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Department of Cardiothoracic Surgery, The University of Southern California, Los Angeles, California
* Address correspondence to Dr DeMeester, Department of Cardiothoracic Surgery, The University of Southern California, Los Angeles, CA 90033 (Email: sdemeester{at}surgery.usc.edu).
Presented at the Minimally Invasive Thoracic Surgery Summit, New York, NY, June 8–9, 2007.
Adenocarcinoma of the esophagus has the fastest rising incidence of any cancer in the United States and develops as a consequence of chronic gastroesophageal reflux disease [1]. Barrett’s esophagus is the precursor lesion from which adenocarcinoma develops, and surveillance programs have led to the detection of high-grade dysplasia and early-stage adenocarcinoma in an increasing number of patients. High-grade dysplasia and intramucosal adenocarcinoma, although potentially lethal, are both curable lesions in most patients [2–4]; however, cure is dependent on complete removal of the neoplastic tissue. Until recently, this was reliably accomplished only with esophagectomy, but new technologies have been developed that allow endoscopic mucosal resection and ablation with preservation of the esophagus. The aim of this article is to explore current options for the management of Barrett’s high-grade dysplasia and intramucosal adenocarcinoma.
The first fundamental issue in the treatment of high-grade dysplasia and intramucosal adenocarcinoma is to cure the patient of the disease. Patients with only high-grade dysplasia are uniformly cured with esophagectomy because invasive cancer has not developed and will not develop after removal of all of the Barrett’s mucosa. However, a number of surgical series have demonstrated that despite extensive pre-resection biopsies, in 30% to 50% of patients thought only to have high-grade dysplasia, the resected specimen will in fact have an invasive cancer [5, 6]. In the absence of a visible ulcer or nodule on endoscopy, these occult adenocarcinomas have always been limited to the mucosa in our experience [5].
In contrast, if a lesion of any sort is seen endoscopically within the columnar-lined portion of the esophagus, that lesion is at high risk to be a cancer. Further, any visible lesion that on biopsy shows adenocarcinoma cannot be assumed to be limited to the mucosa, regardless of the size or appearance of the lesion. Even very small lesions may penetrate into the submucosa, thus the endoscopic appearance of the lesion cannot be used to determine the T stage.
It was hoped that endoscopic ultrasound imaging would allow accurate determination of intramucosal vs submucosal tumor invasion, but even high-frequency 20-MHz probes have not provided acceptable differentiation of these lesions [7]. The only method currently able to accurately determine the depth of invasion of a small visible lesion is endoscopic mucosal resection. This technique enables endoscopic excision of lesions sized up to 1.5 cm along with the adjacent mucosa and submucosa down to the muscularis propria and thereby allows the precise depth of invasion of the tumor to be pathologically determined. We have previously shown the accuracy of endoscopic resection as a staging procedure for early esophageal cancer, and we use it routinely for patients with a visible lesion within the Barrett’s mucosa [8].
The critical importance of accurately determining the depth of invasion of a small esophageal adenocarcinoma is the direct link between depth of invasion and the likelihood of lymph node metastases. Although intramucosal tumors rarely metastasize to lymph nodes, submucosal invasion is associated with lymph node metastases in 30% to 50% of patients [9, 10]. As a consequence, patients with submucosal invasion require not only resection of the diseased mucosa but also a lymph node dissection at the time of esophagectomy. Endoscopic or other therapies that do not address potential lymph node metastases are not appropriate in patients with submucosal or deeper tumor invasion because of the high risk of at least one lymph node metastasis. In contrast, the likelihood of nodal metastases is low (<5%) in patients with a tumor confined to the mucosa [2, 9].
We recently assessed the importance of a lymph node dissection for intramucosal adenocarcinoma and reviewed our experience with three types of esophagectomy—transthoracic en bloc, transhiatal, and vagal sparing—in 85 patients. The importance of this comparison is that although each operation removes the diseased esophagus, the lymphadenectomy that accompanies each approach is substantially different. In particular, no formal node dissection accompanies a vagal-sparing esophagectomy, and typically, none or only a few nodes are removed. Our results confirmed that cancer-related survival is excellent in these patients—95% at 5 years—and is independent of the type of resection and extent of lymphadenectomy [11]. This study confirmed that a lymphadenectomy is not necessary in patients with tumors confined to the mucosa and opens the door for endoscopic therapies for high-grade dysplasia or intramucosal adenocarcinoma.
Another critical issue regarding therapy for high-grade dysplasia and intramucosal adenocarcinoma is procedure-related morbidity and mortality. Traditional esophagectomy is associated with a vagotomy and pyloroplasty, and in addition to the loss of gastric volume that accompanies a gastric pull-up, some patients have problems postoperatively with dumping and diarrhea. Further, although mortality for an esophagectomy in patients with these early lesions in many centers is 1% or less, surgeon and center experience have been shown to be important to achieve these results [12, 13].
These concerns have been widely expressed within the medical community and have prompted exploration of less invasive means of treating patients with high-grade dysplasia and intramucosal adenocarcinoma. However, surgery, as all of medicine, continues to advance, and much of the data demonstrating poor outcome with mortality rates of 5% to 15% for an esophagectomy come from a prior era when patients typically presented with locally advanced tumors and had significant weight loss.
Recent series of esophagectomy in patients with high-grade dysplasia or early-stage esophageal adenocarcinoma present a completely different picture, and many centers now offer a minimally invasive procedure with or without vagal preservation to further minimize the effect of the operation and reduce long-term morbidity [14–16]. In appropriate patients with high-grade dysplasia or intramucosal cancer, I favor a laparoscopic vagal-sparing esophagectomy. This operation preserves the vagal innervation to the pylorus and the remaining gastrointestinal tract and is associated with reduced morbidity, including avoidance of postvagotomy dumping and diarrhea, while maintaining the advantages of complete removal of the diseased esophagus and the Barrett’s epithelium.
The vagal-sparing esophagectomy was first described by Akiyama and colleagues [17] in Japan, and we subsequently adopted it as a means to remove the diseased esophagus in situations where a lymph node dissection was not necessary. The concept of vagal preservation with the potential for reduced morbidity by avoidance of postvagotomy dumping and diarrhea and maintenance of normal gastric volume was attractive for benign conditions and for patients with Barrett’s high-grade dysplasia or intramucosal adenocarcinoma. We subsequently verified that vagal preservation is realistic with an esophagectomy using the stripping technique and have demonstrated a reduced incidence of dumping and diarrhea as well as less postoperative weight loss with a vagal-sparing compared with a standard esophagectomy [18].
In a recent update of our experience with vagal-sparing esophagectomy for Barrett’s dysplasia and intramucosal adenocarcinoma, we again confirmed that preservation of the vagal nerves is feasible during esophagectomy and is associated with reduced morbidity. We specifically showed that infectious, respiratory, and anastomotic complications were all reduced in patients who had a vagal-sparing esophagectomy compared with a transhiatal esophagectomy [11]. Given the equivalent oncologic result, the reduction in morbidity with the vagal-sparing technique should make this the esophagectomy of choice for patients that do not require a lymphadenectomy.
The morbidity and mortality associated with an esophagectomy has also prompted increasing use of endoscopic therapies to treat high-grade dysplasia and in some cases intramucosal adenocarcinoma. Early procedures used photodynamic therapy, but this treatment is associated with a disturbing incidence of esophageal strictures, residual or buried Barrett’s dysplasia, and cancer development, and has been abandoned at many centers [19, 20]. Instead, new techniques including radiofrequency energy (Halo 360 and Halo 90 systems, BARRX Medical Inc, Sunnyvale, CA) appear to ablate Barrett’s dysplasia more effectively and with less risk. In contrast with photodynamic therapy, radiofrequency ablation has not been associated with the development of strictures in the esophagus nor the presence of buried Barrett’s glands [21]. However, the long-term freedom from recurrent Barrett’s dysplasia or adenocarcinoma after radiofrequency ablation remains to be determined.
Endoscopic mucosal resection is also being used to treat Barrett’s dysplasia and early adenocarcinoma. Ell and colleagues [22] recently reported excellent long-term survival of 98% at 5 years using endoscopic mucosal resection alone to treat highly selected patients with early esophageal adenocarcinoma. These patients were carefully screened to have only well-differentiated intramucosal tumors without evidence of lymphovascular invasion. Most patients had short-segment Barrett’s esophagus, and despite relatively short-term follow-up, the rate of metachronous tumor development was high at 11%. This rate will undoubtedly increase with longer follow-up and would also almost certainly be higher if more patients with long-segment Barrett’s esophagus had been part of the study. As a consequence, it is clear that patients with one focus of adenocarcinoma are at high risk for the development of another cancer if any Barrett’s dysplasia is left, and ablation of residual Barrett’s dysplasia should accompany endoscopic therapy for early esophageal adenocarcinoma.
The combination of endoscopic mucosal resection for a nodule or intramucosal cancer and ablation of any residual flat Barrett’s dysplasia is being evaluated at a number of centers for the treatment of patients with high-grade dysplasia or intramucosal adenocarcinoma. The enthusiasm for this approach is partly fueled by the excellent 5-year survival reported by Ell and colleagues [22]. However, several important considerations are worth reviewing before this approach is accepted as the standard of care for these patients.
First, only intramucosal tumors with very favorable histologic features were treated endoscopically, and extension of the criteria to include less favorable tumors (moderate or poor differentiation, lymphovascular invasion) may not produce similar results.
Second, although Ell and colleagues used the traditional 5-year cancer survival mark to evaluate the success of endoscopic therapy, they ignored the reality that many of these patients have a lot of years ahead of them, and cure from one or even several Barrett’s cancers may not be the end of the story. Barrett’s esophagus develops as a consequence of gastroesophageal reflux, and elimination of Barrett’s without concomitant elimination of the reflux in these patients may be similar to pulling weeds out of a garden and expecting them never to grow again.
Third, Ell and colleagues treated patients with pH-guided proton pump inhibitor therapy after the endoscopic resection, but the efficacy of this for prevention of recurrence of Barrett’s dysplasia is unproven. Not surprisingly, many of these patients required large doses of proton pump inhibitors to be adequately acid-suppressed. This speaks to the severity of reflux disease in these patients, and as impedance studies have demonstrated, adequate acid suppression does not equate to elimination of alkaline or weak acid reflux events [23, 24]. One has to suspect that life-long maintenance of this degree of intensive medical therapy is unlikely in most patients. Instead, antireflux surgery may be a more effective therapy and needs to be evaluated in this setting.
A final important issue is long-term quality of life in patients treated for high-grade dysplasia or intramucosal adenocarcinoma because they are likely to be cured of their disease. Quality of life in patients with Barrett’s dysplasia is variable, but many have severe reflux disease with the accompanying problems of regurgitation, nocturnal aspiration, and dysphagia. Gastroenterologists treating these patients often assume that any esophageal-preserving therapy is going to be better than the alternative therapy of an esophagectomy. However, I believe that this is a flawed concept, and avoidance of an esophagectomy at all cost by the medical community is unfounded.
The often-quoted mortality of 5% to 15% for an esophagectomy is not supported by current series in patients with high-grade dysplasia or intramucosal adenocarcinoma [11, 12, 25]. Instead, esophagectomy has been the standard of care for both high-grade dysplasia and early adenocarcinoma, and the excellent results should not be quickly dismissed. I propose that in light of the recent advances in endoscopic procedures that allow esophageal preservation and the new, less invasive and potentially less morbid surgical techniques to remove the esophagus, it is time that we alter our approach to the evaluation of patients with high-grade dysplasia and early esophageal adenocarcinoma.
In addition to determining the stage of the cancer and assessing the overall health of the patient, we should also evaluate the pathophysiologic abnormalities associated with the patient’s reflux disease. In particular, an assessment should be made of the function of the stomach, lower esophageal sphincter, and esophageal body as well as the size of the hiatal hernia, length of Barrett’s, and presence and severity of reflux symptoms. Esophageal preservation might be the preferred therapy in a patient with few symptoms, a small hiatal hernia, normal esophageal body function, and a short segment of Barrett’s esophagus with a low-risk intramucosal carcinoma.
In contrast, patients who are poor candidates for esophageal preservation are those who present with high-grade dysplasia or an intramucosal adenocarcinoma and have severe reflux symptoms or dysphagia, long-segment Barrett’s esophagus with a large, fixed hiatal hernia, and poor esophageal body motility. These patients are best treated with a vagal-sparing esophagectomy, because in my opinion, esophageal preservation only makes sense if the esophagus is worth preserving as determined by a physiologic evaluation. Further, the long-term efficacy of endoscopic mucosal resection and ablation of Barrett’s dysplasia in the setting of severe reflux pathophysiology is unproven, and Barrett’s dysplasia seems likely to recur over time in these patients. Vagal-sparing esophagectomy is also indicated for patients with multiple lesions within long-segment Barrett’s dysplasia or lesions with positive lateral margins after endoscopic mucosal resection.
Thus, the decision to treat high-grade dysplasia or intramucosal cancer endoscopically or with an esophagectomy takes into consideration not just the stage of the lesion but also the pathophysiology of the esophagus and the severity of the underlying reflux disease. In this way, outcomes can be optimized not only for the dysplasia or cancer but also for the patient’s reflux disease and long-term quality of life.
In conclusion, advances in both the surgical and endoscopic therapies for Barrett’s high-grade dysplasia and intramucosal adenocarcinoma offer options for these patients that were unavailable even just a few years ago. To advocate one therapy as always being the best is to take a step backward in an age of increasing individualization of therapy. Rather than a "one size fits all" approach, our understanding of tumor biology and esophageal physiology in conjunction with patient preference should be used to determine the best therapy for an individual patient, preserving the esophagus in those where it makes sense and removing the esophagus when necessary to adequately address the cancer as well as the background pathophysiology that precipitated the development of the malignancy. This approach will require a balanced and updated understanding of the advantages and disadvantages of both endoscopic and surgical therapies by the surgeons and gastroenterologist who treat these patients. Undoubtedly, future studies that assess quality of life and freedom from recurrent Barrett’s dysplasia and cancer will help guide the selection of therapy for an individual patient who presents with high-grade dysplasia or intramucosal adenocarcinoma of the esophagus.
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  H. Pohl, B. Sirovich, and H. G. Welch Esophageal Adenocarcinoma Incidence: Are We Reaching the Peak? Cancer Epidemiol. Biomarkers Prev., June 1, 2010; 19(6): 1468 - 1470. [Abstract] [Full Text] [PDF]
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 J. A. Ajani Gastroesophageal Cancers: Progress and Problems J Natl Compr Canc Netw, October 1, 2008; 6(9): 813 - 814. [Abstract] [PDF]
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