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.     

Limited surgical resection and jejunal interposition for early adenocarcinoma of the distal esophagus

The need for radical resection and extensive lymphadenectomy for early adenocarcinoma of the distal esophagus has recently been challenged. Limited surgical resection and endoscopic mucosal ablation techniques are increasingly proposed and used as less invasive alternatives. Available data indicate that a limited resection of the distal esophagus and esophagogastric junction with jejunal interposition is associated with less morbidity and mortality, provides similar oncologic results, and offers a better quality of life as compared with radical esophagectomy. In contrast, endoscopic ablation and mucosectomy techniques are still plagued by high tumor recurrence rates, particularly in patients with incomplete removal of the underlying Barrett's mucosa, multicentric tumors, or tumors invading into the submucosa. Attention to technical details of limited resection and jejunal interposition is, however, required to avoid complications, poor functional results, and the need for reintervention.     

Endobrachyesophagus and adenocarcinoma of the esophagus

The columnar epithelium lined esophagus is usually the result of a chronic reflux disease. In the literature one can find more and more references to a malignant transformation of this columnar epithelium. Our own observations of 14 patients with an adenocarcinoma in a columnar-lined esophagus support this suspicion. Because the adenocarcinoma of the esophagus has therapeutic consequences other than a squamous carcinoma of the esophagus, the surgery has to give attention to this malignant transformation of the columnar-lined esophagus.     

Barrett's esophagus and adenocarcinoma of the esophagus and gastroesophageal junction

Since 1985, 57 patients with adenocarcinoma of the esophagus and gastroesophageal (GE) junction have undergone surgical resection. In this group, 16 of the tumors arose in a Barrett's esophagus. There was a significant predilection toward white men above the age of 55 (15/16; 94%) in this subgroup. The mean proximal extent of abnormal columnar involvement was 5.4 cm above the gastroesophageal junction (range 2.5 to 11 cm). The mean location of the neoplasm centered in the distal esophagus 1.8 +/- 0.5 cm above the gastroesophageal junction. During the same time period, 30 patients with Barrett's esophagus were seen without associated adenocarcinoma. There were no statistical differences in the proximal extent of columnar involvement or the presence of reflux symptoms between the two groups. There were no significant differences in age, smoking history, and alcohol consumption between patients with benign or malignant Barrett's esophagus as compared to those with adenocarcinoma of the gastroesophageal junction not associated with Barrett's mucosa. The marked male predominance seen in the group with malignant Barrett's esophagus was in contrast to the benign cases (16/30; 53%) but was similar to the adenocarcinoma group, without recognized Barrett's esophagus (38/41; 93%). The mean location of the tumor in the latter was 0.9 +/- 1.2 cm above the gastroesophageal junction and was comparable to the location in the group with Barrett's adenocarcinoma. The 4-year survival rate of patients in the non-Barrett's adenocarcinoma group is approximately 30%. Of those with Barrett's adenocarcinoma, the present 4-year survival rate is 60%. The demographic and morphometric similarities between the Barrett's and non-Barrett's adenocarcinoma groups may be of primary importance in determining the true clinical prevalence of Barrett's adenocarcinoma. Our findings suggest that the sensitivity of endoscopic surveillance may be improved if biopsy specimens are concentrated within the distal 3 cm of the esophagus and the esophagogastric junction. Finally, the reason for the current difference in survival between the Barrett's and non-Barrett's adenocarcinoma groups is uncertain but may be related to endoscopic surveillance permitting earlier diagnosis and treatment.     

Barrett's esophagus and adenocarcinoma

Sixty-two cases of Barrett's esophagus were observed among 707 patients with hiatal hernia (8.7%). The symptomatology of this condition is described. An additional 10 adenocarcinomas were associated with a Barrett's esophagus--a carcinoma prevalence of 13.8%. Differences in pathology and clinical manifestations of nonmalignant and malignant cases were determined. Fifty-one patients with nonmalignant Barrett's esophagus were operated upon conservatively, while 11 underwent resection. Our results favor conservative surgery via an abdominal approach. The patients with adenocarcinomas underwent esophageal resection with six apparent cures from 6 months to 5 years. Histological study showed specialized epithelium in 8 of 10 cases and severe dysplasia in 5. Our clinical study of Barrett's esophagus shows an incidence of malignancy equal to 1 new case per 274 patient-years (1.72%). It is still not firmly established whether correction of reflux will influence the level of columnar epithelium in the esophagus, esophageal dysplasia, and the risk of malignancy.     

Improved survival with neoadjuvant therapy and resection for adenocarcinoma of the esophagus.

OBJECTIVE: This study sought to determine the impact of preoperative chemotherapy and radiation therapy (neoadjuvant therapy) followed by resection in patients with adenocarcinoma of the esophagus. SUMMARY BACKGROUND DATA: Long-term survival in patients with carcinoma of the esophagus has been poor. An increase in the incidence of adenocarcinoma of the esophagus has been reported recently. METHODS: Fifty-eight patients with biopsy-proven adenocarcinoma of the esophagus treated at this institution from January 1951 through February 1993 were studied. Since 1989, 24 patients were entered prospectively into a multimodality treatment protocol consisting of preoperative cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without etoposide, and concomitant mediastinal radiation (30 Gy). Patients were re-evaluated and offered resection. RESULTS: There were no deaths related to neoadjuvant therapy and toxicity was minimal. Before multimodality therapy was used, the operative mortality rate was 19% (3 of 16 patients). With multimodality therapy, there have been no operative deaths (0 of 23 patients). The median survival time in patients treated before multimodality therapy was 8 months and has yet to be reached for those treated with the neoadjuvant regimen (> 26 months, p < 0.0001). The actuarial survival rate at 24 months was 15% before multimodality therapy and 76% with multimodality therapy. No difference in survival was noted in neoadjuvant protocols with or without etoposide (p = 0.827). CONCLUSIONS: Multimodality therapy with preoperative chemotherapy and radiation therapy followed by resection appears to offer a survival advantage to patients with adenocarcinoma of the esophagus.     

Esophageal preservation in esophageal high-grade dysplasia and intramucosal adenocarcinoma

The management of esophageal high-grade dysplasia (HGD) and intramucosal adenocarcinoma remains controversial. Because lymph node involvement is unlikely in this setting, interest in the treatment strategies for esophageal preservation has grown. Esophageal preservation indicates any endoluminal procedure that is used in an attempt to completely eradicate disease while preserving the anatomic structure of the esophagus. The goal of esophagus-preserving approaches is to provide definitive therapy while avoiding the morbidity of esophagectomy. This article describes the patient selection and the status of currently available esophagus-preserving options, and discusses the strategy for treating HGD and intramusocal adenocarcinoma.     

Clinical significance of p53 mutations in adenocarcinoma of the esophagus and cardia

OBJECTIVE: To compare the frequency and spectrum of p53 gene mutations in adenocarcinomas of the esophagus and cardia and to compare clinical and pathologic features in patients with p53 mutant and nonmutant cancers. SUMMARY BACKGROUND DATA: The p53 gene is commonly mutated in human cancers, and a p53 mutation is reported to be present in more than 50% of esophageal adenocarcinomas. Although many studies have investigated the frequency of p53 protein overexpression in adenocarcinomas of the esophagus or esophagogastric junction, few studies have assessed the frequency and clinical significance of p53 mutations in these tumors. In particular, the prognostic importance of p53 mutation is uncertain. Adenocarcinomas of the esophagus and cardia share many epidemiologic and pathologic features, but it is controversial whether they represent the same tumor. A comparison of the frequency and spectrum of mutations in adenocarcinomas of the esophagus and cardia would test whether these tumors are also similar at the molecular level. METHODS: DNA was isolated from microdissected paraffin-embedded tumor tissues of patients who underwent esophagogastrectomy for adenocarcinoma of the esophagus (n = 19), cardia (esophagogastric junction, n = 12), or subcardia (n = 6). Exons 5 to 8 of the p53 gene were analyzed for the presence of mutations using the polymerase chain reaction with single-strand conformation polymorphism and DNA sequencing of bands showing abnormal mobility. The presence of mutation was confirmed by selective hybridization of a mutant-specific oligonucleotide to DNA isolated from the tumor. RESULTS: p53 mutations were identified in 18 of 37 (48.6%) tumors. Patients with p53 mutant tumors were significantly younger and had a significantly poorer prognosis. There was a similar prevalence of p53 mutations in adenocarcinomas of the esophagus (53%) and cardia (58%). In contrast, mutations were relatively uncommon in subcardia adenocarcinomas (one mutant tumor [17%]). The types of mutations found in the esophageal and the cardia cancers were also similar. CONCLUSIONS: Adenocarcinomas of the esophagus and cardia have a similar frequency and spectrum of p53 gene mutations, suggesting that these tumors have a common pathogenesis. Patients with mutations are younger, have signs of more advanced disease, and have a poorer prognosis than patients without mutations.     

The choice of surgical therapy in adenocarcinoma of the cardia

AIM: From 1996 the adenocarcinoma of the esophago-gastric junction (AEG) is divided into 3 types according to Siewert's classification. For AEG type I and III the surgical treatment is codified, while for type II is still controversial. The aim of our study is to understand what is the better surgical treatment for AEG type II. METHODS: From 1990 to 2002 we have performed 111 resections for adenocarcinoma of the cardia: 25 for AEG type I (all esophago-gastric resection), 39 for type II (22 esophago-gastric resection, 17 extended total gastrectomy with esophageal resection) and 47 for type III (8 esophago-gastric resection, 39 extended total gastrectomy with esophageal resection). RESULTS: The morbidity and mortality rates are 17 and 5.4%, without significant difference between the different surgical treatment (p>0.01). The 5 year survival rate is 35%. Significant prognostic factors are the staging TNM (p=0.002) and principally the presence of metastatic lymph nodes (p=0.001). For AEG type II any significant difference in survival is associated with surgical strategy, also in early stage (p>0.01). CONCLUSIONS: According to the results of our study and those of the other authors, who have showed that a 10 cm distance of the neoplasm by the gastric side and the esophageal one could assure oncologic radicality and also that metastatic lymph nodes below pylorus and near greater curvature are uncommon, we can consider esophago-gastric resection for AEG II a speedy, safe and oncologically correct surgical treatment.     

Superficial adenocarcinoma of the esophagus.

OBJECTIVE: Experience with treatment and outcome of superficial adenocarcinoma of the esophagus is limited. The purpose of this study was to evaluate the results of surgical management and identify predictors of survival. METHODS: Between September 1985 and December 1999, 122 patients underwent resection. Eighty-nine percent were men (mean age 63 +/- 10 years; range 35-83 years). Sixty (49%) patients were in endoscopic surveillance programs and 48 (39%) had the preoperative diagnosis of high-grade dysplasia. Forced expiratory volume in 1 second was less than 2 L in 12 (12%). Seventy-five (61%) patients underwent transhiatal esophagectomy. Pathologic stage was N1 in 8 (7%). Pulmonary complications necessitating reintubation (respiratory failure) occurred in 10 (8%) patients. Time-related survival models were developed for decision-making (preoperative), prognosis (operative), and hospital care (postoperative). RESULTS: Operative mortality was 2.5%. Survival at 1, 5, and 10 years was 89%, 77%, and 68%. Preoperative decision-making factors associated with ideal outcome were 1-second forced expiratory volume of more than 2 L, surveillance, preoperative diagnosis of high-grade dysplasia, and planned transhiatal esophagectomy. Prognosis was decreased in younger patients and in those with N1 disease. Postoperative respiratory failure increased mortality. CONCLUSIONS: Surgery is the treatment of choice for superficial adenocarcinoma of the esophagus. The ideal patient has a preoperative diagnosis of high-grade dysplasia found at surveillance, good pulmonary function, and undergoes a transhiatal esophagectomy. Discovery of N1 disease or development of postoperative respiratory failure reduces the benefits of surgery.     

Buried dysplasia and early adenocarcinoma arising in barrett esophagus after porfimer-photodynamic therapy

The restoration of squamous epithelium after photodynamic therapy (PDT) for Barrett esophagus (BE) and its related neoplasms has been noted. It may result in the development of buried neoplasms and/or BE underneath restored squamous epithelium which maintain their potential for malignant transformation. The purpose of this study was to evaluate the prevalence, endoscopic, and histologic characteristics and also response to further treatment of buried neoplastic epithelium developing after PDT. Fifty-two BE patients with high-grade dysplasia (n=19), intramucosal adenocarcinoma (n=28), and invasive adenocarcinoma (n=5) were treated with porfimer PDT. Buried neoplasms completely covered by squamous epithelium were seen in 1 patient before and in 13 patients after PDT. Their prevalence was 0.6% and 7.4% of pre and post-PDT biopsy levels positive for neoplasia (P=0.001). Buried neoplasms, representing the highest grade of residual neoplasm, were noted in a series of 11 post-PDT endoscopies (7.1% of 155 post-PDT endoscopies with neoplastic diagnoses) of 8 patients. Their occurrence after PDT was neither associated with the length of BE, the diffuseness of neoplasms nor the presence of buried lesions before treatment. There was no prevalent location for these lesions in relation to the original segment of BE, although the majority of both surface and buried neoplasms were found in the prior neoplastic sites. Patients with buried neoplasms responded to further treatment similarly to those with only surface neoplasms (8 of 13 vs. 17 of 24) (P=0.33). In conclusion, buried neoplasms are not uncommon after PDT. Thorough endoscopic surveillance with extensive biopsies, especially of the sites previously positive for neoplasia is important to avoid overlooking buried neoplasms that may progress.     

Palliative surgical therapy of incurable esophagus cancer by stomach bypass and endotube

Palliative treatment plays an important role in the management of esophageal carcinoma. On the whole there are more than 50% of the patients where the tumour is already inoperable at the time of diagnosis. From 1977 to 1983 we treated a total of 132 patients affected with esophageal carcinoma. It was only in 44 patients that the tumour could be resected. In 26 cases the approach was thoraco-abdominal, in 18 patients thoracotomy was unnecessary. Only palliative measures were possible for the rest. In recent years we have favoured gastric bypass or endoscopically and radiologically guided intubation for palliative treatment of esophageal carcinomas. In 17 patients a Celestin tube was placed surgically. During the last 2 years we exclusively inserted the tube endoscopically using the Nottingham introducer (n = 32). According to our results the best palliative treatment could be achieved by gastric bypass, restoring normal swallowing. Only 1 of 16 patients died postoperatively. Endoscopic insertion of an esophageal tube should be considered as a second choice treatment. A review of our mortality statistics and complication rate suggest that the Celestin tube should rather not be introduced by open surgery. Radiological and endoscopic investigation preoperatively is strictly advised. Furthermore, the indication for a Celestin tube depends on the localisation of the obstruction. In our view, the commercially available tubes (Medoc, Medinex Ltd.) supplied in 3 standard lengths are perfectly satisfying.     

胰头癌外科疗效的临床分析

目的总结胰头癌的外科疗效，探讨提高胰头癌疗效的综合治疗方法。方法回顾性总结、分析172例胰头癌病人的临床资料及外科疗效，并总结同期106例壶腹周围癌（除外胰头癌）的外科疗效。结果29例胰头癌行根治性切除，切除率为16．9％，切除术后1、3、5年存活率分别为61．5%、26．9％、3．8％，中位生存期为14．6个月；未行手术切除者中位生存期为5．7个月。61例壶腹周围癌（除外胰头癌）行根治性切除，切除率为57．5％（61／106），术后5年生存率为26．9％。结论提高胰头癌的手术切除率有望延长病人的生存期，改进、规范胰头癌术式可提高胰头癌的手术切除率和术后长期生存率。     

Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett's esophagus

The efficacy of photodynamic therapy (PDT) is currently evaluated for the treatment of superficial neoplasms arising in Barrett's esophagus (BE). An accurate assessment of this technique requires the evaluation of biopsies before and after treatment. However, despite the importance of pathology, only a limited number of studies have systematically assessed the mucosal changes after PDT. To evaluate mucosal changes after PDT, and pathologic variables that may impact on the success of this therapy, we analyzed the pre- and post-PDT biopsies of a cohort of patients treated by this modality. Thirty-three patients (mean age, 71 years) with high-grade dysplasia (HGD) and/or intramucosal carcinoma (IMC) arising in BE and followed up after PDT using Porfimer sodium form the basis of this study. In all patients, a review of all pre- and post-PDT biopsies was performed. The variables recorded included the histologic grade and architecture of neoplasms, the distribution of neoplasms, and squamous re-epithelialization. IMC and HGD coexisted in the pre-PDT biopsies of 18 patients (54.5%). IMC and HGD showed a prominent tubular proliferation in 14 patients and displayed a papillary pattern (at least partially) in 19 patients. In post-PDT, patches of specialized columnar epithelium were buried under squamous epithelium in 17 patients (51.5%), and foci of dysplasia/carcinoma covered by squamous epithelium were found in 9 patients (27.3%). HGD and/or IMC were eradicated in 17 patients (eradicated group) and persisted in 16 patients (persistent group). In the persistent group, grade and architecture were unchanged after PDT in 62.5% and 87.5% of patients, respectively. The persistent group was characterized by: 1) a more frequent papillary architecture (P < 0.05), and 2) a diffuse distribution of the neoplasms on pre-PDT biopsies (P = 0.05). Singularly, the persistent neoplastic lesions were observed in the distal esophagus (P < 0.05). A systematic histopathologic evaluation allowed us to draw attention to the fact that distally located and papillary-type neoplasia seem resistant to PDT. The higher than expected incidence of buried residual neoplastic epithelium should also be emphasized since it represents a risk for undetected growth of malignancy.     

Epidemiology and molecular biology of Barrett esophagus

Over the past three decades, there has been a marked change in the epidemiology of esophageal malignancy, with an increasing incidence of esophageal adenocarcinoma. The reasons for this are largely unknown and remain controversial, but several lifestyle risk factors have been proposed, including gastroesophageal reflux disease (GERD). It is hypothesized that chronic GERD results in acute mucosal injury, promotes cellular proliferation, and induces specialized columnar metaplasia (Barrett esophagus). Progression of Barrett esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasia-carcinoma sequence. Dysplasia is widely regarded as the precursor of invasive cancer, and high-grade dysplasia in Barrett epithelium is frequently associated with esophageal adenocarcinoma. Although several molecular alterations have been described in Barrett esophagus, it is anticipated that relatively few will prove to be clinically useful. To date, biomarkers which currently appear to predict the progression of Barrett esophagus to invasive malignancy include aneuploidy, loss of heterozygosity of 17p (implicating the p53 tumor suppressor gene), and cyclin D1 protein overexpression, and with further validation, will most likely be incorporated into routine clinical practice. It is anticipated that models incorporating objective scores of sociodemographic and lifestyle risk factors (ie, age, gender, body mass index), severity of reflux symptoms, endoscopic and histologic findings, and an assessment of a panel of biomarkers will be developed to further define subsets of patients with Barrett esophagus at increased risk for malignant progression, thereby permitting the development of more rational endoscopic surveillance and screening programs.