p27 and Barrett's esophagus: a review*.

The rising prevalence of Barrett's esophagus and Barrett's associated adenocarcinoma in the Western world has stimulated increasing interest in this disease. This has resulted in a plethora of articles concerning its molecular biology, but the tumor suppressor gene, p27, has received little attention. In this article, we review the literature concerning the role of p27 in Barrett's esophagus and its malignant transformation, and we evaluate its possible role as an important clinical biomarker, as well as potential chemopreventive clinical agents aimed at substituting its antitumoral activity.

Malignant transformation of the esophageal mucosa is enhanced in p27 knockout mice.

OBJECTIVE: In a previous study, we showed that experimentally induced gastroduodenal-esophageal reflux in mice treated with a carcinogen can result in Barrett esophagus and Barrett-associated adenocarcinoma. Since we have shown that most Barrett-associated adenocarcinomas in human beings have lost the tumor suppressor gene p27, we sought to determine whether cancer would be more likely to develop in p27 knockout mice than in p27 heterozygous or p27 wild type mice. METHODS: Three groups of mice were treated by esophagojejunostomy resulting in gastroduodenal-esophageal reflux and by a carcinogen (N -methyl-N -benzylnitrosamine): group I (50 wild type), group II (45 p27 heterozygous), and group III (50 p27 knockout). The mice were killed 18 to 20 weeks after operation and studied macroscopically and histopathologically. RESULTS: Barrett esophagus developed in 7 (14%) mice in group I, 4 (8.9%) mice in group II, and 13 (26%) mice in group III. Cancers developed in 30 (60%) mice in group I, 31 (68%) mice in group II, and 43 (86%) mice in group III. Ten percent of the cancers in group I were adenocarcinomas, as were 16.1% in group II, and 23.3% in group III. The difference between rates of Barrett esophagus in groups I and II compared with group III was statistically significant (P =.035), as was true of the cancer rates (P =.006). The percentage of cancers that were adenocarcinomas was highest in group III, but not significantly different from groups I and II. CONCLUSIONS: This experimental mouse model of Barrett esophagus and Barrett- associated adenocarcinoma is similar to what occurs in human beings and may be useful in developing methods to inhibit malignant transformation of Barrett esophagus.

Barrett's esophagus and associated adenocarcinoma in a mouse surgical model.

BACKGROUND: The development of Barrett's esophagus (BE) and Barrett's associated adenocarcinoma (BAA) in the rat after experimental inducement of esophageal reflux of gastric, bile, and pancreatic juice has been reported by others. The purpose of this study was to determine whether similar results could be demonstrated in the mouse model. MATERIALS AND METHODS: One hundred eight Swiss-Webster mice were used in this study and were divided into three groups: Group I, 37 mice with esophagojejunostomy; Group II, 39 mice with esophagojejunostomy and the carcinogen N-methyl-N-benzylnitrosamine (MBN); and Group III, 32 mice with MBN alone. The animals were sacrificed after 19 weeks. Macroscopic and histopathologic examinations were performed. RESULTS: One hundred mice survived and were available for pathologic study. Macroscopic evidence suggested esophagitis in 60.6% of mice in Group I, 62.8% of mice in Group II, and 9% of mice in Group III and suggested tumor in 3% of mice in Group I, 51.4% of mice in Group II, and 53.1% of mice in Group III. Histopathologic analysis disclosed BE in 42.4% of mice in Group I, 20% of mice in Group II, and 12.5% of mice in Group III. Cancer was present in 12.2% of mice in Group I, 54.3% of mice in Group II, and 46.9% of mice in Group III. Adenocarcinoma with or without squamous cell carcinoma was present in 6.1% of mice in Group I, 37.1% of mice in Group II, and 12.5% of mice in Group III. CONCLUSIONS: Esophagojejunostomy plus MBN in the mouse results in BE, BAA, or both in 57.1% of animals, consistent with findings in the rat model after similar interventions.

Standard resection for cancer of the esophagus and cardia.

Standard techniques of esophagectomy are the most common operations currently performed for cancer of the esophagus and cardia. A review of the recent literature discloses a wide difference in findings and postoperative results. A review of the findings and results in 505 operations for cancer of the esophagus on one surgical service from January 1, 1970 to January 1, 1997 reveals a resectability rate of 90%, a hospital mortality rate of 3.3%, a postoperative complication rate of 33.9%, and an adjusted actuarial 5-year survival rate of 24. 7%. As yet, neither the use of neoadjuvant therapy nor extended techniques or resection, even when applied only in patients with low-grade lesions, have provided convincing evidence of their superiority over standard resection techniques.

Cancer of the esophagus and cardia: does age influence treatment selection and surgical outcomes?

BACKGROUND: Some physicians believe that an aggressive surgical approach for the management of cancer of the esophagus and cardia is unwise in elderly patients because of allegedly higher rates of mortality and morbidity and lower rates of survival than those associated with younger patients. We have long advocated an aggressive surgical approach regardless of the patient's age and have reviewed our experience to determine whether age was a factor influencing treatment and outcomes. STUDY DESIGN: From January 1, 1970 to January 1, 1997, 505 patients with cancer of the esophagus or cardia underwent operations by one surgical team using standard surgical techniques. One hundred forty-seven patients (29.1%) were 70 years of age or older and 358 patients (70.9%) were under 70 years of age. Their records and clinicopathologic features were reviewed and compared. RESULTS: The two groups were similar regarding the location of tumors. Tumor cell types were similar except for adenocarcinomas in Barrett's esophagus, which were less common in the older group (15.6% versus 24%; p=0.046). Surgical procedures were similar, as were the rates of resectability and the percentages of R0 resections. The hospital mortality rate was higher in the elderly patients but not significantly so, and the rates of major and minor complications combined were comparable. The differences in postresection pathologic staging were not significant. Satisfactory palliation of dysphagia was comparable between the groups, as were actuarial 5-year survival rates (24.1% of the elderly patients versus 22.4% of the younger patients). CONCLUSIONS: Age should not be a limiting factor in using an aggressive surgical approach for the management of cancer of the esophagus or cardia in patients aged 70 years or older. Such an approach can be performed as safely as in younger patients, with comparable rates of palliation and survival.

Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer.

OBJECTIVE: Endoscopic surveillance of Barrett's esophagus is commonly practiced to detect malignancy in an early and curable stage. However, the cost-effectiveness of this practice has been questioned. To clarify this issue, we undertook a cost analysis of endoscopic surveillance to detect adenocarcinoma in Barrett's esophagus compared with mammography used to detect occult carcinoma of the breast, a widely accepted cancer surveillance technique. METHODS: The rate of esophageal adenocarcinoma detected by endoscopic surveillance was calculated for Duluth Clinic patients with Barrett's esophagus seen from 1980 to 1995 and compared with published rates. The rate of occult breast cancer detection was calculated for all women undergoing surveillance mammography at the Duluth Clinic for the year 1994 and compared with published rates. Costs for screening studies and therapy for cancer treatment for both cancers were calculated based on clinical results and assumptions regarding outcomes derived from published reports, and the costs were compared. RESULTS: Endoscopic surveillance of 149 patients with benign Barrett's esophagus was performed for a total of 510 patient-yr, during which time seven patients developed adenocarcinoma, an incidence of one case per 73 patient-yr of follow-up. Occult breast cancer was detected in 50 of 12,537 mammograms, a detection rate of 0.4%. The incidences in both cases were comparable to published figures. The costs of detecting a case of adenocarcinoma in Barrett's esophagus and occult breast cancer were $37,928 and $54,513, respectively, and those for treatment resulting in cure were $83,340 and $83,292. Cost per life-yr saved was $4,151 for adenocarcinoma in Barrett's esophagus and $57,926 for breast cancer. CONCLUSION: Endoscopic surveillance of patients with Barrett's esophagus compares favorably with the common practice of surveillance mammography to detect early breast cancer, and should therefore be considered to be as cost-effective as surveillance mammography.

Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma.

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell division cycle. It is expressed at the highest levels during the quiescent (G0) and prereplicative (G1) phases, and its degradation is required for entry into the S phase. Because lack of p27 is associated with aggressive behavior in a variety of tumors of epithelial and lymphoid origin, we used immunohistochemistry and in situ hybridization to evaluate the expression of p27 in metaplastic and dysplastic Barrett's epithelium and to assess its prognostic significance in Barrett's associated adenocarcinoma (BAA) of the esophagus. In metaplastic Barrett's epithelium, p27 protein and mRNA were restricted to the superficial third of glands in all cases and extended to the lower third in 4 cases. In contrast, expression of p27 message and protein was both increased and full-thickness, in the 23 cases with high-grade dysplasia adjacent to BAA and in carcinoma in situ. Although all invasive carcinomas had elevated levels of p27 mRNA, 45 (83%) of 54 invasive carcinomas had low p27 protein levels (<50% positive tumor cells). Low p27 protein correlated with higher histological grade (P < 0.0001), depth of invasion (P = 0.0120), presence of lymph node metastasis (P = 0.05), and survival (P = 0.0197). In addition to the nuclear staining, cytoplasmic staining of p27 was noted in 11 of 23 (48%) of cases of dysplasia and in 14 of 54 (26%) adenocarcinomas and confirmed, in a subset of cases, by subcellular fractionation of protein lysates obtained from fresh tumor tissues. Cytoplasmic localization of p27 was also associated with decreased survival (P = 0.0239). Loss of p27 conferred poor prognosis independently of proliferative index, as assessed by Ki-67 (MIB-1) immunostaining, which was not significantly different in survivors versus nonsurvivors. These results show that: (a) distribution of p27 message and protein parallel one another in metaplastic and dysplastic Barrett's epithelium, suggesting transcriptional regulation of the gene in the nonneoplastic setting; (b) p27 is inactivated in the majority of BAA as a result of either post-transcriptional modification or altered subcellular localization; and (c) loss of the cell cycle inhibitor p27 is associated with parameters of aggressive behavior and unfavorable outcome in BAA.

Long esophagomyotomy for diffuse esophageal spasm and related disorders: an historical overview.

In summary, the role of long esophagomyotomy for patients with DES and related motor disorders remains controversial. The results are poorer than those following esophagomyotomy for achalasia, and long-term postoperative follow-up of these patients is essential because early good results may be misleading. Two methods are considered equally effective in avoiding postmyotomy reflux: a 'short,' 'floppy' wrap of the LES, or a sphincter-sparing myotomy when manometry indicates normal functioning of the sphincter. Rarely is a total thoracic esophagomyotomy indicated. Because persistent or recurrent pain is the main cause of poor results, some patients may eventually require total esophagectomy and cervical esophagogastrostomy.

Proposal for improved staging criteria for carcinoma of the esophagus and cardia.

OBJECTIVE: Current staging for carcinoma of the esophagus and cardia remains imprecise. In an effort to improve on presently accepted staging criteria, new and improved criteria were sought. METHODS: A total of 408 specimens resected for carcinoma of the esophagus or cardia between January 1, 1970, and January 1, 1994, were available for analysis. Pathology reports were reviewed, and available histologic slides were examined microscopically. When necessary, paraffin blocks of excised specimens were recut for further pathologic evaluation. On the basis of these findings, tumors were staged according to the criteria of American Joint Committee on Cancer (AJCC). New criteria were established based on the WNM concept and staged accordingly. Survival rates based on these sets of criteria were calculated for each stage, and results were compared. RESULTS: Because our previous studies had shown no advantage provided by the revised AJCC criteria compared with those originally proposed, we modified the WNM system by eliminating the subdivisions of Stage II, reducing the T categories by 1, T3 and T4 having shown no survival differences, and increasing the N categories by 1, depending on the number of nodes involved, e.g. NO = no positive nodes; N1 = 1-4 positive nodes, and N2-5 or more positive nodes. The resulting staging system and 5-year survival rates obtained thereby are as follows: Stage O (TO, is, 1 NO), 88.2%; Stage I (T1N1, T2NO), 50.3%; Stage II (T2N1, T3N0) 22.5%; Stage III (T3N1, any T N2), 10.7%; and Stage IV (M1) 0%. CONCLUSIONS: A new staging scheme for carcinoma of the esophagus and cardia is proposed that provides better prognostic stratification of patients than existing ones.

Failure after esophagomyotomy for esophageal motor disorders. Causes, prevention, and management.

An accurate preoperative diagnosis of an esophageal motor disorder, including its location (the LES, the body of the esophagus, or both), is essential before proceeding with esophagomyotomy. The operative procedure should be performed with careful attention to certain technical details to ensure completeness of the myotomy, to prevent later healing of the myotomy, and to avoid radical cardiomyotomy that might facilitate the subsequent development of GER. Potential hazards are associated with performing a 360 degrees antireflux procedure in the presence of an aperistaltic esophagus. Early operation before the development of megaesophagus is recommended. The excellent results achieved by resection coupled with antrectomy and Roux-en-Y diversion suggest its wider application to patients with one or more previous failed myotomies, particularly patients with stricture and megaesophagus. Long-term surveillance of patients with achalasia is mandatory in view of the known risk of late development of squamous cell carcinoma.

Pseudoachalasia: a report of two cases with comments on possible causes and diagnosis.

Pseudoachalasia is a rare entity with symptoms and radiographic and esophageal manometric findings that may mimic primary achalasia. Two such cases are presented, one of which was associated with gastric carcinoma and the other with carcinoma of the lung.

Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria.

OBJECTIVE: A review of findings and results after standard resection for carcinoma of the esophagus and cardia without neoadjuvant therapy was done to provide a basis for comparison with current reports of radical resection and neoadjuvant therapy. METHODS: A 24-year experience on one surgical service with 454 operations for carcinoma of the esophagus and cardia was reviewed. A comparison of findings and results in three consecutive 8-year intervals was analyzed, and new staging criteria were developed and compared with those currently favored by the American Joint Committee on Cancer. RESULTS: From January 1, 1970, to January 1, 1994, 454 patients with carcinoma of the esophagus or cardia underwent operation, of whom 408 (90%) had esophagogastrectomy with a 30-day mortality rate of 2.5% and an additional hospital mortality rate of 1.2%. Of the 121 complications (30.7%), 71 (18%) were major and 50 (12.7%) were minor. Cardiovascular complications predominated. The overall 5-year survival was 24.7%, with a 33.7% survival after complete resections in the most recent interval under study. Palliation of dysphagia was achieved in nearly 80% of patients who survived the operation. During the three intervals under review, resectability, mortality, and complication rates remained constant. The percentages of left thoracotomies and transhiatal resections increased, and there was a decrease in thoracoabdominal incisions. The percentages of patients with Barrett's esophagus and stage 0 and I tumors increased. The percentage of complete resections (R0) increased, whereas that for resections with residual microscopic tumor (R1) decreased, and there was no change in the percentage of patients with residual gross tumor after resection (R2). Modified WNM staging criteria are proposed that provide better prognostic stratification of the disease than those currently favored by The American Joint Committee on Cancer. CONCLUSIONS: Standard esophagogastrectomy is applicable in 90% of patients with operable carcinoma of the esophagus or cardia, with consistently low mortality and morbidity rates and satisfactory palliation of dysphagia. The 5-year survival (24.7% overall) remains suboptimal, but the current figure for complete resections (33.7%) is encouraging. There is a need for revision of the current American Joint Committee on Cancer staging criteria.

Esophageal achalasia and adenocarcinoma in Barrett's esophagus: a report of two cases and a review of the literature.

Two cases of a rare combination of conditions, achalasia and adenocarcinoma in Barrett's esophagus are reported. Cancer developed 26 years after the onset of gastroesophageal reflux in one and 30 years after esophagomyotomy in the other. Twenty-one cases of Barrett's esophagus and achalasia have now been reported; adenocarcinoma developed in six patients. Only one has survived more than five years after treatment. Long-term surveillance of patients with achalasia is recommended.

Objective assessment of gastroesophageal reflux after short esophagomyotomy for achalasia with the use of manometry and pH monitoring.

The role of an antireflux procedure as an adjunct to esophagomyotomy for achalasia remains a subject of controversy. Little objective documentation exists of this operation's effect on sphincteric competence and the degree of postoperative gastroesophageal reflux. This report of esophageal manometry and 24-hour pH monitoring on 14 patients with esophageal achalasia whom we had previously treated by a short esophagomyotomy without an antireflux procedure provides such documentation. Esophagomyotomy reduced lower esophageal sphincter pressure by 12% to 71% (mean 41%) from a preoperative mean of 26.7 mm Hg to a postoperative mean of 14.6 mm Hg. The number of postoperative episodes of acid reflux per patient in 24 hours was fewer than 29 (normal < 49) in 13 patients, with a median of 12 episodes for the entire group. Esophageal acid exposure, measured as percentage of total time with pH less than 4.0 (normal < 4.5%), was below 4.5% in 10 patients, six of whom had values less than 1%. Among the four patients with values greater than 4.5%, only one had a temporal correlation of symptoms with an episode of acid reflux. Multivariate analysis showed that esophageal acid exposure time correlated only with the level of residual lower esophageal sphincter pressure during the relaxation phase of deglutition. A pressure less than 8 mm Hg was predictive of normal acid contact time (p < 0.001). Mean lower esophageal sphincter pressure, percent reduction in lower esophageal sphincter amplitude, postoperative vector volume, and length of the lower esophageal sphincter did not significantly correlate with amount of esophageal acid exposure. We conclude that a short esophagomyotomy without an antireflux procedure results in a competent lower esophageal sphincter in most patients. Increased esophageal acid exposure, when it occurs, is due to slow clearance of esophageal acid from relatively few reflux episodes and is more likely to occur when there is a high residual pressure during deglutition after myotomy. These findings suggest that the addition of an antireflux procedure to a short esophagomyotomy would not be expected to improve clinical results.

Current status of cricopharyngeal myotomy for cervical esophageal dysphagia.

OBJECTIVE: We have reviewed our experience with cricopharyngeal myotomy for a variety of conditions causing cervical esophageal dysphagia to clarify its indications and results as well as to determine what, if any, ancillary procedures are indicated. METHODS: Eighty-three patients underwent cricopharyngeal myotomy between January 1970 and January 1995, 54 of whom had a pharyngoesophageal diverticulum. The remainder suffered from a variety of motor disorders of the upper esophageal sphincter. Clinical follow-up evaluation was obtained in 71 of the 83 patients (86%). RESULTS: Good or excellent results were obtained in 87% of the patients with pharyngoesophageal diverticula, 100% after myotomy plus diverticulectomy, 87% after myotomy plus diverticulopexy and 67% after myotomy alone. Of patients with hypertensive upper esophageal sphincter, 100% had good or excellent results, whereas only 60% with nonspecific esophageal motor disorders were so evaluated. None of the patients with bulbar palsy or miscellaneous conditions had good or excellent results. CONCLUSIONS: We recommend cricopharyngeal myotomy for all patients with a pharyngoesophageal diverticulum coupled with diverticulopexy for the majority, reserving diverticulectomy for those with recurrent pouches or extremely large pouches (6-8 cm in diameter). Good or excellent results can be expected after myotomy in patients with a hypertensive upper esophageal sphincter. Myotomy is rarely indicated for patients with dysphagia secondary to bulbar palsy. The role of cricopharyngeal myotomy for patients with non-specific esophageal motor disorders remains controversial.

Reoperation after failed antireflex surgery. Review of 101 cases.

Between January 1970 and July 1994, 101 patients underwent reoperation for a failed antireflux procedure. These patients had previously had 160 upper gastrointestinal tract operations, usually a Nissen fundoplication or one of its modifications (87). The chief reason for failure of the original antireflux procedure was faulty surgical technique (65). An incorrect diagnosis accounted for most of the remaining failure (22). Of patients who had follow-up studies, 80% were improved by reoperation, which consisted of takedown or refashioning of the original wrap in the majority of patients (63). A more radical approach is justified after two failed reoperations. Our current preference is for vagotomy, antrectomy, and Roux-en-Y diversion coupled, when indicated, with resection of the esophagogastric junctional area.

Achalasia and squamous cell carcinoma of the esophagus: analysis of 241 patients.

Achalasia of the esophagus is presumed by many to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. There is disagreement, however, as to the precise risk of malignant degeneration and there is no consensus as to either the need for close surveillance of achalasia patients or the surveillance technique that should be employed. A review of the available literature on the subject has disclosed a wide range of reported cancer risks in achalasia patients, from zero to 33 times that of the normal population. Cancers, when discovered, are often unresectable and the median survival when they are resectable is low. A personal experience with 241 achalasia patients treated during the past quarter of a century disclosed that 9 had carcinoma, for a prevalence of 3.7%. Carcinoma developed in 3 of these 9 while they were under our observation. This translates into one cancer per 1,138 patient-years of follow-up, an incidence of 88 per 100,000 population, and a risk 14.5 times that of the age-adjusted and sex-adjusted general population. Because of the low postresection survival rate if treatment is delayed until carcinoma of the esophagus becomes symptomatic, closer surveillance of achalasia patients is recommended than has been the case. Because it seems unlikely that close endoscopic surveillance will prove to be cost-effective, periodic (every 2 to 3 years) blind brush biopsy warrants further study as a means of surveillance.

Vagotomy, antrectomy, and Roux-en-Y diversion for complex reoperative gastroesophageal reflux disease.

OBJECTIVE: Failure of conventional surgical therapy for treatment of patients with gastroesophageal reflux disease (GERD) taxes the ingenuity of the esophageal surgeon. This study defines the role of vagotomy, antrectomy, and Roux-en-Y diversion coupled, when necessary, with resection of the esophagogastric junction as an alternative to other surgical procedures currently employed for these complicated cases. SUMMARY BACKGROUND DATA: Currently, the operation in question rarely is performed in the United States. Other procedures, such as interposition of short or long segments of intestine and total esophagectomy with gastric pull-up, are preferred. However, surgeons from Scandinavia, Great Britain, and Europe have published widely on the subject, some even preferring its use as a primary procedure in GERD. METHODS: This report reviews the indications and results of the operation in 36 patients who underwent operation between January 1970 and January 1994. Follow-up evaluation was available for review in 33 patients observed from 1 to 20 years postoperatively (average, 6 2/3 years). Of these patients, 32 had undergone 66 previous operative procedures on the distal esophagus and stomach ranging from 1 to 6 per patient. There were no hospital deaths, but complications developed in nine patients (25%); only half of these complications were major. Of patients available for follow-up, 85% were improved by the operation, 24 of the 33 having excellent or good results. CONCLUSIONS: The operation of vagotomy, antrectomy, and Roux-en-Y diversion, embodying the principles of acid suppression and alkaline diversion, has proved to be a successful alternative to other operative procedures currently favored in the United States for the treatment of the complex reoperative patient with GERD.