Utilization of Cytokeratins 7 and 20 Does Not Differentiate between Barrett’s Esophagus and Gastric Cardiac Intestinal Metaplasia

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Modern Pathology (Impact Factor: 6.19). 06/2002; 15(6):611-6. DOI: 10.1038/modpathol.3880574
Source: PubMed


Long segment Barrett's esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains. Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining. We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the "Barrett's" pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett's pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences. Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett's pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.

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Available from: Cathy Streutker, Apr 04, 2014
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    • "Cytokeratin (CK)-7 is a 54 kDa polypeptide expressed in a wide variety of epithelial tissues including lung, breast, and fetal human stomach; however, it is not expressed in normal adult gastrointestinal epithelia [16]. Upregulation of CK-7, indicative of dedifferentiation, was evident in Kcne2−/− gastric mucosa at 12 months; in age-matched Kcne2+/+ mice, gastric mucosal positive epithelial cells were much rarer (Figure 2 D). "
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    ABSTRACT: Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 alpha subunit and the KCNE2 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.
    Full-text · Article · Jul 2010 · PLoS ONE
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    • "Ormsby et al. [11] later assessed the utility of CK7/20 patterns in short-segment BE in another study and found that "diagnostic" Barrett CK7/20 pattern was present in 82% of patients with short-segment BE. Although Mohammed et al. [16] found almost the same percentage (81%) for the short-segment BE cases with Ormsby et al. [11], they found the same pattern in 30.7% of patients with intestinal metaplasia in cardia and more interestingly in 55% of biopsies which had either normal or inflamed gastric mucosa without intestinal metaplasia. "
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    ABSTRACT: Background The purpose of the present correlative immunohistochemical study was to assess the utility of cytokeratin (CK7 and CK20) expression in the diagnosis of short-segment Barrett esophagus, particularly its efficacy in differentiating Barrett mucosa from intestinal metaplasia of the gastric cardia and corpus. Methods Two groups of endoscopic biopsy specimens were examined, including 20 endoscopic biopsy specimens of short-segment Barrett esophagus (Group A) and equal number exhibiting Helicobacter pylori associated intestinal metaplasia of the gastric cardia and corpus (Group B). All were investigated by immunohistochemistry using the standard ABC method for CK7 and CK20 expression. Fisher's exact test was used for statistical analysis of Barrett CK7/20 and gastric CK7/20 patterns between the groups. Results The anticipated pattern of reactivity in Barrett mucosa (CK7: strong diffuse positivity in superficial and deep glands; CK20: positivity in surface epithelium and superficial glands) was seen in 2 cases of Group A specimens. The expected gastric pattern (CK7: patchy immunostaining with variable involvement of deep glands; CK20: patchy immunostaining of superficial and deep glands in incomplete intestinal metaplasia / absence of CK7 immunoreactivity with strong CK20 staining in superficial and deep glands in complete intestinal metaplasia) was seen in 8 cases of Group B specimens. The respective sensitivity and false-negativity values of CK7/20 staining for Barrett pattern in Group A were 10% and 90%, respectively. These values for gastric pattern in Group B were 40% and 60%, respectively. The specificity and false-positivity values of both patterns were same (100% and 0%, respectively). There was no statistically significant difference for Barrett pattern between the two groups (P = 0.487), while the observation of gastric pattern was significantly higher in Group B than in Group A (P = 0.02). Conclusions We concluded that these hypothesized and recently applied diagnostic criteria involving CK7 and CK20 immunoreactivity are not reliable in distinguishing short-segment Barrett esophagus from intestinal metaplasia as seen in gastric cardia and corpus.
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    ABSTRACT: Patients with chronic gastro-oesophageal reflux disease are predisposed to Barrett’s metaplasia and oesophageal adenocarcinoma. The availability of molecular markers that can objectively identify patients with Barrett’s oesophagus at increased risk of carcinoma is highly desirable. A literature search was conducted to identify potentially useful biomarkers for genotype-phenotype correlation studies in South African patients with Barrett’s oesophagus. The COX-2, c-myb and c-myc genes selected for mRNA expression analysis were analysed in 26 patients with Barrett’s metaplasia (BM) without dysplasia; 14 with Barrett’s oesophagus and dysplasia (BD); 2 patients with Barrett’s adenocarcinoma (BAC); 19 with erosive oesophagitis (ERD); 25 with non-erosive oesophagitis (NERD) and 19 control individuals with a normal gastroscopy and no gastro-oesophageal reflux disease (GORD) symptoms. In the BD/BAC group, 69% (11/16) showed increased c-myb mRNA expression compared with 35% (9/26) in the BM group (p = 0.03). A statistically significant difference (p = 0.002) in c-myb expression was also observed between Barrett’s patients (20/42, 48%) and the control groups (9/63, 14%). In the BD patients, 21% (3/14) had increased c-myc mRNA expression compared with none in those with BM (p < 0.05) and BAC. No significant differences in mRNA expression levels were observed between ethnic groups for the genes analysed. In an attempt to determine whether the low expression level of c-myc in the study cohort may be related to possible gene-gene interaction, DNA samples of 199 individuals were subjected to genotyping of the functional GT-repeat polymorphism in the promoter region of the NRAMP1/SLC11A1 gene. Both these genes are involved in iron metabolism and c-myc is known to repress NRAMP1/SLC11A1. Genotype and allele frequencies were similar in all the groups studied with the 3/3 genotype being the most common. However, none of the three above-mentioned BD patients with increased c-myc mRNA expression had the 3/3 genotype. Therefore, although small in number, c-myc-NRAMP1/SLC11A1 interaction may be of adverse significance in patients with allele 2. TP53 mutation analysis was performed on 68 Barrett’s patients, and TP53 immuno-staining on oesophageal biopsy specimens of 55 subjects. Sporadic TP53 mutations were not identified in any of the patients with BM or dysplasia without BAC. Immuno-histochemistry staining of 2+ and 3+ intensity was similar in patients with metaplasia and dysplasia (58%). The low mutation frequency and relative non-specificity of TP53 immunostaining observed in Barrett’s patients seem to preclude its widespread use as a screening tool. TP53 mutation detection may however be useful for risk stratification once dysplasia has been diagnosed, as mutations G245R and D281Y were identified in two patients with BAC. Of the genes studied in the South African population, c-myb represents the most useful marker for early detection of an increased cancer risk in Barrett’s patients. In future, patients with Barrett’s oesophagus may benefit from genetic assessment to complement existing cancer surveillance and treatment strategies. Thesis (PhD (Pathology. Anatomical Pathology))--University of Stellenbosch, 2006.
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