Hodgkin's disease of the esophagus: report of a case

Most esophageal malignancies are either squamous carcinomas or adenocarcinomas arising in the background of Barrett's esophagus. We describe a case of an 85-yr-old woman in whom the diagnosis of esophageal malignancy was difficult to confirm despite its endoscopic appearance and previous biopsies. This case illustrates the difficulty in diagnosing Hodgkin's disease of the esophagus. Despite the rarity of this entity, if clinically indicated by symptoms, large, deep biopsies by rigid esophagoscopy should be considered.     

Small adenocarcinomas of the esophagogastric junction: association with intestinal metaplasia and dysplasia

OBJECTIVES: Intestinal metaplasia in Barrett's esophagus predisposes to esophageal adenocarcinoma. Intestinal metaplasia of the cardia is a common finding in persons without cancer. Many adenocarcinomas of the esophagogastric junction are large enough to obliterate any underlying intestinal metaplasia. To estimate how often adenocarcinoma of the esophagogastric junction arises in intestinal metaplasia, we studied small adenocarcinomas of the esophagogastric junction. METHODS: Resection patients had adenocarcinomas 2 cm or smaller, within 2 cm of the esophagogastric junction. Age- and sex-matched controls had resection for squamous carcinoma. Saved and new histological slides from the esophagogastric junction were examined, with additional stains. RESULTS: Intestinal metaplasia was found in 86% (19/22) of adenocarcinoma cases, versus 32% (7/22) of controls (p < 0.001). Intestinal metaplasia with high or low grade dysplasia was associated with 64% (14/22) of adenocarcinomas and with 5% (1/22) of controls (p < 0.001). Excluding four cases with long and three with short Barrett's esophagus, 80% (12/15) of adenocarcinomas had associated intestinal metaplasia, 53% (8/15) with dysplasia. Most adenocarcinoma cases had the incomplete type of intestinal metaplasia with a Barrett type cytokeratin 7/20 staining pattern. Helicobacter pylori were seen in one adenocarcinoma and five control cases. CONCLUSIONS: Most adenocarcinomas of the esophagogastic junction arise in the background of intestinal metaplasia, sometimes in an endoscopically visible Barrett's esophagus, more often in small areas of intestinal metaplasia of the cardia. In cases of adenocarcinoma, the intestinal metaplasia resembled that found in Barrett's esophagus, and was not associated with H. pylori.     

Mutations in c-K-ras 2 gene codon 12 during colorectal tumorigenesis in familial adenomatous polyposis.

Colorectal carcinomas may be induced from adenomas, or they may occur de novo. To clarify the histogenesis of colorectal carcinomas, point mutations in codon 12 of the c-K-ras 2 gene in neoplasias of familial adenomatous polyposis patients were examined. Nineteen colorectal advanced carcinomas, 135 adenomatous polyps, 9 hyperplastic polyps, and 27 normal colonic mucosae were obtained from 48 patients. In 27 normal mucosae and 9 hyperplastic polyps, a mutation in the K-ras gene was not detected. Mutations were detected as follows: 0 of 24 in adenomas with mild atypia, 10 of 77 in adenomas with moderate atypia, and 24 of 34 in adenomas with severe atypia. The incidence of mutations in c-K-ras 2 codon 12 is correlated with the degree of atypia of adenomas. However, only 5 such mutations were detected in 19 advanced carcinomas, indicating that the mutation frequency in advanced carcinomas is much lower than that in adenomas with severe atypia. If a mutation of c-K-ras 2 gene is an important component in the formation of adenocarcinoma, these results did not confirm the successive development from adenomas with severe atypia to advanced carcinomas as the main route for colorectal carcinogenesis in familial adenomatous polyposis patients.     

TP53 mutations in malignant and premalignant Barrett''s esophagus

In order to improve the efficacy of endoscopic surveillance of Barrett's esophagus, markers of neoplastic progression in addition to dysplasia are required. The aim of the present study was to assess TP53 mutational analysis as a method of identifying patients with Barrett's esophagus who are at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. TP53 mutational analysis was initially performed on premalignant and malignant tissue from 30 patients undergoing esophagectomy for adenocarcinoma, and on premalignant biopsies from 48 patients participating in a Barrett's surveillance program. Surveillance patients were followed up endoscopically and histologically for a median of 5 years following TP53 assessment. Mutational analysis was performed by single-strand conformation polymorphism analysis and direct DNA sequencing. TP53 mutations were detected in 10 of 30 esophageal adenocarcinomas, and were more common in well-differentiated carcinomas. An identical TP53 mutation was detected in carcinoma and adjacent dysplasia. Two patients with premalignant Barrett's esophagus had TP53 mutations and one of these patients developed adenocarcinoma on follow up whilst the other has not yet progressed beyond metaplasia. No patient without TP53 mutation developed high-grade dysplasia or adenocarcinoma. TP53 mutations are detected in 33% of esophageal adenocarcinomas and in 4% of premalignant Barrett's esophagus in patients undergoing endoscopic surveillance. TP53 mutation can be detected before the development of high-grade dysplasia or carcinoma, and may be useful in stratifying the risk of adenocarcinoma in patients with Barrett's esophagus.     

Colonic tumorigenesis in rats with 1,2-dimethylhydrazine

Subcutaneous injections of the carcinogen dimethylhydrazine in inbred Fischer 344 male rats induced squamous-cell carcinomas in the ear canal, adenocarcinomas in the small bowel and duodenum, and adenomas and adenocarcinomas in the large bowel. The incidences of the tumors induced in the large bowel and ear canal were dose-related. As for tumors of the large bowel, the average size of adenomas was less than that of adenocarcinomas with massive infiltration beyond the muscularis mucosa. The average size of early adenocarcinomas was greater than that of adenomas but less than that of adenocarcinomas with massive infiltration beyond the muscularis mucosa. Supported by Medical Research Service, Veterans Administration Medical Center, Lexington, Kentucky.     

Prevalence of Barrett's esophagus and expression of mucin antigens detected by a panel of monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma in Japan

Barrett's esophagus (BE) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Moreover, it has been reported that short-segment BE may be associated with adenocarcinoma of the esophagogastric junction. The objective of this study was to define the prevalence of BE and the mucin profile in BE, including the short-segment type, and to compare the mucin profile in BE with the profiles of Barrett's adenocarcinoma and distal esophageal adenocarcinoma among Japanese. In total, 650 adult subjects underwent endoscopic examination for evaluation of BE. Although the prevalence of traditional (long segment) BE was 0.62%, the overall prevalence of BE including short-segment type was 15.7%. In Barrett's epithelium, the short-segment type predominantly had gastric type mucin, while the middle- and long-segment types possessed intestinal mucin, especially colonic type mucin (sulfo-Lewis^a), with high frequency. In Barrett's epithelium with adenocarcinoma, all Barrett's epithelium adjacent to carcinomas showed a predominance of immunoreactivity to sulfo-Lewis^a. In Barrett's adenocarcinomas, colonic type mucin was detected in 100% by monoclonal antibody (MoAb) 91.9H. Small-intestinal mucin and gastric mucin were stained in 50% and 12.5% of the subjects, respectively. Colonic type mucin was also detected with high frequency (80%) in distal esophageal adenocarcinomas without Barrett's epithelium. These data suggest that the epitope, not of small-intestinal type or gastric type mucin, but of colonic type mucin (sulfo-Lewis^a), may be associated with, at least in part, the malignant phenotype of BE. Received: July 28, 1999 / Accepted: February 25, 2000     

Gastric metaplasia of the proximal esophagus associated with esophageal adenocarcinoma and Barrett's esophagus: what is the connection? Inlet patch revisited

BACKGROUND/AIM: The inlet patch is an area of heterotopic gastric mucosa found in the proximal esophagus at the level of the upper esophageal sphincter. Limited data are available regarding this form of gastric metaplasia and its incidence, significance, and possible association with other esophageal diseases. We report our observations of such gastric metaplasias in patients with esophageal adenocarcinoma or Barrett's esophagus and high-grade dysplasia. METHODS: All patients having Barrett's esophagus and adenocarcinoma referred for photodynamic therapy were included in this study. The patients were prospectively evaluated endoscopically for the presence of gastric metaplasia of the proximal esophagus (salmon-colored area of a least 5 mm in diameter with cardia-type gastric metaplasia on biopsy). RESULTS: A total of 36 patients were included in this study: 11 patients with dysplastic Barrett's esophagus (8 males, mean age 79 years) and 25 adenocarcinoma patients (18 males, mean age 71 years). At endoscopy prior to photodynamic therapy, 11 patients (31%; 8 adenocarcinoma, 3 dysplastic Barrett's esophagus) were noted to have an area of gastric mucosa in the proximal esophagus. In each patient, there was at least 5 cm of normal squamous mucosa between gastric metaplasia and distal esophageal pathology. CONCLUSIONS: In this selected group of patients with high-grade dysplastic Barrett's esophagus or adenocarcinoma referred for photodynamic therapy, gastric metaplasia of the proximal esophagus was found in nearly one third. Prospective studies are under way to test more widely for this association and to determine whether this is a marker of disease severity and the result of similar pathogenetic mechanisms.     

Gastric and esophageal Campylobacter pylori in patients with Barrett's esophagus

Campylobacter pylori organisms were found with similar frequency in the stomachs of patients with Barrett's esophagus and in age- and sex-matched controls (10 of 26 vs. 11 of 26). Campylobacter pylori was also observed in esophageal Barrett's mucosa in some patients with gastric C. pylori, but not when gastric infection was absent (4 of 10 vs. 0 of 16). Campylobacter pylori was not detected in esophageal squamous mucosa from patients with Barrett's esophagus or in 25 non-Barrett's patients with gastric C. pylori and histologic changes of esophageal reflux. Overall frequency of ulceration in Barrett's esophagus was 35% (9 of 26), and frequency of ulceration was similar whether or not C. pylori was noted in gastric or Barrett's mucosa.     

Carcinoma of the esophagus with mixed basaloid squamous and glandular differentiation: a distinct histological presentation

Esophageal cancer is the third most common gastrointestinal cancer and ranks among the ten commonest cancers worldwide. Histologically, approx 60% of esophageal cancers are adenocarcinomas and 40% are squamous cell carcinomas (SCC). Other rare cancers of the esophagus include small-cell carcinomas, squamous cell carcinomas with sarcomatous features, adenoid cystic carcinomas, and mucoepidermoid carcinomas. Basaloid squamous cell carcinoma (BSCC) or basaloid squamous carcinoma (BSC) is a distinct clinicopathological entity, seen more frequently in elderly males. Stage at presentation is often advanced and regional adenopathy or distant metastases are not uncommon at presentation. We describe an unusual case report of esophageal BSCC with glandular differentiation. The clinical significance of glandular differentiation in this rare type of tumor is not known.     

Changing disease burden and management issues for esophageal cancer in the Asia-Pacific region

The changing epidemiology of esophageal cancer in developed countries is from squamous cell type to adenocarcinomas arising from Barrett's epithelium and the gastric cardia. This has implications for management of this disease. Earlier diagnosis of cancer from screening high-risk patients with Barrett's esophagus is potentially possible, and mucosal ablation together with acid-suppressive therapies have been investigated to revert Barrett's epithelium in its premalignant stage. When a cancer has developed, the strategies of staging methodology and surgical approaches also differ from those applicable for squamous cell cancers located in more proximal locations of the esophagus. By contrast, in the Asia-Pacific region (with the exceptions of Australia and New Zealand), squamous cell cancers in the middle portion of the esophagus remain the main cell type seen. An overall increase in life expectancy has led to more elderly patients presenting with carcinoma of the esophagus. This is of particular importance when surgical resection is contemplated. Advances in surgical management, multimodality programs, and endoscopic therapies are most marked in recent years. Treatment for patients with esophageal cancer should be individualized. The choice depends on expertise and facilities available, tumor and patient factors, and local economics.     

Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers

OBJECTIVE: Tooth loss has been associated with upper gastrointestinal cancer in several studies, but only one previous study used prospectively collected data. The importance of confounding by Helicobacter pylori has not previously been addressed. The objective was to determine the association between tooth loss and upper gastrointestinal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort and to determine the importance of potentially confounding dietary factors or H. pylori seropositivity. MATERIAL AND METHODS: A prospective cohort study with 29,124 subjects included 49 esophageal squamous cell carcinomas, 66 esophageal/gastric cardia adenocarcinomas, and 179 gastric non-cardia adenocarcinomas occurring between 1985 and 1999. Cox proportional hazards models adjusted for age and education were used to estimate hazard ratios (HRs) and 95% CIs. Odds ratios and 95% CIs were calculated with and without adjustment for H. pylori seropositivity in a nested case-control group to determine whether H. pylori confounded the association between tooth loss and gastric cancer. RESULTS: Tooth loss significantly increased the hazard ratio for gastric non-cardia cancer, the HR (95% CI) for edentulous subjects versus those with < 10 teeth lost was 1.65 (1.09, 2.49, respectively). No statistically significant associations were found between tooth loss and esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma. Confounding by dietary factors, tobacco smoking, or H. pylori did not explain these results. CONCLUSIONS: Tooth loss was associated with increased risk of gastric non-cardia cancer, but not esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma in this Finnish cohort.     

Esophageal Squamous Carcinoma in Five Patients with Barrett''s Esophagus

Adenocarcinoma of the esophagus is a well-known complication of Barrett's esophagus. This report describes five patients (three men and two women) with Barrett's esophagus and squamous carcinoma of the esophagus. All patients had hiatal hernia, and three had a history of tobacco and alcohol use. The tumors were located in the Barrett's mucosa in one case, at the squamocolumnar junction in two cases, and in the squamous-lined mucosa above the Barrett's mucosa in two cases. One patient also had focal adenocarcinoma associated with the squamous carcinoma of the esophagus. Review of the literature identified 11 previously reported cases. Occurrence of esophageal squamous carcinoma in Barrett's esophagus patients suggests a possible relationship between these two conditions, and the need for a careful evaluation of the squamous esophageal mucosa and the squamocolumnar junction at the time of endoscopy.     

Features of early gastric cancer and gastric adenoma by enhanced-magnification endoscopy

Background Changes to the mucosal surface of early gastric carcinomas and gastric adenomas as viewed by enhanced-magnification endoscopy with acetic acid have not been investigated thoroughly. Using this technology, we investigated the appearance of the gastric surface patterns of neoplastic and surrounding nonneoplastic mucosa. Methods Forty-seven consecutive patients with early gastric carcinomas or gastric adenomas underwent enhanced-magnification endoscopy following 1.5% acetic acid instillation. All biopsy specimens were taken from the area at which the enhanced-magnified endoscopic image was obtained. Results Surface patterns of gastric tumors and the surrounding mucosa were classified into five types: type I, small round pits of uniform size and shape; type II, slit-like pits; type III, gyrus and villous patterns; type IV, irregular arrangements and sizes of pattern types I, II and III; type V, destructive patterns of types I, II and III. The predominant pattern of the surrounding mucosa was type III, and most type III mucosa had characteristics of intestinal metaplasia. Although all elevated adenomas showed type II or type III surface patterns, both depressed adenomas showed type IV. Elevated carcinomas showed type III (42.9%) or type IV (57.1%) surface patterns, while depressed carcinomas showed type IV (70%) or type V (30%). Although differentiated tubular adenocarcinomas showed type III (10.3%), type IV (86.2%), or type V (3.5%) surface patterns, all of the signet-ring cell carcinomas and poorly differentiated tubular adenocarcinomas showed type V. Conclusions Enhanced-magnification endoscopy may be useful for identifying gastric tumors and determining the extent of horizontal spread, especially in tumors of the depressed type.     

Cytokeratin subsets for distinguishing Barrett's esophagus from intestinal metaplasia in the cardia using endoscopic biopsy specimens

OBJECTIVES: It has been suggested that Barrett's epithelium and intestinal metaplasia in the gastric cardia have different cyotokeratin (CK) staining patterns and that Barrett's epithelium can be distinguished by CK staining pattern. The aim of this study was to test the utility of CK staining for distinguishing Barrett's esophagus from gastric intestinal metaplasia. METHODS: Topographically mapped gastric biopsy specimens were obtained from patients without Barrett's esophagus, and esophageal biopsies were obtained from patients with long-segment Barrett's esophagus (>3 cm). Serial sections were stained with Genta or El-Zimaity triple stain, and biopsies with intestinal metaplasia were stained with antibodies against CK 4, 13, 7, and 20. RESULTS: Sections from 33 biopsies with Barrett's esophagus, 23 with intestinal metaplasia of the gastric cardia, 27 with intestinal metaplasia of the gastric body, and 33 with intestinal metaplasia of the antrum were examined. CK 4 and CK 13 stained squamous epithelium only. The proposed "diagnostic" CK Barrett's 7/20 pattern was found in only 39% of long-segment Barrett's compared to 35%, 4%, and 24% in intestinal metaplasia from the gastric cardia, body, and antrum, respectively. The criteria proposed had a sensitivity of 45% and a specificity of 65%. CONCLUSIONS: These results do not support keratin phenotyping as a tool for differentiating intestinal metaplasia originating in the cardia from intestinal metaplasia of Barrett's.     

Is intestinal metaplasia a necessary precursor lesion for adenocarcinomas of the distal esophagus,gastroesophageal junction and gastric cardia?

Adenocarcinoma of the distal esophagus and gastroesophageal junction are believed to arise in Barrett's esophagus with intestinal metaplasia. Whether adenocarcinoma can arise in columnar lined esophagus without intestinal metaplasia is in doubt. Whether adenocarcinoma of the gastric cardia arises in intestinal metaplasia of the gastric cardia is also in doubt. We aim to evaluate the relationship of size and stage of adenocarcinoma of the distal esophagus, gastroesophageal junction and gastric cardia to intestinal metaplasia and other types of columnar epithelium. Seventy-four patients who had esophagogastrectomy for adenocarcinomas in this region were examined histologically to assess the frequency of residual intestinal metaplasia in the surrounding epithelium. Tumors without residual intestinal metaplasia were evaluated for the presence of other columnar epithelia and correlated with tumor size and stage. Cardiac mucosa was present around all tumors. Residual intestinal metaplasia was present in 48 (65%) tumors, including 33/38 (87%) distal esophageal, 10/25 (45%) junctional and 5/11 (45%) gastric cardia tumors. The prevalence of intestinal metaplasia was 100% in all tumors that were less than 1 cm in maximum diameter and all intramucosal tumors. The prevalence of residual intestinal metaplasia decreased with increasing tumor size and stage. These data strongly support the contention that adenocarcinomas of this region, including those in the gastric cardia, arise in intestinal metaplastic epithelium. The absence of residual intestinal metaplasia in larger tumors is the result of tumor overgrowing the intestinal metaplasia from which it arose.     

TP53 Gene Mutations Are Rare in Nondysplastic Barrett's Esophagus

In search of potential prognostic markers, we analyzed a large series of tissues of Barrett's esophagus and samples of adenocarcinomas arising in the terrain of Barrett's esophagus for TP53 gene mutations by direct sequencing of exons 5 to 9 of the TP53 gene. While 9 of 21 adenocarcinomas tested (42.9%) contained a TP53 mutation, none of 24 samples from Barrett's esophagus were mutated. This observation suggests that TP53 gene mutation may be a relatively late event in the progression from nondysplastic Barrett's esophagus to adenocarcinoma of esophagus. Therefore, TP53 gene mutations alone are not likely to represent a widely useful prognostic marker of the risk of progression to malignancy, at least not in Barrett's esophagus without dysplasia. This work was supported by grant ND/7009-3 from the Internal Grant Agency of the Ministry of Health of the Czech Republic.     

Gastric surgery is not a risk for Barrett's esophagus or esophageal adenocarcinoma.

BACKGROUND & AIMS: The contribution of duodeno-gastroesophageal reflux to the development of Barrett's esophagus has remained an interesting but controversial topic. The present study assessed the risk for Barrett's esophagus after partial gastrectomy. METHODS: The data of outpatients from a medicine and gastroenterology clinic who underwent upper gastrointestinal endoscopy for any reason were analyzed in a case-control study. A case population of 650 patients with short- segment and 366 patients with long-segment Barrett's esophagus was compared in a multivariate logistic regression to a control population of 3047 subjects without Barrett's esophagus or other types of gastroesophageal reflux disease. RESULTS: In the case population, 25 (4%) patients with short-segment and 15 (4%) patients with long-segment Barrett's esophagus presented with a history of gastric surgery compared with 162 (5%) patients in the control population, yielding an adjusted odds ratio of 0.89 with a 95% confidence interval of 0.54-1.46 for short-segment and an adjusted odds ratio of 0.71 (0.30-1.72) for long-segment Barrett's esophagus. Similar results were obtained in separate analyses of 64 patients with Billroth-1 gastrectomy, 105 patients with Billroth-2 gastrectomy, and 33 patients with vagotomy and pyloroplasty for both short- and long-segment Barrett's esophagus. Caucasian ethnicity, the presence of hiatus hernia, and alcohol consumption were all associated with elevated risks for Barrett's esophagus. CONCLUSIONS: Gastric surgery for benign peptic ulcer disease is not a risk factor for either short- or long-segment Barrett's esophagus. This lack of association between gastric surgery and Barrett's esophagus suggests that reflux of bile without acid is not sufficient to damage the esophageal mucosa.     

Efficacy of endoscopic surveillance of the upper gastrointestinal tract following distal gastrectomy for early gastric cancer

BACKGROUND/AIMS: How endoscopy can be used in the follow-up of the upper gastrointestinal tract in patients who underwent gastrectomy for early gastric cancer remains unclear. METHODOLOGY: Two-hundred and ten patients (137 males and 73 females, aged at initial gastrectomy 27-86, average age 56.5) were followed in the present study. Results of follow-up endoscopy of all patients, pathologic diagnoses of secondary tumors and interval between gastrectomy and detection of secondary tumor were reviewed. Cumulative incidence rate of second tumors in the upper gastrointestinal tract was then analyzed. RESULTS: Secondary tumor was observed by follow-up endoscopy in 7 patients including two gastric, one esophageal, one duodenal carcinoma and 3 gastric adenomas. The interval between initial gastrectomy and diagnosis of secondary tumor ranged from 20 to 71 months (average 51.7 months). All carcinomas were early stage and localized within the mucosa. Three patients with secondary cancer were successfully treated by endoscopic mucosal resection. The cumulative incidence rate of secondary cancer in the gastric remnant, esophagus and duodenum at six years after initial gastrectomy was 1.0, 0.8 and 0.5%, respectively. The overall incidence rate of secondary tumors of the upper gastrointestinal tract at six years after distal gastrectomy was 4.1%. CONCLUSIONS: The present findings indicate that annual follow-up endoscopy of the upper gastrointestinal tract after gastrectomy for early gastric cancer can be introduced to detect carcinoma at an early stage, thus improving the survival rate of gastrectomy patients.