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Endoscopic mucosal resection
Techniques in Gastrointestinal Endoscopy (2010) 12, 108-115
Techniques in GASTROINTESTINAL ENDOSCOPY www.techgiendoscopy.com
Endoscopic mucosal resection Ganapathy A. Prasad, MD, MS, Vikneswaran Namasivayam, MD Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. KEYWORDS: Endoscopic mucosal resection; Dysplasia; Esophageal adenocarcinoma; Barrett’s esophagus; Complications; Outcomes
Endoscopic Mucosal Resection is a well established diagnostic and therapeutic technique in the management of esophageal neoplasia arising in the background of Barrett’s esophagus. It is a valuable adjunct to ablative techniques for the treatment of dysplasia Barrett’s esophagus. This article reviews the rationale, indications, methods and outcomes of endoscopic mucosal resection in Barrett’s esophagus. © 2010 Published by Elsevier Inc.
Endoscopic therapy in patients with Barrett’s espohagus (BE)-related neoplasia has advanced from being considered experimental therapy to being a well-accepted therapeutic option.1,2 The overall goal of endoscopic therapy is the complete and durable elimination of esophageal columnar mucosa to ultimately decrease the incidence of esophageal adenocarcinoma, of which BE is the strongest risk factor.3,4 Techniques available for endoscopic therapy in BE can be broadly categorized into those that provide tissue for histologic examination (endoscopic resection [ER]: focal or circumferential and endoscopic submucosal dissection) and those that do not. The latter can be further classified into: thermal techniques (radiofrequency ablation [RFA], multipolar electrocoagulation, and argon plasma coagulation), photochemical techniques (photodynamic therapy [PDT]), and cryotherapy. Multimodality therapy (using a resection technique to target visible abnormalities followed by an ablation technique to eradicate the remaining BE segment) is most often used for the comprehensive management of BE-associated neoplasia. Endoscopic mucosal resection (EMR) is a technique initially introduced and popularized in Asia, for the treatment of early upper gastrointestinal (esophageal and gastric) cancers.5-7 The technique has been increasingly accepted
The authors report no direct financial interests that might pose a conflict of interest in connection with the submitted manuscript. Address reprint requests to Ganapathy A. Prasad MD, MS, GI Diagnostic Unit, Alfred Main, 200 1st Street SW, Rochester, MN 55905. E-mail: [email protected]
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and practiced in Europe and the United States over the past few years.8-13 Though the technique was initially developed for the endoscopic treatment of malignant lesions, it has also been used for the treatment of benign lesions in the esophagus.14 Most of the early experience with EMR was in its application in the treatment of early esophageal and gastric cancers. It has since evolved into an effective diagnostic, staging, and treatment strategy for gastrointestinal cancers confined to the mucosa. It fulfills the long-identified need to obtain precise information regarding the depth of tumor invasion and neoplastic margins before additional endoscopic ablative therapy. With the proliferation of ablation techniques, the need for EMR is now recommended for any suspicious neoplastic lesion. In this review, we will focus on the indications, methods, and role of EMR in the management of esophageal neoplasia arising in BE.
Why is EMR helpful? The histologic assessment of dysplasia in BE by biopsies is confounded by multiple factors: scattered distribution of dysplasia/neoplasia in the BE segment15 making identification challenging, interobserver variability among interpreting pathologists,16,17 poor predictive value of dysplasia,18 and the inability to assess margins, to name a few. EMR overcomes some of these limitations, making it a valuable tool in the management of patients with BE neoplasia. The interobserver agreement between 9 academic pathologists (in assigning grades of dysplasia on histopathologic
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samples from 25 patients) was compared between biopsy specimens and EMR specimens.19 The authors reported that the interobserver agreement of BE-related neoplasia on EMR specimens is significantly higher compared with biopsy specimens. Increased size of tissue specimens and the ability to assess landmarks, such as the muscularis mucosae, most likely led to these improved outcomes. In addition, providing deeper and larger tissue specimens also leads to upstaging of the diagnosis [in terms of the grade of dysplasia, for example from high-grade dysplasia (HGD) to intramucosal carcinoma (IMCA)] in as many as 40% of subjects following EMR compared with initial biopsy diagnosis.20-22 Precise staging of tumor depth invasion (particularly distinguishing mucosal from submucosal invasion, which has a crucial impact on management: determining suitability for endoscopic therapy) can be achieved by EMR, often with greater accuracy than by endoscopic ultrasound (EUS).20,23 This is of particular importance given that the rate of LN involvement in mucosal lesions is low (5% or less) making them suitable to endoscopic therapy, in contrast to submucosal cancers with substantially higher rates (⬎20%) making them unsuitable to endoscopic therapy. EMR specimens also make assessment of margins possible and the use of EMR margins in predicting residual tumor at esophagectomy has been validated.24 In addition, the performance of EMR does not appear to influence esophagectomy adversely (in terms of intraoperative or perioperative complications), if that were required following EMR.25 EMR may also be used to provide real-time data on pathology with reasonable accuracy to determine whether additional EMR is required or to determine margins of resection, using frozen sections.26
Pre-EMR evaluation The use of EMR as a diagnostic and therapeutic tool hinges on careful assessment and exclusion of widespread metastatic disease in patients being evaluated for BE-related neoplasia. In subjects with HGD or IMCA, determination of disease extension beyond the esophagus (to lymph nodes and other organs) is usually accomplished by EUS and CT scans. However, EUS has only modest accuracy in delineating the T stage of esophageal cancers20,27,28 as the assessment of tumor depth may be confounded by ongoing inflammation as well as the inability to pass the echoendoscope through a stenosed segment. The use of high-frequency ultrasound probes has not improved the accuracy of T staging despite better delineation of the esophageal wall. This may be partly attributed to the difficulties in obtaining perpendicular images with the probe at the gastroesophageal junction, especially if there is a hiatus hernia.23 There is also the problem with acoustical coupling required for ultrasound imaging. The standard balloon devices used compress lesions and make it difficult to even identify early neoplasia,
109 Table 1 Paris classification: The macroscopic classification of type 0 digestive tract lesions, with a superficial appearance at endoscopy Protruding Pedunculated Sessile Nonprotruding and nonexcavated Slightly elevated Completely flat Slightly depressed Elevated and depressed types Excavated Ulcer Excavated and depressed types
0 ⫺ 1p 0 ⫺ 1s 0 0 0 0 0
⫺ ⫺ ⫺ ⫾ ⫾
IIa IIb IIc IIc ⫹ IIa IIa ⫹ IIc
0 ⫾ III 0 ⫾ IIc ⫹ III 0 ⫾ III ⫹ IIc
Adapted from Lambert, et al34
whereas the alternative, water filling the lumen, is not practical in certain areas of the esophagus or stomach. In addition, careful inspection and evaluation of the BE segment using high-definition white light imaging, narrow band imaging, and other promising imaging tools being investigated (such as autofluorescence imaging and confocal endomicroscopy) may enable more precise and accurate identification of visible lesions29 that have been correlated with prevalent advanced dysplasia.30,31 Recent reports have described the use of targeting EMR using these advanced imaging techniques.32 Once lesions are targeted, the endoscopic appearance of the lesion may suggest submucosal spread, making the lesion less suitable for EMR. An international working group had proposed the Paris endoscopic classification to characterize superficial neoplastic lesions by their endoscopic appearance to predict the likelihood of submucosal invasion.33 Most superficial esophageal carcinoma lesions are nonprotruding, and these carry a lower risk of submucosal invasion compared with protruding and excavated lesions.22 Submucosal infiltration in Barrett’s neoplasia is more often encountered in protruding and depressed lesions22 as well as in moderately differentiated tumors compared with well-differentiated tumors in a large study of over 200 EMR specimens (Table 1).
How is EMR performed? ER involves the removal of mucosal and submucosal tissue following submucosal injection, using a variety of techniques. There are many techniques that have been described, as listed below, with cap-assisted techniques being used the most commonly.
EMR Techniques 1. Strip biopsy technique In this technique, a diathermy loop is introduced through the working channel of the endoscope and positioned over a polypoid lesion. The loop is then tightened and the lesion is
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Visible lesion in BE segment.
slowly resected using electric cutting current. This is suitable for polypoid tumors (type 1), but is difficult for flat lesions. Submucosal injection of a solution can lift flat or depressed lesions and make them easier to resect (the liftand-cut technique). Injection of a saline– epinephrine solution into the submucosa lifts the early carcinoma, potentially reducing the risk of perforation. The epinephrine also provides better hemostasis. 2. Grasping technique In addition to the above techniques, EMR using a doublechannel endoscope has been described. In this technique, a grasping forcep is used to pull the target lesion through a diathermy loop, which is introduced through the second
Figure 2 Submucosal injection with lift sign. (Color version of figure is available online at www.techgiendoscopy.com.)
Figure 3 Snare loaded on inner legde of plastic EMR cap. (Color version of figure is available online at www.techgiendoscopy. com.)
channel. This procedure is technically demanding especially at the GEJ, where retroflexion may be needed, and the large diameter of the endoscope makes this difficult.35 3. Suck-and-cut technique This technique is perhaps the most used currently. Inoue and coworkers developed the cap technique (EMRC), improving the effectiveness of EMR compared with the strip biopsy.5 In this technique, a specially developed transparent plastic cap is attached to the end of the endoscope. After submucosal injection under the target lesion, the lesion is sucked into the cap and resected with a snare that was previously loaded into the specially designed groove on the
Figure 4 Resection site after EMR completed. (Color version of figure is available online at www.techgiendoscopy.com.)
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111 scribed.37,38 A standard injection needle is inserted at an oblique angle to inject the solution in to the submucosal space and elevate the lesion. Initial injection of the distal aspect of the lesion has been advocated to optimize visibility and facilitate excision. Injection volumes generally range from 2 to 30 mL and can be repeated during the procedure as necessary.39 Nonlifting of the lesion may be due to incorrect positioning of the needle or may indicate underlying fibrosis or malignant invasion into deeper layers, rendering the lesion unsuitable for EMR.40
EMRC versus EMRL
Figure 5 Band placed over lesion to be resected. (Color version of figure is available online at www.techgiendoscopy.com.)
lower edge of the cap. Marking the perimeter of the lesion before resection can be done, as the margins may become indistinct after the submucosal injection (Figures 1-4). The suck-and-cut technique may also be performed by using a ligation device (EMRL). In this technique, the target lesion is sucked into the ligation device cylinder, and releasing a rubber band around the lesion creates a polyp. The polyp can then be resected at its base, either above or below the band using a hexagonal snare, which is passed through the working channel of the endoscope (Figures 5 and 6). Multiple EMRs may be completed with one intubation with this device, with all EMR specimens being collected together using a net-like device at the end of the procedure. This does require the use of a therapeutic endoscope. The band is not typically strong enough to capture the muscularis propria, and so this limits the depth of the tissue that is caught within the band. However, perforations have been reported using the ligation method.36
These two techniques have been compared in randomized10 and nonrandomized studies.41 An initial nonrandomized study (using historical EMRC controls) reported that EMRC provides larger sample sizes though a subsequent randomized study found that specimen sizes with both the techniques were comparable (except in subjects with prior EMR where EMRL provided bigger specimens). EMRL has been reported to be faster and less expensive (given that multiple resections can be performed with the same snare and kit). The authors suggested that perhaps EMRL should be used to remove smaller lesions and flat dysplasia. Both techniques appear to be equally safe and effective, though EMRL may be technically easier to master given common experience with banding.
Focal versus circumferential EMR EMR can be applied focally (to resect a visible lesion only42,43) or circumferentially (to remove the entire BE
Other technical considerations Most EMR techniques incorporate a submucosal injection to separate the lesion from the muscularis propria. A normal saline solution, with or without epinephrine, is commonly employed. At the author’s institution, saline epinephrine solution in a concentration of 1:200,000 is used to minimize cardiovascular effects, particularly in older patients. However, saline diffuses quickly and the use of other solutions, such as hypertonic saline, 10% glycerol/5% fructose, 50% dextrose and sodium hyaluronate, has been de-
Figure 6 Lesion being resected with hexagonal snare. (Color version of figure is available online at www.techgiendoscopy.com.)
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segment,44,45). Initial studies have used the focal EMR approach with EMR being used to assess and remove only visible lesions for diagnostic and therapeutic purposes followed by ablation of the remaining visible BE segment to reduce the risk of recurrent dysplasia or neoplasia or have opted to survey the remaining BE segment. This is an important concept as one of the limitations of endoscopic therapy is the potential recurrence of dysplasia and neoplasia: ablation aims to reduce recurrence rates (reported to occur in 11-26% of subjects in follow-up12,43,46) by eliminating all at-risk mucosa. Studies have provided some evidence to support this approach; a large nonrandomized cohort study from Europe finding that application of ablative therapy after induction of initial remission with EMR was predictive of decreased recurrence.42 Another large study from the United States also found that presence of any residual dysplastic BE mucosa after initial induction of remission with EMR in patients with IMCA predicted recurrent carcinoma.43 However, randomized studies to support this concept are lacking and critically needed to help guide decision making. An alternative approach to reducing recurrence is circumferential EMR (cEMR), where the entire BE segment is sequentially resected using EMR. This technique aims to remove all at-risk tissue, providing tissue for histopathologic analysis (which may an advantage given the spotty distribution of dysplasia and neoplasia in BE segments) in contrast to ablation techniques, which do not provide tissue for histology. However the need for multiple EMRs with added risk of increased complications, such as perforation and stricture formation, needs to be factored into this approach. Two studies have reported relatively short-term outcomes following this approach. In 1 recent study,45 49 patients were treated with cEMR. Thirty-three had HGD and 16 had IMCA. cEMR therapy was completed in 32 patients by an average of 2.1 sessions. Surveillance biopsies showed normal squamous epithelium in 31 of 32 (96.9%) patients (mean remission time 22.9 months). In all, 10 of 46 patients who continued in the endoscopic protocol had subsquamous Barrett’s epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barrett’s underneath squamous mucosa on most recent surveillance biopsies. cEMR upstaged pre-EMR pathology results in 7 of 49 (14%) of patients and downstaged pathology in 15 of 49 (31%) patients. Notably, 18 of 49 (37%) patients developed symptomatic esophageal stenosis; all were successfully managed by endoscopic treatment. No perforations or uncontrollable bleeding occurred. A second study from Europe47 reported similar results in 41 patients with HGD or IMC. They reported complete squamous epithelialization in 75% of these patients (with a mean follow-up of 31 months), but with complications in 9 patients (14%): these included 2 perforations and 8 bleeds. They reported only 1 stricture. It should be noted that removal of all visible BE epithelium with this technique can be challenging given the circular nature of the device, with
intervening ridges being left out. This may necessitate the use of additional techniques, such as argon plasma coagulation, to eliminate this tissue. The use of an endoscopically placed extracellular matrix scaffold in preventing stricture formation following cEMR has been shown in an animal model48; feasibility and effectiveness in humans will help make this technique more suitable to widespread application. A recent randomized study reported in abstract form49 compared results from these 2 approaches: focal EMR followed by RFA versus cEMR. Forty-seven patients were randomized to these 2 approaches: 25 to cEMR and 22 to RFA. Of note only patients with less than 5 cm of BE were included. Complete eradication of all intestinal metaplasia (CR-IM) was achieved in 95% and 96% of subjects in both groups. The median number of sessions required to reach this end point was similar: 2 in the cEMR group and 3 in the RFA group. In the cEMR group there were more complications: 1 perforation (5%), 5 immediate bleeds, and strictures (86%) compared with the EMR and RFA group which had 1 delayed bleed (5%) and strictures (17%). Given this, the authors favored the approach of focal EMR followed by RFA to ablate the remaining BE segment to the cEMR approach.
Post-EMR care and management of antiplatelet and anticoagulant use EMR is performed as an ambulatory procedure in most Western Centers. In Asia, patients are often hospitalized after EMR. Patients are advised to be on clear liquids for 24 hours following EMR and avoid the use of aspirin and all nonsteroidal anti-inflammatory medications for the next 2 weeks in our unit. They are advised to seek medical attention should they experience any signs of overt gastrointestinal bleeding. Management of anticoagulants depends on the risk status of the patient for thrombosis. Generally, our unit follows standard guidelines in terms of bridging patients at high risk with low molecular weight heparin after stopping anticoagulants and after the procedure until the patient can be anticoagulated with the normal regimen.50 Platelet inhibitors are usually held for a week prior to EMR in patients who are at low risk of thrombosis. In those deemed to be at a high risk of thrombosis, delaying EMR until advisable is reasonable.
Pathologic interpretation of specimens Resected specimens should ideally be interpreted by dedicated GI pathologists. The specimens are fixed in formalin, serially sectioned (“bread-loaf” sectioning), and stained with hematoxylin-eosin. They are assessed for size, histology, tumor grade, extent of tumor penetration and margins (lateral and deep), and completeness of resection.21 EMR specimens provide accurate staging of Barrett’s neoplasia when compared with esophagectomy specimens. Negative EMR mar-
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gins reliably predict the absence of neoplasia at the site of EMR24 and thus obviate the need for additional EMR at that site. Conversely, the presence of submucosal invasion would be an indication to cease EMR as these patients would require surgery.
113 the mortality risk from an esophagectomy.5,46 Patients with HGD and IMCA with visible lesions with a diameter less than 2 cm, no lymphovascular invasion, and well or moderately differentiated histology may be suitable to undergo curative treatment with EMR.8
Invasive adenocarcinoma
Post-EMR complications/limitations EMR is generally well tolerated when performed by experienced endoscopists. The main complications include bleeding, perforation, and esophageal strictures. The overall complication rate is 13-17%42,43 in the two largest reported series, but these included minor bleeding which did not result in a drop in hemoglobin. Serious complications are rare. The rate of esophageal stricture formation is 6-23%.43,51 These are more likely to occur after cEMR52 and when used in combination with PDT.53-55 These are usually amenable to serial dilatations. The risk of bleeding is 0.6-11%,42,43 depending on the definition used in studies. Most of the bleeding episodes reported refer to minor bleeding episodes that do not decrease hemoglobin levels or necessitate blood transfusion. Clinically significant bleeding requiring transfusion, hospitalization, or endoscopic therapy occurs in 3.6%. Arterial bleeding is uncommon. Hemostasis may be secured in the vast majority by the application of hemoclips. Perforations have been reported in 0-2.5% of procedures.42,43,56 The two largest series of EMR in BE did not report any perforations. These may be managed conservatively with the application of hemoclips if they are recognized during the EMR followed by broad spectrum antibiotics. Sealing the perforation with a covered removable esophageal stent has also been reported. EMR is limited in its ability to achieve en bloc resection for lesions larger than 20 mm in diameter.57 Piecemeal resections are required and these are associated with an increased risk of tumor recurrence.58 The lateral margins are difficult to assess with multiple EMR. The rearrangement of multiple specimens obtained from piecemeal resection as well as the artifacts induced by electrocautery can cause uncertainty in pathologic staging. As a result, lateral spread of tumor is not accurately assessed with reconstruction after piecemeal resection.
Indications for EMR in Barrett’s-related neoplasia Barrett’s HGD and intramucosal adenocarcinoma EMR as a component of endoscopic therapy has been accepted as a valid treatment alternative to esophagectomy for HGD and intramucosal adenocarcinoma occurring in the setting of BE.2 Esophageal adenocarcinoma that is confined to the mucosa has a 0-4% risk of lymph node metastases,59,60 though more recent studies have quoted a slightly higher risk of nodal metastases.43-45 This is comparable to
Tumors that extend to the submucosa have a much higher risk of nodal involvement, at least 25%.11,42 Patients with submucosal disease are not candidates for resection and should be considered for surgery. There may be a subgroup of patients with submucosal cancers in whom EMR may yet have a role. Lymph node metastases have been reported to be virtually absent in adenocarcinoma confined to the upper third of the submucosa (sm1).59,61 The Wiesbaden group has shown that patients with tumor invasion confined to the upper third of the submucosa may be considered for ER if the cancers are low grade and do not demonstrate lymphovascular infiltration.62 However accurate delineation of depth of submucosal infiltration requires a full-thickness resection of the submucosa, which presently can only be achieved with surgical resection. Endoscopically resected specimens only contain part of the submucosa. Hence, the fraction of submucosal penetration can only be estimated. A more objective method of stratifying extent of submucosal invasion by measuring the depth from the muscularis mucosa has been described in squamous cell carcinoma and shown to predict the presence of nodal metastases.63 It is noteworthy that these results were obtained from esophagectomy specimens. The measurement of submucosal depth in endoscopically resected specimens may be confounded by artefacts from saline injection and electrocautery during EMR. Based on current evidence, the resection of submucosal esophageal cancers should presently be performed in the context of research protocols.64
Barrett’s low-grade dysplasia Should low-grade dysplasia and nondysplastic BE be treated with ER? The risk of progression to adenocarcinoma in these patients is 0.6% and 0.5% per year, respectively,65 which is lower than the rate of complications from ER. Furthermore, the eradication of intestinal metaplasia has not been shown to obviate the need for continued surveillance in these patients as recurrence of intestinal metaplasia can occur following endoscopic therapy. Expanding current indications to include this subgroup of patients would substantially increase the number of patients eligible for treatment without any foreseeable reduction in the disease burden. Hence, ER of low-grade and nondysplastic BE cannot be recommended at present.
Outcomes Data from single-center cohort studies report complete remission rates of 94-96% in patients undergoing ER with
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or without ablation for HGD and intramucosal adenocarcinoma.42,43 Several sessions of ER may be required to achieve eradication of the dysplastic mucosa. Recurrences of dysplasia or cancer have been reported in 11-21% of patients after a mean follow-up of 43-63 months. These are usually amenable to endoscopic retreatment. The risk of recurrence is higher in patients with long-segment BE and those who had piecemeal resection and/or multifocal neoplasia. Patients who have undergone resection should undergo continued endoscopic surveillance.
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Combination of EMR with ablation ER of modular mucosa may be combined with ablation of the residual dysplastic mucosa by either RFA or PDT in patients with long-segment BE. The ablation is performed at least 4 weeks after the resection to allow for the resected mucosa to heal prior to ablation. The role of combination therapy is less well-defined. It may be associated with a lower risk of recurrence.42 RFA is well tolerated,66 but the risk of esophageal strictures is increased with concomitant PDT.55 cEMR may be associated with lower rates of recurrence, but the rate of esophageal stenoses is much higher at 12-56%.
Acknowledgments This work is supported by The Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, the American College of Gastroenterology (Junior Faculty Development Award to GAP), and the National Cancer Institute (R03 CA 135991-01 to GAP).
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32. Leung KK, Maru D, Abraham S, et al: Optical EMR: Confocal endomicroscopy-targeted EMR of focal high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 69:170-172, 2009 33. The Paris endoscopic classification of superficial neoplastic lesions: Esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 58:S44-S45, 2003 34. Lambert R, et al: Superficial neoplastic lesions in the digestive tract. Endoscopy 37:570-578, 2005 35. Noda M, Kobayashi N, Kanemasa H, et al: Endoscopic mucosal resection using a partial transparent hood for lesions located tangentially to the endoscope. Gastrointest Endosc 51:338-343, 2000 36. Gerke H, Siddiqui J, Parekh KR, et al: Esophageal perforation complicating band ligator-assisted mucosal resection. Gastrointest Endosc 69:153-154, 2009; discussion:154 37. Hirao M, Masuda K, Asanuma T, et al: Endoscopic resection of early gastric cancer and other tumors with local injection of hypertonic saline-epinephrine. Gastrointest Endosc 34:264-269, 1988 38. Yamamoto H, Yube T, Isoda N, et al: A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 50: 251-256, 1999 39. Waye JD: New methods of polypectomy. Gastrointest Endosc Clin North Am 7:413-422, 1997 40. Uno Y, Munakata A: The non-lifting sign of invasive colon cancer [see comment]. Gastrointest Endosc 40:485-489, 1994 41. Peters FP, Kara MA, Curvers WL, et al: Multiband mucosectomy for endoscopic resection of Barrett’s esophagus: Feasibility study with matched historical controls. Eur J Gastroenterol Hepatol 19:311-315, 2007 42. 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 57:1200-1206, 2008 43. Prasad GA, Wu TT, Wigle DA, et al: Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology 137:815-823, 2009 44. Larghi A, Lightdale CJ, Ross AS, et al: Long-term follow-up of complete Barrett’s eradication endoscopic mucosal resection (CBEEMR) for the treatment of high grade dysplasia and intramucosal carcinoma. Endoscopy 39:1086-1091, 2007 45. 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 104:2684-2692, 2009 46. Pech O, Gossner L, May A, et al: Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc 62:24-30, 2005 47. Lopes CV, Hela M, Pesenti C, et al: Circumferential endoscopic resection of Barrett’s esophagus with high-grade dysplasia or early adenocarcinoma. Surg Endosc 21:820-824, 2007 48. Nieponice A, McGrath K, Qureshi I, et al: An extracellular matrix scaffold for esophageal stricture prevention after circumferential EMR. Gastrointest Endosc 69:289-296, 2009 49. van Vilsteren FG, Pouw RE, Seewald SE, et al: A multicenter randomized trial comparing stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s esophagus containing high grade
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dysplasia and/or early cancer. Gastrointest Endosc 69:AB 133, -939, 2009 Eisen GM, Baron TH, Dominitz JA, et al: Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 55:775-779, 2002 Pech O, Gossner L, Manner H, et al: Prospective evaluation of the macroscopic types and location of early Barrett’s neoplasia in 380 lesions. Endoscopy 39:588-593, 2007 Seewald S, Ang TL, Gotoda T, et al: Total endoscopic resection of Barrett esophagus. Endoscopy 40:1016-1020, 2008 Buttar NS, Wang KK, Lutzke LS, et al: Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest Endosc 54:682-688, 2001 Pacifico RJ, Wang KK, Wongkeesong LM, et al: Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett’s esophagus. Clin Gastroenterol Hepatol 1:252-257, 2003 Prasad GA, Wang KK, Buttar NS, et al: Predictors of stricture formation after photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 65:60-66, 2007 Kodama M, Kakegawa T: Treatment of superficial cancer of the esophagus: A summary of responses to a questionnaire on superficial cancer of the esophagus in Japan. Surgery 123:432-439, 1998 Ishihara R, Iishi H, Takeuchi Y, et al: Local recurrence of large squamous-cell carcinoma of the esophagus after endoscopic resection. Gastrointest Endosc 67:799-804, 2008 Esaki M, Matsumoto T, Hirakawa K, et al: Risk factors for local recurrence of superficial esophageal cancer after treatment by endoscopic mucosal resection. Endoscopy 39:41-45, 2007 Buskens CJ, Westerterp M, Lagarde SM, et al: Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features. Gastrointest Endosc 60:703-710, 2004 Ancona E, Rampado S, Cassaro M, et al: Prediction of lymph node status in superficial esophageal carcinoma. Ann Surg Oncol 15:32783288, 2008 Westerterp M, Koppert LB, Buskens CJ, et al: Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 446:497-504, 2005 Manner H, May A, Pech O, et al: Early Barrett’s carcinoma with “low-risk” submucosal invasion: Long-term results of endoscopic resection with a curative intent.. Am J Gastroenterol 103:2589-2597, 2008 Tajima Y, Nakanishi Y, Ochiai A, et al: Histopathologic findings predicting lymph node metastasis and prognosis of patients with superficial esophageal carcinoma: Analysis of 240 surgically resected tumors. Cancer 88:1285-1293, 2000 Badreddine RJ, Prasad GA, Lewis JT, et al: Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma. Clin Gastroenterol Hepatol 8:248253, 2010 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 4:566-572, 2006 Pouw RE, Sharma VK, Bergman JJ, et al: Radiofrequency ablation for total Barrett’s eradication: A description of the endoscopic technique, its clinical results and future prospects. Endoscopy 40:1033-1040, 2008
Techniques in GASTROINTESTINAL ENDOSCOPY www.techgiendoscopy.com
Endoscopic mucosal resection Ganapathy A. Prasad, MD, MS, Vikneswaran Namasivayam, MD Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. KEYWORDS: Endoscopic mucosal resection; Dysplasia; Esophageal adenocarcinoma; Barrett’s esophagus; Complications; Outcomes
Endoscopic Mucosal Resection is a well established diagnostic and therapeutic technique in the management of esophageal neoplasia arising in the background of Barrett’s esophagus. It is a valuable adjunct to ablative techniques for the treatment of dysplasia Barrett’s esophagus. This article reviews the rationale, indications, methods and outcomes of endoscopic mucosal resection in Barrett’s esophagus. © 2010 Published by Elsevier Inc.
Endoscopic therapy in patients with Barrett’s espohagus (BE)-related neoplasia has advanced from being considered experimental therapy to being a well-accepted therapeutic option.1,2 The overall goal of endoscopic therapy is the complete and durable elimination of esophageal columnar mucosa to ultimately decrease the incidence of esophageal adenocarcinoma, of which BE is the strongest risk factor.3,4 Techniques available for endoscopic therapy in BE can be broadly categorized into those that provide tissue for histologic examination (endoscopic resection [ER]: focal or circumferential and endoscopic submucosal dissection) and those that do not. The latter can be further classified into: thermal techniques (radiofrequency ablation [RFA], multipolar electrocoagulation, and argon plasma coagulation), photochemical techniques (photodynamic therapy [PDT]), and cryotherapy. Multimodality therapy (using a resection technique to target visible abnormalities followed by an ablation technique to eradicate the remaining BE segment) is most often used for the comprehensive management of BE-associated neoplasia. Endoscopic mucosal resection (EMR) is a technique initially introduced and popularized in Asia, for the treatment of early upper gastrointestinal (esophageal and gastric) cancers.5-7 The technique has been increasingly accepted
The authors report no direct financial interests that might pose a conflict of interest in connection with the submitted manuscript. Address reprint requests to Ganapathy A. Prasad MD, MS, GI Diagnostic Unit, Alfred Main, 200 1st Street SW, Rochester, MN 55905. E-mail: [email protected]
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and practiced in Europe and the United States over the past few years.8-13 Though the technique was initially developed for the endoscopic treatment of malignant lesions, it has also been used for the treatment of benign lesions in the esophagus.14 Most of the early experience with EMR was in its application in the treatment of early esophageal and gastric cancers. It has since evolved into an effective diagnostic, staging, and treatment strategy for gastrointestinal cancers confined to the mucosa. It fulfills the long-identified need to obtain precise information regarding the depth of tumor invasion and neoplastic margins before additional endoscopic ablative therapy. With the proliferation of ablation techniques, the need for EMR is now recommended for any suspicious neoplastic lesion. In this review, we will focus on the indications, methods, and role of EMR in the management of esophageal neoplasia arising in BE.
Why is EMR helpful? The histologic assessment of dysplasia in BE by biopsies is confounded by multiple factors: scattered distribution of dysplasia/neoplasia in the BE segment15 making identification challenging, interobserver variability among interpreting pathologists,16,17 poor predictive value of dysplasia,18 and the inability to assess margins, to name a few. EMR overcomes some of these limitations, making it a valuable tool in the management of patients with BE neoplasia. The interobserver agreement between 9 academic pathologists (in assigning grades of dysplasia on histopathologic
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samples from 25 patients) was compared between biopsy specimens and EMR specimens.19 The authors reported that the interobserver agreement of BE-related neoplasia on EMR specimens is significantly higher compared with biopsy specimens. Increased size of tissue specimens and the ability to assess landmarks, such as the muscularis mucosae, most likely led to these improved outcomes. In addition, providing deeper and larger tissue specimens also leads to upstaging of the diagnosis [in terms of the grade of dysplasia, for example from high-grade dysplasia (HGD) to intramucosal carcinoma (IMCA)] in as many as 40% of subjects following EMR compared with initial biopsy diagnosis.20-22 Precise staging of tumor depth invasion (particularly distinguishing mucosal from submucosal invasion, which has a crucial impact on management: determining suitability for endoscopic therapy) can be achieved by EMR, often with greater accuracy than by endoscopic ultrasound (EUS).20,23 This is of particular importance given that the rate of LN involvement in mucosal lesions is low (5% or less) making them suitable to endoscopic therapy, in contrast to submucosal cancers with substantially higher rates (⬎20%) making them unsuitable to endoscopic therapy. EMR specimens also make assessment of margins possible and the use of EMR margins in predicting residual tumor at esophagectomy has been validated.24 In addition, the performance of EMR does not appear to influence esophagectomy adversely (in terms of intraoperative or perioperative complications), if that were required following EMR.25 EMR may also be used to provide real-time data on pathology with reasonable accuracy to determine whether additional EMR is required or to determine margins of resection, using frozen sections.26
Pre-EMR evaluation The use of EMR as a diagnostic and therapeutic tool hinges on careful assessment and exclusion of widespread metastatic disease in patients being evaluated for BE-related neoplasia. In subjects with HGD or IMCA, determination of disease extension beyond the esophagus (to lymph nodes and other organs) is usually accomplished by EUS and CT scans. However, EUS has only modest accuracy in delineating the T stage of esophageal cancers20,27,28 as the assessment of tumor depth may be confounded by ongoing inflammation as well as the inability to pass the echoendoscope through a stenosed segment. The use of high-frequency ultrasound probes has not improved the accuracy of T staging despite better delineation of the esophageal wall. This may be partly attributed to the difficulties in obtaining perpendicular images with the probe at the gastroesophageal junction, especially if there is a hiatus hernia.23 There is also the problem with acoustical coupling required for ultrasound imaging. The standard balloon devices used compress lesions and make it difficult to even identify early neoplasia,
109 Table 1 Paris classification: The macroscopic classification of type 0 digestive tract lesions, with a superficial appearance at endoscopy Protruding Pedunculated Sessile Nonprotruding and nonexcavated Slightly elevated Completely flat Slightly depressed Elevated and depressed types Excavated Ulcer Excavated and depressed types
0 ⫺ 1p 0 ⫺ 1s 0 0 0 0 0
⫺ ⫺ ⫺ ⫾ ⫾
IIa IIb IIc IIc ⫹ IIa IIa ⫹ IIc
0 ⫾ III 0 ⫾ IIc ⫹ III 0 ⫾ III ⫹ IIc
Adapted from Lambert, et al34
whereas the alternative, water filling the lumen, is not practical in certain areas of the esophagus or stomach. In addition, careful inspection and evaluation of the BE segment using high-definition white light imaging, narrow band imaging, and other promising imaging tools being investigated (such as autofluorescence imaging and confocal endomicroscopy) may enable more precise and accurate identification of visible lesions29 that have been correlated with prevalent advanced dysplasia.30,31 Recent reports have described the use of targeting EMR using these advanced imaging techniques.32 Once lesions are targeted, the endoscopic appearance of the lesion may suggest submucosal spread, making the lesion less suitable for EMR. An international working group had proposed the Paris endoscopic classification to characterize superficial neoplastic lesions by their endoscopic appearance to predict the likelihood of submucosal invasion.33 Most superficial esophageal carcinoma lesions are nonprotruding, and these carry a lower risk of submucosal invasion compared with protruding and excavated lesions.22 Submucosal infiltration in Barrett’s neoplasia is more often encountered in protruding and depressed lesions22 as well as in moderately differentiated tumors compared with well-differentiated tumors in a large study of over 200 EMR specimens (Table 1).
How is EMR performed? ER involves the removal of mucosal and submucosal tissue following submucosal injection, using a variety of techniques. There are many techniques that have been described, as listed below, with cap-assisted techniques being used the most commonly.
EMR Techniques 1. Strip biopsy technique In this technique, a diathermy loop is introduced through the working channel of the endoscope and positioned over a polypoid lesion. The loop is then tightened and the lesion is
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Visible lesion in BE segment.
slowly resected using electric cutting current. This is suitable for polypoid tumors (type 1), but is difficult for flat lesions. Submucosal injection of a solution can lift flat or depressed lesions and make them easier to resect (the liftand-cut technique). Injection of a saline– epinephrine solution into the submucosa lifts the early carcinoma, potentially reducing the risk of perforation. The epinephrine also provides better hemostasis. 2. Grasping technique In addition to the above techniques, EMR using a doublechannel endoscope has been described. In this technique, a grasping forcep is used to pull the target lesion through a diathermy loop, which is introduced through the second
Figure 2 Submucosal injection with lift sign. (Color version of figure is available online at www.techgiendoscopy.com.)
Figure 3 Snare loaded on inner legde of plastic EMR cap. (Color version of figure is available online at www.techgiendoscopy. com.)
channel. This procedure is technically demanding especially at the GEJ, where retroflexion may be needed, and the large diameter of the endoscope makes this difficult.35 3. Suck-and-cut technique This technique is perhaps the most used currently. Inoue and coworkers developed the cap technique (EMRC), improving the effectiveness of EMR compared with the strip biopsy.5 In this technique, a specially developed transparent plastic cap is attached to the end of the endoscope. After submucosal injection under the target lesion, the lesion is sucked into the cap and resected with a snare that was previously loaded into the specially designed groove on the
Figure 4 Resection site after EMR completed. (Color version of figure is available online at www.techgiendoscopy.com.)
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111 scribed.37,38 A standard injection needle is inserted at an oblique angle to inject the solution in to the submucosal space and elevate the lesion. Initial injection of the distal aspect of the lesion has been advocated to optimize visibility and facilitate excision. Injection volumes generally range from 2 to 30 mL and can be repeated during the procedure as necessary.39 Nonlifting of the lesion may be due to incorrect positioning of the needle or may indicate underlying fibrosis or malignant invasion into deeper layers, rendering the lesion unsuitable for EMR.40
EMRC versus EMRL
Figure 5 Band placed over lesion to be resected. (Color version of figure is available online at www.techgiendoscopy.com.)
lower edge of the cap. Marking the perimeter of the lesion before resection can be done, as the margins may become indistinct after the submucosal injection (Figures 1-4). The suck-and-cut technique may also be performed by using a ligation device (EMRL). In this technique, the target lesion is sucked into the ligation device cylinder, and releasing a rubber band around the lesion creates a polyp. The polyp can then be resected at its base, either above or below the band using a hexagonal snare, which is passed through the working channel of the endoscope (Figures 5 and 6). Multiple EMRs may be completed with one intubation with this device, with all EMR specimens being collected together using a net-like device at the end of the procedure. This does require the use of a therapeutic endoscope. The band is not typically strong enough to capture the muscularis propria, and so this limits the depth of the tissue that is caught within the band. However, perforations have been reported using the ligation method.36
These two techniques have been compared in randomized10 and nonrandomized studies.41 An initial nonrandomized study (using historical EMRC controls) reported that EMRC provides larger sample sizes though a subsequent randomized study found that specimen sizes with both the techniques were comparable (except in subjects with prior EMR where EMRL provided bigger specimens). EMRL has been reported to be faster and less expensive (given that multiple resections can be performed with the same snare and kit). The authors suggested that perhaps EMRL should be used to remove smaller lesions and flat dysplasia. Both techniques appear to be equally safe and effective, though EMRL may be technically easier to master given common experience with banding.
Focal versus circumferential EMR EMR can be applied focally (to resect a visible lesion only42,43) or circumferentially (to remove the entire BE
Other technical considerations Most EMR techniques incorporate a submucosal injection to separate the lesion from the muscularis propria. A normal saline solution, with or without epinephrine, is commonly employed. At the author’s institution, saline epinephrine solution in a concentration of 1:200,000 is used to minimize cardiovascular effects, particularly in older patients. However, saline diffuses quickly and the use of other solutions, such as hypertonic saline, 10% glycerol/5% fructose, 50% dextrose and sodium hyaluronate, has been de-
Figure 6 Lesion being resected with hexagonal snare. (Color version of figure is available online at www.techgiendoscopy.com.)
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segment,44,45). Initial studies have used the focal EMR approach with EMR being used to assess and remove only visible lesions for diagnostic and therapeutic purposes followed by ablation of the remaining visible BE segment to reduce the risk of recurrent dysplasia or neoplasia or have opted to survey the remaining BE segment. This is an important concept as one of the limitations of endoscopic therapy is the potential recurrence of dysplasia and neoplasia: ablation aims to reduce recurrence rates (reported to occur in 11-26% of subjects in follow-up12,43,46) by eliminating all at-risk mucosa. Studies have provided some evidence to support this approach; a large nonrandomized cohort study from Europe finding that application of ablative therapy after induction of initial remission with EMR was predictive of decreased recurrence.42 Another large study from the United States also found that presence of any residual dysplastic BE mucosa after initial induction of remission with EMR in patients with IMCA predicted recurrent carcinoma.43 However, randomized studies to support this concept are lacking and critically needed to help guide decision making. An alternative approach to reducing recurrence is circumferential EMR (cEMR), where the entire BE segment is sequentially resected using EMR. This technique aims to remove all at-risk tissue, providing tissue for histopathologic analysis (which may an advantage given the spotty distribution of dysplasia and neoplasia in BE segments) in contrast to ablation techniques, which do not provide tissue for histology. However the need for multiple EMRs with added risk of increased complications, such as perforation and stricture formation, needs to be factored into this approach. Two studies have reported relatively short-term outcomes following this approach. In 1 recent study,45 49 patients were treated with cEMR. Thirty-three had HGD and 16 had IMCA. cEMR therapy was completed in 32 patients by an average of 2.1 sessions. Surveillance biopsies showed normal squamous epithelium in 31 of 32 (96.9%) patients (mean remission time 22.9 months). In all, 10 of 46 patients who continued in the endoscopic protocol had subsquamous Barrett’s epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barrett’s underneath squamous mucosa on most recent surveillance biopsies. cEMR upstaged pre-EMR pathology results in 7 of 49 (14%) of patients and downstaged pathology in 15 of 49 (31%) patients. Notably, 18 of 49 (37%) patients developed symptomatic esophageal stenosis; all were successfully managed by endoscopic treatment. No perforations or uncontrollable bleeding occurred. A second study from Europe47 reported similar results in 41 patients with HGD or IMC. They reported complete squamous epithelialization in 75% of these patients (with a mean follow-up of 31 months), but with complications in 9 patients (14%): these included 2 perforations and 8 bleeds. They reported only 1 stricture. It should be noted that removal of all visible BE epithelium with this technique can be challenging given the circular nature of the device, with
intervening ridges being left out. This may necessitate the use of additional techniques, such as argon plasma coagulation, to eliminate this tissue. The use of an endoscopically placed extracellular matrix scaffold in preventing stricture formation following cEMR has been shown in an animal model48; feasibility and effectiveness in humans will help make this technique more suitable to widespread application. A recent randomized study reported in abstract form49 compared results from these 2 approaches: focal EMR followed by RFA versus cEMR. Forty-seven patients were randomized to these 2 approaches: 25 to cEMR and 22 to RFA. Of note only patients with less than 5 cm of BE were included. Complete eradication of all intestinal metaplasia (CR-IM) was achieved in 95% and 96% of subjects in both groups. The median number of sessions required to reach this end point was similar: 2 in the cEMR group and 3 in the RFA group. In the cEMR group there were more complications: 1 perforation (5%), 5 immediate bleeds, and strictures (86%) compared with the EMR and RFA group which had 1 delayed bleed (5%) and strictures (17%). Given this, the authors favored the approach of focal EMR followed by RFA to ablate the remaining BE segment to the cEMR approach.
Post-EMR care and management of antiplatelet and anticoagulant use EMR is performed as an ambulatory procedure in most Western Centers. In Asia, patients are often hospitalized after EMR. Patients are advised to be on clear liquids for 24 hours following EMR and avoid the use of aspirin and all nonsteroidal anti-inflammatory medications for the next 2 weeks in our unit. They are advised to seek medical attention should they experience any signs of overt gastrointestinal bleeding. Management of anticoagulants depends on the risk status of the patient for thrombosis. Generally, our unit follows standard guidelines in terms of bridging patients at high risk with low molecular weight heparin after stopping anticoagulants and after the procedure until the patient can be anticoagulated with the normal regimen.50 Platelet inhibitors are usually held for a week prior to EMR in patients who are at low risk of thrombosis. In those deemed to be at a high risk of thrombosis, delaying EMR until advisable is reasonable.
Pathologic interpretation of specimens Resected specimens should ideally be interpreted by dedicated GI pathologists. The specimens are fixed in formalin, serially sectioned (“bread-loaf” sectioning), and stained with hematoxylin-eosin. They are assessed for size, histology, tumor grade, extent of tumor penetration and margins (lateral and deep), and completeness of resection.21 EMR specimens provide accurate staging of Barrett’s neoplasia when compared with esophagectomy specimens. Negative EMR mar-
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gins reliably predict the absence of neoplasia at the site of EMR24 and thus obviate the need for additional EMR at that site. Conversely, the presence of submucosal invasion would be an indication to cease EMR as these patients would require surgery.
113 the mortality risk from an esophagectomy.5,46 Patients with HGD and IMCA with visible lesions with a diameter less than 2 cm, no lymphovascular invasion, and well or moderately differentiated histology may be suitable to undergo curative treatment with EMR.8
Invasive adenocarcinoma
Post-EMR complications/limitations EMR is generally well tolerated when performed by experienced endoscopists. The main complications include bleeding, perforation, and esophageal strictures. The overall complication rate is 13-17%42,43 in the two largest reported series, but these included minor bleeding which did not result in a drop in hemoglobin. Serious complications are rare. The rate of esophageal stricture formation is 6-23%.43,51 These are more likely to occur after cEMR52 and when used in combination with PDT.53-55 These are usually amenable to serial dilatations. The risk of bleeding is 0.6-11%,42,43 depending on the definition used in studies. Most of the bleeding episodes reported refer to minor bleeding episodes that do not decrease hemoglobin levels or necessitate blood transfusion. Clinically significant bleeding requiring transfusion, hospitalization, or endoscopic therapy occurs in 3.6%. Arterial bleeding is uncommon. Hemostasis may be secured in the vast majority by the application of hemoclips. Perforations have been reported in 0-2.5% of procedures.42,43,56 The two largest series of EMR in BE did not report any perforations. These may be managed conservatively with the application of hemoclips if they are recognized during the EMR followed by broad spectrum antibiotics. Sealing the perforation with a covered removable esophageal stent has also been reported. EMR is limited in its ability to achieve en bloc resection for lesions larger than 20 mm in diameter.57 Piecemeal resections are required and these are associated with an increased risk of tumor recurrence.58 The lateral margins are difficult to assess with multiple EMR. The rearrangement of multiple specimens obtained from piecemeal resection as well as the artifacts induced by electrocautery can cause uncertainty in pathologic staging. As a result, lateral spread of tumor is not accurately assessed with reconstruction after piecemeal resection.
Indications for EMR in Barrett’s-related neoplasia Barrett’s HGD and intramucosal adenocarcinoma EMR as a component of endoscopic therapy has been accepted as a valid treatment alternative to esophagectomy for HGD and intramucosal adenocarcinoma occurring in the setting of BE.2 Esophageal adenocarcinoma that is confined to the mucosa has a 0-4% risk of lymph node metastases,59,60 though more recent studies have quoted a slightly higher risk of nodal metastases.43-45 This is comparable to
Tumors that extend to the submucosa have a much higher risk of nodal involvement, at least 25%.11,42 Patients with submucosal disease are not candidates for resection and should be considered for surgery. There may be a subgroup of patients with submucosal cancers in whom EMR may yet have a role. Lymph node metastases have been reported to be virtually absent in adenocarcinoma confined to the upper third of the submucosa (sm1).59,61 The Wiesbaden group has shown that patients with tumor invasion confined to the upper third of the submucosa may be considered for ER if the cancers are low grade and do not demonstrate lymphovascular infiltration.62 However accurate delineation of depth of submucosal infiltration requires a full-thickness resection of the submucosa, which presently can only be achieved with surgical resection. Endoscopically resected specimens only contain part of the submucosa. Hence, the fraction of submucosal penetration can only be estimated. A more objective method of stratifying extent of submucosal invasion by measuring the depth from the muscularis mucosa has been described in squamous cell carcinoma and shown to predict the presence of nodal metastases.63 It is noteworthy that these results were obtained from esophagectomy specimens. The measurement of submucosal depth in endoscopically resected specimens may be confounded by artefacts from saline injection and electrocautery during EMR. Based on current evidence, the resection of submucosal esophageal cancers should presently be performed in the context of research protocols.64
Barrett’s low-grade dysplasia Should low-grade dysplasia and nondysplastic BE be treated with ER? The risk of progression to adenocarcinoma in these patients is 0.6% and 0.5% per year, respectively,65 which is lower than the rate of complications from ER. Furthermore, the eradication of intestinal metaplasia has not been shown to obviate the need for continued surveillance in these patients as recurrence of intestinal metaplasia can occur following endoscopic therapy. Expanding current indications to include this subgroup of patients would substantially increase the number of patients eligible for treatment without any foreseeable reduction in the disease burden. Hence, ER of low-grade and nondysplastic BE cannot be recommended at present.
Outcomes Data from single-center cohort studies report complete remission rates of 94-96% in patients undergoing ER with
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or without ablation for HGD and intramucosal adenocarcinoma.42,43 Several sessions of ER may be required to achieve eradication of the dysplastic mucosa. Recurrences of dysplasia or cancer have been reported in 11-21% of patients after a mean follow-up of 43-63 months. These are usually amenable to endoscopic retreatment. The risk of recurrence is higher in patients with long-segment BE and those who had piecemeal resection and/or multifocal neoplasia. Patients who have undergone resection should undergo continued endoscopic surveillance.
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Combination of EMR with ablation ER of modular mucosa may be combined with ablation of the residual dysplastic mucosa by either RFA or PDT in patients with long-segment BE. The ablation is performed at least 4 weeks after the resection to allow for the resected mucosa to heal prior to ablation. The role of combination therapy is less well-defined. It may be associated with a lower risk of recurrence.42 RFA is well tolerated,66 but the risk of esophageal strictures is increased with concomitant PDT.55 cEMR may be associated with lower rates of recurrence, but the rate of esophageal stenoses is much higher at 12-56%.
Acknowledgments This work is supported by The Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, the American College of Gastroenterology (Junior Faculty Development Award to GAP), and the National Cancer Institute (R03 CA 135991-01 to GAP).
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