Endoscopic Mucosal Resection
- Author: Bruce D Greenwald, MD; Chief Editor: Kurt E Roberts, MD more...
Endoscopic mucosal resection (EMR) is a technique used for the staging and treatment of superficial neoplasms of the gastrointestinal (GI) tract. This technique was first developed in Japan for the treatment of early gastric cancer and has since spread in use throughout the world for various indications, including dysplastic Barrett mucosa and sessile colonic neoplasms. The utility of EMR rests in its ability to do the following:
Provide accurate histologic staging of superficial GI neoplasms
Provide a minimally invasive technique for removal of superficial malignancies
Several variations of EMR are currently used, including injection-assisted, cap-assisted, and ligation-assisted techniques. All adhere to the basic principles of identification and demarcation of the lesion, submucosal injection to lift the lesion, and endoscopic snare resection. By virtue of its overall safety and efficacy in appropriately selected patient populations, EMR has become firmly integrated into the diagnostic and treatment algorithms of superficial GI malignancies.
Endoscopic and ultrasonographic characterization of lesions
Several classification systems for the staging of early GI cancers that may aid in the prediction of lymph node metastases have been developed. Much of this work has been pioneered by Japanese gastroenterologists for the staging and treatment of EGC. The Japanese Society of Gastrointestinal Endoscopists (JSGE), working from large databases of early gastric cancer resections, classified lesions according to their endoscopic features and the implied risk of mural invasion. The subsequent Paris classification, developed in 2002 at an international consensus meeting, echoed the structure of the JSGE system.
Superficial (Type 0) lesions are divided into polypoid (0-I) and nonpolypoid categories (0-II), which are further subcategorized as pedunculated (0-Ip), sessile (0-Is), slightly elevated (0-IIa), flat (0-IIb), slightly depressed (0-IIc), or excavated (0-III). (See the image below.)
In the Vienna classification, lesions are divided into two broad categories, noninvasive (low-grade dysplasia, high-grade dysplasia [HGD]) and invasive (intramucosal cancer, cancer that infiltrates the submucosa).
High-frequency (≥20 MHz) endoscopic ultrasonography (EUS) produces an image of the mucosal wall comprising nine separate layers differentiated by their echogenicity. By carefully examining the depth of lesion penetration into the mucosal and submucosal layers (see the image below), one may determine the risk of lymph node metastases with greater precision. The mucosal layer is divided into upper, middle, and lower layers: m1 (epithelium), m2 (lamina propria), and m3 (muscularis mucosae). The submucosa is similarly divided into three layers: sm1, sm2, and sm3. The sm1 layer is further divided into sublayers a, b, and c on the basis of the lateral spread within the layer.
EMR may be considered for definitive treatment of superficial premalignant and well-differentiated to moderately differentiated malignant lesions of the GI tract in the absence of lymph node or distant metastases (T1mN0M0). It also plays an integral role in the staging algorithm of early GI cancers by providing a larger resection specimen than standard forceps biopsy, allowing accurate T staging and establishing the presence of lymphovascular involvement. Furthermore, pathologic examination of EMR resection specimens frequently leads to significant alterations in patient management.
Squamous cell carcinoma of esophagus
Previous criteria from the JSGE include a lesion size less than 2 cm and involvement of less than one third of the esophageal circumference. Disease-specific survival rates after EMR are as high as 95%, with a low rate of complications.[7, 8, 9] Staging EMR may be performed on lesions lacking architectural or EUS features suggestive of deep submucosal invasion (see Technical Considerations, below).
Barrett esophagus with dysplasia and early adenocarcinoma
The indications for EMR of Barrett esophagus (BE) with dysplasia (BE-D) and early adenocarcinoma (EAC) in BE are evolving. Interest in EMR as an adjunct or alternative to ablative therapies for BE with or without dysplasia or intramucosal carcinoma is growing. Accurate pathologic staging, the potential for cure, and a favorable safety profile are reported advantages of EMR in this setting.[10, 11, 12]
As with squamous neoplasms, accepted indications include well-differentiated to moderately differentiated lesions limited to the mucosal layer that are 2 cm or less in size. Investigations have demonstrated the efficacy of EMR applied to the treatment of larger lesions, as well as the complete eradication of BE with favorable results.
Early gastric cancer
As an established alternative to surgery, guidelines for the use of EMR in the treatment of early gastric cancer have been published by the JSGE. Criteria for treatment include well-differentiated to moderately differentiated intestinal type adenocarcinomas or papillary carcinomas of the following types :
Type I to 0-IIa lesions measuring less than 2 cm
Type 0-IIb to type 0-IIc without ulceration less than 1 cm
Expansion of these criteria has been proposed to include the following :
Lesions that are well-differentiated and up to 3 cm without ulceration or ulcer scar
Mucosal lesions less than 2 cm with ulcer or ulcer scar
sm1 lesions less than 2 cm without ulcer or ulcer scar
Poorly differentiated cancer less than 1 cm
EMR has been used in the treatment and staging of ampullary and periampullary adenomas, EACs, and ampullary submucosal lesions. Additional applications include nonampullary adenomas, neuroendocrine tumors, and submucosal lesions. Available evidence suggests that duodenal EMR may be associated with a substantial rate of complications, particularly in the treatment of submucosal lesions (see Technique, Complications).
EMR has been applied to the evaluation of submucosal lesions due in part to the often scant cellularity of fine-needle aspiration (FNA) specimens and the inability to establish the presence of malignancy with such specimens. In a study of gastric submucosal lesions 2 cm or less in size, EMR was shown to be safe and resulted in complete resection in a single session with the injection-assisted or cap-assisted techniques. Definitive histologic diagnosis was obtained in all cases, compared with an accuracy of 45.5% for EUS alone. Because of the risk of bleeding and perforation, treatment should be restricted to lesions arising in the submucosal layer as defined by EUS.
EMR is commonly used for the resection of laterally spreading benign lesions or EAC of the colon. The “lift-and-cut” technique is most commonly used, as opposed to cap-assisted or ligation-assisted EMR (see Technique). Appropriate indications include the following :
Well-differentiated or moderately differentiated tumors confined to the mucosa
Type 0-IIa lesions smaller than 2 cm
Type 0-IIb lesions smaller than 1 cm
Type 0-IIc lesions smaller than 1 cm
Additional indications also include those patients who refuse surgical intervention or in whom significant comorbidities are prohibitive. Successful removal of larger lesions has been well documented but is associated with higher recurrence rates, highlighting the need for intensive surveillance after EMR (see Periprocedural Care, Monitoring and Follow-up).[18, 19, 20]
Contraindications include the presence of or a high index of suspicion for lymph node or distant metastases (see Technical Considerations, below).
The nonlifting sign, defined as the failure of a lesion to elevate above the surrounding mucosa after submucosal injection underneath the lesion, has been established as a highly accurate and specific predictor of submucosal invasion by colonic lesions.
Biopsy of the lesion before EMR may result in a false-positive result due to fibrosis at the biopsy site. Because the result of mucosal biopsies is unlikely to alter treatment algorithms, biopsy prior to referral for EMR should be avoided. If biopsy is undertaken, minimization of the time interval between biopsy and EMR may help reduce false-positive results.
The presence of coagulopathy is a relative contraindication, in view of the risk of bleeding. Any contraindication that applies to standard endoscopy (eg, severe cardiopulmonary comorbidities) is also applicable to EMR.
Given the increasing risk of lymph node metastases associated with deeper tumor invasion of the wall, determination of the depth of lesion penetration is an integral step before EMR is considered. Early data from Japanese studies of therapy for early gastric cancer demonstrated that the risk of lymph node metastases increases from 2.7% for lesions confined to the mucosa to 18.6% with submucosal invasion. Additional analysis revealed that both endoscopic features of the lesion and the precise depth of penetration within the mucosal and submucosal layers further influence this risk.
The following two methods can be used to predict the depth of penetration:
Analysis of the endoscopic mucosal features of the target lesion (see the first image below)
Pre-EMR EUS and high-frequency EUS (see the second image below)
Certain lesion characteristics detectable on endoscopy (see Endoscopic and Ultrasonographic Characterization of Lesions, above) have been associated with risk of submucosal invasion, including the following :
Depression of the lesion
Size greater than 15 mm
Failure to lift with submucosal injection of saline (see Contraindications, above)
Smooth nonindented circumference for elevated (0-IIa) or depressed (0-IIc) lesions
For those lesions with submucosal invasion, the risk of lymph node metastases is further modified by the presence or absence of lymphovascular invasion on histologic examination. In one study of HGD and EAC in BE, lymph node metastases were detected in 0%, 23%, and 69% of lesions within the sm1, sm2, and sm3 layers, respectively. Similarly, in a study of more than 3000 patients who had undergone gastrectomy with lymph node dissection for early gastric cancer, no lymph node metastases were seen with well-differentiated to moderately differentiated lesions smaller than 3 cm that were confined to the mucosal or sm1 layers without lymphovascular invasion.
Standard EUS, with a probe frequency of 7.5-12 MHz, is the most commonly used method of determining the presence of lymph node metastases immediately before EMR. Compared with high-frequency EUS, standard EUS provides greater tissue penetration, displaying a five-layer mucosal wall while allowing visualization of locoregional lymph nodes. In evaluating for lymph node metastases in BE-HGD and EAC in BE, EUS demonstrated an accuracy of 93% in one series. In a second study, EUS identified suspicious lymph node metastases in 28% of patients referred for EMR of BE-HGD and BE-EAC, and FNA confirmed metastases in 71% of these cases.
The impact of the information provided by EUS beyond that of a careful endoscopic examination has been questioned. As a result, the use of EUS before EMR has been somewhat controversial.[29, 30] Nonetheless, EUS remains the most widely accepted method of assessing for the presence of lymph node metastases immediately before EMR.
EMR should be performed by experienced operators in a center of expertise. Appropriate adjuncts to treatment should be readily available in the procedure room (see Periprocedural Care). Additionally, interventional radiology and surgical backup should be available in the event of uncontrolled hemorrhage or perforation.
Tools specific to endoscopic mucosal resection (EMR) are discussed in more detail elsewhere (see Technique). Additional equipment includes the following:
Retrieval net or basket for specimen retrieval
Injection needle and dilute epinephrine
Hemostatic clips and hot biopsy forceps for control of bleeding and repair of small perforations
Specimens should be labeled according to their location (particularly within the esophagus and stomach), spread and pinned at the periphery of the specimen to a backing, and stored in formalin solution.
As a rule, EMR can be safely performed with procedural sedation. Appropriate consideration should be given to cardiopulmonary comorbidities and anesthesia support.
The procedure is performed with the patient in the left lateral decubitus position.
Monitoring and follow-up
Surveillance recommendations following EMR are evolving. Series with modest numbers of patients have demonstrated favorable long-term results in appropriately selected patient populations.
Follow-up studies of EMR of early squamous cell carcinoma of the esophagus have demonstrated 5-year survival rates of 95%, with no cancer-related deaths.[9, 31] In addition, similar 5-year survival comparable to that with esophagectomy has been demonstrated. Risk factors for recurrence include resection of multiple or large circumferential lesions.
Large series studying EMR for the treatment of high-grade dysplasia (HGD) and intramucosal adenocarcinoma within Barrett esophagus (BE) have demonstrated complete eradication in 60-99% of patients, with a recurrence rate of 11-30% at 3 years.[34, 35, 36] Risk factors for recurrence and metachronous lesions include larger lesion size, piecemeal resection, long-segment BE (see the video below), incomplete resection, and multifocal dysplasia.[37, 38, 39]
In most instances, metachronous lesions can be treated successfully with repeat EMR. Combination with ablative modalities such as photodynamic therapy and radiofrequency ablation (RFA; see the videos below) may serve to reduce recurrences. Investigations have also reported successful complete eradication of BE in as many as 96.9% of patients with short-segment BE, though concerns have been raised regarding subsquamous BE and stricture rates.[5, 6, 13]
In view of the lack of large prospective studies with long-term follow-up, resumption of standard endoscopic surveillance is recommended as outlined in guidelines published by the American Gastroenterological Association (AGA) and the American Society for Gastrointestinal Endoscopy (ASGE).[40, 41, 42] As more data emerge regarding EMR in combination with ablative therapies such as RFA, this recommendation will probably be modified, as was the case with surveillance recommendations regarding colonic adenomas.
Early gastric cancer
The Japanese experience has demonstrated excellent long-term results of EMR for early gastric cancer.[24, 44] For example, a study of more than 100 patients reported no local recurrence or distant metastases over 9 years of follow-up. The primary factors associated with durable remission rates are as follows:
Achievement of a resection margin of at least 2 mm
Complete en-bloc resection
Additional factors associated with recurrence include multiple synchronous cancers, lesion size greater than 2 cm, and lesion location in the upper body and lesser curvature.[46, 47]
One large study of EMR-ampullectomy reported a success in 84% of 168 patients with a recurrence rate of 8%. Two additional small series reporting results of EMR for nonampullary lesions demonstrated successful eradication in 100% of patients, with no local recurrence.[49, 50]
Successful resection of submucosal tumors has been reported in relatively small series in 79-95% of patients using ligation-assisted EMR, simple snare, or an insulated-tip knife; however, long-term follow-up data are lacking.[51, 52] The role of EMR in the evaluation of submucosal lesions rests largely in the acquisition of an adequate specimen for histopathologic analysis in instances of uncertain diagnosis.
Reports of long-term outcomes following EMR of flat premalignant lesions and early colorectal cancer vary widely, with recurrence rates ranging from 0% to 40%.[53, 54] Variations in technical expertise and heterogeneity in lesions included for treatment are partially responsible for this wide disparity. Overall, however, most recurrences are amenable to repeat endoscopic treatment during surveillance colonoscopy. As with early gastric cancer, en-bloc resection and lesion size of 2 cm or less are associated with lower local recurrence rates.
Argon plasma coagulation (APC) has been used to ablate resection margins with the aim of reducing local recurrence following piecemeal resection, with mixed results. Two of three well-designed studies reported a reduction in recurrence of up to 50% with the use of APC.[54, 55, 56]
Because of the risk of remnant tissue or local recurrence, close surveillance is generally recommended. Repeat colonoscopy may be performed within as little as 4-6 weeks to ensure that all dysplastic tissue has been resected or ablated. Follow-up colonoscopy with surveillance biopsies is most often performed 3-6 months after EMR, and subsequent surveillance is adjusted according to the status of recurrence.
Before endoscopic mucosal resection (EMR) is initiated, the extent of the target lesion should be clearly established. Once resection has commenced, mucosal landmarks may be obscured. Furthermore, visible abnormalities in early neoplastic lesions are often difficult to ascertain. Saline or water irrigation is often used; spraying of 1% acetylcysteine aids in the dissipation of adherent mucus. A combination of magnification high-definition white-light endoscopy and narrow-band imaging or chromoendoscopy (see the image below) is useful.
Additional techniques include confocal laser endomicroscopy and optical coherence tomography, though both are limited to study protocols in tertiary centers. The periphery of the lesion may be marked using superficial cautery marks.
Several EMR techniques have been developed, all of them based on the principles of “lifting” the target mucosa and resecting the lesion by applying the cautery (see the image below). The main approaches are as follows:
Early work with another variant, "underwater" EMR, suggests that this approach may prove to be an effective and safe alternative to traditional EMR.
The injection-assisted (or “inject-and-cut”) technique consists of submucosal injection of an aqueous solution followed by the application of a snare cautery for lesion resection. Submucosal injection is a well-established technique that creates a submucosal cushion underneath the lesion, mitigating the risk of transmural thermal injury during the application of cautery.
The injection is delivered via a standard injection needle and is based on the principle that the solution will “seek” the submucosal layer because of the presence of loose connective tissue within this layer. An automated pump is commercially available that facilitates uniform submucosal injection (ERBE, USA). A modification of this technique, the “inject-lift-and-cut” technique or “strip biopsy,” uses a tissue grasper passed through a second working channel to provide traction on the target mucosa during resection.
Typically, 5-50 mL of solution is injected beneath the lesion. During colonic EMR, injection of the distal margin of the lesion first often aids visualization during resection. The addition of dilute staining dyes (eg, indigo carmine or methylene blue) assists in identification of the deep and lateral resection margins.
Results with saline, the most commonly used solution, are often limited by the relatively rapid absorption of the injection; thus, multiple injections are often necessary. This problem has been addressed by the invention of combination needle and snare devices, as well as the study of various injection solutions. The addition of dilute epinephrine to standard saline provides a limited increase in cushion durability.
Other solutions that have demonstrated longer-lasting cushions include hyaluronic acid, hydroxypropyl methylcellulose, glycerol, and fibrinogen solutions, though most are not widely available and are limited by cost considerations.[60, 61, 62] It is noteworthy that injection of autologous blood has shown superior results with respect to cushion durability.[63, 64] An increased incidence of local inflammatory reactions has been demonstrated with the use of hypertonic saline, hypertonic dextrose, and hydroxypropyl methylcellulose, limiting their use in practice.
This technique uses a combination of submucosal injection, aspiration of tissue into a clear soft plastic cap attached to the tip of the endoscope, and snare excision. Various single-use devices that include a combination of cap and specially designed snare are commercially available. Typically, the snare is opened within the distal internal rim of the cap, tissue is aspirated within the cap and snare, the snare is closed around the captured tissue, and a standard snare cautery is applied to excise the tissue. Caps are available in various sizes and have either a flat (cylindrical) or oblique end, with the latter assisting in tissue aspiration within the tubular esophagus (see the image below).
Born from the extrapolation of tissue acquisition during variceal band ligation to EMR, this technique involves the application of bands around aspirated tissue and subsequent snare-cautery resection. In theory, the band will incorporate the mucosal and submucosal layers while leaving the muscularis propria in situ as a consequence of insufficient contractile force. In the simplest form of the procedure, a standard variceal band ligator device is used to aspirate the target lesion and apply a band around it (see the images below). After removal of the banding device, a separate snare is used to resect the lesion.[66, 67]
A submucosal injection may also be made before tissue aspiration, though this step is not universally applied. A commercially available mucosectomy device (Duette Multi-Band Mucosectomy Device; Wilson-Cook, Winston-Salem, NC) includes a modified multiband ligator with a hexagonal snare that can be passed within the working channel with the ligation device in place.
Practice variations in technique include the following :
Closure of the snare above versus below the band
Initial application of multiple bands versus resection following the application of each band during resection of larger lesions
EMR is primarily performed on an outpatient basis. After the procedure, patients typically receive general instructions regarding medication use, diet, and symptom management. Patients are often prescribed a clear liquid diet on the day of the procedure with diet advancement as tolerated thereafter. All patients should receive high-dose proton pump inhibitor therapy after foregut lesion resections.
Infrequently, patients may experience pain that can be managed with nonnarcotic analgesia. Management of anticoagulants should be discussed with the patient’s primary providers prior to the day of procedure. Patients should be instructed to seek medical attention if they experience fever, nausea or vomiting, hematochezia, or melena.
EMR is generally safe in experienced centers, though several complications have been described.
Bleeding is the most common complication of EMR, reported in an average of 10% of patients in several large series.[69, 70, 71] Immediate bleeding is typically managed by the application of hemostatic endoscopic clips, hot biopsy forceps, or bipolar coaptive coagulation. Delayed bleeding, occurring from 6 hours to 7 days after EMR, has been reported in 5-14% of patients. Immediate bleeding has been identified as an independent predictor of delayed hemorrhage.[72, 73]
Perforation is a rare complication of EMR, with reported rates of 0.3–0.5%.[74, 45] Small perforations are amenable to endoscopic closure with endoscopic clips.[75, 76, 77] Urgent surgical consultation and intravenous broad-spectrum antibiotics are indicated for larger defects.
Stricture formation is a late complication of EMR within the esophagus that has been reported in up to 6% of patients. Resections of lesions occupying three quarters of the luminal circumference and resection lengths in excess of 3 cm have been identified as risk factors. Strictures typically respond well to serial endoscopic dilation.[78, 79]
The most common complication associated with ampullectomy is pancreatitis, occurring in 10% of cases. Bleeding, perforation, cholangitis, and delayed papillary stenosis are also infrequently reported. Placement of prophylactic duct stents may serve to mitigate the risks of ductal occlusion.
EMR of submucosal lesions is associated with a relatively high incidence of complications, with reported rates of bleeding approaching 40% and perforation rates of 0.8%.
Little comparison has been made between techniques in randomized controlled trials, although the inject-and-cut techniques are generally more technically demanding than the cap-assisted and ligation-assisted techniques. A single randomized study comparing injection with cap-assisted EMR and ligation-assisted EMR without injection within the esophagus found no significant difference in safety.
Although transient bacteremia has been reported with colonic EMR, routine antibiotic prophylaxis is not generally recommended.
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