Huiping Yu

Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with β-catenin

Backgrounds and aimsLgr5 is a member of the G protein receptor super-family and was shown recently to be a stem cell marker for cells with intestinal differentiation. Its over-expression has been demonstrated in hepatocellular, basal cell carcinoma, and ovarian cancers but the underlying mechanisms are poorly understood. The aim of this study was to investigate if Lgr5 over-expression was correlated with human colorectal carcinogenesis and its potential correlation with β-catenin.MethodsThe study was carried out on a tissue microarray that consisted of 102 colorectal carcinomas (CRC; M:F = 55:47), 18 colon adenoma, and 12 colon normal mucosa cases. Immunostains were performed with the standard EnVision method with primary antibodies against Lgr5, β-catenin, and p53 antigens. Immunoreactivity of neoplastic cells to each antibody was double-blindly semi-quantified by two pathologists and the data were analyzed with the Chi-square and Spearman rank correlation tests. Subsequently, expression of Lgr5 in tissue sections of tumor centre and invasive margins of 21 cases of CRC certified to be immunoreactive of Lgr5 in TMA were evaluated and possible differences of Lgr5 expression between them were analyzed.ResultsLgr5 immunoreactivity was observed only in single cells in the base of normal colon mucosal crypts but high in 28% (five out of 18) adenomas, and significantly higher in 54% (55/102, p = 0.016) CRC cases. In normal mucosa, adenoma, and CRC, β-catenin expression was seen in 25% (three out of 12), 27% (five out of 18), and 81% (83/102) cases, respectively, in contrast to 0, 0, and 40% (41/102) for p53 expression, respectively. In CRC, Lgr5 expression was more intense in women than men (p < 0.0001), and positively correlated with β-catenin expression (p < 0.001), but not with patients’ ages, tumor sizes, nodal status, TNM stages, and p53 expression. Different expression of Lgr5 between tumor centre and invasive margins was not found (p > 0.05).ConclusionsThe results suggest that up-regulation of Lgr5 expression, especially in female patients, may play an important role in colorectal carcinogenesis, probably through the WNT/β-catenin pathway, but not involve the progression of the CRC.

Comparison of gastro-oesophageal junction carcinomas in Chinese versus American patients.

Huang Q, Fan X, Agoston A T, Feng A, Yu H, Lauwers G, Zhang L & Odze R D 
(2011) Histopathology59, 188–197

Clinicopathological characterisation of small (2 cm or less) proximal and distal gastric carcinomas in a Chinese population

Summary Clinicopathological characteristics of small gastric carcinoma have not been well defined in Chinese patients. The aim of this study was to investigate and compare small proximal (PGC, n = 111) with distal (DGC, n = 202) gastric carcinoma in 313 consecutive surgically resected small (⩽2 cm) gastric carcinomas diagnosed with the WHO criteria. PGC patients were significantly older (average age 63 years versus 59 in DGCs) with a male/female ratio of 3:1. Most tumours were clustered along the lesser curvature (74% in PGCs and 65% in DGCs). Compared to DGCs, PGCs showed a protruded gross pattern significantly more frequently and were significantly better differentiated with a significantly wider histomorphological spectrum. Surprisingly, PGCs were composed of significantly fewer signet-ring cell carcinomas (1% versus 16% in DGCs) but were significantly more deeply invasive, compared to DGCs. Lymph node metastasis was detected in 23% overall, but was significantly less frequent in PGCs (16%) than in DGCs (26%) (p < 0.05). However, the difference in survival between the two groups was not statistically significant. Our results demonstrate that in Chinese patients, PGCs display distinct clinicopathological characteristics, compared to DGCs.

Worse Prognosis in Papillary, Compared to Tubular, Early Gastric Carcinoma

Purpose: Papillary early gastric carcinoma (EGC) is uncommon but shows worse prognosis in our most recent study in a Chinese population with unknown reasons. The aim of the present study was to further investigate risk factors for worse prognosis in patients with papillary adenocarcinoma, compared to those with tubular adenocarcinoma. Methods: We searched the electronic pathology databank for radical gastrectomy cases over an 8-year period at a single medical center in Nanjing, China, and identified consecutive 240 EGC cases that were classified as either papillary (n=59) or tubular (n=181) EGC tumors in accordance with the World Health Organization (WHO) gastric cancer diagnosis criteria. We investigated and compared clinicopathologic risk factors for prognosis between papillary and tubular EGC groups. All patients were followed up and their 5-year survival rate was compared statistically with the Kaplan-Meier method with a log rank test. Results: Compared to tubular EGCs, papillary EGCs were significantly more common in elderly patients, more frequently occurred in the proximal stomach with protruding/elevated growth patterns, submucosal invasion, and a micropapillary component. Although lymphovascular invasion (16.9%), nodal (13.6%) and distant (11.8%) metastases in papillary EGCs were more frequent than those (8.3%, 7.2%, and 3.7%, respectively) in tubular EGCs, the differences approached but did not reach statistically significant levels. Significant risk factors for nodal metastasis included lymphovascular invasion in both EGC groups, but the ulcerative pattern and submucosal invasion only in tubular EGCs. The 5-year survival rate was significantly worse in papillary (80.5%) than in tubular (96.8%) EGCs. Conclusions: Compared to tubular EGCs, papillary EGCs diagnosed with the WHO criteria in Chinese patients were more frequent in elderly patients, proximal stomach and showed the significantly worse 5-year survival rate with more protruding/elevated growth patterns and the micropapillary component. Further studies in larger samples are urgently needed to validate these findings for precision individualized EGC patient management.

Su1985 Unique Clinicopathologic Features of Early Proximal Gastric Cancer Diagnosed With Who Criteria: Implications for Endoscopic Resection

Introduction: Recent studies in the U.S. have reported steadily rising rates of cardia (CAR) gastric cancer, whereas rates of non-cardia (NCAR) gastric cancer have been declining. In addition, racial/ethnic disparities in CAR vs. NCAR gastric cancer exist, with significantly greater proportions of Asians having NCAR sub-types of cancer. Our study aims to evaluate disparate outcomes between CAR vs. NCAR gastric cancer, with a focus on identifying specific risk factors associated with these differences. Methods: Using data from California Pacific Medical Center, a tertiary referral center in northern California, we retrospectively analyzed adult patients with gastric cancer diagnosed from 2000-2012. Anatomic site-specific comparisons (CAR vs. NCAR cancers) were performed using chi-square testing for categorical variables and Students t-test for continuous variables. Long-term overall survival was evaluated using Kaplan Meier methods and log-rank testing. Overall 1, 3, and 5-year survival between CAR and NCAR cancers were stratified by sex, race/ethnicity, cancer stage, and histologic subtype. Multivariable Cox proportional hazards models were adjusted for age, sex, race/ethnicity, tobacco or alcohol use, cancer stage, treatment received, and anatomic site. Results: Overall, from 2000-2012 there were a total of 587 patients with gastric cancer (68.5% with NCAR and 31.5% with CAR). No significant difference in mean age of diagnosis was observed between NCAR and CAR cancers (69.3 +/0.7 vs. 67.1 +/0.9, p=0.076). While the majority of gastric cancer patients were white, there was significantly greater proportion of Asians in the NCAR cohort (39.3%, n=158). Compared to patients with NCAR cancers, significantly higher rates of tobacco use (35.8% vs. 52.6 %, p<0.001) and alcohol use (28.5% vs. 55.2%, p<0.001) were seen in CAR cancer patients. In addition, patients with NCAR cancers were more likely to be foreign born (79.4% vs. 51.4%, p=0.001). Overall 5-year survival was significantly higher among patients with NCAR cancers compared to CAR cancers (40.6% vs. 33.9%, p<0.001). However, after adjusting for multiple variables in a multivariate Cox proportional hazards model, the survival difference between NCAR and CAR gastric cancers was no longer significant (HR, 1.03; 95% CI, 0.76-1.39, p=0.87). Conclusions: Significant differences in demographics and clinical characteristics existed between NCAR and CAR gastric cancers. These differences may explain the significantly higher survival observed in patients with NCAR vs. CAR cancers. However, after adjusting for these differences in a multivariate regressionmodel, the survival advantage among patients with NCAR cancers was no longer present.

Mo1555 Small Carcinomas in the Proximal Stomach Show Clinicopathologic Features Dissimilar to Those in the Distal Stomach

determined by a wound healing assay. In xenografted model (NCI-N87), mice were injected (SC; 200 ug/head, 10 mg/kg or IV; 300 ug/head, 15 mg/kg) with CP-RUNX (HM85R) for 3 weeks. This experiment showed that local or systemic delivery of CP-RUNX3 could significantly reduce tumor growth (p<0.05). p21Cip1/Waf1 and VEGF expression in lung and tumor were also significantly increased and decreased, respectively. Conclusion: These results suggest that In Vivo protein replacement therapy with cell-permeable and tissuedistributable recombinant proteins containing MTD can intervene in an abnormally active or dysfunctional intracellular process. Therefore, we conclude that intracellular delivery of RUNX3 with MTD could be useful for treating gastric cancer.

Heterogeneous expression of Lgr5 as a risk factor for focal invasion and distant metastasis of colorectal carcinoma

Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a downstream target gene of the Wnt/β-catenin signaling pathway and identified as a marker of cancer stem-like cells of colorectal carcinoma (CRC). Here, the heterogeneous expression pattern of Lgr5 and its clinical significance were studied by the method of immunohistochemistry in 204 CRC tumors at various pTNM stages. Lgr5 expression was found in 82.4% (168/204) cases, significantly more common in neoplastic cells at the infiltrative front (n = 59.5%, 110/185) or at the expanding front (n = 36.4%, 59/162) than at the tumor center (n = 16.7%, 34/204; P < 0.01). Tumor budding (TB) was discovered with significantly higher Lgr5 expression (n = 39.3%, 57/145, P = 0.03) and significantly positively correlated between Lgr5 expression and TB grade (r = 0.19, P = 0.02). Additionally, both positive Lgr5 expression and a high TB grade were significantly correlated to the depth of tumor invasion, lymph node metastasis, pTNM stage, and perineural invasion (P < 0.01). The study results suggest that heterogeneous expression of Lgr5 may be a risk factor for local invasion and distant metastasis of CRC.

M1921 Gastric Cardiac Cancer Involving the Esophagus Can Be Better Staged by the 7th Than the 6th Edition of AJCC Cancer Staging System

G A A b st ra ct s included patients was 10.21 for CD31 and 11.85 for CD34 in all patients, while VEGF was positive only in 18 patients (45%). The microvessel density was higher in patients with advanced TNM stage, as assessed by both methods (CD31, CD34). Moreover, there was a correlation between the microvessel density and the risk of UGIB (p=0.0436 for CD31 and p=0.0138 for CD34, respectively). VEGF expression was well correlated with TNM stage (especially with the M stage, p<0.0001) and also with the risk of upper GI bleeding (p= 0.0138).Survival rate after first year of follow-up was 37.5% and 30% respectively after two years of follow-up. Survival rate was positively correlated with MVD (reaching statistical significance), while VEGF expression was not correlated with survival rate.Conclusions: According to the results of our study, MVD was involved in local advanced disease, while VEGF was correlated to distant metastasis in gastric cancer patients. There was a clear correlation between VEGF, MVD and the risk of upper GI bleeding. However, the result of our study should be confirmed in future studies with a large number of patients included and preferably multicentric design.