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  1. 1. Annals of Surgical Oncology 15(10):2903–2909 DOI: 10.1245/s10434-008-0057-1 Barrett’s Esophagus (BE) and Carcinoma in the Esophageal Stump (ES) After Esophagectomy with Gastric Pull-Up in Achalasia Patients: A Study Based on 10 Years Follow-Up Julio Rafael Mariano da Rocha, MD, Ulysses Ribeiro Jr., MD, ´ Rubens A. A. Sallum, MD, Sergio Szachnowicz, MD, and Ivan Cecconello, MD Department of Gastroenterology, University of Sao Paulo Medical School, Rua Oscar Freire, 1546 Apto 171, ˜ 05409-010 Sao Paulo, SP, Brazil ˜ Background: Subtotal esophagectomy and gastric pull-up with cervical anastomosis is the main treatment for advanced achalasia. This surgical technique has been associated to esophagitis and also Barrett’s epithelium following esophagectomy. Aim: To analyze late clinical, endoscopic, and pathologic findings in the esophageal stump (ES) mucosa after subtotal esophagectomy in patients treated for advanced chagasic achalasia. Methods: 101 patients submitted to esophagectomy and cervical gastroplasty were fol- lowed-up prospectively for a mean of 10.5 ± 8.8 years. All patients underwent clinical, endoscopic and histopathological evaluation every 2 years. Gastric acid secretion was also assessed. Results: The incidence of esophagitis in the esophageal stump (45.9% at 1 year; 71.9% at 5 years, and 70.0% at 10 years follow-up); gastritis in the transposed stomach (20.4% at 1 year, 31.0% at 5 years, and 40.0% at 10 or more years follow-up), and the occurrence of ectopic columnar metaplasia and Barrett’s Esophagus in the ES (none until 1 year; 10.9% between 1 and 5 years; 29.5% between 5 and 10 years; and 57.5% at 10 or more years follow- up), all rose over time. Gastric acid secretion returns to its preoperative values 4 years post- operatively. Esophageal stump cancer was detected in the setting of chronic esophagitis in five patients: three squamous cell carcinomas and two adenocarcinomas. Conclusion: (1) Esophagitis and Barrett’s esophagus in the esophageal stump rose over time. (2) These mucosal alterations and the development of squamous cell carcinoma and adenocarcinoma are probably due to exposure to duodenogastric reflux, and progressively higher acid output in the transposed stomach. Key Words: Achalasia—Megaesophagus—Barrett’s esophagus—Cervical esophageal stump cancer—Esophagectomy. Surgical techniques targeting the esophagogastric sents the main treatment for the advanced stage of this junction (i.e., Heller myotomy and partial fundopli- disease.1 It is a safe procedure with acceptable mor- cation) result in poor outcome in the treatment of ad- bidity and mortality, and reasonable postoperative vanced form of chagasic achalasia.1 Esophagectomy outcome for benign disease.1,2 However, complica- and gastric pull-up with cervical anastomosis repre- tions of both refluxates (gastric and duodenal-pan- creatic) in the esophageal stump have been observed Published online July 10, 2008. during long-term follow-up.3 This condition has been Address correspondence and reprint requests to: Julio Rafael associated with esophagitis and also Barrett’s epithe- Mariano da Rocha, MD; E-mail: jrmarian@terra.com.br lium following esophagectomy,4 and may serve as a Published by Springer Science+Business Media, LLC Ó 2008 The Society of model of mucosal alterations study in the esophageal Surgical Oncology, Inc. 2903
  2. 2. 2904 J. R. M. da ROCHA ET AL. mucosa. We have previously demonstrated and re- entire stomach was utilized for gastric transposition ported the presence of Barrett’s epithelium in the until January 1999, and a thin gastric tube (3.5 cm esophageal cervical stump in adult patients.4–6 width) after this time. The mean length of the cervical The pathophysiology of Barrett’s esophagus is not esophageal stump was 5 cm. Pyloroplasty was per- completely known, but it is hypothesized to result from formed in all patients. chronic reflux of acid and bile, which harm the esophageal mucosa with the development of columnar Clinical and Radiological Assessment metaplasia with potentially premalignant phenotype. Barrett’s metaplasia is common in the general popu- Before and after surgical treatment all the patients lation and the risk of progression to dysplasia and were assessed by clinical, radiological, and endoscopic cancer is 6–8 per 1,000 per year in individuals with long examinations. Postoperatively, clinical and endoscopic segment (length >3 cm), demonstrating the need to evaluation was performed at 1 year, 5 years, and 10 or better understand this entity and the mechanisms that more years after the operation. The following clinical leads to its establishment and progression.7 parameters were studied: dysphagia, regurgitation, Barrett’s esophagus following esophagectomy may heartburn, diarrhea, dumping syndrome, fasting gastric be of relevance since it is possible to estimate the residues and body mass index (BMI). duration of the reflux, as well as the amount and type of refluxates in the stump. Imaging Control Additionally, it is noteworthy that the risk of esophageal squamous cell carcinoma development is X-ray study of upper gastrointestinal tract and increased in chagasic achalasia. The incidence varies gastric emptying time was studied before and after from 1% to 8.6% and it is 33 times more frequent surgical treatment. than in the general population.8 Thus, the aim of this investigation was to analyze Endoscopic Assessment late clinical, endoscopic, and pathologic findings in the esophageal remnant mucosa after esophagectomy and Upper gastrointestinal endoscopy and also multi- gastric pull-up with cervical anastomosis in patients ple esophageal and gastric biopsies were performed in treated for advanced chagasic achalasia. We could all patients every 2 years. The presence of esophagitis delineate the effects of the continuum refluxate on the (Savary–Miller grades 1–4), metaplastic columnar esophageal stump mucosa resulting in esophagitis, mucosa, and/or Barrett’s esophagus was recorded, as development of Barrett’s epithelium and carcinoma. well as the length of any esophageal columnar mu- cosa in the esophageal stump. The presence of gas- tritis, or bile in the transposed stomach was also PATIENTS AND METHODS described. From January 1977 to December 2005, 101 pa- Gastric Acid Secretion Studies tients with advanced chagasic achalasia (severe dys- phagia, dilation greater than 7 cm, sigmoid Gastric acid secretion studies were performed on esophagus, esophageal atony, and complications of 28 patients (6 and 48 months postoperative). Secre- previous surgical therapies) were submitted to sub- tion was assessed by acid secretion test (basal secre- total esophagectomy and gastric pull-up with pylo- tion and pentagastrin-stimulated maximum acid roplasty. Fifty patients were men (49.5%), and mean output [MAO]). age was 45.6 ± 12.5 years (range 17–75 years). The patients were followed up prospectively for a mean of Pathologic Assessment 10.5 ± 8.8 years (range 2–40 years). This study was approved by the Research and Collected biopsies were stained by hematoxylin Ethics Committee of the University of Sao Paulo ˜ and eosin (H&E) and the pathological results were Medical School. reviewed by experienced pathologists. Columnar epithelium in the esophageal remnant was defined by Surgical Procedure the presence of esophageal columnar epithelium with or without specialized intestinal metaplasia. Esoph- A transhiatal subtotal esophagectomy with gastric agitis was graded histologically according to the pull-up to the cervical region was performed. The established criteria.9 Ann. Surg. Oncol. Vol. 15, No. 10, 2008
  3. 3. ESOPHAGEAL STUMP CARCINOMA AFTER ESOPHAGECTOMY 2905 FIG. 2. Stomach in mediastinal position with elongated shape and good passage of the contrast to the duodenum. FIG. 1. Barium study of the upper gastrointestinal tract, showing a TABLE 2. Endoscopic findings after esophagectomy and sigmoid esophagus with stasis of the contrast. gastric pull-up in 101 advanced chagasic achalasia patients 1 Year 5 Years 5–10 >10 Years TABLE 1. Symptoms after esophagectomy and gastric (%) (%) Years (%) (%) pull-up in 101 advanced chagasic achalasia patients Normal 53.6 41.6 23.0 29.9 Esophagitis 45.9 71.9 — 70.0 1 Year (%) 5 Years (%) >10 Years (%) Gastritis 20.4 31.1 — 40.0 Columnar epithelium 0 10.9 29.5 57.5 Dysphagia 21.8 9.2 6.8 Regurgitation 54.5 64.6 77.3 Heartburn 41.6 56.9 65.9 Diarrhea 30.3 10.1 0 Dumping syndrome 10.1 1 0 Weight gain 79.6 86.3 87.1 1-5 Ys 5-10 Ys 10-15 Ys 100 90 80 70 Statistical Analysis 60 Nonparametric data were analyzed using chi- 50 40 squared and Fisher’s exact test for contingency 30 tables, and the Wilcoxon’s test and Mann–Whitney 20 U-test were used to compare pre- and postoperative 10 findings. For parametric data, an unpaired t-test was 0 used for comparison of differences between means in Mild Moderate Severe the groups. Statistical significance was endorsed by a FIG. 3. Grade of gastritis in 101 advanced chagasic achalasia pa- P-value of less than 0.05. tients. Ann. Surg. Oncol. Vol. 15, No. 10, 2008
  4. 4. 2906 J. R. M. da ROCHA ET AL. TABLE 3. Gastric acid secretion studies on 28 advanced chagasic achalasia patients who had undergone esophagectomy with gastric pull-up Gastric acid BS BS 6 months BS 4 years MAO MAO 6 months MAO 4 years output preoperative postoperative postoperative P value* preoperative postoperative postoperative P value* Mean 1.23 1.02 1.43 0.035 16.25 8.59 14.44 0.043 Median 1.2 0.84 1.23 15 7.08 13.25 Standard deviation 0.801 1.035 0.96 8.00 6.89 8.31 Minimum 0.3 0.4 0.7 1.48 0 4.36 Maximum 3.9 3.83 4.48 37.44 29.44 35.4 * Wilcoxon nonparametric test; BS, basal secretion; MAO, pentagastrin-stimulated maximum acid output. 18 RESULTS 16 14 The indication for esophagectomy in this study 12 population was advanced chagasic achalasia, as 10 exemplified by Fig. 1. 8 Late clinical symptoms after esophagectomy and 6 gastric pull-up are shown in Table 1. 4 Complete postoperative resolution of the dyspha- 2 0 gic syndrome was obtained in all 44 patients fol- Pre-operative Post-operative Post-operative lowed-up for 10 or more years (from 10 to 40 years) 6 months 48 months except in three patients (6.82%) who still complained BS MAO of mild dysphagia. Significant postoperative body weight increase was also noted, particularly in those FIG. 4. Gastric acid secretion returns to normal preoperative patients who exhibited preoperative larger body values after 4 years of surgical treatment (BS = basal/MAO); 28 patients. weight deficit. Postoperative diarrhea occurred frequently up to 1 year (30.3%), but it was of mild degree from the third month on. There was a rapid resolution of this conditions (Table 3). Acidity recovery can be seen in symptom after 1 year of postoperative follow-up and Fig. 4. it was attributed to vagotomy and pyloroplasty. H2 blockers and, more recently, proton pump Based on postoperative imaging studies, the inhibitors were administered in all patients in order to stomach assumed an elongated shape with longitu- prevent peptic ulcer formation at the esophageal dinal mucosal folds in mediastinal position (Fig. 2). remnant or transposed gastric tube. Nevertheless, the Late endoscopic findings are demonstrated in use of such medications did not avoid the occurrence Table 2. The prevalence of esophagitis increased after of Barrett’s esophagus, however, there was a ten- the first postoperative year from 45.92% to 71.88% dency to delay the appearance and the size of after 5 years, and 70.0% after 10 or more years columnar epithelium. In cases of more severe biliar postoperatively. Thus, there was a steady rate of reflux (12.9%), bile binding agents, including cole- esophagitis after 5 postoperative years (Table 2). stiramine were utilized sporadically. There was also a significant increase in the grade of Thirty-six patients had developed columnar meta- esophagitis severity over time. plasia during follow-up (Fig. 5). Among those, Diffuse gastritis in the transposed stomach oc- intestinal metaplasia in the esophageal remnant was curred at increased rate after 5 years of follow-up evident in 23 patients during follow-up (Fig. 6). The (Fig. 3). The presence of bile at the esophageal rem- relationship between the presence of columnar nant in these patients was evidenced by endoscopic metaplasia and intestinal metaplasia can be observed examinations. in Fig. 7. Columnar metaplasia was detected in the The severity of clinical symptoms did not relate to esophageal remnant in 11/101 (10.9%) of the patients the worsening of esophagitis over time. followed-up between 1 and 5 years after surgery; 18/ Gastric acid secretion studies revealed the acidity 61 (29.5%) of the patients between 5 and 10 years capacity of the gastric epithelium to return to pre- after surgery, and 23/40 (57.5%) followed-up 10 or operative conditions, both in basal and stimulated more years after the operation. Ann. Surg. Oncol. Vol. 15, No. 10, 2008
  5. 5. ESOPHAGEAL STUMP CARCINOMA AFTER ESOPHAGECTOMY 2907 FIG. 5. Metaplastic columnar mucosa in the esophageal stump. Red salmon color mucosa may be seen. 30 28,5 26,2 25 21,6 20 15 10,1 10 26.2 5 0 0 1 0 < 12 18-60 60-120 > 120 months months months months Columnar Metaplasia Intestinal metaplasia FIG. 7. Relationship between the columnar epithelium and the presence of intestinal metaplasia. Considering the 61 patients followed-up for 5 or more years, 46 cases (75.4%) presented esophagitis and three of those developed squamous cells carci- noma in the esophageal stump. One of these cases was a patient with in situ squamous cell carcinoma bordering Barrett’s epithelium, detected 15 years after the operation. The others were diagnosed in advanced stage (inoperable), 22 and 34 years after operation. These latter two patients had been lost to FIG. 6. Histological appearance of the Barrett’s epithelium with follow-up for 8 or more years and returned for the presence of specialized cells (intestinal metaplasia) (9400). evaluation due to severe dysphagia caused by an advanced carcinoma in the esophageal stump. Barrett’s esophagus was always preceded by Two of the patients with intestinal metaplasia in esophagitis and was first observed at 1 year and the esophageal remnant (2/23), had developed high- 6 months postoperatively. grade dysplasia, 13 and 19 years after the operation. There was a highly significant association between The close follow-up of these two patients have per- the development of Barrett’s epithelium and the time mitted the diagnosis of in situ adenocarcinoma, 1 and interval post esophagectomy. On the other hand, 3 years after the initial dysplasia identification, there was no statistically significant association be- respectively (Fig. 8). They were treated successfully tween esophagitis and age, sex, and body mass index by endoscopic mucosal resection and are still being (data not shown). followed up now. Ann. Surg. Oncol. Vol. 15, No. 10, 2008
  6. 6. 2908 J. R. M. da ROCHA ET AL. time. (2) Increasing incidence of diffuse gastritis of the transposed stomach, starting at 5 years follow-up and more, significantly associated with esophagitis in the esophageal remnant. (3) Development of squa- mous cell carcinoma in three cases in the esophageal remnant. (4) Development of in situ adenocarcinoma in the esophageal remnant in two cases, treated suc- cessfully by endoscopic resection. The pathogenesis concerning these mucosal alter- ations, could be explained by the following factors: (1) resection of gastroesophageal transition; (2) recovery of gastric acid secretion 4 years after sur- gery; (c) higher serum gastrin levels, and simulta- neous biliopancreatic and acid-peptic reflux to the transposed stomach and esophageal remnant.4–6,14–19 In patients that underwent esophagectomy mainly for cancer, O’ Riordan et al.18 reported a 50% inci- FIG. 8. In situ adenocarcinoma in the Barrett’s epithelium of the esophageal stump (9400). dence of columnar metaplasia above the anastomosis in 48 postesophagectomy patients, with a median follow-up of 26 months (range 12–67 months). Spe- DISCUSSION cialized intestinal metaplasia was detected in 54% of those patients. The prevalence of columnar meta- Esophagectomy and gastric pull-up with cervical plasia did not relate to the magnitude of acid or bile anastomosis is currently the procedure of choice in reflux, to preoperative neoadjuvant therapies, or to the management of advanced chagasic achalasia.1,2 the original tumor histology. However, the duration Nonetheless, this type of reconstruction after esoph- of the reflux was the most significant parameter, with ageal resection causes modifications in anatomy and increasing prevalence over time. The authors con- physiology on the upper gastrointestinal tract.10–12 cluded that the duration of acid and bile reflux, ra- Gastric and duodenal refluxate have been docu- ther than the volume of reflux, underlies the mented in 60–80% of esophageal resected patients.12 development of metaplasia. In 1991 and 1992 we reported the presence of Bar- In the present investigation, we did not find any rett’s epithelium developed in the esophageal stump Barrett’s esophagus until 1 year and 6 months of of chagasic achalasia patients.4–6 Resection or dis- follow-up; at 2 years of follow-up we could detect ruption of natural antireflux mechanisms, esopha- only 1/101 patient (0.98%) with Barrett ‘s esophagus; geal-gastric direct anastomosis, pyloroplasty, however the incidence of Barrett’s rose to 11.2% in impairment of gastric motility, recovery of acid 5 years and 57.5% in 10 or more years of follow-up. secretion from gastric conduit, and impaired motility The Barrett’s incidence may be lower in this investi- of esophageal remnant all contribute to esophageal gation because chagasic achalasia patients have stump mucosal damage.10–13 decreased preoperative gastric acid secretion.20 We sought in this study to evaluate the impact of It is well known that bile salts injure both the long-term continuous refluxate in the esophageal gastric and the esophageal mucosa and their harmful stump mucosa. effects are strengthened by the action of gastric Barrett’s esophagus might occur in the esophageal secretion.3,11–13 The latter mechanism seems to be remnant in the cases of chronic esophagitis of long- responsible for esophagitis in the esophageal rem- standing duration.4–6,14–19 This hypothesis was con- nant, similar to what occurs in patients with reflux firmed with the endoscopic diagnosis and histologic esophagitis and Barrett’s esophagus with the organ in proof of the existence of Barrett’s esophagus in the the normal position. remaining cervical esophagus. Barrett’s esophagus in the esophageal cervical Long-term follow-up has revealed complications stump begins with columnar type epithelium, between that, if adequately treated, do not influence the clin- 18 and 60 months and generally changes to intestinal ical outcome, but lead to a number of concerns: (1) pattern between 5 and 10 years. The length of Bar- Increasing incidence of esophagitis and Barrett’s rett’s esophagus varies between 1 and 4 cm and often esophagus in the esophageal cervical stump over appears in a fingerlike form. Barrett’s esophagus is Ann. Surg. Oncol. Vol. 15, No. 10, 2008
  7. 7. ESOPHAGEAL STUMP CARCINOMA AFTER ESOPHAGECTOMY 2909 always preceded by esophagitis in the esophageal REFERENCES cervical stump, lasting for at least 1 year before the appearance of Barrett’s esophagus. It is important to 1. Pinotti HW, Cecconello I, da Rocha JM, et al. Resection for achalasia of the esophagus. Hepatogastroenterol 1991; 38:470– emphasize that the clinical symptoms showed no 3. marked change despite worsening of esophagitis and/ 2. Pinotti HW, Habr-Gama A, Cecconello I, et al. The surgical or the diagnosis of Barrett’s esophagus in the treatment of megaesophagus and megacolon. Dig Dis 1993; 11:206–15. esophageal cervical stump over time, in any patient. 3. Aly A, Jamieson GG. Reflux after oesophagectomy. Br J Surg This factor is relevant, because it demonstrates the 2004; 91:137–41. necessity of yearly endoscopic examination in these 4. Rocha JRM, Cecconello I, Sallum RAA, et al. Barrett’s esophagus in the esophageal stump after subtotal esophagec- patients, even when they are asymptomatic. tomy with cervical esophagogastroplasty. Arq Bras Cir Dig These data show that areas of esophagitis were 1991; 6:20–2. being gradually replaced by Barrett’s esophagus over 5. Rocha JRM, Cecconello I, Zilberstein B, et al. Barrett’s esophagus in the esophageal stump after subtotal esophagec- time, mainly after 5 years postoperatively. It is also tomy with cervical esophagogastroplasty. Rev Hosp Clin Fac important to highlight that Barrett’s esophagus was Med Sao Paulo 1992; 47:69–70. always documented endoscopically and microscopi- 6. Rocha JRM, Cecconello I, Ribeiro U Jr, et al. Reflux esoph- agitis and ectopic columnar epithelium (Barrett’s Esophagus) cally. in esophageal stump after cervical gastroplasty. Am J Gastro- The complications previously diagnosed and trea- enterol 2005; 100:499. ted in our follow-up (esophagitis, Barrett’s esopha- 7. Thomas T, Abrams KR, De Caestecker JS, et al. Meta anal- ysis: Cancer risk in Barrett’s oesophagus. Aliment Pharmacol gus, and alkaline reflux gastritis) were of low Ther 2007; 26:1465–77. incidence until 5 years of postoperative follow-up.4–6 8. Ribeiro U Jr, Posner MC, Safatle-Ribeiro AV, et al. Risk Nevertheless, at 10 and more years after operation, factors for squamous cell carcinoma of the oesophagus. Br J Surg 1996; 83:1174–85; Review. we observed a marked increase in the incidence and 9. Ismail-Beigi F, Horton PF, Pope CE 2nd. Histological conse- degree of esophagitis, Barrett’s esophagus, and dif- quences of gastroesophageal reflux in man. Gastroenterology fuse gastritis. Considering these findings, this opera- 1970; 58:163–74. 10. Holscher AH, Voit H, Buttermann G, et al. Function of the ¨ tive procedure needs to be re-evaluated in young intrathoracic stomach as esophageal replacement. World J patients with benign diseases. 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Regeneration of cardiac type mu- The incidence and degree of esophagitis and Bar- cosa and acquisition of Barrett mucosa after esophagogas- rett’s esophagus in the esophageal stump rose over trostomy. Gastroenterology 1997; 72:669–75. 16. Oberg S, Johansson J, Wenner J, et al. Metaplastic columnar time. These mucosal alterations and the development mucosa in the cervical esophagus after esophagectomy. Ann of squamous cell carcinoma (15–34 years postopera- Surg 2002; 235:338–45. tively) and adenocarcinoma (14–22 years postopera- 17. Dresner SM, Griffin SM, Wayman J, et al. Human model of duodenogastroesophageal reflux in development of Barrett’s tively) are probably due to greater exposure to metaplasia. Br J Surg 2003; 90:1120–8. duodenogastroesophageal reflux, and progressively 18. O’Riordan JM, Tucker ON, Byrne PJ, et al. Factors influ- higher acid output in the transposed stomach. encing the development of Barrett´s epithelium in the esopha- geal remnant postesophagectomy. Am J Gastroenterol 2004; 99:205–11. 19. Lord RV, Wickramasinghe K, Johansson JJ, et al. Cardiac mucosa in the remnant esophagus after esophagectomy is an ACKNOWLEDGEMENTS acquired epithelium with Barrett’s-like features. Surgery 2004; The authors are indebted to Professor Mitchell C. 136:633–40. 20. Troncon LE, Barbosa AJ, Romanello LM, et al. Antral gastrin Posner, University of Chicago, for revising the cell population in patients with chagasic megaesophagus and manuscript and for his helpful suggestions. megacolon. Braz J Med Biol Res 1994; 27:645–53. Ann. Surg. Oncol. Vol. 15, No. 10, 2008
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