Cytokeratin 7/20 and MUC1, 2, 5AC, and 6 expression patterns in Barrett's esophagus and intestinal metaplasia of the stomach: intestinal metaplasia of the cardia is related to Barrett's esophagus.

Intestinal metaplasia (IM) in endoscopic biopsies obtained from close to the gastroesophageal junction may represent IM of the cardia (CIM) or Barrett's esophagus (BE), which have different malignant potentials despite similar morphology. This study compared cytokeratin (CK) 7/20 and mucin (MUC1, 2, 5AC, and 6) immunopatterns in biopsies from BE (n = 41), CIM (n = 35), and antral gastric IM (AIM, n = 37) to evaluate their roles as diagnostic aids. CK7 and CK20 expression was described as absent, patchy (superficial and deep), continuous superficial only, continuous deep only, and diffuse. Eleven different combinations of CK7/20 expression were seen. Since CK20 staining was positive in all cases, four main patterns were defined on the basis of the observed CK7 staining as 1, absent; 2, patchy (superficial and/or deep); 3, diffuse; and 4, continuous superficial only. Overall CK7 positivity (regardless of pattern) was higher in BE and CIM than in AIM. CK patterns 3 and 4 were also higher in BE and CIM than in AIM. For either pattern 3 or 4, the positive and negative predictive values for BE versus AIM were 95% and 67%, respectively. MUC1 was rarely expressed in BE and CIM compared with AIM, whereas the opposite was noted for MUC5AC expression. MUC2 and MUC6 expression was similar in all locations. In conclusion, diffuse or continuous superficial CK7 staining is highly characteristic of BE and CIM and contrasts with AIM. It is, however, not very sensitive. CK20 profiles have no added value. Mucin expression also differs between BE and CIM versus AIM, but the specificity of any pattern is insufficient for distinction in individual cases. Importantly, CK and MUC expression patterns in BE and CIM are virtually indistinguishable, limiting their use in this differential and raising the question of whether they are biologically related.

'Cardiac-type' (mucinous) mucosa and carditis are both associated with Helicobacter pylori-related gastritis.

BACKGROUND: Adenocarcinoma of the gastro-oesophageal junction is rapidly increasing in incidence and there is much interest in precursor lesions. The aetiology of inflammation of the gastric cardia (carditis) and the concept of the cardia as a native zone of mucinous gastric glands are disputed. AIMS: To investigate the relationship between the type of cardiac mucosa and carditis with various histological and clinical parameters. METHODS: Ninety-eight sets of gastric biopsies (cardia, corpus, incisura and antrum) were obtained prospectively in young patients (median age 40 years) who presented to the outpatient clinic with symptoms of gastro-oesophageal reflux (n = 25) or other upper gastrointestinal symptoms. Patients with neoplasia or Barrett's oesophagus were excluded. The presence (n = 19) or absence of oesophagitis at endoscopy was recorded. The degree of inflammation, Helicobacter pylori density, intestinal metaplasia and atrophy were scored according to the Sydney classification and the type of cardiac mucosa (oxyntic or mucinous) was noted. RESULTS: We found that carditis and mucinous-type cardiac mucosa were strongly associated with H. pylori-related gastritis (P = 0.00019 and P = 0.006, respectively) but not with clinical or endoscopic gastro-oesophageal reflux. Mucinous mucosa in the cardia was only seen in 17% of biopsies. CONCLUSION: H. pylori-related gastritis is associated with mucinous-type cardiac mucosa as well as with carditis. The former strongly points to expansion of mucinous cardiac mucosa in H. pylori gastritis. This probably represents metaplasia of oxyntic to mucinous mucosa and raises the possibility of a role in carcinogenesis of the gastro-oesophageal junction.

Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via the retinoblastoma pathway.

AIM: Disruption of cell cycle regulation is a critical event in carcinogenesis, and alteration of the retinoblastoma (pRb) tumour suppressor pathway is frequent. The aim of this study was to compare alterations in this pathway in proximal and distal gastric carcinogenesis in an effort to explain the observed striking epidemiological differences. METHODS: Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissue samples: (a) biopsies showing normal mucosa, (b) biopsies showing intestinal metaplasia and, (c) gastric cancer resection specimens including uninvolved mucosa and tumour. RESULTS: In the antrum there were highly significant trends for increased p16 expression with concomitant (and in the group of carcinomas inversely proportional) decreased pRb expression from normal mucosa to intestinal metaplasia to uninvolved mucosa (from cancer resections) to carcinoma. In the cardia, there were no differences in p16 expression between the various types of tissue samples whereas pRb expression was higher in normal mucosa compared with intestinal metaplasia and tissue from cancer resections. CONCLUSION: Alterations in the pRb pathway appear to play a more significant role in distal gastric carcinogenesis. It may be an early event in the former location since the trend towards p16 overexpression with concomitant pRb underexpression was seen as early as between normal mucosa and intestinal metaplasia. Importantly, the marked differences in expression of pRb and p16 between the cardia and antrum strongly support the hypothesis that tumours of the two locations are genetically different which may account for some of the observed epidemiological differences.

Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays.

The aims of this study were (1) to compare protein expression of adenomatous polyposis coli (APC) gene, beta-catenin, and E-cadherin between proximal and distal gastric adenocarcinomas and (2) to investigate their use as markers of cancer risk in intestinal metaplasia (IM). The epidemiology of proximal (cardia and gastroesophageal junction) and distal (antrum and corpus) gastric carcinomas is strikingly different despite similar morphologies. Carcinoma of the distal stomach is decreasing in incidence, whereas proximal carcinomas are increasing in incidence more than any other cancer in the Western world. This phenomenon has so far not been satisfactorily explained. IM is a well-established precursor for adenocarcinoma in the distal stomach but less so in the proximal stomach. However, its specificity as a predictor of gastric carcinoma is very low. Abnormalities of APC, beta-catenin, and E-cadherin are implicated in carcinogenesis of the stomach and may show aberrant expression at early stages of the neoplastic process. This study evaluated their immunoprofiles in 3 groups: biopsies showing normal mucosa (n = 108), biopsies showing IM (n = 99), and gastric cancer resections (n = 117). In the last group, carcinoma and noninvolved mucosa were studied. All groups included material from both proximal and distal locations. The results of this study showed that there were no differences between proximal and distal locations with regard to APC, beta-catenin, or E-cadherin expression. In both locations, high normal expression rates for all 3 molecules were present in biopsies showing normal gastric mucosa or IM and noninvolved mucosa from gastric cancer resections. In carcinomas, there was a significant decrease in both APC and E-cadherin expression, whereas beta-catenin showed abnormal cytoplasmic and nuclear staining. Diffuse-type cancers showed significantly lower E-cadherin expression than intestinal types. Noninvolved mucosa from cancer resections showed normal APC, beta-catenin, and E-cadherin expression regardless of adjacent tumor type and whether the mucosa was morphologically normal or showed IM. In conclusion, proximal and distal gastric carcinomas show no differences in expression of APC, beta-catenin, or E-cadherin; thus, the observed abnormalities do not seem to contribute to the observed epidemiologic differences between these tumors. Because loss of APC, decreased E-cadherin, or abnormal beta-catenin expression did not occur in IM, even when associated with carcinoma these immunostains are unlikely to be of value in the assessment of malignant potential in IM.

CD44v6: a potential marker of malignant transformation in intestinal metaplasia of the stomach? An immunohistochemical study using tissue microarrays.

OBJECTIVE: Intestinal metaplasia is a well-established risk factor in the development of stomach cancer. However, since the specificity is low it would be of great practical value to find a marker to separate cases of intestinal metaplasia into low and high risk for progression to dysplasia/carcinoma. So far this has not been achieved. CD44 is a cell surface molecule involved in cell-cell and cell-matrix interactions, and the spliced variant 6 has been shown to play a role in the progression of gastric carcinoma. The aim of this study was therefore to evaluate CD44v6 as a marker of increased cancer risk in intestinal metaplasia. METHODS: The current study investigated immunohistochemical CD44v6 expression in biopsies of normal gastric mucosa (n = 154) and gastric mucosa with intestinal metaplasia (n = 127). A third group consisted of cancer gastrectomies (n = 117) in which both tumour and uninvolved mucosa was studied. Proximal (cardia) and distal (corpus/antrum) locations were noted in all cases. RESULTS: There was a significant sequential increase in CD44v6 expression from normal mucosa and mucosa showing intestinal metaplasia to uninvolved mucosa adjacent to cancers without and with intestinal metaplasia to tumour. The most striking increase was from 'normal' to intestinal metaplastic mucosa adjacent to cancers. There were no differences between proximal and distal cases in any group. CONCLUSION: These findings strongly suggest that CD44v6 expression is a late phenomenon in the transformation of intestinal metaplasia to dysplasia/cancer. It may therefore be a useful marker of cancer risk in patients with intestinal metaplasia.

Lack of association between hepatitis C viral RNA in serum and liver and histologic gradings: a study on Irish anti-D-treated patients.

In this study the authors applied a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect hepatitis C virus (HCV) RNA in 15 frozen liver biopsy samples from anti-D-treated patients. They also correlated the presence or absence of HCV RNA in the serum and liver of each patient with their histologic gradings. RNA was extracted from 36 frozen liver biopsy samples. These included 15 liver biopsy samples from patients infected with HCV through contamination of anti-D blood products. Three of these 15 anti-D-treated patients were receiving alpha-interferon treatment at the time of liver biopsy. Nine frozen liver biopsy samples from patients with a history of intravenous drug abuse were included as positive controls. HCV-negative frozen liver biopsy samples from 12 noninfected patients were used as negative controls. RNA was also extracted from six frozen skin biopsy specimens to check for cross-contamination of samples. Eleven of 15 anti-D-treated patients were HCV RNA positive by RT-PCR, with 100% correlation between HCV RNA in the serum and liver. The nine frozen liver biopsy samples from the intravenous drug abuse patients (positive controls) were also RT-PCR positive for HCV RNA. The 12 noninfected samples and the negative control biopsy samples were negative for HCV. Twenty-seven percent of the recombinant immunoblot assay-positive patients were serum and liver HCV RNA negative. HCV-positive patients receiving alpha-interferon therapy at the time of biopsy had cleared the virus from the serum and the liver. There was no correlation between the presence or absence of serum and liver HCV RNA with the histologic grading. This lack of correlation shows clearly the importance of histopathologic evaluation of liver biopsy samples in monitoring HCV-associated liver disease progression. In addition, this finding indicates that one cannot rely only on the presence or absence of HCV RNA in either serum or liver tissue as a parameter in monitoring HCV-associated liver disease progression in this unique cohort of anti-D-treated patients.