Annals of Surgical Oncology 9:222-227 (2002)
© 2002 Society of Surgical Oncology
High-Grade Dysplasia Within Barrett’s Esophagus: Controversies Regarding Clinical Opinions and Approaches
Mazin F. Al-kasspooles, MD,
Hank C. Hill, MD,
Hector R. Nava, MD,
Judy L. Smith, MD,
Harold O. Douglass, MD and
John F. Gibbs, MD
From Roswell Park Cancer Institute, Department of Surgical Oncology, State University of New York at Buffalo, Buffalo, New York.
Correspondence: Address correspondence and reprint requests to: John F. Gibbs, MD, Associate Professor of Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263; Fax: 716-845-3434; E-mail: john.gibbs{at}roswellpark.org
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ABSTRACT
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Abstract: Barrett’s esophagus with high-grade dysplasia is a well-known risk factor for the development of esophageal adenocarcinoma, which has become the predominant form of esophageal cancer in the United States. This review addresses four major fundamental issues that shape our treatment decisions regarding high-grade dysplasia within Barrett’s esophagus: (1) the poorly defined natural history of high-grade dysplasia in its progression to adenocarcinoma, (2) the potentially high morbidity and mortality of esophageal resection for high-grade dysplasia, (3) the difficulty in detecting cancer among dysplastic cells during endoscopy, and (4) the controversial role of endoscopic mucosal ablative therapy for high-grade dysplasia. Until there are more accurate surveillance methods, better biochemical or molecular markers in predicting cancerous progression, or more effective minimally invasive methods of treatment, esophagogastrectomy must be considered the standard means of managing patients with Barrett’s esophagus and high-grade dysplasia. Regular rigorous systematic surveillance and endoscopic mucosal ablation are alternative treatment options that are available but should be used only under strict conditions. The decision to proceed in a certain direction is quite complex and challenging and ideally requires the feedback of patients who are properly educated about the controversies surrounding this disease.
Key Words: Barrett’s esophagus • High-grade dysplasia • Esophageal adenocarcinoma • Esophagogastrectomy • Photodynamic therapy
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INTRODUCTION
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Recent developments in the detection and treatment of adenocarcinoma of the esophagus are becoming more important as its incidence continues to increase in the United States and other industrialized countries.1–4 Modern surgical series have shown a change in the pattern of esophageal cancer in the United States, from predominantly squamous cell carcinoma seen before the 1970s to adenocarcinoma5–8 in the 1990s.
Barrett’s esophagus, the most frequently associated risk factor for esophageal adenocarcinoma, increases the chance of developing adenocarcinoma by at least 40 times when compared with the general population.9–13 Furthermore, high-grade dysplasia in the presence of Barrett’s esophagus dramatically increases this risk, the degree to which is still unclear. Current investigational efforts have focused on Barrett’s esophagus with high-grade dysplasia and the detection and eradication of its malignant transformation to esophageal adenocarcinoma.
There are three main options in the treatment of high-grade dysplasia: (1) partial or total esophagectomy with partial gastrectomy, (2) continued regularly scheduled surveillance with multiple biopsies until the development of early cancer, and (3) minimally invasive endoscopic mucosal ablative therapy, such as photodynamic therapy. Until recently, the only acceptable treatment was esophagogastrectomy. However, continued improvement in the detection of adenocarcinoma among dysplastic cells has opened avenues for changing treatment paradigms. Furthermore, less invasive methods of treatment when compared with the traditional esophagectomy continue to evolve into more effective and available options.
At least four major fundamental issues shape our clinical approach to high-grade dysplasia in Barrett’s esophagus: (1) the poorly defined natural history of high-grade dysplasia in its progression to adenocarcinoma, (2) the potentially high morbidity and mortality of esophageal resection for high-grade dysplasia, (3) the difficulty in detecting cancer among dysplastic cells, and (4) the controversial role of endoscopic mucosal ablative therapy for high-grade dysplasia. This study reviews some of the current literature on these topics and discusses their effect on the increasingly controversial and challenging treatment of patients with Barrett’s esophagus and high-grade dysplasia.
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NATURAL HISTORY OF HIGH-GRADE DYSPLASIA
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The true natural history of high-grade dysplasia transformation to invasive cancer is unknown.14–18 Table 1 summarizes recent studies analyzing the incidence of adenocarcinoma formation for patients diagnosed with high-grade dysplasia who subsequently underwent regular surveillance. The incidence of cancer formation varied from 19% to 59%. Reid et al.18 reported a large review of 322 patients observed prospectively over a 15-year period. Seventy-five patients had a baseline tissue diagnosis of high-grade dysplasia, and 59% of them developed adenocarcinoma over a 5-year period. However, 27 patients (31%) who did not have a baseline diagnosis of high-grade dysplasia subsequently developed cancer during surveillance over 5 years. Only 3.8% of those with a diagnosis of metaplasia alone, low-grade dysplasia, or indefinite changes progressed to cancer over the same time interval. This study also presented preliminary evidence suggesting that a subset of patients with Barrett’s esophagus and favorable characteristics on flow cytometry might be at a lower risk of developing adenocarcinoma.
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MORTALITY FROM ESOPHAGECTOMY
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Consideration of morbidity and mortality after esophagectomy is an important factor when deciding the best treatment option for patients with high-grade dysplasia within Barrett’s esophagus. The current standard of care is either partial or total esophagogastrectomy. Obviously, in patients who are poor surgical candidates, such an option may not even be appropriate. However, in those who can tolerate a major operation, proceeding to an esophagectomy is not a clear-cut decision. As less aggressive options become available, the physician must weigh the risks and benefits associated with surgical versus nonsurgical modalities with the patient.
Patti et al.19 and Begg et al.20 reported surgical mortalities in high-volume institutions compared with those with a low volume (fewer than 30 esophagogastrectomies per year). Approximately 80% of esophagectomies are performed in low-volume institutions.19 Low-volume centers were noted to have mortality rates of approximately 17%, compared with approximately 4% in high-volume centers.
Furthermore, the morbidity associated with an esophagectomy is not trivial. Besides the functional changes that come with replacing the esophagus with another conduit (most commonly the stomach), the complication rate is high. Edwards et al.21 collectively reviewed data on the complications of esophagectomies in 68 patients from 8 studies spanning from 1985 to 1995. Overall, serious complications occurred in 47% of patients. The mortality rate was 6%. Major morbidity included anastomotic stricture (13%), anastomotic leak (thoracic or cervical; 7%), dumping syndrome (4%), delayed gastric emptying (3%), gastric outlet obstruction (3%), recurrent aspiration (3%), wound infection (1%), colon necrosis (1%), pyloric channel ulcer (1%), pulmonary embolus (1%), and chylothorax (1%). Four of these patients required additional major surgical procedures. It is those aforementioned outcomes that have led physicians to seek less invasive yet effective methods of managing high-grade dysplasia within Barrett’s esophagus.
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INCIDENCE OF CANCER AFTER ESOPHAGECTOMY FOR HIGH-GRADE DYSPLASIA
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Despite the relatively high morbidity and mortality of esophageal resection, the presence of endoscopically missed esophageal cancers in resected specimens of patients with high-grade dysplasia makes clinicians wary of recommending less aggressive treatment. Table 2 summarizes results from some of the recent larger retrospective studies presenting data on the incidence of unsuspected cancer in resected esophageal specimens for high-grade dysplasia.22–24 These studies have demonstrated the incidence of missed esophageal cancer to be anywhere22–37 from 0% to 73%. One of the larger series, by Heitmiller et al., 24 studied 30 consecutive esophagectomy specimens for high-grade dysplasia and found an overall cancer incidence of 43%. Even more alarming was that 5 (17%) of the 30 specimens contained stage II or III cancers, which are associated with a much poorer 5-year survival. Therefore, it is this uncertainty—the possibility of missing the true histological diagnosis—that has led most clinicians to conclude that the gold standard treatment for high-grade dysplasia in Barrett’s esophagus is esophagogastrectomy. Such a statement must be considered true until one or more of the following exist: (1) more sensitive surveillance methods for detecting small cancers to safely observe patients, (2) less invasive methods of treating high-grade dysplasia that can also effectively eradicate early cancers within the dysplastic cells, or (3) better markers, either biochemical or molecular, to predict the progression to and invasion by cancer.
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TABLE 2. Incidence and stage of incidental esophageal cancer found in patients with Barrett’s esophagus after esophagectomy for high-grade dysplasia22–24
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BIOMARKERS
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With the advent of more conservative treatment modalities for Barrett’s esophagus with high-grade dysplasia, distinguishing those patients who will progress to invasive cancer with potential biomarkers has become more important in selecting therapy and monitoring its success. This is currently an area of intensive research and includes the study of cell proliferative factors, cyclo-oxygenase-2, growth factors and oncogenes, secretory factors, cell cycle regulating factors, adhesion molecules, and aneuploidy and chromosomal and structural abnormalities.38 The relevance of the changes in the vast majority of these potential biomarkers is unclear. Most need to be evaluated more carefully in prospective longitudinal studies. At present, abnormal ploidy status, p16 and p53 gene abnormalities, and allelic losses are the most extensively documented biological changes,38 although their relative significance and prognostic importance have yet to be determined.
Finding clinically relevant biomarkers would clearly be beneficial. It could potentially eliminate a major conflicting factor in assessing the malignant potential of Barrett’s esophagus: the existence of considerable inter- and intraobserver variation regarding the histopathological classification of dysplasia.39 Furthermore, if found to be more prognostically significant than current histopathological classifications, applying such biological information for screening patients with nondysplastic Barrett’s esophagus, who have a lower incidence of malignant transformation, might prove to be more cost-effective. However, until such biochemical or molecular markers become more reliable and informative, clinicians who wish to observe such patients must continue to use the more traditional approach of frequent endoscopic surveillance, segmental four-quadrant biopsies, and the usual pathologic evaluation.
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RELIABILITY OF ENDOSCOPIC SURVEILLANCE
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The reliability of endoscopic surveillance once again comes from investigating esophagectomy specimens after various forms of surveillance (Table 3).30,32,34–37 In general, patients with Barrett’s esophagus and high-grade dysplasia are endoscoped with segmental four-quadrant biopsies every 3 to 6 months once the tissue diagnosis is made. The technique of endoscopic esophageal surveillance of high-grade dysplasia is important. When random biopsies are performed, the percentage of missed cancer30 is nearly 50%. A more vigorous system of endoscopic surveillance, such as four-quadrant biopsies at 2-cm intervals and biopsies of all visual lesions, has resulted in improved malignancy detection.32,34–36 In a study by Levine et al.,32 a vigorous systematic endoscopic biopsy protocol that used jumbo forceps successfully identified 7 patients with high-grade dysplasia and 19 with adenocarcinoma among 28 patients. Two patients with a preoperative diagnosis of adenocarcinoma had only high-grade dysplasia in the resected specimens. The authors of this prospective study cited several reasons for their improved accuracy when compared with the other studies. Most notably, the other reports were retrospective and lacked information on any preoperative endoscopic observations and biopsy protocols. The authors’ conversion to a four-quadrant 1-cm-interval endoscopic biopsy protocol with a large-channel endoscope, jumbo biopsy forceps, and a turn-and-suction biopsy technique to evaluate all patients with high-grade dysplasia successfully identified 48 adenocarcinomas in 45 patients.37 It is interesting to note that only 39% of patients who had endoscopic biopsy cancer diagnoses had cancer detected in the esophagectomy specimens, suggesting a therapeutic benefit to this method as well. In the same study, the authors hypothetically modeled an endoscopic protocol in which four-quadrant biopsies were taken every 2 cm, and they found that the 2-cm model would have detected only 71% of the cancers.
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ENDOSCOPIC ABLATION
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An attractive alternative to esophagectomy for high-grade dysplasia would be a less invasive yet effective treatment such as endoscopic mucosal ablation. Endoscopic mucosal ablation can be divided into three main techniques that are being used today: thermal forms, mucosal resection, and photodynamic therapy.
The thermal therapies include multipolar coagulation, heat probe therapy, argon plasma coagulation, argon laser therapy, potassium-titanyl-phosphate–yttrium-aluminum-garnet laser therapy, and neodymium:yttrium-aluminum-garnet laser therapy.40 Of these, the most commonly used devices are multipolar coagulation and heat probe therapy. The depth of penetration that these devices can achieve is variable. In general, thermal ablation methods are used to treat only nondysplastic Barrett’s mucosa or Barrett’s mucosa with low-grade dysplasia. Unfortunately, thermal ablation techniques seem to be associated with a significant incidence of residual intestinal metaplasia underlying the new squamous epithelium.40 After healing, the presence of potential premalignant islands covered by superficial layers of normal-appearing mucosa may give a false sense of security after treatment. Moreover, there is a trend toward the redevelopment of Barrett’s mucosa as time passes after the initial therapy.
Endoscopic mucosal resection is a relatively new procedure used to treat high-grade dysplasia within Barrett’s esophagus. It was originally developed in Japan to treat early adenocarcinomas of the stomach and squamous cell carcinomas of the esophagus.41 The technique involves injecting the submucosal space with a mixture of epinephrine and saline, thus elevating the targeted area. This so-called pseudopolyp is then removed with a polypectomy snare. Two recent studies assessed its use in patients with high-grade dysplasia.42,43 Nijhawan and Wang43 treated 25 patients by endoscopic mucosal resection. These patients were suspected of having either early cancers or high-grade dysplasia. Forty-four percent of the patients had their diagnoses altered after the resection. Although the follow-up period is too short to comment on the effectiveness of this technique as treatment for either high-grade dysplasia or early adenocarcinoma, it seems useful in confirming or establishing a diagnosis of cancer versus high-grade dysplasia. It is important to note that from a technical standpoint, a lesion must be identified to raise a pseudopolyp; therefore, the technique would be difficult or impossible to perform in patients with diffuse, long-segment Barrett’s esophagus with high-grade dysplasia when the actual area of high-grade dysplasia is unclear.
Photodynamic therapy is currently considered the most attractive minimally invasive therapeutic modality. However, only a few centers in the United States offer this mode of treatment. Photodynamic therapy first involves the systemic injection of a photosensitizer (Photofrin, QLT PhotoTherapeutics Inc, Vancouver, BC, Canada).44 Twenty-four to 48 hours later, the drug, which has been preferentially concentrated in a specific tissue (in this case, Barrett’s esophagus with high-grade dysplasia), is then activated by a light of proper wavelength and power to produce singlet oxygen radicals and subsequent cell death. Devitalized tissue is then washed out 48 hours after this treatment. When compared with thermal forms of treatment, photodynamic therapy is easier to perform and may be associated with fewer major side effects, such as stricture formation and perforation.45 A common side effect is phototoxicity (sunburn); this occurs in approximately 20% to 30% of patients.
In the largest series in the literature, Overholt et al.46 treated 100 consecutive patients with Barrett’s esophagus or T1 or T2 cancers. In this study, there were 78 men and 22 women. The follow-up period ranged from 4 to 84 months, with a mean of 19 months. Ages of patients varied from 33 to 83 years, with a mean age of 66 years. All underwent photodynamic therapy, requiring one to three treatments, followed by maintenance omeprazole. Most patients (73%) needed only one treatment. All patients had follow-up endoscopy, with debridement of devitalized tissue 48 hours later. Endoscopy and biopsies were performed at 1 week and then 3, 6, and 12 months. Identification of residual Barrett’s mucosa was aided with Lugol’s solution staining of squamous tissues. Esophageal repair took approximately 2 to 3 months. First there was granulation of tissue followed by epithelialization. Eighty-three percent of patients also required additional laser treatment 3 to 6 months later for residual Barrett’s esophagus. Seventy-three percent of these patients had high-grade dysplasia. Of these 73 patients, 66 (90%) either cleared their dysplasia or were downstaged to low-grade dysplasia. Forty-three of 100 patients had no residual Barrett’s esophagus at the final examination. Another impressive finding was that the cancer was eliminated in 10 (77%) of 13 patients with T1 lesions. Subsquamous glandular mucosa was found in only 2 of 100 patients. Esophageal strictures occurred in 34% of patients, but all eventually responded to dilation.
Currently, photodynamic therapy is still considered investigational in the treatment of high-grade dysplasia within Barrett’s esophagus. Our institution is presently evaluating the use of a new photosensitizer, 2-(1-hexyloxyethyl)-2-devinylpyropheophorbide-a. Preliminary results suggest that it is equally as effective as Photofrin but is associated with less phototoxicity (H. R. Nava, unpublished data, August 2001). A randomized prospective study comparing photodynamic therapy with other acceptable forms of treatment of high-grade dysplasia is necessary. An international randomized prospective study is under way for the treatment of high-grade dysplasia. In this study, patients are randomized onto one of two groups: photodynamic therapy and omeprazole versus surveillance and omeprazole.
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CONCLUSIONS
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Until there are more accurate, less invasive, and less costly surveillance methods, predictive biochemical or molecular markers, or proven effective minimally invasive treatment modalities, esophagogastrectomy must remain the gold standard in the treatment of patients with Barrett’s esophagus and high-grade dysplasia. A decision to proceed in any other direction requires diligence and perseverance. If performed regularly, rigorously, and systematically, surveillance is a reasonable way to safely observe patients with high-grade dysplasia within Barrett’s esophagus, selecting those patients with malignant transformation for surgical resection. However, surveillance carries the risk of missing early cancers, with the chance that they may progress to higher stages. Endoscopic mucosal ablation, especially in the form of photodynamic therapy, is another attractive, potentially less morbid treatment option that is promising yet still investigational. Patients must be educated about the disease and its surrounding controversies. Ultimately, their feedback may play a crucial role in the decision process. For instance, a young individual with Barrett’s esophagus and high-grade dysplasia may elect esophageal resection rather than lifelong surveillance and the associated risk of delayed cancer diagnosis. However, if the patient strongly desires to retain his or her esophagus, then endoscopic ablation may be a reasonable option.
Received for publication August 6, 2001.
Accepted for publication December 5, 2001.
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TOP
ABSTRACT
INTRODUCTION
