005), and a decrease in MUC5AC expression (P=0.001) in gastric epithelial dysplasia. CDX2 expression was also gradually decreased from gastric epithelial dysplasia, to early and advanced gastric cancers (present in 64, 40 and 27% of the cases, respectively). A negative correlation was also observed between CDX2 expression and the depth of tumor invasion. Our results indicate that CDX2 expression is associated with specific morphological and mucin phenotypes of gastric epithelial dysplasias, and decreases progressively with the advancing stage of gastric cancers, suggesting a possible tumor suppressor role for CDX2.

Expression of beta-catenin and its mechanism of delocalization in intestinal-type early gastric cancer based on mucin expression.

The biological characteristics of intestinal-type early gastric cancers (ICs) differ based on mucin phenotypes. Beta-catenin delocalization is a predictive marker of aggressive biological behavior (submucosal invasion and lymph node metastasis) of ICs. The presumptive causative genetic alterations leading to delocalization of beta-catenin in ICs are still controversial, and there are only a few reports regarding beta-catenin expression in gastric cancer based on mucin phenotypes. Therefore, in the current study, the expression and mechanisms of delocalization of beta-catenin were elucidated on the basis of mucin phenotypes in 109 cases of ICs. There was increased cytoplasmic and nuclear beta-catenin expression (delocalization) in ICs with a predominant intestinal mucin phenotype (ICIP; 46.3% [25/54 cases]) compared to ICs with a predominant gastric mucin phenotype (ICGP; 20% [11/55 cases]). There were no beta-catenin or APC mutations in ICs. APC promoter hypermethylation was present in 49 of 105 (46.7%) cases of ICs. There was a significant relationship between APC promoter hypermethylation and beta-catenin delocalization in ICs, especially in ICIPs. There was no relationship between beta-catenin delocalization and APC gene loss of heterozygosity in ICs. In conclusion, we showed that beta-catenin delocalization was more evident in ICIPs, and APC promoter hypermethylation might play a role in delocalization of beta-catenin, especially in ICIPs.

Is it possible to predict the procedural time of endoscopic submucosal dissection for early gastric cancer?

Endoscopic submucosal dissection (ESD) has been expected to be a possible curative treatment, especially for node-negative early gastric cancer (EGC). We investigated the influential factors on the procedural time of gastric ESD with a Flex knife for the estimation. In 222 intestinal-type EGC resected by ESD experts with established techniques, age, sex, location, circumference, gross type, tumor size, tumor depth, ulcerative findings, the period of ESD, the operator, and the experience of the operator were retrospectively analyzed. Predictors with a significant difference, as determined by multivariate analysis, were used to compose a predictive formula of procedural time. Location, gross type, tumor depth, ulcerative findings, and tumor size were considered influential factors on the procedural time by univariate analysis. Location in the upper-third of the stomach, presence of ulcerative findings, and > 20 mm in size were independent factors, as determined by multivariate analysis. Procedural time (min) was nearly equal to the maximal tumor size (mm) multiplied by 2.5, and an additional 40 min was required if the tumor was located in the upper-third of the stomach or had ulcerative findings (in both situations, an additional 80 min was needed). The procedural time of ESD with a Flex knife for EGC can be predicted by tumor size, location, and existence of ulcerative findings. The estimation of procedural time may be very useful to determine the operation schedule.

Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria

Endoscopic submucosal dissection (ESD) is a novel, promising endoscopic technique for gastrointestinal neoplasms. We aimed to elucidate the feasibility of ESD as curative treatment for intestinal-type early gastric cancer (EGC) potentially without lymph-node metastases. For the short-term analysis, 276 consecutive, intestinal-type EGCs, which fulfilled the criteria for node-negative EGC in 231 patients who had undergone ESD from January 2000 to March 2007, were retrospectively investigated. For the long-term analysis, 212 lesions checked by endoscopy later than 1 year or recurrence within 1 year after ESD were assessed for local recurrence, and 208 patients followed for over 1 year or to death within 1 year after ESD were assessed for metastases and survival. All lesions/patients were divided into three groups: intramucosal cancer without ulcerative findings (M-Ul[-]); intramucosal cancer with ulcerative findings, < or = 3 cm (M-Ul[+]); and slight invasive cancer into submucosa (< 500 microm), < or = 3 cm (SM1). En bloc and complete resection rates were 96.7 % and 91.7 %, respectively. During a median follow-up of 36 months (range 2 - 93 months), two local recurrences occurred (0.9 %), which were detected at 2 and 6 months after ESD, respectively. During a median follow-up of 38 months (range 6 - 97 months), the 5-year overall and disease-specific survival rates were 96.2 % and 100 %, respectively, with neither lymph node nor other-organ metastasis; one patient died due to other disease 6 months after ESD. No disease-related death occurred. No significant differences were found between the groups in short- and long-term analyses. The prognostic analyses demonstrated the validity of the criteria of node-negative intestinal-type EGC as curability criteria for ESD. ESD can be proposed as an alternative method to gastrectomy for the treatment of these EGCs.

Correlation between the expression abnormalities of E-cadherin-β-catenin complex and lymph node metastasis (LNM) in early gastric cancer

15105 Background: Therapy for early gastric cancer (GC) varies according to risk of LNM. When the possibility of LNM is very remote, the primary lesion can be resected by the minimally invasive endoscopic surgery only. Therefore, useful parameters predicting LNM are needed. E-cadherin, a component of the cell-cell junctional structure, is known to correlate with GC. In vitro, previous studies elucidated that disorders of cell-cell junction increased the potential of metastasis, and that phosphorylation of β-catenin by c-erbB-2 induced loss of membranous E-cadherin and β-catenin, resulting in junctional structure disorders. Here we evaluated significance of analysis of these molecules in LNM prediction in early GC. Methods: The clinicopathological features and immunohistochemical expressions of E-cadherin, β-catenin, and c-erbB-2 in the primary lesion were studied in 28 patients (LNM +ve group: 14, LNM1 -ve group: 14) selected from 272 patients who underwent radical surgery for early GC between April 2000 to March 2004 at our hospital. All the patients consented to use of their stomach tissues for the clinical study afterwards. Statistical analysis was performed by t-test or χ2 test. Results: The clinicopathological features showed no significant differences between both groups. Loss of the membranous E-cadherin was noticed in 12 (85%) of the 14 LNM +ve patients, and in 8 (57%) of the 14 LNM -ve patients (p=0.209). This result was more remarkable in the intestinal type GC as the corresponding figures were 83% (5 of 6 ) and 16% (1 of 6) (p=0.083), respectively. Loss of the membranous β-catenin also showed a remarkable similar trend in the intestinal type GC, and the corresponding figures were 100% (6 of 6) and 50% (3 of 6) (p=0.182), respectively. Two patients showed over-expression of c-erbB2 and nuclear accumulation of β-catenin, and both had intestinal type GC with LNM. Conclusions: These results suggested that the same molecular signal pathway - as in vitro - including E-cadherin, β-catenin, and c-erbB2 induced LNM in early GC (intestinal type). We concluded that analysis of the expressions of these molecules is useful for not only LNM prediction but also determination of the therapeutic modality especially in intestinal type early GC. No significant financial relationships to disclose.