Esophageal adenocarcinoma (EAC) is an often deadly cancer with an incidence in Western countries that has continued to rise in the past few decades.1,2 In 2004, 8000 incidences of EAC occurred in the United States, representing a 2- to 6-fold increase in the past 20 years.3 In general, EAC affects Caucasian men (men are affected 6 to 8 times > women, and Caucasians 3 to 4 times > African-Americans) in their 50s to 60s, with an annual increase of 4% to 10% since the 1970s, making EAC the fastest rising malignancy among white men in the United States.2,4,5 Risk factors include both genetic and environmental factors, including central obesity, smoking, and diet.2,6 The 5-year survival rate for esophageal and gastroesophageal junction cancers is low at only 15% to 20%.7
Chronic gastroesophageal reflux disease is associated with the metaplastic transformation of normal squamous epithelium to specialized intestinal metaplasia within the esophagus (Barrett's esophagus).1 This premalignant condition of Barrett's esophagus can progress to low-grade dysplasia (LGD) or high-grade dysplasia (HGD), and in some cases to EAC.8 Gastroesophageal reflux disease affects approximately 20% of adults in the United States,9 with Barrett's esophagus diagnosed in 10% to 15% of these patients with reflux disease who undergo endoscopy, and 5.6% of patients without chronic reflux symptoms.10 However, patients without chronic reflux may also develop Barrett's esophagus, suggesting the presence of multiple associated risk factors.11 Currently, Barrett's esophagus is the only recognized pathologic precursor to EAC.12 Barrett's esophagus is associated with a 0.50% to 0.75% risk of progressing to EAC per year, with the greatest risk in patients with dysplastic Barrett's. Because esophagectomy may be associated with significant morbidity, endoscopic therapies for premalignant Barrett's esophagus and early EAC have been developed and studied.
Pathology of Barrett's Esophagus
With the emergence of new modalities for treating EAC and preinvasive lesions, accurate pathologic diagnosis and staging have become critically important.
The seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual13 redefines Tis (carcinoma in situ) as equivalent to HGD in glandular mucosa in the esophagus. Although the term carcinoma in situ is not favored by gastrointestinal pathologists as a diagnostic term in Barrett's esophagus, having been supplanted by the terms high-grade dysplasia and intramucosal carcinoma (Table 1), it is retained for tumor registry reporting purposes as specified by law in many states. Invasion into the lamina propria is characterized by the finding of single neoplastic cells or small clusters of cells, separate from the larger dysplastic glands, without extension into deeper layers.
Pathologic Evaluation of Neoplasia in Barrett's Esophagus
The alteration of the microanatomy of the superficial layers of the esophagus is an underappreciated finding that may result in erroneous staging on endoscopic ultrasound (EUS).14 The muscularis mucosa varies in organization from relatively sparse bundles of smooth muscle in the cervical esophagus to a thickened reticulated network in the distal esophagus. The muscularis mucosa is commonly duplicated and thickened in Barrett's esophagus; the thicker outer muscularis mucosa layer, considered the original muscularis mucosa, may be confused with the muscularis propria and lead to overestimation of the depth of invasion on both endoscopic evaluation and examination of endoscopic mucosal resection (EMR) specimens. Although limited data are available on risk of metastasis related to subdivisions of T1a lesions, studies of esophagectomy specimens indicate that, overall, a low risk is present, ranging from 0% to 1.3% for T1a carcinomas compared with 18% to 22% for T1b tumors.15,16 Early studies17 attributed the link between depth of tumor invasion and increasing risk of metastasis to a richer lymphatic network in the submucosa than in the lamina propria. However, recent work reporting immunohistochemical studies specific for lymphatic endothelium suggests that the lamina propria in the normal esophagus in fact has an extensive network of lymphatic vessels,18 and the increasing risk of metastases in T1b lesions cannot be entirely explained based on lymphatic density.
Disease Staging
EAC survival rates correlate with disease staging. Therefore, accurate staging of EAC is crucial because treatment varies according to the initial staging of the disease.19–21 EUS, CT, and PET are typically the imaging modalities used to stage advanced EAC. The role of EUS in Barrett's dysplasia is limited, with most studies showing low yield.22 Although EUS is appropriate in staging early adenocarcinoma to rule out lymph node metastasis, accurate assessment of depth of invasion is difficult.23 The overall accuracy of EUS for T staging ranges from 72% to 76%.21,24 The sensitivity, specificity, and accuracy for T1 disease were 80%, 100%, and 91%, respectively, and for T3 disease were 78%, 80%, and 80%, respectively (P < .05).21 Given that the risk of lymph node metastasis significantly differs between T1a and T1b disease, this differentiation is important but can be difficult to ascertain via EUS.25 Because of this difficulty, EMR of visible lesions is the current standard,26 and allows both accurate staging and possible curative treatment at the same session.
Surveillance: The Importance of Novel Imaging Techniques
Determining which patients are appropriate to undergo endoscopic therapy for Barrett's esophagus is based on accurately identifying those who are at risk. Current guidelines recommend using systematic 4-quadrant biopsies every 2 cm for detecting dysplasia within Barrett's, because this technique had a 13-fold increase in yield over nonsystematic biopsies,27 probably because the greater number of biopsies yields more tissue sampling for detecting dysplasia.27 However, this approach is still random within the Barrett's mucosa and results in sampling error. Directed biopsies of suspicious dysplastic tissue are likely to have a higher yield for detecting dysplastic areas. Standard white-light endoscopic imaging is useful for detecting grossly visible lesions but may be less sensitive at detecting early or subtle mucosal changes.28 Newer imaging techniques, including narrow band imaging (NBI), chromoendoscopy, optical coherence tomography, and laser confocal microscopy, are being evaluated to determine their possible advantages over standard white-light endoscopy in detecting dysplasia.28
NBI is a high-resolution endoscopic imaging modality used to better evaluate the more superficial mucosal surface. The shorter wavelength of red, green, and blue light in NBI limits the depth of light penetration, allowing visualization of more superficial detail.29 In a study of 63 patients with Barrett's esophagus evaluating 200 mucosal areas showed that flat mucosa with regular mucosal and vascular patterns were associated with intestinal metaplasia, whereas irregular mucosal or vascular patterns or abnormal blood vessels were associated with high-grade intraepithelial neoplasm.29 In this study, NBI had a high sensitivity (94%) with reasonable specificity (76%).29 A second study with NBI showed similar sensitivity (100%) and specificity (98.7%).30 Although NBI results are promising, the technology is generally used as an adjunct to standard 4-quadrant biopsies.31 Other imaging techniques have been or are being studied, including endocytoscopy, optical coherence tomography, and confocal laser endomicroscopy, although these are largely being evaluated in the research setting and are not currently used in clinical practice.31–37 Ultimately, improved imaging modalities may improve diagnostic yield and lessen the need for a large number of biopsy specimens.
Endoscopic Therapies
It is largely believed that a gradual progression occurs in Barrett's esophagus, from nondysplastic Barrett's esophagus to LGD to HGD to EAC.38 As patients progress along this dysplasia spectrum, the risk for developing EAC increases. Patients with nondysplastic Barrett's esophagus have a 0.5% per year risk of progressing to EAC.39,40 The literature on patients with LGD reflects variable reports41,42 because of overdiagnoses leading to underestimation of progression risk. In a study of 147 patients diagnosed with LGD, only 15% cases were confirmed through expert pathology review, with a 13.4% per patient year incidence of progression to HGD or EAC, compared with 0.49% per patient year for patients who were downgraded to nondysplastic Barrett's esophagus.43 Therefore, confirmation by an expert pathologist is key for patients with LGD, because true LGD indicates a substantially higher risk of EAC and should change management in these patients.44
For patients with Barrett's esophagus and HGD, esophagectomy has been the gold standard given the risk of occult invasive EAC, which has been estimated to be as high as 40%.45,46 Esophagectomy was also previously the standard treatment for intramucosal adenocarcinoma, even though the incidence of lymph node metastasis is less than 1% for these patients.47 However, esophagectomy has significant surgical morbidity and mortality,48,49 leading to the development of nonsurgical endoscopic alternatives.
EMR
EMR helps stage disease and resects tissue for therapeutic invention. EMR allows for complete histopathologic review of resected tissue that helps to better diagnostically stage disease.50 If submucosal invasion is found, patients can then be referred for surgical resection, because these lesions have an 18% to 22% risk of lymph node metastasis depending on the depth of invasion into the submucosa.50,51 If the lesion is confined to the mucosa and resection margins are clear, EMR can be curative because of the very low risk for lymph node metastases.15,16 However, a 14% to 47% risk of synchronous or recurrent lesions exists within other areas of Barrett's tissue,52 leading to the strategy of complete Barrett's eradication EMR (CBE-EMR) or target lesion–directed EMR combined with one of the ablative techniques described later. EMR can be performed using a variety of techniques, including free-hand, lift-and-cut, cap-assisted, or band-assisted (Figure 1).52,53
CBE-EMR has been used in some centers to resect the epithelial tissue of all Barrett's esophagus cases to reduce the risk of synchronous or metachronous lesions. Complete remission ranges from 94% to 97% for patients undergoing CBE-EMR for HGD or intramucosal adenocarcinoma, with focal radiofrequency ablation used in some cases.54 However, stricture formation can occur in up to 50% of patients, along with bleeding or perforation.52 Most of the esophageal strictures and bleeding were amenable to endoscopic treatment.52 However, treating long-segment Barrett's esophagus with CBE-EMR may result in longer strictures that are more difficult to treat,31 and therefore these cases may be best treated with focal EMR in combination with one of the ablations techniques described later.31,55,56
The major advantage of EMR over ablation is that it enables tissue acquisition for histopathologic staging, which may change or affect treatment options for the patient. One study showed that 45% of 49 patients had their pathologic diagnosis changed (14% upstaged, 31% downstaged) after review of the EMR specimens compared with the initial biopsy specimens.54 In patients initially diagnosed with HGD who were upstaged, 4 had advanced pathology (intramucosal adenocarcinoma with lymphatic channel invasion or submucosal carcinoma) seen only after EMR, who were then properly referred for esophagectomy.54 All 4 patients had visible nodular lesions on endoscopy.54 EMR upstaging is likely the result of sampling error or limited biopsy specimen depth with forceps biopsy specimens.54 EMR downstaging may be attributable to crush artifact with forceps biopsy specimens or complete resection of HGD or intramucosal adenocarcinoma foci.54 Nonetheless, this study reinforces the importance of EMR for staging, because the 4 patients in this study would otherwise have been inappropriately treated with ablation for presumed HGD if their diagnoses had not been upstaged.54 Thus, the esophagus must be carefully examined for nodules before initiation of therapy so that the appropriate initial technique is chosen.
Ablation Techniques
Argon Plasma Coagulation: Argon plasma coagulation (APC) is a thermal cautery device that uses a constant flow of ionized argon gas to transmit high-frequency current to the tissue to cause superficial (2–3 mm depth) tissue destruction.57 This allows the mucosal Barrett's esophagus to be treated without the concern for deeper cauterization that could incur more complications. Studies vary, with a rate of 84% to 100% for complete squamous reconstitution, and a relapse rate of 3% to 11% per year.57,58 Some of this variability in results may be secondary to higher-powered APC (90W vs. 60W) and higher-dose proton pump inhibitors in different studies, although higher-powered APC may also induce more complications, including pleural effusions, strictures, and perforation.57,58 A case has been reported of adenocarcinoma arising under the neosquamous mucosa after apparently successful APC; so called “buried adenocarcinoma.”59 This relates to the concern for “buried Barrett's esophagus” and “buried dysplasia” that may arise deeper to the neosquamous mucosa, which is produced by ablation. Given the varied Barrett's esophagus recurrence and procedure complication rate, APC is currently less routinely performed, because other techniques, such as radiofrequency ablation or cryotherapy, may be more beneficial.
Endoscopic mucosal resection of an esophageal nodule. (A) Subtle area of nodularity seen at the gastroesophageal junction (arrow). (B) Esophageal nodule seen on narrow band imaging shows increased vascularity suspicious for carcinoma (arrow). (C) Nodule resected using band-assisted endoscopic mucosal resection. The area is inspected and no evidence of perforation is seen. (D) The full specimen is retrieved and submitted to pathology. Final diagnosis is intramucosal (T1a) carcinoma associated with Barrett's esophagus.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 8; 10.6004/jnccn.2011.0073
Multipolar Electrocoagulation: Multipolar electrocoagulation (MPEC) uses a 50W energy source with a probe to apply firm pressure to the mucosa in areas of intestinal metaplasia until a white coagulum develops.60 No studies have been performed in patients with HGD, and are only reported for ablation in patients with nondysplastic Barrett's esophagus. These studies show complete eradication rates of 89% to 100% but also show the highest adverse events of dysphagia (19%) and odynophagia (16%) compared with other ablative techniques.50 MPEC is also very focal in its treatment areas and may be difficult to use in patients with long-segment Barrett's esophagus. MPEC is no longer routinely performed for this indication.
Laser Therapies: Some studies have used laser therapy for tissue destruction. The diode laser uses a continuous-wave 940-nm diode laser at a power of 40W with 2.1-mm diameter noncontact fibers that are positioned 1 cm from the mucosal surface to produce a whitening of tissue, signifying denaturation of proteins.61 Using the diode laser therapy, a 65% complete ablation rate was achieved,61 similar to the 67% complete ablation rate with the 1064-nm neodymium yttrium aluminum garnet (Nd:YAG) laser.62 The 940-nm diode laser creates a more superficial ablation than the 1064-nm YAG laser, which may explain the higher complications of perforation, bleeding, and stricture noted with the YAG laser.61–63 However, laser therapy has a limited area of treatment, and therefore requires numerous sessions to ablate large areas of metaplastic tissue, limiting its use in long-segment Barrett's esophagus.61 Laser therapy is largely experimental and not used in clinical practice.
Photodynamic Therapy: Photodynamic therapy involves first administering a light-sensitizing agent that accumulates in the Barrett's esophagus tissue before performing light-activation therapy that causes free oxygen radical formation and ischemic necrosis for tissue destruction.64,65 Porfimer sodium is the most commonly used photosensitizer and is given intravenously 48 hours before the procedure.65 Alternatively, oral 5-aminolevulinic acid has been used.65 Light activation is performed via endoscopy and the use of diffusing light fibers that are placed next to the target tissue, which causes excitation of the photosensitizer and tissue destruction as described earlier.52 One study of 103 patients with LGD, HGD, or intramucosal adenocarcinoma found successful tissue ablation in 93%, 78%, and 44%, respectively.66 Four patients (4.9%) had subsquamous (“buried”), nondysplastic, metaplastic tissue, and 3 patients (4.6%) had subsquamous adenocarcinoma.66 An overall stricture rate of 30% was also seen, with a 50% stricture rate in patients receiving 2 sessions of photodynamic therapy.66 These stricture rates are much higher than those with APC (2.9%) or radiofrequency ablation (1.9%).50 Photosensitivity is also a major side effect in up to 69% of patients.50 Given the subsquamous Barrett's esophagus tissue with neoplastic potential, reports of subsquamous adenocarcinoma, and high stricture rates, photodynamic therapy is now used less frequently because of the availability of alternative ablation techniques.52
Radiofrequency Ablation: Radiofrequency ablation uses either a cylindrical balloon with embedded electrodes or a focal ablation device to deliver a preset amount of thermal energy to the target tissue for tissue ablation.52,67 For patients with long-segment Barrett's esophagus, ablation using the balloon is preferred. In contrast, the focal ablation device is preferred in the presence of short-segment Barrett's esophagus or when areas of residual intestinal metaplasia remain after prior treatments. If balloon ablation is used, a sizing balloon is first inserted into the esophagus to determine the optimal size for the circumferential ablation balloon to ensure adequate contact with the mucosa.52 With both devices, ablation is then achieved by performing 2 separate applications of direct thermal energy using the ablation device, while cleaning the coagulation tissue from the ablation zone and electrodes in between ablations (Figure 2).52,67 This allows for uniform ablation of Barrett's esophagus tissue.
Early studies with radiofrequency ablation focused on ablation of nondysplastic Barrett's esophagus tissue. In a study of 100 patients, a 70% complete remission rate of Barrett's esophagus was seen at 1 year, with no evidence of stricture formation or buried Barrett's esophagus among the 4306 biopsies evaluated.68 At the time of this initial study, only balloon-based ablation was available, contributing to the lower complete remission rates. A follow-up study at 2.5 years showed a 98% complete remission rate of Barrett's esophagus after stepwise circumferential therapy with focal ablation therapy of remaining Barrett's esophagus.69 The most recent follow-up study at 5 years has now shown a 92% complete remission rate of Barrett's esophagus, with 8% having nondysplastic Barrett's esophagus; however, focal radiofrequency ablation reinduced complete remission in all of these patients.70 Furthermore, no buried Barrett's esophagus, dysplasia, strictures, or serious adverse events were seen in this group of patients.70
Radiofrequency ablation of dysplastic Barrett's esophagus. (A) Short-segment Barrett's esophagus is seen on high-definition endoscopy. (B) Narrow band imaging allows for easier detection of intestinal metaplasia and increases the ability to identify dysplastic areas. (C) Ablation is performed using the focal radiofrequency ablation device. (D) On surveillance at follow-up examination, only a focal area of Barrett's esophagus remains (arrow), best detected with narrow band imaging. This was successfully treated with repeat focal ablation.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 8; 10.6004/jnccn.2011.0073
A recent landmark multicenter, sham-controlled trial of 127 patients with dysplastic Barrett's esophagus were randomly assigned to undergo radiofrequency ablation or a sham procedure, with outcomes measured at 1 year.67 In patients with LGD and HGD, complete eradication rates of dysplasia were 91% and 81%, respectively, in the radiofrequency ablation group compared with 23% and 19%, respectively, in sham procedure control groups.67 Overall, complete eradication of Barrett's esophagus was 77% in the radiofrequency ablation group and only 2.3% in the control group, with less disease progression (4% vs. 16%) and cancers (1% vs. 9%).67 Adverse events in the radiofrequency ablation group included more chest pain, one upper gastrointestinal bleed treated endoscopically, and a 6% esophageal stricture rate that were all successfully treated with endoscopic dilation.67 Longer-term data from this cohort have only been published in abstract form, but the response seems to be durable. Based on the data, radiofrequency ablation should be given serious consideration as first-line therapy in patients with dysplasia,71 with EMR used for resection of any visible nodules, as discussed later.
Cryotherapy: Cryotherapy, the most recent modality for endoscopic mucosal ablation, sprays liquid nitrogen on target areas to freeze tissue, causing intracellular disruption and ischemia with relative extracellular matrix preservation, resulting in less fibrosis.72,73 Few studies have been conducted and no controlled studies have been published with cryotherapy. A recent study of 60 patients who completed all planned treatments with cryotherapy found a 97% complete eradication rate for patients with HGD and a 57% complete resolution rate of Barrett's esophagus.74 The stricture rate in this study was 5% and subsquamous Barrett's esophagus was noted in 3% of patients.74 Controlled trials are needed to evaluate this modality of treatment, although early results seem promising.
Combination EMR With Ablation Therapy
For patients with visible lesions in the setting of HGD or early EAC, a combination approach of EMR with additional ablation techniques has been used.55,56,75–78 In a study of 44 patients with HGD or early EAC with visible (nodular) lesions, EMR was first used to remove the visible lesion, then radiofrequency ablation was performed to ablate the remaining Barrett's esophagus tissue.75 Initial EMR provided histologic evaluation in addition to flattening the mucosal surface before radiofrequency ablation for uniform tissue destruction.75 Complete eradication of dysplasia and Barrett's esophagus was achieved in 98% of patients, with no dysplasia recurrence at 21-month follow-up.75 Five adverse events occurred in patients after EMR: 4 mild bleedings managed endoscopically and 1 esophageal perforation managed endoscopically.75 Complications after ablation included a 9% dysphagia rate, which improved with esophageal dilation (all had prior widespread EMR), and a 4% chest pain rate requiring hospitalization with conservative treatment.75 The authors speculated that the higher rate of complications after ablation was likely related to ablation in areas of scarring from prior EMR. However, the controlled, uniform ablation with radiofrequency ablation resulted in minimal submucosal scarring, allowing for focal EMR after radiofrequency ablation for persistent Barrett's esophagus, representing a significant advantage over APC and photodynamic therapy, which cause submucosal scarring and make EMR difficult after ablation.75
A more recent multicenter study included 23 patients with early EAC or HGD with focal EMR followed by serial radiofrequency ablation.76 In this study, “escape” EMR was permitted in which focal areas of visibly abnormal tissue were removed with EMR postablation.76 Complete eradication of neoplasia and Barrett's esophagus was achieved in 95% and 88% of patients after radiofrequency ablation, respectively, and 100% and 96% of patients after radiofrequency ablation with escape EMR, respectively, with 22-month follow-up.76 Of those who experienced complete Barrett's esophagus eradication, 3 patients (13%) had evidence of Barrett's esophagus on follow-up endoscopies, which supports current practice of continued surveillance endoscopies in patients after ablation.76 However, follow-up biopsies of neosquamous epithelium in 22 patients after radiofrequency ablation showed resolution of genetic abnormalities and no buried glandular mucosa.77
Most recently, a multicenter, randomized control trial compared stepwise radical endoscopic resection (widespread EMR) with focal EMR followed by radiofrequency ablation in 47 patients with early EAC or HGD and a Barrett's esophagus segment of 5 cm or less with follow-up of 24 months.78 Complete eradication of neoplasia was comparable (100% widespread EMR, 96% EMR/radiofrequency ablation) as was complete eradication of Barrett's esophagus (92% widespread EMR, 96% EMR/radiofrequency ablation).78 However, an 88% stricture rate was seen in the widespread EMR group versus 14% in the EMR/radiofrequency ablation group, with all 14% in the EMR/radiofrequency ablation group developing strictures at the larger EMR resection sites.78 Therefore, focal EMR followed by radiofrequency ablation may be a preferred approach, especially in patients with longer-segment Barrett's esophagus.78 Overall, the combination of radiofrequency ablation and EMR has gained popularity for Barrett's esophagus eradication given the low stricture and complication rate, and now serves as an alternative to esophagectomy.
Surveillance Postendoscopic Treatment
Surveillance after completion of endoscopic therapy is critical because dysplastic Barrett's may recur after apparent complete eradication. Recurrence of “buried Barrett's” (subneosquamous intestinal metaplasia [SSIM]) or Barrett's esophagus at the neosquamous–columnar border is a major concern.77 When SSIM occurs, it seems to reside in the deep epithelium or the lamina propria.79 Therefore, biopsy specimens should include lamina propria tissue or be deeper to assess for this possible SSIM.79 Biopsy depth and adequacy were compared using cold forceps in patients who were ablation-naïve (controls) versus those who had undergone photodynamic therapy or radiofrequency.80 Approximately 90% of specimens from all groups were adequate to detect SSIM, showing this technique to be an appropriate surveillance approach after ablation.80 In addition to SSIM or Barrett's esophagus recurrence at the neosquamous–columnar junction, a recent case report showed squamous cell dysplasia within the neosquamous epithelium on surveillance, 4-quadrant biopsies after prior cryoablation followed by radiofrequency ablation with complete response posttherapy.81 Given the concerns for SSIM, Barrett's esophagus recurrence at the neosquamous–columnar junction, and neosquamous dysplasia, surveillance is critical after completion of endoscopic therapy. The exact timing and approach to surveillance after ablation are still unknown and further studies are needed before recommendations can be made. However, patients should likely remain on their proton pump inhibitor therapy for life. Furthermore, consideration should be given to surgical therapy if persistent reflux is shown on esophageal testing to prevent disease recurrence.
Conclusions
EAC is an often deadly cancer with a rising incidence in Western countries. True LGD or HGD carry a much higher risk of progression to esophageal cancer, and therefore these patients should be treated more aggressively than those without dysplasia. Flat dysplastic Barrett's esophagus is now being treated with ablative techniques, with strong clinical data supporting the use of radiofrequency ablation. Furthermore, nodular Barrett's esophagus or early esophageal neoplasia (T1a disease) can safely be treated endoscopically with EMR. Endoscopists who treat dysplastic Barrett's esophagus should be familiar with both ablation and resection techniques, because both may be required in an individual patient. As always, appropriate treatment is best determined after careful discussion with patients in a multidisciplinary environment. However, endoscopic therapy offers an attractive alternative to esophagectomy, which was previously the only treatment for HGD and EAC.
References
- 1↑
Phillips WA, Lord RV, Nancarrow DJ et al.. Barrett's esophagus. J Gastroenterol Hepatol 2011;26:639–648.
- 2↑
el-Serag HB. The epidemic of esophageal adenocarcinoma. Gastroenterol Clin North Am 2002;31:421–440, viii.
- 3↑
Forman D. Re: the role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:1013–1014; author reply 1014.
- 4↑
Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049–2053.
- 5↑
Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287–1289.
- 6↑
Beddy P, Howard J, McMahon C et al.. Association of visceral adiposity with oesophageal and junctional adenocarcinomas. Br J Surg 2010;97:1028–1034.
- 7↑
Sharma P, McQuaid K, Dent J et al.. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310–330.
- 8↑
Vaira D, Gatta L, Ricci C et al.. Gastroesophageal reflux disease and Barrett's esophagus. Intern Emerg Med; in press.
- 9↑
Camilleri M, Dubois D, Coulie B et al.. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol 2005;3:543–552.
- 10↑
Rex DK, Cummings OW, Shaw M et al.. Screening for Barrett's esophagus in colonoscopy patients with and without heartburn. Gastroenterology 2003;125:1670–1677.
- 11↑
Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett's esophagus in asymptomatic individuals. Gastroenterology 2002;123:461–467.
- 12↑
Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710–717.
- 13↑
Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471–1474.
- 14↑
Mandal RV, Forcione DG, Brugge WR et al.. Effect of tumor characteristics and duplication of the muscularis mucosae on the endoscopic staging of superficial Barrett esophagus-related neoplasia. Am J Surg Pathol 2009;33:620–625.
- 15↑
Leers JM, Demeester SR, Oezcelik A et al.. The prevalence of lymph node metastases in patients with T1 esophageal adenocarcinoma: a retrospective review of esophagectomy specimens. Ann Surg 2011;253;271–278.
- 16↑
Barbour AP, Jones M, Brown I et al.. Risk stratification for early esophageal adenocarcinoma: analysis of lymphatic spread and prognostic factors. Ann Surg Oncol 2010;17:2494–2502.
- 17↑
Rice TW, Zuccaro G Jr, Adelstein DJ et al.. Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg 1998;65:787–792.
- 18↑
Yajin S, Murakami G, Takeuchi H et al.. The normal configuration and interindividual differences in intramural lymphatic vessels of the esophagus. J Thorac Cardiovasc Surg 2009;137:1406–1414.
- 19↑
Gebski V, Burmeister B, Smithers BM et al.. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007;8:226–234.
- 20
Cunningham D, Allum WH, Stenning SP et al.. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.
- 21↑
Choi J, Kim SG, Kim JS et al.. Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer. Surg Endosc 2010;24:1380–1386.
- 22↑
Waxman I. EUS and EMR/ESD: is EUS in patients with Barrett's esophagus with high-grade dysplasia or intramucosal adenocarcinoma necessary prior to endoscopic mucosal resection? Endoscopy 2006;38(Suppl 1):S2–4.
- 23↑
Liberale G, Van Laethem JL, Gay F et al.. The role of PET scan in the preoperative management of oesophageal cancer. Eur J Surg Oncol 2004;30:942–947.
- 24↑
Shimpi RA, George J, Jowell P, Gress FG. Staging of esophageal cancer by EUS: staging accuracy revisited. Gastrointest Endosc 2007;66:475–482.
- 25↑
Pech O, Gunter E, Dusemund F et al.. Accuracy of endoscopic ultrasound in preoperative staging of esophageal cancer: results from a referral center for early esophageal cancer. Endoscopy 2010;42:456–461.
- 26↑
Young PE, Gentry AB, Acosta RD et al.. Endoscopic ultrasound does not accurately stage early adenocarcinoma or high-grade dysplasia of the esophagus. Clin Gastroenterol Hepatol 2010;8:1037–1041.
- 27↑
Abela JE, Going JJ, Mackenzie JF et al.. Systematic four-quadrant biopsy detects Barrett's dysplasia in more patients than nonsystematic biopsy. Am J Gastroenterol 2008;103:850–855.
- 28↑
Garud SS, Keilin S, Cai Q, Willingham FF. Diagnosis and management of Barrett's esophagus for the endoscopist. Therap Adv Gastroenterol 2010;3:227–238.
- 29↑
Kara MA, Ennahachi M, Fockens P et al.. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett's esophagus by using narrow band imaging. Gastrointest Endosc 2006;64:155–166.
- 30↑
Sharma P, Bansal A, Mathur S et al.. The utility of a novel narrow band imaging endoscopy system in patients with Barrett's esophagus. Gastrointest Endosc 2006;64:167–175.
- 31↑
Seewald S, Ang TL, Groth S et al.. Detection and endoscopic therapy of early esophageal adenocarcinoma. Curr Opin Gastroenterol 2008;24:521–529.
- 32
Pohl H, Koch M, Khalifa A et al.. Evaluation of endocytoscopy in the surveillance of patients with Barrett's esophagus. Endoscopy 2007;39:492–496.
- 33
Isenberg G, Sivak MV Jr, Chak A et al.. Accuracy of endoscopic optical coherence tomography in the detection of dysplasia in Barrett's esophagus: a prospective, double-blinded study. Gastrointest Endosc 2005;62:825–831.
- 34
Qi X, Sivak MV, Isenberg G et al.. Computer-aided diagnosis of dysplasia in Barrett's esophagus using endoscopic optical coherence tomography. J Biomed Opt 2006;11:044010.
- 35
Canto MI. Endomicroscopy of Barrett's esophagus. Gastroenterol Clin North Am 2010;39:759–769.
- 36
Kiesslich R, Gossner L, Goetz M et al.. In vivo histology of Barrett's esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006;4:979–987.
- 37↑
Dunbar KB, Okolo P III, Montgomery E, Canto MI. Confocal laser endomicroscopy in Barrett's esophagus and endoscopically inapparent Barrett's neoplasia: a prospective, randomized, double-blind, controlled, crossover trial. Gastrointest Endosc 2009;70:645–654.
- 39↑
Provenzale D, Schmitt C, Wong JB. Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999;94:2043–2053.
- 40↑
Achkar E, Carey W. The cost of surveillance for adenocarcinoma complicating Barrett's esophagus. Am J Gastroenterol 1988;83:291–294.
- 41↑
Sharma P, Falk GW, Weston AP et al.. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin Gastroenterol Hepatol 2006;4:566–572.
- 42↑
Conio M, Blanchi S, Lapertosa G et al.. Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study. Am J Gastroenterol 2003;98:1931–1939.
- 43↑
Curvers WL, ten Kate FJ, Krishnadath KK et al.. Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated. Am J Gastroenterol 2010;105:1523–1530.
- 44↑
Dent J. Barrett's esophagus: a historical perspective, an update on core practicalities and predictions on future evolutions of management. J Gastroenterol Hepatol 2011;26(Suppl 1):11–30.
- 45↑
Pellegrini CA, Pohl D. High-grade dysplasia in Barrett's esophagus: surveillance or operation? J Gastrointest Surg 2000;4:131–134.
- 46↑
Ferguson MK, Naunheim KS. Resection for Barrett's mucosa with high-grade dysplasia: implications for prophylactic photodynamic therapy. J Thorac Cardiovasc Surg 1997;114:824–829.
- 47↑
Stein HJ, Feith M, Bruecher BL et al.. Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg 2005;242:566–573.
- 48↑
Gasper WJ, Glidden DV, Jin C et al.. Has recognition of the relationship between mortality rates and hospital volume for major cancer surgery in California made a difference?: a follow-up analysis of another decade. Ann Surg 2009;250:472–483.
- 49↑
Patti MG, Corvera CU, Glasgow RE, Way LW. A hospital's annual rate of esophagectomy influences the operative mortality rate. J Gastrointest Surg 1998;2:186–192.
- 50↑
Menon D, Stafinski T, Wu H et al.. Endoscopic treatments for Barrett's esophagus: a systematic review of safety and effectiveness compared to esophagectomy. BMC Gastroenterol 2010;10:111.
- 51↑
Wang KK, Wongkeesong M, Buttar NS. American Gastroenterological Association technical review on the role of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology 2005;128:1471–1505.
- 52↑
Chennat J, Waxman I. Endoscopic treatment of Barrett's esophagus: from metaplasia to intramucosal carcinoma. World J Gastroenterol 2010;16:3780–3785.
- 53↑
Kantsevoy SV, Adler DG, Conway JD et al.. Endoscopic mucosal resection and endoscopic submucosal dissection. Gastrointest Endosc 2008;68:11–18.
- 54↑
Chennat J, Konda VJ, Ross AS et al.. Complete Barrett's eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma—an American single-center experience. Am J Gastroenterol 2009;104:2684–2692.
- 55↑
Prasad GA, Wu TT, Wigle DA et al.. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus. Gastroenterology 2009;137:815–823.
- 56↑
Pech O, Behrens A, May A et al.. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett's oesophagus. Gut 2008;57:1200–1206.
- 57↑
Madisch A, Miehlke S, Bayerdorffer E et al.. Long-term follow-up after complete ablation of Barrett's esophagus with argon plasma coagulation. World J Gastroenterol 2005;11:1182–1186.
- 58↑
Mork H, Al-Taie O, Berlin F et al.. High recurrence rate of Barrett's epithelium during long-term follow-up after argon plasma coagulation. Scand J Gastroenterol 2007;42:23–27.
- 59↑
Van Laethem JL, Peny MO, Salmon I et al.. Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett's oesophagus. Gut 2000;46:574–577.
- 60↑
Allison H, Banchs MA, Bonis PA, Guelrud M. Long-term remission of nondysplastic Barrett's esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up. Gastrointest Endosc 2011;73:651–658.
- 61↑
Polese L, Angriman I, Scarpa M et al.. Diode laser treatment of Barrett's esophagus: long-term results. Lasers Med Sci 2011;26:223–228.
- 62↑
Fisher RS, Bromer MQ, Thomas RM et al.. Predictors of recurrent specialized intestinal metaplasia after complete laser ablation. Am J Gastroenterol 2003;98:1945–1951.
- 63↑
Weston AP, Sharma P. Neodymium:yttrium-aluminum garnet contact laser ablation of Barrett's high grade dysplasia and early adenocarcinoma. Am J Gastroenterol 2002;97:2998–3006.
- 64↑
Gross SA, Wolfsen HC. The role of photodynamic therapy in the esophagus. Gastrointest Endosc Clin N Am 2010;20:35–53, vi.
- 65↑
Wang KK, Lutzke L, Borkenhagen L et al.. Photodynamic therapy for Barrett's esophagus: does light still have a role? Endoscopy 2008;40:1021–1025.
- 66↑
Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett's esophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointest Endosc 2003;58:183–188.
- 67↑
Shaheen NJ, Sharma P, Overholt BF et al.. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 2009;360:2277–2288.
- 68↑
Sharma VK, Wang KK, Overholt BF et al.. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett's esophagus: 1-year follow-up of 100 patients. Gastrointest Endosc 2007;65:185–195.
- 69↑
Fleischer DE, Overholt BF, Sharma VK et al.. Endoscopic ablation of Barrett's esophagus: a multicenter study with 2.5-year follow-up. Gastrointest Endosc 2008;68:867–876.
- 70↑
Fleischer DE, Overholt BF, Sharma VK et al.. Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial. Endoscopy 2010;42:781–789.
- 71↑
Bulsiewicz WJ, Shaheen NJ. The role of radiofrequency ablation in the management of Barrett's esophagus. Gastrointest Endosc Clin N Am 2011;21:95–109.
- 72↑
Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524–529.
- 74↑
Shaheen NJ, Greenwald BD, Peery AF et al.. Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 2010;71:680–685.
- 75↑
Pouw RE, Gondrie JJ, Sondermeijer CM et al.. Eradication of Barrett esophagus with early neoplasia by radiofrequency ablation, with or without endoscopic resection. J Gastrointest Surg 2008;12:1627–1636.
- 76↑
Pouw RE, Wirths K, Eisendrath P et al.. Efficacy of radiofrequency ablation combined with endoscopic resection for barrett's esophagus with early neoplasia. Clin Gastroenterol Hepatol 2010;8:23–29.
- 77↑
Pouw RE, Gondrie JJ, Rygiel AM et al.. Properties of the neosquamous epithelium after radiofrequency ablation of Barrett's esophagus containing neoplasia. Am J Gastroenterol 2009;104:1366–1373.
- 78↑
van Vilsteren FG, Pouw RE, Seewald S et al.. Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial. Gut 2011;60:765–773.
- 79↑
Biddlestone LR, Barham CP, Wilkinson SP et al.. The histopathology of treated Barrett's esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy. Am J Surg Pathol 1998;22:239–245.
- 80↑
Overholt BF, Dean PJ, Galanko JA, Lightdale CJ. Does ablative therapy for Barrett esophagus affect the depth of subsequent esophageal biopsy as compared with controls? J Clin Gastroenterol 2010;44:676–681.
- 81↑
Dua KS, Merrill JT, Komorowski R. Neosquamous epithelium after Barrett's ablation: cause for concern? Gastrointest Endosc, in press.
