daw
10-11-2005, 04:40 PM
From American Journal of Clinical Pathology
Rab11a Immunohistochemical Analysis Does Not Distinguish Indefinite, Low-, and High-Grade Dysplasia in Barrett Esophagus
Marie E. Robert, MD; Mary Kay Washington, MD, PhD; Jeffrey R. Lee, MD; R. Goldenring, MD, PhD; Mary P. Bronner, MD; John R. Goldblum, MD; K. Greenson, MD; Marian M. Haber, MD; John A. Hart, MD; Laura W. Lamps, MD; Gregory Y. Lauwers, MD; David Lewin, MD; Audrey J. Lazenby, MD; Montgomery, MD; James M. Crawford, MD, PhD
Abstract
Our aim was to determine whether p53 and Rab11a immunoreactivity enhance diagnostic assessment of esophageal dysplasia. Histologic sections from 68 cases of Barrett esophagus obtained as part of a 12-institution study were stained with antibodies to p53 and Rab11a, randomized, and coded. The mucosal surface layer and deeper glands were scored blindly on a semiquantitative scale. The correlations between p53 and Rab11a scoring with the consensus diagnosis of dysplasia were analyzed. The histologic scale was as follows: no dysplasia, indefinite, low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, and invasive carcinoma. Rab11a staining was most prominent in epithelia negative for dysplasia but with regenerative features. There was an inverse relationship between Rab11a staining and findings of surface dysplasia (P < .02, χ2). However, statistical significance largely reflected loss of Rab11a immunoreactivity in intramucosal and invasive carcinoma, which was not a diagnostic dilemma. There was a strong positive correlation of p53 immunoreactivity with an increasing degree of epithelial dysplasia and carcinoma (P < .03, χ2). Rab11a immunoreactivity did not enhance the diagnostic assessment of dysplasia in Barrett esophagus. The previously reported positive correlation of p53 immunoreactivity with the presence of dysplasia in Barrett esophagus was confirmed.
Introduction
Barrett esophagus is reported in 8% to 24% of patients undergoing endoscopy for chronic symptomatic gastro-esophageal reflux disease.[1] Identification and follow-up of Barrett esophagus is essential because the patients have an increased risk of esophageal mucosal dysplasia and carcinoma. A particularly strong relationship has been established between specialized intestinal-type Barrett epithelium and the risk of dysplasia-adenocarcinoma.[2-5]
The detection of preneoplastic changes in patients with Barrett esophagus relies almost solely on the careful histologic evaluation of esophageal mucosal biopsy specimens. However, experts in the field acknowledge that the histologic diagnosis of dysplasia is by nature a subjective assessment.[4,6,7] High-grade dysplasia and early adenocarcinoma can be identified on biopsy specimens with a high degree of reproducibility and interobserver agreement. Histologic identification of low-grade dysplasia is subject to considerable variation among trained observers.[6,8] Consequently, much effort has been given to elucidating more objective biomarkers in the dysplasia-adenocarcinoma sequence so as to identify patients at greatest risk for developing cancer. Attention has been given almost exclusively to changes in nuclear programming, especially p53 mutations or loss of heterozygosity, p16 mutations, DNA ploidy, and G1/S DNA content in higher grade lesions.[9-19] Reliable identification of low-grade dysplasia remains problematic, and molecular markers of low-grade dysplasia have not been identified.
The progression of a metaplastic epithelium through dysplasia to adenocarcinoma is attributable to changes in nuclear regulation. However, histologic identification of dysplasia involves assessment of cytoplasmic and nuclear alterations, such as epithelial polarity and the nuclear/cytoplasmic ratio. The possibility that markers of cellular polarity might assist in identifying dysplasia, especially low-grade dysplasia, has begun to be explored only recently.[20] The identification of molecular markers of altered cellular polarity is an attractive alternative to nuclear markers for low-grade dysplasia.
Rab11a is a small guanosine triphosphate-binding protein expressed in a number of polarized epithelial tissues in association with intracellular vesicles involved in the apical recycling system.[21-24] Rab11a is expressed in the supranuclear cytoplasm of gastric fundic, ileal, and colonic epithelia, the squamous epithelium of the esophagus, and in a number of well-differentiated colonic adenocarcinoma and esophageal adenocarcinoma cell lines. Studies have revealed that Rab11a has a critical role in vesicle recycling to the plasma membrane.[21-23] Given the phenotypic changes in cell morphologic features that accompany dysplasia, the possibility that Rab11a staining might provide important diagnostic information in esophageal dysplasia merits examination. An initial study[25] indicated that an increase in Rab11a immunoreactivity correlated with the histologic diagnoses of low-grade dysplasia, consistent with a defect in apical trafficking within the dysplastic mucosal epithelial cells. However, this initial study was performed on material from 1 institution and on a limited number of patient samples. The biopsy specimens were graded by 3 workers from a single institution. The current study is a multi-institutional assessment of the validity of using Rab11a immunostaining for the diagnosis of mucosal dysplasia in Barrett esophagus.
complete article: http://www.medscape.com/viewarticle/513567?src=mp
Rab11a Immunohistochemical Analysis Does Not Distinguish Indefinite, Low-, and High-Grade Dysplasia in Barrett Esophagus
Marie E. Robert, MD; Mary Kay Washington, MD, PhD; Jeffrey R. Lee, MD; R. Goldenring, MD, PhD; Mary P. Bronner, MD; John R. Goldblum, MD; K. Greenson, MD; Marian M. Haber, MD; John A. Hart, MD; Laura W. Lamps, MD; Gregory Y. Lauwers, MD; David Lewin, MD; Audrey J. Lazenby, MD; Montgomery, MD; James M. Crawford, MD, PhD
Abstract
Our aim was to determine whether p53 and Rab11a immunoreactivity enhance diagnostic assessment of esophageal dysplasia. Histologic sections from 68 cases of Barrett esophagus obtained as part of a 12-institution study were stained with antibodies to p53 and Rab11a, randomized, and coded. The mucosal surface layer and deeper glands were scored blindly on a semiquantitative scale. The correlations between p53 and Rab11a scoring with the consensus diagnosis of dysplasia were analyzed. The histologic scale was as follows: no dysplasia, indefinite, low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, and invasive carcinoma. Rab11a staining was most prominent in epithelia negative for dysplasia but with regenerative features. There was an inverse relationship between Rab11a staining and findings of surface dysplasia (P < .02, χ2). However, statistical significance largely reflected loss of Rab11a immunoreactivity in intramucosal and invasive carcinoma, which was not a diagnostic dilemma. There was a strong positive correlation of p53 immunoreactivity with an increasing degree of epithelial dysplasia and carcinoma (P < .03, χ2). Rab11a immunoreactivity did not enhance the diagnostic assessment of dysplasia in Barrett esophagus. The previously reported positive correlation of p53 immunoreactivity with the presence of dysplasia in Barrett esophagus was confirmed.
Introduction
Barrett esophagus is reported in 8% to 24% of patients undergoing endoscopy for chronic symptomatic gastro-esophageal reflux disease.[1] Identification and follow-up of Barrett esophagus is essential because the patients have an increased risk of esophageal mucosal dysplasia and carcinoma. A particularly strong relationship has been established between specialized intestinal-type Barrett epithelium and the risk of dysplasia-adenocarcinoma.[2-5]
The detection of preneoplastic changes in patients with Barrett esophagus relies almost solely on the careful histologic evaluation of esophageal mucosal biopsy specimens. However, experts in the field acknowledge that the histologic diagnosis of dysplasia is by nature a subjective assessment.[4,6,7] High-grade dysplasia and early adenocarcinoma can be identified on biopsy specimens with a high degree of reproducibility and interobserver agreement. Histologic identification of low-grade dysplasia is subject to considerable variation among trained observers.[6,8] Consequently, much effort has been given to elucidating more objective biomarkers in the dysplasia-adenocarcinoma sequence so as to identify patients at greatest risk for developing cancer. Attention has been given almost exclusively to changes in nuclear programming, especially p53 mutations or loss of heterozygosity, p16 mutations, DNA ploidy, and G1/S DNA content in higher grade lesions.[9-19] Reliable identification of low-grade dysplasia remains problematic, and molecular markers of low-grade dysplasia have not been identified.
The progression of a metaplastic epithelium through dysplasia to adenocarcinoma is attributable to changes in nuclear regulation. However, histologic identification of dysplasia involves assessment of cytoplasmic and nuclear alterations, such as epithelial polarity and the nuclear/cytoplasmic ratio. The possibility that markers of cellular polarity might assist in identifying dysplasia, especially low-grade dysplasia, has begun to be explored only recently.[20] The identification of molecular markers of altered cellular polarity is an attractive alternative to nuclear markers for low-grade dysplasia.
Rab11a is a small guanosine triphosphate-binding protein expressed in a number of polarized epithelial tissues in association with intracellular vesicles involved in the apical recycling system.[21-24] Rab11a is expressed in the supranuclear cytoplasm of gastric fundic, ileal, and colonic epithelia, the squamous epithelium of the esophagus, and in a number of well-differentiated colonic adenocarcinoma and esophageal adenocarcinoma cell lines. Studies have revealed that Rab11a has a critical role in vesicle recycling to the plasma membrane.[21-23] Given the phenotypic changes in cell morphologic features that accompany dysplasia, the possibility that Rab11a staining might provide important diagnostic information in esophageal dysplasia merits examination. An initial study[25] indicated that an increase in Rab11a immunoreactivity correlated with the histologic diagnoses of low-grade dysplasia, consistent with a defect in apical trafficking within the dysplastic mucosal epithelial cells. However, this initial study was performed on material from 1 institution and on a limited number of patient samples. The biopsy specimens were graded by 3 workers from a single institution. The current study is a multi-institutional assessment of the validity of using Rab11a immunostaining for the diagnosis of mucosal dysplasia in Barrett esophagus.
complete article: http://www.medscape.com/viewarticle/513567?src=mp