Geoffrey W.B. Clark

Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients

The value of endoscopic surveillance of Barretts esophagus and the appropriate management of high-grade dysplasia remain unclear. Seventeen patients who were referred from endoscopic surveillance programs for management of high-grade dysplasia or adenocarcinoma developing in Barretts esophagus were compared with 35 patients who had a newly recognized Barretts adenocarcinoma, who had not been in a surveillance program. The referral diagnosis in the surveyed group was adenocarcinoma in six and high-grade dysplasia in 11. After repeat endoscopy with aggressive biopsy, two additional patients with adenocarcinoma were identified. Of the nine patients who underwent esophagectomy for high-grade dysplasia, five had invasive adenocarcinoma in the esophagectomy specimen, which had been missed before the operation, despite the fact that the median number of biopsy specimens obtained per 2 cm of Barretts mucosa was 7.8 (range 1.5 to 15.0). Overall, 13 patients in the surveyed group had adenocarcinoma, 12 staged early and one staged intermediate by the WNM classification. Surveyed patients were operated on at an earlier stage than the nonsurveyed patients (10 early, 14 intermediate, and 11 late stage tumors; chi 2 = 15.6, p < 0.01). Despite the presence of adenocarcinoma in 13 of the 17 surveyed patients, their survival was significantly better than that of the nonsurveyed group (chi 2 = 5.8, p < 0.05). Patients referred from surveillance programs for Barretts esophagus have a better outcome and earlier stage tumors than nonsurveyed patients. Inasmuch as multiple biopsy procedures do not exclude the presence of adenocarcinoma, continued surveillance of high-grade dysplasia is dangerous and potentially destructive to surveillance efforts.

Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma

The operative specimens from 43 patients undergoing en bloc esophagectomy for adenocarcinoma of the lower esophagus or cardia were analyzed. Depth of invasion of the tumor and extent and location of lymph node metastases were determined. Postoperative recurrence was identified from positive findings on successive 3-month computed tomographic scans. Positive nodes occurred in 33% (2/6) of intramucosal tumors, 67% (6/9) of intramural tumors, and 89% (25/28) of transmural tumors (p < 0.01). Commonly involved nodes were those in the lesser curve of the stomach (42%), parahiatal nodes (35%), paraesophageal nodes (28%), and celiac nodes (21%). Excluding perioperative deaths, follow-up was complete for 38 patients. Twenty patients had recurrence. Fifteen patients (40%, 15/38) had nodal recurrence: cervical, 7.9% (3/38); superior mediastinal, 21% (8/38); and abdominal, 24% (9/38) (retropancreatic in 7 and retrocrural in 2). Of 5 patients with nodal recurrence alone, 3 (60%) had recurrence at sites outside the margins of resection. Patients with four metastatic nodes or less had a survival advantage over those with more than four (p < 0.05). There was no difference in survival according to location of nodal metastases. Two (22.2%) of 9 patients with celiac node metastases survived longer than 4 years. Adenocarcinoma of the lower esophagus and cardia spreads widely to mediastinal and abdominal nodes, and death can occur from nodal disease. Rates of lymph node metastases increase with the depth of the primary tumor. Patients with lymphatic metastases can be cured particularly if there are fewer than four nodes involved. Curative surgical therapy necessitates wide lymph node resection to ensure removal of all metastatic nodes.

Does duodenal juice reflux into the esophagus of patients with complicated GERD? Evaluation of a fiberoptic sensor for bilirubin.

BACKGROUND It is controversial whether duodenal juice can damage esophageal mucosa in patients with gastroesophageal reflux disease (GERD). The issue remains unresolved partly because of difficulties in detecting the presence of duodenal juice in the lower esophagus. OBJECTIVES AND METHODS This study utilized an in vitro portable spectrophotometer with a fiberoptic probe capable of detecting bile as a marker of duodenal juice. Absorbance/concentration curves were established with known bilirubin concentrations at pH 1.4 and pH 7.7. Esophageal pH and bilirubin absorbance were monitored in vivo over a 24-hour period in 20 healthy volunteers to determine the absorbance threshold for clinical use. The study population consisted of 21 patients with GERD. Four had no mucosal injury, 5 erosive esophagitis, and 12 Barretts esophagus. RESULTS The correlation between absorbance and bilirubin concentration was 0.98 and 0.99 for acid and alkaline environments, but bilirubin absorbance was 35% less in an acid environment. Using an absorbance threshold of 0.14, patients with GERD taken in toto had elevated esophageal exposure to bilirubin. No difference was observed in bilirubin exposure between reflux patients without mucosal injury and controls. Highest exposure occurred in patients with Barretts esophagus. An important observation was that esophageal bilirubin exposure frequently occurred during periods when the esophageal pH was in the normal range. CONCLUSIONS The fiberoptic probe accurately detects esophageal bilirubin as a marker of duodenal juice. Esophageal exposure to bilirubin is uncommon in normal subjects. Patients with erosive esophagitis and Barretts metaplasia have increased esophageal exposure to duodenal juice compared to normal subjects. Reflux of duodenal juice into the esophagus can occur when the esophageal pH is within its normal range and is undetectable by pH monitoring alone.

Effect of gastroduodenal juice and dietary fat on the development of barrett's esophagus and esophageal neoplasia: An experimental rat model

AbstractBackground: Reflux of duodenal content into the lower esophagus of rats enhances the formation of nitrosamine-induced esophageal cancer and results in the induction of adenocarcinoma. We investigated the extent of the mucosal injury that was produced when the lower esophagus of rats was exposed to the reflux of gastroduodenal juice in the presence or absence of a carcinogen and tested the hypothesis that induction of esophageal cancer in this model would be influenced by the intake of dietary fat. Methods: Esophagoduodenostomy with gastric preservation was performed in 165 Sprague-Dawley rats in order to expose the lower esophagus to the reflux of gastroduodenal juice. Postoperatively selected groups of rats were treated with the carcinogen methyl-n-amylnitrosamine (MNAN). Subsequently, rats were fed diets of differing fat and calorie content for 20 weeks until they were put to death. Results: Refluxed gastroduodenal juice, in the absence of MNAN, induced esophageal inflammatory changes (diffuse papillomatosis and hyperkeratosis) in 38 of 39 rats (97%), specialized columnar metaplasia (Barretts esophagus) in four of 39 (10%), dysplasia in three of 39 (8%), and squamous cell carcinoma in one of 39 (3%). Diet did not influence the incidence of neoplasia in the absence of MNAN treatment. In rats treated with MNAN, refluxed gastroduodenal juice induced inflammation in 110 of 111 rats (99%), columnar metaplasia in 14 of 111 (13%), and cancer in 63 of 111 (57%). Fifty-eight percent of esophageal tumors were squamous cell carcinoma and 42% were adenocarcinoma. The highest incidence of tumors was observed in rats fed the semipurified high-fat diet (24 of 29; 83%) compared with rats fed the semipurified control diet (13 of 29; 45%), semipurified, calorie-restricted diet (15 of 27; 55%), and chow diet (11 of 26; 42%), p<0.05. Conclusions: Reflux of gastroduodenal content into the lower esophagus of rats can induce both Barretts metaplasia and neoplasia. Addition of a carcinogen increases the tumor yield and results in a proportion of the lesions being adenocarcinoma. This carcinogenic process is promoted by a diet with a high fat content.

Barrett's esophagus : The significance of p53 in clinical practice

OBJECTIVE The authors provide an updated review the molecular biology of the p53 tumor suppressor gene with reference to its role in the malignant degeneration of Barretts esophagus. SUMMARY BACKGROUND DATA Appreciation of the function of the tumor suppressor gene p53 has given new insight into regulation of the cell cycle, and the gene appears to play an important role in many solid tumors. Esophageal adenocarcinoma is increasing in frequency in the western world at an alarming rate and is unique because there is a clear metaplasia (Barretts mucosa)/ dysplasia/carcinoma sequence. p53 malfunction arises as an early event in this carcinogenic process and has been demonstrated in patients with nondysplastic Barretts metaplasia. The possible causes of p53 malfunction in this setting are discussed. The most reliable method for the detection of p53 mutations is DNA sequencing. p53 immunohistochemistry appears too insensitive to act as a reliable marker for the presence of a mutation and cannot be used as a reliable marker for the future development of cancer. CONCLUSIONS High-grade dysplasia within Barretts mucosa remains the best clinical predictor of adenocarcinoma. The mutational spectrum observed in these tumors should provide clues to their etiology.

Short-segment Barrett's Esophagus: a prevalent complication of gastroesophageal reflux disease with malignant potential☆

The significance of finding specialized intestinal epithelium localized to the region of the gastroesophageal junction is unclear. We tested the hypothesis that short segments of specialized intestinal epithelium are a consequence of gastroesophageal reflux disease and are premalignant. Two hundred forty-one patients with reflux symptoms underwent gastroscopy with rigorous biopsy. Barrett’s esophagus was diagnosed when specialized intestinal epithelium was present on biopsy. Patients with Barrett’s esophagus were subdivided according to the length of Barrett’s mucosa: short-segment Barrett’s (<3 cm) and extended Barrett’s (≥3 cm). Esophageal function was evaluated by manometry and 24-hour pH monitoring. In another 16 patients with small noncircumferential adenocarcinomas, the endoscopic length of Barrett’s mucosa was recorded. Thirty-three patients (14%) had short-segment Barrett’s and 37 (15%) had extended Barrett’s esophagus. Patients with short-segment Barrett’s esophagus had significantly more acid exposure than patients without specialized intestinal epithelium. Eighty-one percent of patients with short-segment Barrett’s esophagus had incresed esophageal acid exposure as did 100% of those with extended Barrett’s esophagus. All lengths of Barrett’s mucosa were associated with poor esophageal sphincter function and reduced contraction amplitudes in the distal esophagus. Twelve percent of patients with short-segment Barrett’s esophagus had dysplasia. The length of Barrett’s mucosa was ≤3 cm in 25% (4 of 16) of patients with early Barrett’s adenocarcinoma. Short-segment Barrett’s esophagus is commonly associated with gastroesophageal reflux disease. Further, short segments of specialized intestinal epithelium are premalignant in nature.

Motility in the hunt-lawrence pouch after total gastrectomy

PURPOSE The aim of this study was to evaluate motility patterns of the Hunt-Lawrence pouch and the jejunal limb of patients reconstructed with a pouch after total gastrectomy, and to compare the findings in symptomatic patients to those without symptoms after the operation. PATIENTS AND METHODS Thirty-three patients who had undergone post-gastrectomy pouch reconstruction were studied using a water-perfused motility system. In 21, the pouch was connected by a Roux-en-Y, and, in 12, by a jejunal interposition. Twenty-eight patients were asymptomatic, including 17 connected by a Roux-en-Y and 11 by a jejunal interposition. Five patients were by a jejunal interposition. Five patients were symptomatic, including 4 connected by Roux-en-Y Y and 1 by jejunal interposition. A control group consisted of 5 healthy volunteers who had not undergone operation. RESULTS The motility phases in the pouch and jejunal limb of asymptomatic patients were of shorter duration than those of controls, and they followed a random sequence instead of a normal progression from phase I to II to III. Motility features were similar in the pouch and the jejunal limb. Orthograde propagation of phase III-like activity was reduced and may contribute to the pouch storage function. Four of the 5 symptomatic patients showed highly abnormal motility with hypomotile or obstructive patterns. The technique of connecting the pouch--jejunal interposition of Roux-en-Y--did not affect the motility findings. CONCLUSIONS The altered motility occurs after a Hunt-Lawrence pouch reconstruction in asymptomatic patients. Symptoms after gastrectomy are associated with further disturbed motility that can be differentiated from the motility changes in asymptomatic patients.

Dysplasia in Barrett’s Esophagus: Diagnosis, Surveillance and Treatment

Barretts esophagus is a premalignant metaplastic change in the lining of the distal esophagus. It represents a peculiar form of healing which occurs in response to chronic gastroesophageal reflux disease. The condition should be considered in all patients undergoing endoscopy for symptoms of reflux disease and is confirmed when any biopsy shows the presence of specialized intestinal metaplasia irrespective of the macroscopic appearance of the distal esophagus. Endoscopic surveillance with multiple biopsy sampling of the esophageal mucosa is indicated for all medically fit patients with Barretts esophagus. The diagnosis of dysplastic change within this abnormal mucosa requires histological examination of the biopsies by 2 independent but experienced pathologists. Identification of high-grade dysplasia heralds the development of invasive cancer and offers the physician an opportunity to intervene. Despite extensive endoscopic sampling of the esophageal mucosa the differentiation between high-grade dysplasia and invasive adenocarcinoma is unreliable. Esophagectomy remains the treatment of choice for patients with high-grade dysplasia since adenocarcinoma of the esophagus carries such a poor prognosis.

Postcholecystectomy syndrome and its association with ampullary stenosis

Fifty-six consecutive patients returning with recurrent or persistent upper abdominal pain after cholecystectomy were studied by endoscopic retrograde cholangiopancreatography, abdominal ultrasound and morphine neostigmine test. In 44 patients, pain recurred within 6 months after cholecystectomy. Forty patients were demonstrated on endoscopic retrograde cholangiopancreatography to have moderate to marked ampullary stenosis, which occurred as an isolated abnormality in 32 patients and in association with pancreatitis in 8. Thirteen patients were found to have pancreatitis, and 6 had retained common duct stones. In five patients no definite abnormality was demonstrated. The morphine neostigmine test was positive in 16 of 17 patients with isolated ampullary stenosis and in only 1 of 8 with pancreatitis. This test may be helpful in patients who are to undergo cholecystectomy. In those with positive results, endoscopic retrograde cholangiopancreatography would help assess the size of the ampullary sphincter so that sphincteroplasty could be done at the time of cholecystectomy in appropriate patients.

Pancreas divisum and its association with choledochal sphincter stenosis: Diagnosis by endoscopic retrograde cholangiopancreatography and endoscopic biliary manometry

Choledochal sphincter stenosis was demonstrated in 37 of 90 patients with pancreas divisum. In 21 of the patients, stenosis was diagnosed during ERCP by endoscopic calibration of the choledochal sphincter, delayed drainage of contrast material from the bile duct, or a dilated common duct with or without elevation of the serum alkaline phosphatase level. In 12 patients, stenosis was diagnosed during endoscopic manometry with the demonstration of elevated basal choledochal sphincter pressures. Stenosis was initially diagnosed during surgery in four patients. Common duct diameters were normal in all patients who had not had cholecystectomy. Choledochal sphincter stenosis was confirmed in all patients who subsequently underwent sphincteroplasty. The surgical approach to patients with pancreas divisum and intractable obstructive pain should include sphincteroplasty of both the major and minor sphincters rather than the minor sphincter alone.