Gastric Mucin Phenotype Research Articles

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma

ObjectiveEarly gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in...

Kinesin Family Member B18 Is Related to Gastric Mucin Phenotype and Contributes to Gastric Cancer Progression by Regulating Epithelial-Mesenchymal Transition

Introduction: Gastric cancer (GC) remains a common health concern worldwide and is the third leading cause of death in Japan. It can be broadly classified into gastric and intestinal mucin phenotypes using immunohistochemistry. We previously reported numerous associations of kinesin family member (KIF) genes and mucin phenotypes with GC. However, no previous studies have reported on the importance of KIF18B in GC using immunostaining. Thus, in this study, we investigated the expression and functions of KIF18B, which is highly expressed in gastric mucin phenotype GC. Methods: We performed RNA-seq of gastric and intestinal mucin type GCs, and clinicopathological studies of the KIF18B we found were performed using 96 GC cases. We also performed functional analysis using GC-derived cell lines. Result: RNA-seq showed the upregulation of matrisome-associated genes in gastric mucin phenotype GC and a high expression of KIF18B. KIF18B was detected in 52 of the 96 GC cases (54%) through immunohistochemistry. Low KIF18B expression was significantly associated with poor overall survival (p < 0.01). Other molecules that were significantly associated with KIF18B were MUC5AC and claudin 18; these were also significantly associated with the gastric mucin phenotype. KIF18B small interfering RNA (siRNA)-transfected GC cells showed greater growth and spheroid colony formation than the negative control siRNA-transfected cells. Furthermore, expression of snail family transcriptional repressor 1 and cadherin 2 was significantly increased and that of cadherin 1 was significantly decreased in KIF18B siRNA-transfected GC cells. Conclusion: These findings not only suggest that KIF18B may be a useful prognostic marker, but also provide insight into the pathogenesis of the GC phenotype.

BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer.

Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 low-grade atypical GHPs (19.6%), 7 high-grade atypical GHPs (6.9%), and 5 intramucosal cancer samples (4.9%). GHP atypia was more common in the elderly and increased with increasing polyp size. In particular, polyps larger than 1 cm were associated with a higher grade and cancer. Furthermore, mucus production decreased with increasing atypia. Although no correlation was found between atypia and Helicobacter pylori infection or intestinal metaplasia, enhanced proliferative ability (Ki-67) did correlate with atypia, as did nuclear 8-hydroxy-2’-deoxyguanosine levels. Interestingly, 4-hydroxynonenal levels in granulation tissue and the area ratio of granulation tissue within polyps also correlated with GHP atypia. In five cases of HPAGC, three cases exhibited caudal type homeobox transcription factor (CDX2)-positive cells and a mixed mucin phenotype, which is considered to be related to H. pylori infection. By contrast, two cases were CDX2 negative, with a gastric mucin phenotype, and H. pylori infection was not observed in the tumor or the surrounding mucosa. In these cases, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (V600E) was detected. All cancer samples showed high stemness and p53 protein accumulation, but no KRAS mutations. The molecular and phenotypic characteristics of the cases characterized by BRAF mutations may represent a novel subtype of HPAGC, reflecting a conserved pathway to oncogenesis that does not involve H. pylori infection. These findings are worthy of further investigation in a large-scale study with a substantial cohort of HPAGC patients to establish their clinical significance.

Clinical and phenotypical characteristics of submucosal invasive carcinoma in non-ampullary duodenal cancer.

ObjectiveThe rare incidence of submucosal invasive non-ampullary duodenal carcinoma has led to scant information in literature; therefore, we compared the clinicopathological features between submucosal invasive carcinoma (SM-Ca), mucosal carcinoma (M-Ca), and advanced carcinoma (Ad-Ca).MaterialsWe retrospectively analyzed 165 patients with sporadic non-ampullary duodenal carcinomas (SNADCs) from four institutions between January 2003 and December 2018. The SNADCs were divided to three groups according to histological diagnosis: SM-Ca, M-Ca, and Ad-Ca. The clinicopathological characteristics and mucin phenotypes were compared between groups.ResultsAmong the 165 SNADCs, 11 (7%) were classified as SM-Ca, 70 (42%) as M-Ca, and 84 (51%) as Ad-Ca. We found that all SM-Ca (P = 0.013) and most Ad-Ca (P = 0.020) lesions were located on the oral-Vater; however, an almost equal distribution of M-Ca lesions was found between the oral- and anal-Vater. No significant difference was observed between the tumor diameter of M-Ca and SM-Ca; however, 45% (5/11) of SM-Ca were ≤10 mm. A total of 73% (8/11) of SM-Ca were classified as gastric phenotype and no lesions were classified as intestinal phenotype; whereas most M-Ca were classified as intestinal phenotype (67%, 8/12).ConclusionsSM-Ca lesions were all located on the oral-Vater and were highly associated with the gastric mucin phenotype, which were different from the features of most M-Ca.

Gastric mucin phenotype indicates aggressive biological behaviour in early differentiated gastric adenocarcinomas following endoscopic treatment

BackgroundThe distribution of mucin phenotypes and their relationship with clinicopathological features in early differentiated gastric adenocarcinomas in a Chinese cohort are unknown. We aimed to investigate mucin phenotypes and analyse the relationship between mucin phenotypes and clinicopathological features, especially biological behaviours, in early differentiated gastric adenocarcinomas from endoscopic specimens in a Chinese cohort.MethodsImmunohistochemical staining of CD10, MUC2, MUC5AC, and MUC6 was performed in 257 tissue samples from patients with early differentiated gastric adenocarcinomas. The tumour location, gross type, tumour size, histological type, depth of invasion, lymphovascular invasion, mucosal background and other clinicopathological parameters were evaluated. The relationship between mucin phenotypes and clinicopathological features was analysed with the chi-square test.ResultsThe incidences of gastric, gastrointestinal, intestinal and null phenotypes were 21 %, 56 %, 20 and 3 %, respectively. The mucin phenotypes were related to histology classification (P < 0.05). The proportion of the gastric phenotype became greater during the transition from differentiated to undifferentiated (P < 0.05). Complete intestinal metaplasia was higher in the gastric and intestinal phenotypes than in the gastrointestinal phenotype (P < 0.05). Tumours with poorly differentiated adenocarcinoma were mainly of the gastric phenotype, which was significantly higher than that of purely differentiated tubular adenocarcinoma (P < 0.05), and the depth of invasion in the mixed type was deeper (P < 0.05). Neither recurrence nor metastasis was detected.ConclusionsThe mucin phenotype of early-differentiated gastric adenocarcinoma has clinical implications, and the gastric phenotype has aggressive biological behaviour in early differentiated gastric cancers, especially in those with poorly differentiated adenocarcinoma or papillary adenocarcinoma components.

Clinicopathological characteristics of mucin phenotype and its relation to the malignant potential in early differentiated gastric adenocarcinoma

Objectives Mucin phenotype is a tool to classify gastric cancer, but the relationship between mucin phenotype and its malignancy is still controversial. This study aimed to clarify the relationship between mucin phenotype and the malignant potential of gastric cancer. Methods A total of 82 cases of early-stage differentiated adenocarcinoma (submucosal invasion cases) obtained from surgeries were studied by immunohistochemistry. Gastric mucin phenotype and E-cadherin expression were analyzed in the mucosal and submucosal layer. E-cadherin expression was analyzed by using imaging software (ImageJ) for objective data analysis. Furthermore, the mucin phenotypic shift was analyzed from mucosa to submucosa. Results We found that: (1) tumors with intestinal mucin phenotype had statistically more venous invasion in the submucosal lesion; (2) tumors with an intestinal phenotype that showed venous invasion in the submucosal lesion had a higher percentage of tumors that showed loss of phenotype; (3) no dominant change in E-cadherin expression was observed from the mucosa to submucosa. Conclusion Tumors with loss of phenotype and submucosal intestinal phenotype showed predominantly more venous invasion, so examining the identification of phenotypes and phenotype shifts can be expected to be a factor that influences treatment strategies after endoscopic treatment or after surgical resection.

Diagnostic algorithm of magnifying endoscopy with crystal violet staining for non-ampullary duodenal epithelial tumors.

Little is known about the usefulness of magnifying endoscopy with crystal violet staining (ME-CV) for the diagnosis of duodenal tumors. We assessed the ability of ME-CV to distinguish Vienna classification (VCL) category 4/5 (C4/5) from category 3 (C3) non-ampullary duodenal epithelial tumors (NADETs). A total of 76 NADETs were studied. We retrospectively analyzed the diagnostic values of the white light endoscopy (WLE) scoring system and the ME-CV algorithm with receiver operating characteristic (ROC) curves, and three endoscopists calculated the sensitivity, specificity, accuracy, and the area under the curve (AUC) of each. The diagnostic values were tested among NADETs overall and among subgroups of tumors with gastric, gastrointestinal or intestinal mucin phenotypes. Inter-observer agreement of the diagnostic results was also calculated. According to the VCL, 54 lesions (71.1%) were regarded as C3 and 22 lesions (28.9%) as C4/5. The sensitivity, specificity, accuracy and AUC of ME-CV were higher than those of the WLE scoring system (63.6 vs 54.5, 85.2 vs 75.9, 78.9 vs 69.7, 0.744 vs 0.652, respectively). Inter-observer agreements of the WLE scoring system and ME-CV were both moderate (kappa 0.45 and 0.41). ME-CV had higher sensitivity, specificity, accuracy and AUC than those of the WLE scoring system among the gastric and intestinal phenotypes of NADETs. ME-CV is appropriate for the diagnosis of C4/5 and C3 NADETs.

Annexin A10 is involved in the induction of pancreatic duodenal homeobox‑1 in gastric cancer tissue, cells and organoids.

Gastric cancer (GC) is the third most common cause of cancer‑related death in the world. Annexin A10 (ANXA10), a member of the Annexin family, is a calcium‑/phospholipid‑binding protein; however, little is known concerning its functions. It is still unclear what molecule is involved in the induction of ANXA10. In the present study, we performed immunohistochemistry to evaluate the expression of ANXA10, pancreatic and duodenal homeobox‑1 (PDX1) and mucin phenotype markers in 130GC samples. ANXA10 was detected in 63(48%) of the 130GC cases and loss of ANXA10 was significantly correlated with disease progression and poor clinical outcomes in GC. PDX1 was significantly correlated with ANXA10 in GC cases and cell lines. Although PDX1 was not significantly correlated with the GC cases with any of the mucin phenotypes, ANXA10 was preferentially detected in the GC cases with the gastric mucin phenotype. As a further investigation, we generated organoids derived from human GC and identified the duplication of the mucin phenotypes of GC by immunohistochemistry. The repression effect on cell growth that was observed in the ANXA10‑knockdown cell lines was also clearly observed in the human gastric organoids. We demonstrated that the expression of ANXA10 was correlated with the gastric mucin phenotype and ANXA10 was involved in the induction of PDX1 expression in GC. We also provided evidence that GC organoids represent a powerful tool for scrutinizing the biology of GC, especially with regard to the mucin phenotype.

1207 Differences of Gastric Cancer Characteristics Between With and Without Helicobacter pylori Eradication

INTRODUCTION: Although the rate of gastric cancer (GC) after Helicobacter pylori (H. pylori) eradication has gradually increased over time, the features of GC following eradication remain to be examined. In this study, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. METHODS: 50 subjects with GC following eradication [HP(-) group] and 151 patients with GC with H. pylori infection [HP(+) group] were enrolled in this study. Clinicopathological features, such as age, gender, endoscopic atrophy, tumor form, location, depth of invasion, histology, were assessed. The manifestation of GC was further evaluated using immunohistochemistry of Ki-67, CDX22, p53, claudin18, E-cadherin, c-myc and In situ hybridization for detecting Epstein-Barr virus (EBV). RESULTS: Macroscopic analysis revealed a significantly higher ratio of depressed type/elevated type in HP(-) group compared with HP(+) group (30/19 vs. 61/77, P = 0.041). Tumor size was significantly greater in HP(-) group compared with the HP(+) group (13.02 ± 7.10 vs. 16.53 ± 11.12, P = 0.0019). The gastric mucin phenotype was more predominant in HP(-) group compared with HP(+) group, and the proportion of CDX2-positive cases was lower in HP(-) group (8 out of 18; 44.4%) compared with HP(+) group (18 out of 19; 94.7%) (P = 0.00082). Ki-67 labeling index was significantly lower in HP(-) group (32.03 ± 22.15) compared with the HP(+) group (79.20 ± 14.87, P &lt; 0.0001). No patient in HP(-) group showed significant expression of EBV infection. CONCLUSION: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in morphology, mucin phenotype, and proliferation rate. It is necessary to be careful about these differences in GC screening.

Gastric foveolar-type adenomas endoscopically showing a raspberry-like appearance in the Helicobacter pylori -uninfected stomach.

Background and study aims Foveolar-type adenoma is described as a very rare tumor that occurs in individuals without Helicobacter pylori (HP) infection and diagnosed as adenocarcinoma in the Japanese Classification of Gastric Carcinoma (JCGC). However, we have frequently encountered patients with foveolar-type adenoma that endoscopically resembles a hyperplastic polyp, suggesting that it has just been overlooked to date. Here, we analyzed clinicopathological characteristics of a special subtype of foveolar-type adenoma showing specific endoscopic findings. Patients and methods From a total of 212 patients with gastric cancer resected during a 22-month period, we enrolled 14 (6.6 %) diagnosed with foveolar-type adenoma (adenocarcinoma in JCGC). HP infection status was determined by eradication history, HP serum IgG antibody level, urea breath test, and endoscopic and histological findings. All lesions were observed using white-light endoscopy and narrow-band imaging with magnification endoscopy (NBIME). Endoscopically resected lesions were histologically examined. Results None of 14 patients had a current or past history of HP infection. All lesions were visualized on non-atrophic gastric mucosa as small reddish protrusions with fine granular surface, showing a raspberry-like appearance. NBIME showed papillary or gyrus-like microstructures with irregular capillary. Lesions were histologically diagnosed as foveolar-type adenoma showing MUC5AC-positive gastric mucin phenotype. Ki-67 was overexpressed (median labeling index 69.9 %, range 28.4 – 92.1 %), though all lesions were an intraepithelial tumor without stromal invasion. p53 over-staining was not seen in any. Conclusions Raspberry-like lesions on non-atrophic gastric mucosa in HP-uninfected individuals should be evaluated for the possibility of a special subtype of foveolar-type adenoma.

Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells.

Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

Endoscopic and clinicopathological features of intramucosal, histologically mixed-type, low-grade, well-differentiated gastric tubular adenocarcinoma with the potential for late-onset lymph node metastasis

BackgroundIntramucosal, histologically mixed-type, low-grade (LG), well-differentiated gastric tubular adenocarcinomas (tub1s; LG-tub1s) have larger mean diameters and exhibit a higher frequency of the gastric mucin phenotype (G-phenotype) than pure LG-tub1s. In proportion to their increases in diameter, G-phenotype differentiated-type early gastric cancer (EGC) tumours reportedly grow to eventually contain (an) undifferentiated-type component(s) and LG-tub1s, which are included in differentiated-type EGCs, reportedly exhibit changes in their glandular architectural and cytological atypia grades from LG to high-grade (HG) and can grow to contain a moderately differentiated tubular adenocarcinoma (tub2) component and undifferentiated components. Because they generally show a higher frequency of malignancy relative to tumours with a higher atypia grade and lower differentiation degree, it is suggested that, among mixed-type LG-tub1s, G-phenotype LG-tub1s containing an HG-tub2 component (LG-tub1s > HG-tub2) with undifferentiated components might lead to late-onset metastasis to lymph nodes even after a successful endoscopic submucosal dissection (ESD). We aimed to clarify the endoscopic and clinicopathological features of these G-phenotype LG-tub1s > HG-tub2.MethodsOf the 13,217 oesophagogastroduodenoscopies performed at our institutions between September 2008 and March 2016, 185 EGC lesions were evaluated in this retrospective observational study. Among these EGC lesions, 60 intramucosal LG-tub1s were divided into 53 tub1 (44 pure LG-tub1s and nine LG-tub1s containing HG-tub1) lesions and seven LG-tub1 > tub2 (LG-tub1 containing LG- and HG-tub2) lesions.ResultsThe frequencies of the superficial depressed type (P = 0.026), reddish colour (P = 0.006), HG of contained tub2s (P = 0.006), and G-phenotype (P = 0.028) were significantly higher in the LG-tub1 > tub2 group than those in the tub1 group. However, the largest lesion of the LG-tub1 > tub2 group had a superficial flat appearance, an isochromatic colour, an HG-tub2 and an undifferentiated component, and a large diameter greater than 30 mm, and it exhibited a G-phenotype.ConclusionsIntramucosal G-phenotype LG-tub1s > HG-tub2 are potential premalignant stomach neoplasms that may have specific endoscopic and clinicopathological features. However, G-phenotype LG-tub1s > HG-tub2 with undifferentiated component, which potentially show higher malignancy than those without undifferentiated components might change from a reddish to isochromatic colour. Accurately diagnosing, treating, and following-up G-phenotype LG-tub1s > HG-tub2 might decrease the number of patients who experience late-onset metastasis after ESD.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors).

ObjectiveEpithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors.Materials and methodsAmong duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands.ResultsAs for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands.ConclusionsAbout 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.

Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and nuclear staining of β-catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicillin secretion trap (CAST) analyses revealed that CDH17, REG4, OLFM4, HOXA10, DSC2, TSPAN8 and TM9SF3 are upregulated in GC and that CLDN18 is downregulated in GC. Expression of CDH17, REG4, HOXA10 and DSC2 and downregulation of CLDN18 are observed in the intestinal phenotype of GC. In contrast, OLFM4 is expressed in the gastric phenotype of GC. Expression of TSPAN8, TM9SF3 and HER2 are not associated with either gastric or intestinal phenotypes. Ectopic CDX2 expression plays a key function in the GC intestinal phenotype. MUC2, CDH17, REG4, DSC2 and ABCB1 are direct targets of CDX2. Importantly, these genes encode transmembrane/secretory proteins, indicating that the microenvironment as well as cancer cells are also different between gastric and intestinal phenotypes of GC.

An Inverse Relationship between the Expression of the Gastric Tumor Suppressor RUNX3 and Infection withHelicobacter pyloriin Gastric Epithelial Dysplasia

Background/AimsThis study was performed to determine the association between RUNX3 expression and Helicobacter pylori infection in premalignant gastric lesions.MethodsWe examined 107 patients with gastric epithelial dysplasia who had undergone endoscopic mucosal resection or submucosal dissection. All tissue samples were evaluated by RUNX3 staining and subclassified by immunophenotype. H. pylori infection in dysplastic lesions and the normal surrounding tissue was examined by silver staining, and cagA status was assessed by polymerase chain reaction.ResultsThe loss of RUNX3 expression was observed in 62 cases (57.9%), and an association with H. pylori infection was found in 54 cases (50.5%). The infection rate with the cagA-positive H. pylori strain was 63.0%. In RUNX3-negative lesions, the rate of H. pylori infection (p=0.03) and the frequency of category 4 lesions (according to the revised Vienna classification) were high (p=0.02). In addition, the gastric mucin phenotype was predominant. In RUNX3-negative category 4 lesions, the rate of cagA-positive H. pylori infection rate was high but not significantly increased (p=0.08).ConclusionsInfection with H. pylori is associated with inactivation of RUNX3 in early gastric carcinogenesis. This mechanism was prominent in gastric cancer with a gastric mucin phenotype.

The relationship between mucin phenotype and clinicopathological factors, proliferative activity and p53 expression in gastric hyperplastic polyps.

Gastric hyperplastic polyps (GHPs) are the most common polypoid lesion of the stomach, and their malignant potential has been demonstrated. In the present study, we evaluated the mucin phenotypes of GHPs and investigated the relationships among mucin phenotypes and clinical-pathological factors, proliferative activity and p53 expression in GHPs. The CD10, MUC2, MUC5AC and MUC6 expression patterns of 238 GHPs were examined by immunohistochemical staining. The GHP mucin phenotypes were divided into 4 subtypes: the gastric mucin phenotype (G-type), the intestinal mucin phenotype (I-type), the mixed or gastrointestinal mucin phenotype (GI-type) and the unclassified mucin phenotype (U-type). The G and GI types were observed in 58% and 42% of the GHPs, respectively. However, no I or U type GHPs were found in the present study. The GI type was more common in lesions with dysplasia or carcinoma than in polyps without dysplasia or carcinoma (P<0.001). P53-positivity rate and high index of Ki-67 tumors were significantly more common in the GI-type than in the G-type polyps (P<0.001). The mucin phenotype may serve as a useful marker for the malignant potential of GHPs, and GI-type GHPs should be considered to be a lesion with malignant potential.

Mucin Expression in Gastric Cancer: Reappraisal of Its Clinicopathologic and Prognostic Significance

The clinical validity of mucin expression in gastric cancer is debated. Whereas several reports demonstrate a correlation between mucin expression and prognosis, others deny such an association. This survival analysis study aims to elucidate the prognostic significance of mucin expression in gastric cancer. A retrospective survival analysis was done with 412 cases of gastric cancer characterized on the basis of MUC immunohistochemistry using MUC2, MUC5AC, MUC6, and CD10 antibodies; the cases were divided into those with a gastric, an intestinal, or a null mucin phenotype based on the predominant mucin. There was no association between mucin expression and survival when considering overall gastric cancers or the advanced gastric cancer subtype. However, early gastric cancers with a gastric mucin phenotype showed longer survival than those with an intestinal mucin phenotype (P = .01) or a null phenotype (P = .01). In particular, MUC5AC-positive early gastric cancers resulted in longer survival than did those that did not express MUC5AC (P = .009). The loss of MUC5AC expression was identified as an independent, poor prognostic factor in early gastric cancers using the Cox regression proportional hazard model (hazard ratio, 3.50; P = .045). MUC5AC expression is significantly associated with patient survival and can be used to predict outcomes in the gastric cancers, especially in the early gastric cancers.

Predictable Marker for Regression of Barrett's Esophagus by Proton Pump Inhibitor Treatment in Korea

Background/AimsThere has been no report regarding the regression of Barrett's esophagus (BE) by continuous treatment of proton pump inhibitor (PPI). The aim of this study was to determine the regression rate of BE by PPI and predictable markers related to regression.MethodsThirty-five patients diagnosed as BE were consecutively enrolled and most of them took continuous PPI. The 25 patients underwent endoscopic surveillance and received biopsy. If the specialized intestinal metaplasia (SIM) was lost at any point of surveillance and did not recur, the case was regarded as the regression group. The proportion of SIM was graded and the mucin phenotype was decided using immunohistochemistry for MUC2, MUC5AC and MUC6. To assess the cell proliferation indexes and the degree of intestinal maturation, immunohistochemistry for Ki67 and CDX2 were performed.ResultsThe regression of BE occurred in the 11 (44%) patients. The clinical and demographic factors showed no difference between the regression (n = 11) and persistence group (n = 14). The lower grade of SIM (P < 0.001) and gastric predominant mucin phenotype (P = 0.018) were more frequent, and the number of Ki67 positive cell per gland (P = 0.008) and the mean extent of CDX2 (P = 0.022) were lower in the regression group than in the persistence group.ConclusionsThe regression of BE by PPI treatment was frequent in Korea. The immunohistochemical detection of mucin phenotype, grade of SIM, Ki67 and CDX2 expression in Barrett's mucosa could be useful as a predictable marker for regression of SIM in BE.

Barrett-Ösophagus

Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett's esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.

Microsatellite Instability Status in Gastric Cancer: A Reappraisal of Its Clinical Significance and Relationship with Mucin Phenotypes

BackgroundGastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear.MethodsMSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed.ResultsOut of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197).ConclusionsOur data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.