Nondysplastic Barrett Esophagus
It is our practice to put every patient with Barrett esophagus on proton pump inhibitor (PPI) therapy indefinitely. There are data demonstrating that patients on PPIs have a lower rate of progression to dysplasia and adenocarcinoma than patients not taking PPIs. In one study, the cumulative incidence of dysplasia was significantly lower among patients who received PPI after Barrett esophagus diagnosis than in those who received no therapy or histamine receptor antagonists. Furthermore, among those on PPIs, a longer duration of use was associated with a less frequent occurrence of dysplasia. Every patient diagnosed with Barrett esophagus should be treated with a PPI whether or not symptomatic GERD is present.
At present there are not enough data to support ablative therapies for nondysplastic Barrett esophagus. In the future, biomarkers may provide better risk stratification justifying endoscopic ablation of nondysplastic Barrett esophagus in high-risk patients. However, given that the vast majority of patients with Barrett esophagus do not progress to adenocarcinoma, the use of these methods for this indication cannot currently be recommended.
Data suggest that, despite long-term antisecretory therapy, long segments of Barrett esophagus do not regress. Normalization of SIM has been described in cases of "ultra-short" Barrett esophagus and short-segment Barrett esophagus. Patients with long segments of Barrett esophagus should be informed that their Barrett esophagus will not regress and that they should remain on PPI therapy indefinitely and undergo surveillance endoscopies.
Cyclooxygenase (COX)-2 inhibitors (both aspirin and nonsteroidal anti-inflammatory drugs [NSAIDs]) are being studied as chemoprevention of Barrett esophagus progression. A study of esophagectomy specimens correlating COX-2 immunopositivity and clinical course demonstrated that tumors expressing higher levels of COX-2 were more likely to be associated with distant metastases, local recurrence, and reduced survival. A recent meta-analysis of cohort studies estimated that aspirin use was inversely associated with esophageal adenocarcinoma (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.52–0.79) with a similar reduction in risk observed for NSAIDs (OR 0.65, 95% CI 0.50–0.85). Statin medications have also been proposed as chemopreventive agents for esophageal carcinoma. A recent large case-control study demonstrated that patients with Barrett esophagus on antisecretory therapy who filled prescriptions for either NSAID medications or statin medications had a reduced risk of developing esophageal adenocarcinoma. In the future, chemoprevention of Barrett esophagus progression may become the standard of care if further human clinical studies can substantiate these findings.
Abnet CC, Freedman ND, Kamangar F, et al. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis. Br J Cancer.
El-Serag HB, Aguirre TV, Davis S, et al. Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett's esophagus. Am J Gastroenterol
Horwhat JD, Baroni D, Maydonovitch C, et al. Normalization of intestinal metaplasia in the esophagus and esophagogastric junction: incidence and clinical data. Am J Gastroenterol
Nguyen DM, Richardson P, El-Serag HB. Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus. Gastroenterology
In indefinite-grade dysplasia, nuclear enlargement, crowding, hyperchromatism, prominence of the nucleoli, and mild stratification can be seen but are confined to the lower portion of the glands, whereas the upper portion of the glands and surface epithelium show less abnormality or are normal. The diagnosis of dysplasia should be made with caution when atypical changes do not involve the mucosal surface.
Active inflammation due to GERD may cause nuclear changes that mimic both low-grade and high-grade dysplasia. If a biopsy specimen is obtained adjacent to an ulcer and numerous neutrophils infiltrate the epithelium, the diagnosis of dysplasia may not be possible and the diagnosis of "indefinite for dysplasia" may be assigned.
If Barrett esophagus surveillance biopsy specimens are obtained and indefinite-grade dysplasia is the highest grade lesion found, aggressive antisecretory therapy should be instituted and repeat surveillance biopsies should be performed in 3 months.
Low-grade dysplasia is characterized by mucosal cells with nuclei that are larger and hyperchromatic, with irregular contours that are basally located in the cell with minimal or no stratification (Plate 11). As with other grades of dysplasia, the interpretations of low-grade dysplasia biopsy specimens should be considered for review by experts in esophageal pathology. Extensive surveillance biopsies should be done to confirm that low-grade dysplasia is the highest grade lesion in a Barrett esophagus segment.
Histopathologic findings of low-grade dysplasia in Barrett esophagus. The surface epithelium
displays nuclear stratification, limited to the lower half of the cytoplasm. (Used with permission from Jason Hornick, MD, PhD, Brigham and Womenâs Hospital.)
Several clinical studies have not demonstrated a significantly increased malignant potential of Barrett esophagus with low-grade dysplasia. In these studies, the risk of progression to esophageal adenocarcinoma was not significantly higher in patients with low-grade dysplasia than in those without dysplasia. In addition, some case series have demonstrated a transient nature to low-grade dysplasia, which can regress and revert to nondysplastic Barrett esophagus on subsequent biopsies. More recent data suggest that the extent of low-grade dysplasia measured as the mean proportion of low-grade dysplastic crypts may be a more significant predictor of esophageal adenocarcinoma outcome than the presence of low-grade dysplasia alone.
The natural history of low-grade dysplasia is variable; it can persist for long periods of time or even revert to nondysplastic Barrett esophagus. A repeat EGD with surveillance biopsies should be performed within 3–6 months after low-grade dysplasia is detected to confirm it is the highest grade lesion present and then annually as long as low-grade dysplasia persists. Given the emerging data regarding the implications of a large dysplastic burden, a shorter interval may be considered if multiple biopsies reveal a large number of low-grade crypts.
Sharma P. Low-grade dysplasia in Barrett's esophagus. Gastroenterology
Srivastava A, Hornick JL, Li X, et al. Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett's esophagus. Am J Gastroenterol
. 2006;102: 483–493.
The accurate pathologic diagnosis of high-grade dysplasia is critically important because therapeutic intervention may be initiated based on its diagnosis. Histopathologically, at low magnification power, distortion of the glandular architecture is usually present and may be marked. The glands are composed of branching and lateral budding of crypts and a villi-form configuration of the mucosal surface. Most importantly, the diagnosis of high-grade dysplasia requires that the dysplastic epithelium on the mucosal surface demonstrate loss of nuclear polarity and the absence of a consistent relationship of nuclei to each other (Plate 12).
Histopathologic findings of high-grade dysplasia in Barrett esophagus. There is full-thickness
nuclear stratification and the mucosa has a villous appearance. (Used with permission from Jason Hornick, MD, PhD, Brigham and Womenâs Hospital.)
The clinical implications of the presence of high-grade dysplasia in Barrett esophagus remain somewhat controversial. Owing to the risk of occult, coincident malignancy in a Barrett esophagus segment as well as the higher risk of progression to malignancy, the previous standard recommendation was that all patients diagnosed with high-grade dysplasia undergo esophagectomy once the diagnosis was confirmed by two experienced GI pathologists. Esophagectomy is a very invasive surgery and is associated with 3–10% mortality and up to 45% morbidity. Subsequent studies found that the rate of progression to esophageal adenocarcinoma in patients with high-grade dysplasia can vary widely from 15–60% and, in a subset of patients, may not occur at all. A recent retrospective review of patients referred for esophagectomy for Barrett esophagus with high-grade dysplasia or intramucosal carcinoma found that only 6.7% had submucosal invasion, suggesting that endoscopic therapies could have been considered. Therefore, the recommendations regarding the management of high-grade dysplasia have become more patient specific and tailored to each clinical scenario.
It is imperative that the diagnosis of high-grade dysplasia be confirmed by two expert GI pathologists prior to formulating a treatment plan. Extensive surveillance biopsies must be performed every 1 cm in all four quadrants of the Barrett esophagus segment in order to rule out the presence of any occult malignancy. Any suspicious nodules or ulcerations must be extensively sampled. An assessment of the patient's operative risk should be performed. After the preceding information has been obtained, a treatment plan can be formulated with the patient's input regarding the risks and benefits of each course of action.
The extent of high-grade dysplasia present in a patient's Barrett esophagus segment has been shown to correlate with the patient's likelihood of progression to cancer. These findings suggest that patients with "focal" high-grade dysplasia (ie, involving five or fewer crypts) on a single biopsy may be surveyed endoscopically, and more invasive treatment may be optimal only for patients who progress to frank adenocarcinoma.
If a patient is found to have high-grade dysplasia in a nodule or a focal, discrete lesion, endoscopic mucosal resection (EMR) should be considered. This is a method of endoscopically resecting the mucosal layer of the esophagus after separating it from the muscular layer with a submucosal injection of saline (Plates 13 and 14) or band ligation. The main risks of EMR include bleeding and perforation. An endoscopic ultrasound should be performed prior to considering EMR to confirm that the stage of the lesion is superficial and appropriate for endoscopic resection. If the resected specimen is removed en bloc, the completeness of cancer resection may be assessed pathologically. Frequently EMR is combined with an endoscopic ablative technique, such as radiofrequency ablation or photodynamic therapy, to treat high-grade dysplasia and intramucosal carcinoma.
Nodule of high-grade dysplasia in Barrett esophagus.
Same area shown in Plates 13 after endoscopic mucosal resection.
Photodynamic therapy is a mucosal ablation technique whereby a patient is given a photosensitizer intravenously that is preferentially taken up by dysplastic cells. After a time delay, laser light of a certain wavelength is used to illuminate the tissue and activate the photosensitizer, which then interacts with oxygen to mediate cell injury (Plates 15, 16, and 17). The lining of the esophagus is ablated with a transmural burn, which can cause odynophagia and chest pain immediately following illumination. The risks of photodynamic therapy include posttreatment strictures, atrial fibrillation, and pleural effusions. This therapy is typically used alone in patients who are not operative candidates with extensive, diffuse high-grade dysplasia or intramucosal carcinoma. The overall mortality and long-term survival in patients with high-grade dysplasia who are treated with photodynamic therapy appears to be comparable to that of those treated with esophagectomy.
Barrett esophagus with high-grade dysplasia and intramucosal adenocarcinoma.
Barrett esophagus. Same area as in Plate 15 showing illumination with laser light during photodynamic therapy.
Barrett esophagus segment 48 hours after illumination; same area as in Plates 15 and 16.
Various other endoscopic ablative techniques have been developed to treat dysplastic Barrett esophagus epithelium, including radiofrequency ablation, focal thermal, and cryoablation methods. Long-term comparative studies are needed to determine which method is the safest and most effective; however, it appears that radiofrequency ablation holds significant promise, with a recent study demonstrating a 90% eradication rate for high-grade dysplasia. This has been corroborated in a randomized, sham-controlled trial of radiofrequency ablation in 127 patients that demonstrated eradication rates of 90% and 81% for low-grade and high-grade dysplasia, respectively.
The treatment of high-grade dysplasia has evolved over time from a standard recommendation of esophagectomy for all patients to a more case-specific, less-invasive approach. Once the diagnosis has been confirmed by two expert GI pathologists, the patient's operative risk, the focality of the dysplasia, and the local surgical and endoscopic expertise should be considered before deciding on intensive surveillance, endoscopic ablation, or a surgical approach.
Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-grade dysplasia in Barrett's esophagus correlated with risk of adenocarcinoma. Gastroenterology
Ganz RA, Overholt BF, Sharma VK, et al. Circumferential ablation of Barrett's esophagus that contains high-grade dysplasia: a U.S. Multicenter Registry. Gastrointest Endosc
Prasad GA, Wang KK, Buttar NS, et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett's esophagus. Gastroenterology
Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology
Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med.
Spechler SJ, Lee A, Ahnen D, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: a follow-up of a randomized controlled trial. JAMA.
Wang VS, Hornick JL, Sepulveda JA, et al. Low prevalence of submucosal invasive carcinoma at esophagectomy for high-grade dysplasia or intramucosal adenocarcinoma in Barrett's esophagus: a 20-year experience. Gastrointest Endosc
Weston AP, Sharma P, Topalovski M, et al. Long-term follow-up of Barrett's high-grade dysplasia. Am J Gastroenterol
. 2000;95: 1888–1893.