Patients with gastroesophageal reflux disease and Barrett esophagus have an increased risk of developing adenocarcinoma of the esophagus. It is uncertain whether molecular or proliferative alterations are present in the early stages of disease.

One hundred thirty-eight patients with gastroesophageal reflux disease symptoms were subjected to upper gastrointestinal endoscopy with biopsies of the esophageal mucosa. p53 protein expression and the Ki-67 proliferation index were determined by immunohistochemical studies. Patients were divided into 4 groups according to histopathologic diagnosis: G1, normal epithelium (n=58); G2, mild esophagitis (n=42); G3, moderate esophagitis (n=23), and G4, severe esophagitis (n=15).

p53 overexpression was detected in 7% of G1, 21.4% of G2, 52.2% of G3, and 60% of G4 patients. There were significant differences between G1 and G3 or G4 (P<0.001) and between G2 and G4 (P<0.05). The Ki-67 index was 21.3+/-19.5% in G1, 30.8+/-23.4% in G2, 47.1+/-23.2% in G3, and 48.3+/-25.7% in G4. Significant differences in the Ki-67 index were found between groups: G1 x G3 (P<0.001), G1 x G4 (P<0.001), G2 x G3 (P=0.026), and G2 x G4 (P=0.046). p53 and Ki-67 overexpression were correlated with the severity of esophagitis (P<0.001).

p53 overexpression and the Ki-67 (MIB-1) index were correlated with histologic findings of inflammation in the esophageal mucosa, particularly in the moderate and severe forms of chronic esophagitis.

Gastroesophageal reflux disease (GERD) is a major risk factor for the development of esophageal adenocarcinoma (ACE). Many molecular alterations occur in esophageal carcinogenesis, yet the exact mechanism of ACE development remains unknown. This study aims to determine p53 protein and Ki-67 expression in esophageal mucosa of patients with GERD and study the correlation between these markers and the progression from normal squamous epithelium to esophagitis, columnar epithelium with or without intestinal metaplasia and ACE. We analyzed p53 protein and Ki-67 expression in biopsies of 200 patients with GERD and 35 patients with ACE. Those biopsies were classified into five groups: (i) G1 normal squamous epithelium (58); (ii) G2 esophagitis (80); (iii) G3 columnar epitheliums without intestinal metaplasia (30); (iv) G4, columnar epitheliums with intestinal metaplasia (32); and (v) G5 ACEs (35). p53 protein overexpression was found in 7% (4) of G1, 37.5% (30) of G2, 30% (9) of G3, 62.5% (20) of G4, and 71.4% (25) of G5 (p < 0.001). Ki-67 index increased according to the severity of histopathological diagnoses. Ki67 index was 21.3 +/- 19.5% in G1, 38.8 +/- 24.9% in G2, 37.7 +/- 26.3% in G3, 52.8 +/- 24.6% in G4, and 57.1 +/- 25.1% in G5 (P < 0.001). Linear correlation between p53/Ki67 expression and the multistep progression from squamous epithelium to ACE was observed (P < 0.001 and P < 0.05). Our results indicate that overexpression of p53 and increased Ki-67 could be associated with the development and progression to ACE in patients with GERD.

The histological changes that occur in the squamous epithelium in response to acute acid challenge was examined in healthy controls and proton pump inhibitor-treated gastroesophageal reflux disease (GERD) patients and related to the state of untreated erosive GERD in a saline-controlled, randomized perfusion study. In the basal state a stepwise significant increase in the thickness of the basal cell layer, papillary length, and dilatation of intercellular spaces (DIS) was seen when the three groups were compared. Acid perfusion induced a slight increase in the height of the basal cell layer mainly in healthy volunteers; this layer appears to be reactive to acute acid challenge as well as to acid suppressive therapy. DIS increases promptly in response to acute acid exposure in the healthy epithelium but no changes were seen in the lengths of the papillae or regarding DIS in the GERD patients. A protective effect of luminal nitric oxide on DIS development is suggested.

The majority of dysplasias and adenocarcinomas in Barrett's esophagus are closely associated with the specialized columnar epithelium. In this study, we performed an immunohistochemical analysis of columnar metaplasia presenting in short-segment Barrett's esophagus (SSBE).

The endoscopic biopsy specimens obtained from 91 patients were analyzed. Ten were cases of long-segment Barrett's esophagus (LSBE) and 81 had SSBE. Expression of MUC2, MUC5AC, Con A and CD10 was evaluated using immunohistochemical staining.

All samples from LSBE (n = 9) were histologically diagnosed as specialized columnar epithelium. The 81 SSBE samples were divided into gastric fundic-type (n = 26), junctional-type (n = 16) and specialized columnar epithelium (n = 39). In the specialized columnar epithelium of SSBE, there was a predominance of goblet cell-type metaplasia proposed by Watanabe et al. which is characterized by MUC2-positive pyloric epithelium (66.7%). The total percentage of non-goblet cell-type and goblet cell-type was 76.9%. In contrast, 80% of LSBE revealed the large intestinal-type or the large and small intestinal-type. The long oval and villous pit by magnifying endoscope suggests the presence of the specialized columnar epithelium, but the phenotypic classification of Watanabe's criteria was not associated with the endoscopic pit pattern.

Intestinal metaplasia in Barrett's esophagus changes immunohistochemically with progress of the disease.

Histological criteria for the diagnosis of reflux esophagitis include basal zone hyperplasia, stromal papillae elongation, and inflammatory infiltrate. However, endoscopic esophageal biopsy specimens may include little or no lamina propria. Intraepithelial T lymphocytes, seen in hematoxylin and eosin-stained sections as cells with irregular nuclear contours (CINC), may have a higher density in children with esophagitis. We evaluated the diagnostic accuracy of a numerical score built up by grading the "classical" parameters and its correlation with CINC density in grasp biopsy specimens obtained from children undergoing esophagogastroduodenoscopy with and without esophagitis. We analyzed esophageal biopsy specimens from 349 children (median age, 5 years) subdivided in 4 groups according to the previous routine histology report: group 1, 144 children with esophagitis; group 2, 65 controls; group 3, 51 children with dubious esophagitis; and group 4, 75 children with esophagitis on endoscopy but a normal histology report. A numerical value was assigned to each parameter; the sum of these values represented the histological score. We also evaluated intraepithelial CINC density (ie, number of CINC per high-power field). We separately analyzed histological sections with and without lamina propria. For both total score and for CINC density, we calculated a cutoff using a receiver operating characteristic curve. Cutoffs of 6 for score and of 4 for CINC density provided the best sensitivity and specificity. Sensitivity of the histological score was better in biopsy specimens containing lamina propria (94%) than in those without lamina propria (4%). Sensitivity of CINC density was satisfactory in both specimens with (78%) and without (75%) lamina propria. Specificity was satisfactory for both parameters. In conclusion, when lamina propria was present in sections of endoscopic esophageal biopsy specimens, histological score provided a better diagnostic accuracy for the diagnosis of esophagitis. However, when no lamina propria was present, as was the case in 67% of our children, CINC density had better sensitivity. In addition, this latter parameter showed esophageal mucosa damage in 34% of previously dubious cases or cases with esophagitis at endoscopy but a previous routine histology report of normal mucosa.