The comparison of histologic gastritis in patients with duodenal ulcer, chronic gastritis, gastric ulcer and gastric cancer

This study was designed to investigate the differences of histologic gastritis according to the endoscopic diagnosis, and between H. pylori positive and negative gastritis, using the Sydney system. A total of 122 patients (42 duodenal ulcer, 31 chronic gastritis, 35 gastric ulcer and 14 gastric cancer) underwent endoscopy with biopsies from the antrum and body. Among the 122 patients, 104 (85%) were H. pylori positive. H. pylori density of the antrum was significantly higher in duodenal ulcer than in chronic gastritis, gastric ulcer, and gastric cancer. The positivity of intestinal metaplasia was lowest in duodenal ulcer and highest in gastric cancer. H. pylori density as well as grade of activity, inflammation and atrophy were significantly higher in the antrum than in the body in duodenal ulcer, while in chronic gastritis, gastric ulcer and gastric cancer there was no difference of H. pylori density, activity, inflammation and atrophy between the antrum and body. The grade of activity and chronic inflammation were significantly higher in H. pylori positive patients than in H. pylori negative patients in both the antrum and body. In conclusion, the gastritis of duodenal ulcer was mainly localized to the antrum, while the gastritis of chronic gastritis, gastric ulcer or gastric cancer was rather uniform in the antrum and body. H. pylori seemed to be related to the development of chronic inflammation and activity.     

Helicobacter pylori infection and chronic gastritis in gastric cancer.

AIMS: To investigate the prevalence of Helicobacter pylori associated chronic gastritis in patients with gastric cancer. METHODS: Serum IgG antibodies for H pylori were determined in 54 consecutive patients with gastric carcinoma. The prevalence of H pylori in gastric mucosa was also examined histologically (modified Giemsa) in 32 patients from whom adequate biopsy specimens of the antrum and corpus were available. Thirty five patients with gastrointestinal tumours outside the stomach and 48 with non-gastrointestinal malignancies served as controls. RESULTS: Of the 54 patients, 38 (70%) had H pylori antibodies (IgG) in their serum (three additional patients had H pylori antibodies IgA, class specific but not IgG specific). This prevalence was significantly higher (p less than 0.05) than that (49%) in the 35 controls. No differences in prevalence of H pylori antibodies were found between gastric cancer cases of intestinal (IGCA) or diffuse (DGCA) type, both these types showing H pylori antibodies (IgG) in 71% of the patients. In the subgroup of 32 subjects, five patients had normal gastric mucosa and four showed corpus limited atrophy ("pernicious anaemia type" atrophy of type A). All of these nine patients had no evidence of current or previous H pylori infection in serum (no IgG antibodies) or in tissue sections (negative Giemsa staining). The remaining 23 patients had antral or pangastritis, and all had evidence of current or previous H pylori infection. CONCLUSIONS: H pylori associated chronic gastritis was the associated disease in 75% of the patients with gastric cancer occurring equally often in both IGCA and DGCA groups. About 25% of cases seem to have a normal stomach or severe corpus limited atrophy, neither of which showed evidence of concomitant H pylori infection.     

Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.     

Increased expression of interleukin-6 gene in gastritis and gastric cancer

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.     

OLGA gastritis staging in young adults and country-specific gastric cancer risk

Geographical differences have been shown in the clinical outcomes of Helicobacter pylori-associated gastritis phenotypes and in gastric cancer risk. This study tested whether the Operative Link on Gastritis Assessment (OLGA) staging correlated with gastric cancer risk in populations from 3 continents. Mapped gastric biopsies were obtained from 316 dyspeptic adults aged less than 41 years from 8 geographic areas that differed in gastric cancer risk. Gastric atrophy was assessed according to internationally validated criteria. Gastritis stage was established according to the OLGA staging system. The most prevalent gastritis stages were 0 to II, which included all subjects entered from Chile, Germany, India, Italy, and Thailand. Gastritis Stages III and IV were limited to the Chinese and Korean populations. Indians had a high prevalence of H pylori infection without high-stage gastritis. In populations at different cancer risk, the gastritis OLGA stage mirrored the gastric cancer incidence. Gastritis staging identifies a subgroup of higher-risk patients.     

Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal-type gastric cancer tumorigenesis

Intestinal-type gastric cancer (IGC) has a clear and multistep histological evolution. No studies have comprehensively explored gastric tumorigenesis from inflammation through low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC). We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic information within the process. RNA expression profiles of 94 gastroscopic biopsies from 47 patients, including gastric precancerous lesions (GPL: LGIN and HGIN), EGC, and paired controls, were detected by Agilent Microarray. During IGC tumorigenesis from LGIN through HGIN to EGC, the number of activity-changed tumor hallmarks increased. LGIN and HGIN had similar expression profiles when compared to EGC. We observed an increase in the stemness of gastric epithelial cells in LGIN, HGIN, and EGC, and we found 27 consistent genes that might contribute to dedifferentiation, including five driver genes. Remarkably, we perceived that the immune microenvironment was more active in EGC than in GPL, especially in the infiltration of lymphocytes and macrophages. We identified a five-gene signature from the gastric tumorigenesis process that could independently predict the overall survival and disease-free survival of GC patients (log-rank test: p < 0.0001), and the robustness was verified in an independent cohort (n > 300) and by comparing with two established prognostic signatures in GC. In conclusion, during IGC tumorigenesis, cancer-like changes occur in LGIN and accumulate in HGIN and EGC. The immune microenvironment is more active in EGC than in LGIN and HGIN. The identified signature from the tumorigenesis process has robust prognostic significance for GC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

早期胃癌临床诊治的若干问题

胃癌是全球范围内死亡率最高的恶性肿瘤之一,而胃癌的早期发现和规范化治疗是改善胃癌患者的重要手段。随着医疗技术的发展,早期胃癌的检出率逐年提高,并且手术方式逐渐从传统开腹根治术向内镜切除和腹腔镜手术过渡。本课题组通过多年系列研究,联合国内外最新发现对早期胃癌临床生物学特征、分期系统评估和综合治疗方案等方面进行深入研究,为指导早期胃癌临床诊治提供科学依据。     

The histogenesis and early invasion of gastric cancer

A three-dimensional analysis of the histogenesis of gastric cancer was made by examining minute, microscopic lesions of less than 500 mu. Cancer develops from the generative cell zone (G-zone) of the atrophic gastric glands and intestinal metaplastic glands. They then bud or branch and infiltrate into the propria interstitial tissue. The G-zone of the cancerous glands showed marked expansion with complete loss of normal cell kinetics of gastric glands and with hardly any signs of differentiation into pyloric glands. In the adjacent glands there were also expansion of the G-zone and formation of loop-shaped glands with abnormal branching and anastomosis sometimes leading to the formation of a network of glands. These changes are compatible with those of abnormal differentiation accompanying atrophy or intestinal metaplasia and are considered to express a preinvasive cancer.     

Multifocal early gastric cancer: morphology and histogenesis

69 foci from 27 multifocal EGC are compared morphologically with 90 solitary EGC. In the multifocal group there was a preponderance of gross types IIa and IIb, Small and Minute carcinomas, an intramucosal growth pattern and a well differentiated intestinal histotype. Although the differences in gross type and tumor size are related in some measure to the stage of neoplastic growth at the time of diagnosis, the higher frequency of well differentiated intestinal carcinomas in multifocal EGC probably reflects a different histogenesis. This hypothesis seems to be borne out by the greater extent of intestinal metaplasia and the larger number of dysplastic foci detectable in the surrounding gastric mucosa.     

Bacteria of the gastric antrum and their relation to chronic gastritis

Biopsy samples from the gastric antrum were taken from 61 patients. On bacteriological culture, Campylobacter pylori was isolated in 27 subjects. Thirty-four patients had chronic gastritis, as seen in routine-stained histological sections. By means of the May-Grünwald-Giemsa (MGG) staining technique, bacteria were demonstrated in sections from 26 subjects. Of these, 22 had gastritis histologically. In 13 subjects, structures similar to Campylobacter pylori were found in MGG-stained sections, 11 of these having chronic active gastritis histologically. Scanning electron microscopy demonstrated bacteria with the typical appearance of Campylobacter pylori, but other types of bacteria were also found, both on electron microscopy and on bacteriological culture. The study confirms that there is an increased frequency of histological gastritis when Campylobacter pylori is present in the samples (p = 0.009). However, a causative role of the bacteria could not be demonstrated in this study, and bacterial penetration into the epithelium was not observed.     

Helicobacter pylori genotypes and types of gastritis in first-degree relatives of gastric cancer patients

The frequency of Helicobacter pylori vacA alleles, cagA, and jhp0947 and their association with types and advanced forms of gastritis in 143 first-degree relatives of gastric cancer (GC) patients was assessed. The subjects included 64/143 with antral-predominant gastritis, 68/143 with pangastritis, and 11/143 with corpus-predominant gastritis, with or without atrophy or intestinal metaplasia (IM). Further classification included the severity of atrophy or IM. Group I (40/143) included the subjects with moderate-marked atrophy or IM, group II (58/143) those with no atrophy or IM, and group III (45/143) with mild atrophy or IM. The frequency of vacA s1 was 79.7%, vacA s2 20.3%, m1 49.7%, m2 50.3%, cagA 76.2%, and jhp0947 58%. The most prevalent combination was vacAs1 cagA (+) (65.7%) (P=0.001). Of the 143 subjects, 85 (59.4%) showed atrophy or IM, and 40/85 (47%) developed the moderate-marked atrophy or IM. No significant correlation was found between genotypes and the types of gastritis, non-atrophy, atrophy, or IM and severe forms of atrophy or IM (P>0.05). It is proposed that H. pylori genotype status might not be considered as an important determinant of the types and advanced forms of gastritis in the first-degree relatives of GC patients.     

Small early gastric cancer with special reference to macrophage infiltration.

The authors investigate the tumor-infiltrating cells in small early gastric cancer (EGC) (<10 mm) and describe the ultrastructural features and interactions of macrophages with tumor cells and other inflammatory cells. Sections from 20 small EGCs were stained by immunohistochemical methods for CD20, UCHL1, CD4, CD8, and CD68 (electron microscopic examination was used in 6 of the 20). In all of the tumors, CD68-positive macrophages accounted for most tumor-infiltrating cells, with UCHL1-positive T lymphocytes, eosinophils, and neutrophils being the next most frequent. We found only a few CD20-positive B lymphocytes. Electron microscopic analysis revealed macrophages with many phagocytic vesicles, cellular debris, and apoptotic bodies. These morphologic data show that macrophages are actively phagocytic. The tumor cells in contact with macrophages showed no cytopathic changes. These data do not support a macrophage-mediated cancer lysis like the ones reported in some systems in vitro. Contacts among macrophages and other inflammatory cells formed a recurrent ultrastructural hallmark and suggest a communication among varying inflammatory cell types during the precocious host response to gastric neoplasia.     

Multifocal early gastric cancer of mixed type.

A report of three selected gastric resection specimens presents the problems of histological classification of individual early gastric cancer, illustrated in discrepancies between macroscopic or endoscopic, and histologic identification. Multifocal origin and different types of gastric cancer are demonstrated in all three cases. Problems related to exact histologic classification of this mixed type are discussed together with the prognosis and surgical consequences.     

Clinicopathologic characteristics of early gastric cancer in Korea

Gastric cancer is the most common cause of cancer related death in Korea. Early gastric cancer (EGC), confined to mucosa or submucosa, regardless of lymph node metastasis, is known to have a favorable prognosis. From 1976 to 1995, four thousand nine hundred and twenty eight gastric cancer patients underwent operation at the Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea. Of these, 1,117 patients (22.6%) were diagnosed as EGC and underwent curative operation. Clinicopathologic characteristics were reviewed and survival data was analyzed. The proportion of EGC has increased during the last two decades, from 14.9% during 1976-1985 to 25.8% for 1986-1995. EGC has a wide age distribution range from the thirties to the sixties, with highest incidence in the sixties. The male to female ratio is 1.8:1, without any significant change in last two decades. Most lesions are located in the lower third of stomach (52.3%), and the lesser curvature (52.2%) was the most frequent site in the transverse axis. Macroscopically, the depressed type was the most common (66.1%) followed by the elevated, flat and mixed types, in that order. Tumor confined to the mucosa layer was seen in 52.5%, and lymph node involvement in 11.7%. The depth of tumor invasion correlated with tumor size and regional lymph node involvement. On histopathologic examination, signet ring cell type accounted for 29.6% of all EGCs. Overall 5-year survival rate was 92.7% and the presence of lymph node metastasis significantly affected survival (84.6% versus 96.2%) (p<0.05). In conclusion, the proportion of EGC, in terms of the gastric cancers operated upon, has been increasing in Korea over the last two decades. The introduction of active diagnostic approaches and diagnostic modalities could improve early diagnosis and the cure rate of gastric cancer in Korea.