T (Thomsen–Friedenreich) antigen and other simple mucin-type carbohydrate antigens in precursor lesions of gastric carcinoma

In a previous report we suggested that T antigen appeared to be associated with gastric carcinoma. To verify this hypothesis and characterize the pattern of expression of simple-mucin type carbohydrate antigens (Tn. sialyl-Tn and T before and after neuraminidase) in normal gastric mucosa and precursor lesions of gastric carcinoma, we studied the mucosa adjacent to 100 cases of gastric carcinoma, gastric biopsies of 60 dyspeptic patients, eight adenomatous polyps and eight hyperplastic polyps. The expression of the antigens was more related to the cell type and underlying lesions than to the coexistence of carcinoma. The most distinctive findings concerned intestinal metaplasia, dysplasia and hyperplastic lesions. In intestinal metaplasia, Tn was found mostly in columnar cells and sialyl-Tn in goblet cells. T was more prevalent in incomplete intestinal metaplasia than in complete. A high prevalence of sialyl-Tn expression and cell membrane immunoreactivity for T antigen, similar to those previously found in gastric carcinomas, were observed in three adenomatous polyps, one hyperplastic polyp, five cases of adenomatous dysplasia in the neighbourhood of intestinal carcinomas and four cases of marked foveolar hyperplasia, three of which were from the mucosa adjacent to diffuse carcinomas. We conclude that adenomatous and hyperplastic lesions share with gastric carcinomas features of aberrant glycosylation, namely the cell membrane expression of T antigen.     

Modifications of gastric mucosa in diffuse and intestinal cancer

The study was made of 29 intestinal type gastric carcinomas, 37 diffuse type gastric carcinomas and stomach mucosa (SM). Both carcinomas slightly differed by frequency of the fundal glands atrophy. Intestinal type was characterized by a higher frequency of antral glands atrophy, intestinal metaplasia, particularly of colon type. Intestinal cell differentiation was about the same in both types. Hyperplasia of lining and endocrine cells in the fundal part of the mucosa was more frequent and neuroendocrine differentiation was more pronounced in diffuse stomach carcinoma. It is suggested that environmental impacts including helicobacter pylori result in proliferation of the epithelium, intestinal metaplasia, dysplasia and carcinoma of the intestinal type. Diffuse carcinoma is associated with proliferation of glandular epithelium (parietal, endocrine, cervical) due to genetic factors, hypergastrinemia caused by fundal gland atrophy, alkalization of the mucosa due to Helicobacter pylori infection.     

Well-differentiated adenocarcinoma mimicking complete-type intestinal metaplasia in the stomach.

We describe extremely well-differentiated intestinal-type adenocarcinomas of the stomach which mimic complete-type intestinal metaplasia. It is often difficult to discriminate such neoplastic lesions from inflamed or regenerative changes of intestinal metaplasia histologically. The aim of this study was to elucidate the clinicopathologic features of this unique carcinoma. Eight cases of gastric carcinoma of this type that were invasive beyond the muscularis mucosae were selected for mucin histochemical and immunohistochemical analyses. The carcinomas showed the following features: (1) predominant cells that had differentiated to mature neoplastic cells, with features of small intestinal absorptive cells (complete-type intestinal metaplastic cells), which have sialomucin, MUC2-positive cells, and brush border features detected by CD10 (56C6) staining; (2) neoplastic tubules in the mucosa showing branching, tortuous, anastomosing, and plexiform structures, which were more pathognomonic than the cytological features; (3) lesions distributed predominantly in the middle third of the stomach and surrounded by the fundic mucosa; and (4) zonal distribution of Ki-67-positive proliferative cells like those of intestinal metaplasia in the lower third to half of the cancerous tubules in the mucosa. The lesions consisted mainly of illusory carcinoma; however, there were foci of pathognomonic elements in some areas of the tumors. Several biopsy samplings of the lesion would ensure the histopathologic diagnosis. This unique lesion forms a subgroup of intestinal-type carcinomas of the stomach and is suggested to have a close link with complete-type intestinal metaplasia, previously ignored as a precancerous lesion.     

Gastric or intestinal phenotypic expression in the carcinomas and background mucosa of multiple early gastric carcinomas

AIMS: The differences in phenotypic expression between multiple early gastric carcinomas (EGCs) and solitary EGCs were evaluated in this study. METHODS AND RESULTS: Fifty-three cases (53 lesions) of solitary EGCs and 50 cases (112 lesions) of multiple EGCs were studied. According to the classification of intestinal metaplasia, the phenotypes of carcinomas and background mucosa were classified into four categories-complete intestinal type, incomplete intestinal type, gastric type and unclassified type-based on the combination of expression of CD10 (small intestinal brush border), MUC2 (intestinal goblet cell), HGM (gastric foveolar epithelium) and Con A (gastric pyloric glands). The incidence of gastric-type carcinomas (48%) and the incidence of incomplete intestinal-type background mucosa (75%) among the multiple EGCs was higher than among the solitary EGCs. There was a significant difference in distribution of phenotypic expression of carcinomas and background mucosa between the solitary EGCs and the multiple EGCs, the latter being associated with incomplete intestinal metaplasia. CONCLUSIONS: Both the carcinomas and the background mucosa of multiple EGCs have an unstable status, since they more commonly possess the hybrid phenotype of the stomach and the small intestine than does solitary EGC. Such instability is considered to contribute to a high neoplastic potential and the multiple occurrence of carcinomas.     

Ki-67在胃癌及癌旁组织中的表达

目的:探讨Ki-67在胃癌和癌旁黏膜上皮中的表达、分布特征及其在胃癌组织发生学上的意义。方法:采用免疫组化方法对36例胃癌及癌旁组织进行检测。结果:胃腺癌与癌旁伴异型增生慢性萎缩性胃炎Ki-67阳性率无显著性差异;胃腺癌与癌旁伴高、中增殖型肠上皮化生慢性萎缩性胃炎Ki-67阳性率无显著性差异(P>0.05)。结论:Ki-67是一种较好的癌前标志物,胃黏膜上皮异型增生和高、中增殖型肠上皮化生萎缩性胃炎与胃癌的发生密切相关。     

p53 mutations and microsatellite instabilities in the subtype of intestinal metaplasia of the stomach

To investigate the potential implication of the subtype of intestinal metaplasia in the progression to the gastric carcinoma, we analyzed the mutations of the p53 gene and microsatellite instability (MSI) both in the complete type (type I) and in the sulphomucin-secreting incomplete type (type III) intestinal metaplasia located adjacent to the gastric carcinoma. p53 mutations were observed in 13.3% of type I, in 6.6% of type III intestinal metaplasia, and in 40% of gastric carcinoma. The difference between p53 mutations observed in type I and type III intestinal metaplasia was not statistically significant. No identical mutation of the p53 gene was found in the intestinal metaplasia and carcinoma specimens from the patients. There was no case of intestinal metaplasia showing MSI. In gastric carcinomas, MSI was observed in six cases (40%). The cases harboring BAT-26 instability did not have the mutation of the p53 gene. These data suggest that intestinal metaplasia adjacent to gastric carcinoma, irrespective of its subtype, do not have the genetic alterations as showing in their carcinoma tissues.     

Helicobacter pylori and gastric carcinoma

A retrospective study was performed on gastric carcinomas to establish the prevalence of Helicobacter pylori infection in gastric epithelium adjacent to the tumour. A total of 105 carcinomas were studied. The overall prevalence of Helicobacter pylori infection was 59%. The prevalence in different age cohorts from patients with gastric carcinoma was compared with that in patients suffering from non-ulcer dyspepsia and, based on serological testing, with that in healthy blood donors. The presence of Helicobacter pylori in cancer patients aged 41-50 and 51-60 was significantly higher than in blood donors. No difference was seen in comparison with non-ulcer dyspepsia patients. The presence of Helicobacter pylori showed an inverse correlation with the extent of intestinal metaplasia. The intestinal type of carcinoma was associated with a higher bacterial load than the diffuse type. These data suggest that the presence of Helicobacter pylori in gastric mucosa could play a role in the pathogenesis of gastric carcinoma, especially in the young age group.     

Mucin histochemical analysis of minute gastric differentiated adenocarcinoma

Fifty-six surgically resected intramucosal differentiated adenocarcinomas (DA) of the stomach with a maximum diameter of less than 5 mm were analyzed by mucin histochemistry. Gastric type phenotypic expression was observed in 41.1% of cases, intestinal type in 28.6% and gastric-intestinal type in 28.6% of all cancers. Gastric type phenotypic expression was the most frequent. As the tumor diameter increased, the incidence of DA with gastric phenotype tended to decrease. Intestinal metaplasia of the cancer's surrounding mucosa was absent or slight in DA with gastric phenotype, but moderate to severe in DA with gastric-intestinal phenotype and intestinal phenotype. Morphologically and mucin histochemically, intestinal metaplasia surrounding DA with gastric phenotype was immature and incomplete compared with DA with gastric-intestinal phenotype or intestinal phenotype. It is suggested that a large amount of DA with gastric phenotype is histogenetically derived from the gastric gland proper without intestinal metaplasia. However, as the tumor grows and intestinal metaplasia progresses, intestinal type phenotypic expression appears and then DA with gastric phenotype changes into DA with gastric-intestinal phenotype or intestinal phenotype.     

Time-dependent expression of intestinal phenotype in signet ring cell carcinomas of the human stomach

Signet ring cell carcinomas of the stomach are thought to arise from the proper gastric mucosa without intestinal metaplasia. It was recently reported that intestinal phenotypes appear along with tumor progression. In this study, we performed several experiments to reconsider the significance of this intestinalization in the growth of signet ring cell carcinoma. We applied mucin histochemistry with monoclonal antibodies MUC2 (Ccp58) and M1 (45M1), and paradoxical concanavalin A staining for class III mucin [PCS(III)] reaction to 29 intramucosal and 25 deeply invasive carcinomas of this type and correlated the phenotypic expression with the size of the mucosal spread and the depth of tumor invasion. It was found that the larger the size of the mucosal lesion, the more frequently the intestinal phenotypes were demonstrated. There was no significant increase in the expression of the intestinal phenotype as the tumor invaded the deeper part of the mucosa or as the intestinal metaplasia increased in the background mucosa. The intestinal expression appeared to be suppressed in the earlier phase of deep invasion. In the mucosal part of the tumor, the intestinal phenotype was often expressed regionally and incompletely, coexisting with gastric phenotypes at the cellular and the tissue levels. These findings indicate that the expression of the intestinal phenotype is a time-dependent and unstable phenomenon probably based on the accumulation of genetic changes and plays a neutral role in progression of signet ring cell carcinomas.     

Immunohistochemical detection of O-acetylated sialomucins in intestinal metaplasia and carcinoma of the stomach

Eighty-two selected gastric mucosal biopsy or resection specimens were stained both conventionally, to classify subtypes of intestinal metaplasia and carcinoma, and immunohistochemically with a mouse monoclonal antibody (MMM-17), raised against normal human colonic mucin, which has an affinity for di- and/or tri-O-acetylated sialomucin. The aims of the study were to reassess the prevalence of O-acetylated sialomucins in normal, metaplastic and carcinomatous gastric mucosa and to investigate whether the production of these mucins by intestinal metaplasia is related to its associated mucosal pathology. O-acetylated sialomucins were not seen in normal mucosa. They were, however, prevalent in all sub-types of metaplastic (64.8%) and carcinomatous (42.9%) mucosa. Type 1 intestinal metaplasia was significantly more likely to contain this type of mucin if Helicobacter pylori infection was identifiable in the adjacent gastric mucosa (81.0% v. 38.5%, P < 0.025). Type 3 showed a similar, albeit nonsignificant, relationship (100% v. 62.5%). O-acetylated sialomucins are, therefore, much more prevalent in gastric intestinal metaplasia and carcinoma than previously recognized by conventional staining techniques. The production of this type of mucin by intestinal metaplasia may reflect an adaptive response to alterations in the luminal environment such as an increase in bacterial content.     

肠上皮生化,异型增生及胃癌的细胞动力学研究

48 specimens of gastric mucosa, including those of normal mucosa, intestinal metaplasia, atypical hyperplasia and carcinoma, were studied with in vitro 3H-TdR double labeling autoradiographic technique. On the basis of cell kinetics, intestinal metaplasia might be divided into two types: Type A consisted of those cases in which the values of LI, Ts and Tc were approximately closer to those of normal mucosa. The labeling cells appeared in the lower two thirds of the intestinalized glands, including small intestinal type and the complete type of colonic intestinal metaplasia. In type B, the average values of LI were higher. Ts and Tc values approximated those found in carcinoma a. Type B consisted mostly of the incomplete type of colonic intestinal metaplasia. The above evidence suggests that type B intestinal metaplasia is precancerous.     

Absence of either gastric or intestinal phenotype in microscopic differentiated gastric carcinomas

Differentiated gastric carcinoma (DGC) corresponds roughly to the intestinal type of gastric carcinoma described by Laurén. It has been suggested that DGCs arise from intestinalized gastric mucosa, but recent findings regarding their mucin expression do not support this hypothesis. To evaluate the histogenetic relationship between DGCs and intestinal metaplasia, lesions that are as small as possible should be examined. Twenty-five DGCs, ranging in their greatest dimension from 0.4 to 2.7 mm, were collected and divided into two groups by size. Group A consisted of 13 lesions less than 1.4 mm across, and group B of 12 lesions 1.4 mm or more. The presence of mucin and a brush border was assessed by immunostaining with antibodies against human gastric mucin, pyloric-gland-type mucin, Muc-2 glycoprotein, and CD10 antigen, and the lesions were classified as having the gastric phenotype (G-type), intestinal phenotype (I-type), mixed gastric and intestinal phenotype (M-type), or null phenotype (N-type). Thirteen (52%) of the 25 lesions were N-type, 5 (20%) lesions were G-type, 5 (20%) were I-type, and 2 (8%) were M-type. Group A had a larger proportion of N-type lesions than B (10/13, or 77%, vs. 3/12, or 25%; p = 0.027, chi-square test for proportions). Group B had a larger proportion of G-type lesions than A (5/12, or 42%, vs. 0/13, or 0%; p = 0.033). The phenotypes of the carcinomas and their surrounding mucosa were unrelated. Therefore, DGCs may arise from gastric mucosa affected by intestinal metaplasia or not, without having either the gastric or intestinal phenotype.     

Morphological characteristics of Epstein-Barr virus-related early gastric carcinoma: A case-control study

A strong association between Epstein-Barr virus (EBV) and gastric carcinoma has been demonstrated by the uniform presence of EBV In all carcinoma cells, episomal monocionallty, elevated antibodies, and a unique 'lace pattern' in the mucosa. The present study is concerned with morphological changes of Intramucosal carcinoma and submucosal Invasion. reactive lymphocytes, and with atrophy and Intestinal metaplasia of the surrounding mucosa. Fifty-two EBV-positive early gastric carcinomas were matched by age, sex, and site of tumor with 103 EBV-negative carcinomas, all of which had previously been examined by serial cut-sections of the tumors and surrounding mucosa. Epstein Barr virus Involvement was strongly associated with lace pattern morphology as demonstrated previously, and with lymphocytic Infiltration In and around the tumor nests In the mucosa. The Infiltrating lymphocytes In the tumor nests were mainly composed of CD8+ T lymphocytes. Lympho-epithelioma (LE)-like carcinoma, was observed in the sub mucosal portions of 13 of 31 EBV-positive cases with such Invasions, Including 12 of 29 with lace pattern morphology in the mucosa. The majority of the surrounding gastric mucosa showed moderate to severe atrophy with marked depletion of parietal cells, complete-type intestinal metaplasia in EBV-positive cases, and Helicobacter pyiori (H. pyiori ) Infection for both EBV positive and EBV-negative cases. it is suggested that EBV infection may occur in the atrophic gastric epithelial cells associated with intestinal metaplasla and H. pylori Infection, leading to the development of carcinoma. Such cancers show lace pattern and marked lymphocytic reaction in the mucosa, with some tendency for histological change and lymphocytic reaction during the invasive process without lymph node metastasis.     

The expression of Lewis antigens in neoplasms of the gastrointestinal tract

The indirect immunoperoxidase technique has been used to demonstrate Lea and Leb antigens in paraffin sections of both morphologically normal gastric and colonic mucosae and their neoplastic counterparts. Expression differed in various regions of the gastrointestinal tract: Leb occurred most frequently in the stomach and Lea most frequently in the colon. Coexpression of Lea and Leb occurred in only 5% of cases of normal mucosa, in 65% of gastric carcinomas and in 82% of carcinomas of the colon. Furthermore, 75% of cases of intestinal metaplasia in gastric mucosa and 30% of tubular adenomas, 50% of villous adenomas and 70% of tubulovillous adenomas in the colon co-expressed Lea and Leb antigens. In this study, the expression of Lewis antigens in carcinoma was found to differ from that of adjacent normal mucosa in 95% of cases of gastric carcinoma and 100% of cases of colonic carcinoma. The differences were shown by antigen acquisition and/or deletion. Similar changes were shown in 88% of cases of intestinal metaplasia in gastric mucosa, 20% of cases of tubular adenomas and 57% of cases of villous and tubulovillous adenomas of colon.     

Assessment of proliferating cell nuclear antigen expression in precursor stages of gastric carcinoma using the PC10 antibody to PCNA

Immunohistochemistry using the PC10 antibody to proliferating cell nuclear antigen (PCNA) was applied to archival material from mucosa adjacent to gastric carcinoma ('normal', hyperplasia, complete and incomplete intestinal metaplasia and dysplasia) and non-cancer controls (normal and complete intestinal metaplasia). Overall, increased PCNA indices, with expansion and altered location of the proliferative zones, were observed in carcinoma fields and compared with controls ( P ≤0.001). These differences were particularly significant in 'normal' mucosa far from carcinoma as compared with normal in controls ( P ≤0.001). In carcinoma 'fields' distinct patterns of PCNA expression were noted in complete and incomplete intestinal metaplasia. Similarly, in dysplastic lesions high PCNA indices were present either throughout the gland or found predominantly in the upper compartment. We conclude that these differences in PCNA index and staining patterns might prove useful in monitoring the evolution of the disease in the follow-up of patients at risk of developing gastric cancer.     

Immunocytochemical detection of lactoferrin in human gastric carcinomas and adenomas

In gastric carcinomas, including 20 cases of intestinal type and 10 cases of diffuse type, in adenomas with mild to severe dysplasia (20 cases), and in hyperplastic polyps (10 cases), the presence of lactoferrin was investigated by immunohistochemistry. Incomplete or complete intestinal metaplasia or both and normal gastric mucosa were also tested. Preoperative hematocrit and serum iron levels (18 patients) were recorded. An evident reactivity for lactoferrin was encountered in intestinal type carcinomas, adenomas, and incomplete intestinal metaplasia, whereas diffuse-type carcinomas, hyperplastic polyps, and complete intestinal metaplasia were always unstained; mucous neck cells of the antrum and body were also positive for lactoferrin. The results are discussed in relation to the increased requirement of iron by neoplastic cells, although in gastric carcinomas serum iron levels appear to be unrelated to the immunohistochemical presence of lactoferrin.     

Immunohistologic study of intestinal antigen beta-2-MA in gastric tumors

Immunologic techniques were used to examine localization of the intestinal antigen beta-2-MA in 87 cases of malignant gastric tumors and 25 cases of non-neoplastic diseases of the stomach. The antigen was identified in 46.4% of gastric carcinomas. The presence of the antigen was not found to be related to a histological type of cancer. The beta-2-MA antigen was detected in the areas of intestinal metaplasia alone in 48% of the cases and in combination with malignant tumors in 50.9%. The antigen was found to be more common in the mucosa adjacent to those of diffuse cancer than in the mucosa located around cancer of intestinal type (p less than 0.01). beta-2-MA is one of the antigens showing intestine-differentiated cells in a number of gastric tumors and may be useful for immunological studies of gastric neoplastic types.     

Villin,intestinal brush border hydrolases and keratin polypeptides in intestinal metaplasia and gastric cancer; an immunohistologic study emphasizing the different degrees of intestinal and gastric differentiation in signet ring cell carcinomas

Summary Gastric carcinomas have been assayed for the presence of villin and for the small intestinal hydrolases aminopeptidase N and sucrase isomaltase. These proteins seem not to be present in normal stomach epithelium. However intestinal metaplasia in stomach, and tumour cells in the glandular patterns of gastric carcinoma were positive for all three markers, showing characteristic apical positivity. In contrast, in diffuse gastric carcinomas the percentage of signet ring cells positive for these markers varied from 10–100% with each marker showing a similar percentage of positive cells. Testing of gastric carcinomas with antibodies specific for different keratin polypeptides showed that while all 7 tumours were positive for keratins 8 and 18,2 were also positive for keratin 7. In the keratin 7 positive tumours all tumour cells were keratin 7 positive. The keratin 8 antibody also reacted on routinely fixed specimens. Thus gastric carcinomas reveal different degrees of gastric and intestinal differentiation