1 esd vs emr

Guideline

JGES guidelines for colorectal endoscopic submucosaldissection/endoscopic mucosal resection

Shinji Tanaka,1,2 Hiroshi Kashida,1 Yutaka Saito,1 Naohisa Yahagi,1 Hiroo Yamano,1Shoichi Saito,1 Takashi Hisabe,1 Takashi Yao,2 Masahiko Watanabe,2,3 Masahiro Yoshida,4Shin-ei Kudo,1 Osamu Tsuruta,1 Ken-ichi Sugihara,2 Toshiaki Watanabe,2 Yusuke Saitoh,1Masahiro Igarashi,1 Takashi Toyonaga,1 Yoichi Ajioka,2 Masao Ichinose,1Toshiyuki Matsui,1,3 Akira Sugita,3 Kentaro Sugano,4 Kazuma Fujimoto1 and Hisao Tajiri1

1Japan Gastroenterological Endoscopy Society, 2Japanese Society for Cancer of the Colon and Rectum, 3JapaneseSociety of Coloproctology and 4Japanese Society of Gastroenterology, Tokyo, Japan

Colorectal endoscopic submucosal dissection (ESD) has becomecommon in recent years. Suitable lesions for endoscopic treat-ment include not only early colorectal carcinomas but also manytypes of precarcinomatous adenomas. It is important to establishpractical guidelines in which the preoperative diagnosis ofcolorectal neoplasia and the selection of endoscopic treatmentprocedures are properly outlined, and to ensure that the actualendoscopic treatment is useful and safe in general hospitalswhen carried out in accordance with the guidelines. In coopera-tion with the Japanese Society for Cancer of the Colon andRectum, the Japanese Society of Coloproctology, and the Japa-nese Society of Gastroenterology, the Japan GastroenterologicalEndoscopy Society has recently compiled a set of colorectal

ESD/endoscopic mucosal resection (EMR) guidelines usingevidence-based methods. The guidelines focus on the diagnosticand therapeutic strategies and caveat before, during, and afterESD/EMR and, in this regard, exclude the specic procedures,types and proper use of instruments, devices, and drugs.Although eight areas, ranging from indication to pathology, wereoriginally planned for inclusion in these guidelines, evidence wasscarce in each area. Therefore, grades of recommendation weredetermined largely through expert consensus in these areas.

Key words: colorectal tumor, early colorectal carcinoma, endo-scopic mucosal resection (EMR), endoscopic submucosal dissec-tion (ESD), guidelines

INTRODUCTION

AT PRESENT, WE can select various techniques inendoscopic treatment for colorectal tumors. Basically,complete en bloc resection is indicated for early colorectalcarcinoma regardless of tumor size. Although endoscopicsubmucosal dissection (ESD) has made it possible, colorec-tal ESD is technically more difficult to carry out than upper-gastrointestinal ESD and, hence, it is essential to preventcomplications such as perforation. However, among epithe-lial colorectal tumors that can be treated by endoscopic treat-ment, there are many adenomatous lesions that may be

regarded as precarcinomatous in addition to early carcino-mas. Therefore, accurate and qualitative preoperative diag-nosis of lesions and the selection of appropriate treatment onthe basis of a precise diagnosis are essential.

In this capacity the Guidelines Committee of the JapanGastroenterological Endoscopy Society (JGES) drafted theColorectal ESD/EMR Guidelines (hereinafter referred to asthe Guidelines) with the aim of ensuring the appropriateclinical introduction of colorectal ESD in relation to endo-scopic mucosal resection (EMR). These guidelines focus onthe diagnostic and therapeutic strategies and stipulationsbefore, during, and after EMR and ESD and do not containspecific information about the procedures, types and properuse of instruments, devices, and drugs. In the Guidelines,differences between colorectal EMR and ESD, preoperativediagnosis, and perioperative care are also described on thebasis and strength of clinical evidence.

We created the Guidelines in accordance with the Proce-dures for the Evaluation, Selection, and Publication of

Corresponding: Shinji Tanaka, Endoscopy and Medicine, Hiro-shima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551,Japan. Email: [email protected] guidelines have been published in Gastroenterol. Endosc.2014: 56; 15981617 (in Japanese).Received 12 November 2014; accepted 2 February 2015.

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Digestive Endoscopy 2015; 27: 417434 doi: 10.1111/den.12456

2015 The AuthorsDigestive Endoscopy 2015 Japan Gastroenterological Endoscopy Society

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Japanese Clinical Practice Guidelines in Medical Informa-tion Network Distribution Service (MINDS) 2007,1 takinginto account levels of evidence and grades of recommenda-tion with regard to evaluating evidence-based medicine(Table 1), as reported previously.2 Although eight areas,ranging from indication to pathology, were originallyplanned for inclusion in the guidelines, evidence in each areawas scarce, which has resulted in the grades of recommen-dation being mostly determined through expert consensus.

We established six categories for evaluation, as follows:indications, techniques, complications, treatment outcome(recurrence, metastasis, and prognosis), postoperative followup, and pathology. For each clinical question (CQ), system-atic document retrieval was done by searching PubMed andIgaku Chuozasshi for articles published from 1985 to 2012.For insufficient or unsearchable documents, hand searchingwas also done. The retrieved documents were evaluated, andpertinent documents were adopted. Subsequently, a state-ment and an explanation were created for each CQ. Membersof the Guidelines Creation Committee set the levels ofevidence and the grades of recommendations in their respon-sible fields by using the MINDS Grade of Recommenda-tions, as described above. For the created statements, ninemembers of the Guidelines Creation Committee voted byusing the Delphi method, as reported previously.2

INDICATION FOR ENDOSCOPIC ORSURGICAL TREATMENT

Basic principles

WHEN EARLY COLORECTAL carcinoma is diag-nosed, the patient is recommended to undergo endo-scopic or surgical treatment (level of evidence: IVb, gradeof recommendation: B). When surgical treatment wascarried out, the 5-year survival rate of colorectal carcinomawas reported to be 94.3% for stage 0 and 90.6% for stage I.Curability was reported to be 92.7% when endoscopic treat-ment was carried out.3 Thus, excellent results could beobtained from both surgical treatment and endoscopictreatment.4,5

In cases where the risk exceeds the benefit of endoscopictreatment, such as when a patients general condition isextremely poor, it is recommended to abandon the treatment(level of evidence: V, grade of recommendation: C1). Inparticular, the application of endoscopic treatment to elderlypatients (65 years) must be carefully considered. Manyelderly patients have poor general condition and suffer fromcomorbidities. The frequency of complications associatedwith endoscopic treatment is high in these patients.6 In con-trast, some reports have indicated that endoscopic treatmentcould be safely carried out even for elderly patients.7,8 Forvery elderly patients (85 years), endoscopic treatmentshould be done only when the expected advantage is likely tooutweigh the risk of complications associated with the resec-tion, while also considering the average life expectancy,comorbidities, and body age of the patient.

When carrying out endoscopic treatment, a patientsgeneral condition and medications must be verified, andinformed consent must be obtained (level of evidence: VI,grade of recommendation: C1). Before carrying out endo-scopic treatment, a patients comorbidities and medicationsmust be thoroughly evaluated. In particular, hemorrhagemay develop when a patient taking an antithrombotic agent(anticoagulant or antiplatelet) undergoes endoscopic treat-ment without discontinuing the drug, whereas a cerebrocar-diovascular event may occur if the patient discontinues themedication. After evaluating both risks, the decision shouldbe made regarding whether the patient should continue totake the medication. If drug discontinuation is decided, theoptimal timing for drug discontinuation and resumptionmust be carefully evaluated.2 The risk of thromboembolismdiffers depending on the status of the patients underlyingdisease, and the type and time of placement of artificialvalves or stents. The risk of hemorrhage differs dependingon the kind of endoscopic examination and treatment. BothESD and EMR are considered to have a high risk ofhemorrhage.

Table 1 Levels of evidence and grades of recommendations:MINDS Grade of Recommendations

Levels of evidenceI: Systematic review/meta-analysisII: Several randomized controlled trialsIII: Non-randomized controlled trialIVa: Analytical epidemiological study: cohort studyIVb: Analytical epidemiological study: casecontrol study,

cross-sectional studyV: Descriptive study (case report and case series)VI: Opinions of special committees and individual experts

that are not based on patient dataGrades of recommendations

A: Strong scientic evidence exists and the therapy isstrongly recommended

B: Scientic evidence exists and the therapy isrecommended

C1: No scientic evidence exists but the therapy isrecommended

C2: No scientic evidence exists and the therapy is notrecommended

D: Scientic evidence of ineffectiveness or danger exists andthe therapy is not recommended

MINDS, Medical Information Network Distribution Service.

418 S. Tanaka et al. Digestive Endoscopy 2015; 27: 417434


As a general rule, written informed consent (IC) for car-rying out endoscopic treatment must be obtained from thepatient. The IC form must contain the following items: (i)name and condition of the patients disease; (ii) reasons forrecommending endoscopic treatment; (iii) actual details ofthe procedure to be carried out; (iv) expected outcomes; (v)predicted risks; (vi) alternative methods that could substitutefor endoscopic treatment and information on the compari-son; and (vii) prognosis if the patient does not undergoendoscopic treatment.9 When it is difficult to sufficientlycommunicate with a patient, IC must be obtained from anappropriate representative.With regard to the use of sedationduring endoscopic treatment, it is advisable to obtain IC inwhich the expected effect and risk of complications are com-pletely explained in a written document.

Indication for endoscopic treatment

Non-carcinomaResection is recommended for adenomas 6 mm in size.Resection is recommended for superficial depressed-typelesions (type 0IIc) even when the lesion is 5 mm in size.Typical hyperplastic polyps 5 mm in size that are present inthe distal colon may be left untreated (level of evidence: IVb,grade of recommendation: B). Among adenomas and earlycarcinomas, the carcinoma rate of protruded-type and super-ficial elevated-type lesions 5 mm in size is low, and theseadenomas are very unlikely to become a T1 (submucosal[SM]) carcinoma. However, the rate of SM invasion (i.e. theT1 [SM] carcinoma rate of lesions >6 mm) increases as thesize of the lesion increases.1015 Despite an extensive searchof the literature, we could find no clear evidence regardingthe carcinoma rate and prognosis of microlesions 5 mm insize in cases where it is left untreated. Some studies reportedthat colorectal adenomas 5 mm in size that had been fol-lowed for several years showed minimal changes.1618 There-fore, prompt treatment is not required for protruded-type andsuperficial protruded-type adenomas 5 mm in size. Super-ficial depressed-type lesions exhibit a certain carcinoma rateand a certain rate of SM invasion even when their size is5 mm.10,11,13,14 Although adenomas themselves are benign, itis expected that their removal will prevent the developmentof colorectal carcinoma.19,20 Most colorectal neoplasms areadenomas,9 and these adenomas can be cured by using EMRor piecemeal EMR techniques.21,22 For some neoplasms,endoscopic treatment is technically difficult to carry outdepending on the site or size of the lesion.

According to genetic-pathological analyses, somecolorectal carcinomas are assumed to develop from serratedlesions through the so-called serrated pathway. However, thenatural history and carcinoma rate of serrated lesions havenot been sufficiently elucidated. The risk for colorectal car-cinoma is reported to be high in patients with sessile serratedadenoma/polyp (SSA/P).2327 However, data on how often

and how fast carcinoma development occurs within theSSA/P itself have been insufficient.2832 Large or dysplasticSSA/P has the potential of developing into a carcinoma. Incontrast, the possibility of carcinoma development is consid-ered to be extremely low for typical hyperplastic polyps5 mm in size present in the distal colon or rectum.33

CarcinomaAmong early colorectal carcinomas (Tis/T1), lesions withlittle possibility of lymph node metastasis and higher expec-tancy of curability with en bloc resection on the basis of thesize and the location are usually treated endoscopicallybecause such cases are expected to be curable. Obviousclinical T1b carcinomas (submucosal invasion depth1000 m) are usually treated surgically. When endoscopictreatment is carried out for colorectal carcinomas, en blocresection is the principal approach; however, piecemealresection is also acceptable when the possibility of submu-cosal invasion can be definitively excluded and if the treat-ment is appropriately carried out (level of evidence: IVb,grade of recommendation: B).

In early colorectal carcinomas, lymph node metastasis isdifficult to predict. In contrast, invasion depth can be veryprecisely predicted when image-enhanced endoscopy, mag-nifying endoscopy, and/or endoscopic ultrasonography(EUS) are used concurrently (discussed below).

Among the endoscopic treatments, ESD is the most suit-able method for en bloc resection.3440 Piecemeal EMR maymake it difficult to establish a pathological diagnosis of theinvasion depth and to determine a free resection margin. Thenumber of resected pieces must be minimized, and the regionsuspected to contain a carcinoma should not be sectioned.With a larger tumor size and a greater number of resectedpieces, the local recurrence rate increases.4143 When carry-ing out piecemeal EMR, magnifying endoscopic observa-tion, which is the best way to identify the carcinomatous partof the lesion, should be carried out before the treatment, andthe carcinomatous area should not be sectioned. Otherwise,it would be difficult to evaluate the invasion depth or vesselinvasion, and an additional treatment such as lymph nodedissection might not be done even when it is necessary incase of submucosal invasive carcinoma.

Laterally spreading tumors (LST) are classified intogranular type (LST-G) and non-granular type (LST-NG). InLST-NG, the pseudo-depressed type (PD), which isexpressed as IIc+IIa or IIa+IIc according to the JapaneseClassification of Colorectal Carcinoma,44 is associated withmultifocal invasion, the foci of which are often difficult topredict. In addition, LST-NG (PD) is frequently associatedwith fibrosis. Therefore, in many cases, EMR is not suitablefor LST-NG (PD).45 Considering the high possibility of deepsubmucosal invasion in LST-NG (PD), whether the lesion isindicated for surgical operation or for endoscopic treatmentshould be carefully considered. To determine the indication

Digestive Endoscopy 2015; 27: 417434 Colorectal ESD/EMR guidelines 419


for ESD or EMR for LST, overall judgment based on thesubclassification of LST (Fig. 1) and on the pit pattern diag-nosis by using magnifying observation is useful.46 Thedetails of evaluating lesions for the ESD technique are pre-sented in a draft proposed by the Colorectal ESD Standard-ization Implementation Working Group (Table 2).34,35,38,47,48

PREOPERATIVE DIAGNOSIS

Distinction between adenomaand adenocarcinoma

BEFORE CARRYING OUT colorectal ESD or EMR, itis important to distinguish between adenoma andadenocarcinoma in order to determine whether the lesion isbenign or malignant and to characterize the marginal demar-cation of the lesion. In the large intestine, adenoma andcarcinoma in/with adenoma lesions are often detected inaddition to early carcinomas without adenoma. Therefore,not only the malignancy of an entire lesion but also thecarcinomatous and adenomatous parts of the lesion must becorrectly assessed and distinguished. Consequently, thera-peutic strategies such as the use of ESD or EMR, selection ofpiecemeal EMR, and a deliberate planned sectioning line canbe determined.49

When image-enhanced endoscopy and magnifyingobservation are used, a distinction between adenoma and

Figure 1 Subtypes of laterally spread-ing tumors (LST) (classication shouldbe done on the basis of imagesobtained by using indigocarmine dyespraying). (a) Homogeneous type: LST-G(Homo). (b) Nodular mixed type: LST-G(Mix). (c) Flat-elevated type: LST-NG (F).(d) Pseudo-depressed type: LST-NG(PD). LST-G, laterally spreading tumorgranular type; LST-NG, laterally spread-ing tumor non-granular type.

Table 2 Indications for ESD for colorectal tumors

Lesions for which endoscopic en bloc resection is required1) Lesions for which en bloc resection with snare EMR is

difcult to apply LST-NG, particularly LST-NG (PD) Lesions showing a VI-type pit pattern Carcinoma with shallow T1 (SM) invasion Large depressed-type tumors Large protruded-type lesions suspected to be carcinoma2) Mucosal tumors with submucosal brosis

3) Sporadic localized tumors in conditions of chronicinammation such as ulcerative colitis

4) Local residual or recurrent early carcinomas afterendoscopic resection

Partially modied from the draft proposed by the Colorectal ESDStandardization Implementation Working Group.Including LST-G, nodular mixed type.As a result of a previous biopsy or prolapse caused by peristalsis ofthe intestine.EMR, endoscopic mucosal resection; ESD, endoscopic submucosaldissection; LST-G, laterally spreading tumor granular type; LST-NG,laterally spreading tumor non-granular type; PD, pseudo-depressed;SM, submucosal.



adenocarcinoma with high accuracy can be achieved (levelof evidence: IVb, grade of recommendation: B). For distinc-tion between adenoma and adenocarcinoma, lesion color,surface unevenness, presence of depression, and fold con-vergence must be confirmed by ordinary observation andchromoendoscopic observation. At present, magnifyingobservation (pit pattern diagnosis) using dye spraying (indi-gocarmine, crystal violet etc.) and image-enhancement tech-nology (narrow band imaging [NBI], blue laser imaging[BLI] etc.) could be used for diagnosing lesions on the basisof a detailed visualization of fine surface structures (surfacepattern) and microvessels.5052 The diagnostic accuracy rateof discriminating neoplastic from non-neoplastic lesions wasreported to be approximately 80% for standard observation,including magnifying chromoendoscopic observation,9698% for pit pattern observation, and 95% for magnifyingobservation using NBI and BLI.5359 The accuracy rate ofdiscrimination between adenoma and carcinoma was7090% for pit pattern observation, and a similar rate wasobtained for NBI. Thus, distinction between adenoma andadenocarcinoma with high accuracy can be achieved withmagnifying endoscopic observation.6064 However, it wasrecently indicated that some lesions that had been previouslydiagnosed as non-neoplastic exhibited neoplastic prolifera-tion (SSA/P). Research on the diagnosis and treatment ofthese lesions is currently ongoing.65,66

In addition, it is better to avoid carrying out a biopsy inorder to distinguish between adenoma and adenocarcinoma(level of evidence: V, grade of recommendation: C1). In thecase of superficial-type lesions, because biopsy as a preop-erative diagnosis may cause fibrosis in the submucosal layerand lead to a positive non-lifting sign, subsequent endo-scopic treatment will be difficult. Therefore, it is better toavoid carrying out a biopsy for making a preoperative diag-nosis.38,47 For large lesions such as LST-G,44 which, in manycases, are carcinoma in adenoma, a simple biopsy may notshow an accurate yield as a qualitative diagnosis. Therefore,a diagnosis based on magnifying endoscopic observation asan optical biopsy (histological diagnosis by endoscopicimaging without forceps biopsy) is more effective.

Diagnosis of invasion depthFor early colorectal carcinoma, it is necessary to estimate thedegree of SM invasion before carrying out endoscopic treat-ment (level of evidence: IVb, grade of recommendation: B).The risks of vascular invasion and lymph node metastasisdiffer according to the SM invasion depth of the carcinoma.For deep invasive T1 (SM) carcinoma, the risk of incompleteresection is high in endoscopic treatment. Therefore, thedegree of SM invasion must be estimated before carrying outendoscopic treatment. Furthermore, to carry out accurate

pathological evaluation of endoscopically resected speci-mens, it is important to indicate the part of SM invasion inthe whole lesion.49

When diagnosing invasion depth, if a deep depression,expansive appearance, submucosal tumor-like margin, ordefective extension is detected during ordinary or chromo-endoscopic observation, deep SM invasion may be consid-ered; the accuracy rate of deep SM invasion is 7080%.67,68

In pit pattern diagnosis with dye-spraying magnifying endo-scopic observation, an accuracy rate of approximately 90%can be obtained if the VN-type pit pattern is observed. Theaccuracy rate of protruded-type lesions tends to be slightlylower than that of superficial-type lesions.6971 Althoughmagnifying observation using NBI/BLI is slightly inferior topit pattern diagnosis in terms of accuracy, a similar outcomecan be obtained.7274 The accuracy rate is approximately 80%when ultrasonography is used; however, the visualizationcapacity is affected by the condition and morphology of thelesion.7579 These diagnostic methods have certain advan-tages and disadvantages. As diagnostic accuracy differsaccording to the macroscopic type and growth type of thelesion, appropriate diagnostic methods should be combinedas the situation requires.

TECHNIQUES

Denition of ESD and EMR

IN EMR,80,81 a physiological saline solution or a sodium

hyaluronate solution8284 is locally injected into the sub-mucosa of a superficial-type tumor through the injectionneedle. The lesion is strangled with a snare and thenresected by applying high-frequency current. Althoughpolyp resection in cold polypectomy is carried out withoutapplying high-frequency current, high-frequency current isessential in EMR and is fundamentally applied. In piece-meal EMR, a large nodule or carcinomatous region is firstcut into a large piece to accurately carry out histologicaldiagnosis, and the residual flat part is then deliberatelycut into pieces; this is also known as planned piecemealEMR.

In ESD, a physiological saline solution or a sodium hyal-uronate solution is locally injected into the submucosa of atumor through the injection needle. The circumference of thelesion is then incised using a needle-type knife for ESD withelectrical cutting current produced by the equipment, and thesubmucosal layer is then dissected. This technique can resectthe lesion in one piece regardless of its size.37,39,8588 In April2012 in Japan, the National Health Insurance scheme beganoffering coverage for expenses incurred for ESD proceduresfor early-stage malignant colorectal tumors 2050 mm insize.



In the Guidelines, specific terminology is used to distin-guish several forms of ESD, as follows.A technique in whichdissection of the submucosal layer is completed withoutusing a snare is defined as actual (narrowly defined)ESD.89,90 Likewise, a technique in which snaring is donewithout dissecting the submucosal layer after incising thecircumference of the lesion alone, by using a knife for ESDor the tip of a snare, is defined as precutting EMR.91 Finally,a technique in which the submucosal layer is dissected andsnaring is carried out after the ESD procedure (mucosalincision + submucosal dissection), by using a knife for ESDor the tip of a snare, is defined as hybrid ESD.89,90,92 Otherterminologies for precutting EMR91 and hybrid ESD arereported in the literature, but the Guidelines use the termsdefined above.

Choosing between ESD and EMREn bloc resection is desirable as an endoscopic treatment forearly colorectal carcinoma. However, piecemeal EMR is per-missible for some adenoma and carcinoma in adenomalesions when appropriately carried out. When carrying outpiecemeal EMR, magnifying endoscopic observation shouldbe carefully carried out before the treatment, and the carci-nomatous area should never be cut into pieces (level ofevidence: III, grade of recommendation: B).

The reason for this restriction is that if SM invasive car-cinoma was cut into pieces, pathological diagnosis for theinvasion depth and lymph-vascular invasion would be diffi-cult, and necessary additional treatment might not bedone.21,39,45,93,94 Previous reports showed that when piecemealEMRwas carried out, magnifying endoscopic observation ofthe lesion margin and ulcer base after the resection is usefulto decrease the local residual/recurrence rate.95 To confirmlocal residual/recurrence, follow-up colonoscopy should bedone approximately 6 months after the treatment.42,9698

The frequency of T1 (SM) carcinoma increases as thetumor size increases. With multi-piecemeal resection, whichmakes the pathological reconstruction of a tumor difficult,histological evaluation is also difficult and the local residual/recurrence rate is higher.42,92,96,97 For large lesions with a sizegreater than half of the circumference of the colorectallumen, piecemeal EMR should be avoided, and ESD or asurgical operation should be done based on the skill level ofthe endoscopist, the therapeutic environment of the hospital,the condition of patient, and the status of the lesion.38,86,87

Following the development of the requisite devices andthe establishment of appropriate methods, colorectal ESDcan be safely and accurately carried out by experts. However,when carrying out ESD, it is important to prepare variousdevices (ESD knives, devices, distal attachments, local injec-tion agents such as sodium hyaluronate,8284 a carbon dioxide

insufflator,85 and endoscopic clips to prevent and treatadverse events, such as perforation, and to ensure that thereare appropriate facilities for hospitalization and surgicaltreatment.

Endoscopic treatment for lesions positivefor non-lifting signAlthough the majority of such lesions are T1 carcinomas, alesion exhibiting a positive non-lifting sign can potentiallybe a mucosal tumor (adenoma or mucosal carcinoma).Therefore, if a lesion is endoscopically judged as a mucosaltumor, ESD/EMR is appropriate (level of evidence: III,grade of recommendation: B).

For mucosal lesions that are non-lifting sign positive99101

(including adenomas) and residual/recurrence lesions, ESDcan resect those lesions for which EMR is generally difficultto apply and for which en bloc resection is desirable (inparticular, lesions suspected to be early carcinoma and LST-NG). However, ESD must be carefully carried out whilechecking for perforation.37,45,102104

The non-lifting sign, first reported by Uno et al.,99,100 is asign that helps diagnose the depth of carcinoma invasion andis often used in clinical practice. However, one multicenterstudy101 that compared the diagnostic accuracy based onconventional endoscopic observation with that based on thenon-lifting sign has shown that the diagnostic ability of thenon-lifting sign for deep SM invasive carcinoma had a sen-sitivity of 61.5%, specificity of 98.4%, positive predictivevalue of 80.0%, negative predictive value of 96.0%, anddiagnostic accuracy of 94.8%.

For conventional endoscopic observation for deep SMinvasive carcinoma, the above measures were 84.6%, 98.8%,88.0%, 98.4%, and 97.4%, respectively. Therefore, conven-tional endoscopic observation was superior to the non-liftingsign in terms of sensitivity (84.6% vs 61.5%). Superficial-type colorectal tumors sometimes exhibit a positive non-lifting sign as a result of peristaltic motion or fibrosis causedby biopsy, although such lesions are usually of the mucosaltype.99,100 Therefore, preoperative endoscopic diagnosisshould be made carefully by magnifying endoscopic obser-vation before endoscopic treatment for neoplastic lesions.Once the lesion targeted is diagnosed as carcinoma, then theinvasion depth should be diagnosed by magnifying endos-copy, and biopsy should be avoided.

Endoscopists who carry out colorectal ESD should beregistered with the JGES or must possess skills similar tothose of registered endoscopists in Japan. Familiarity withesophageal and gastric ESD alone may be insufficient. Theminimum requirements for endoscopists are as follows: (i)having sufficient understanding of the anatomical features ofthe large intestine; (ii) having the ability to carry out the



axis-keeping shortening technique when inserting a colono-scope; (iii) having the skill to carry out an insertion tech-nique by which the colorectal endoscope could be smoothlyand accurately advanced to the cecum in the shortest dis-tance possible; and (iv) having familiarity with the basictechniques of polypectomy, EMR, piecemeal EMR, hemo-stasis, and clip suture. Experience with gastric ESD ishelpful in preparation for colorectal ESD. If the experienceof the endoscopist is limited to colorectal examination,colorectal ESD should be carried out only after sufficienttraining in ESD by using living or isolated porcine stomachor colon.105107

COMPLICATIONS DURING PROCEDURES

MAIN ACCIDENTAL COMPLICATIONS duringcolonoscopic treatment are perforation and bleeding.Perforation is the condition in which the abdominal cavity isvisible from the colorectal lumen because of mural tissuedefects. The presence of free air is not always detected onX-ray examination. In contrast, the condition in which thetissue defect reaches other parenchymal organs is defined aspenetration. Various definitions have been proposed forbleeding, such as a decrease in hemoglobin by >2 mg/dL orthe requirement for blood transfusion. However, these defi-nitions have not been established on the basis of solid evi-dence. The presence of marked bloody stool after treatmentor the requirement for a certain measure for hemostasis aftertreatment is often defined as delayed bleeding.With regard tothe frequency of these accidental complications, perforationrates during endoscopic resection are reported to be 0.05%,0.580.8%, and 2%14% for polypectomy, EMR, and ESD,respectively. Moreover, the delayed bleeding rates arereported to be 1.6%, 1.15%1.7%, and 0.7%2.2% for pol-ypectomy, EMR, and ESD, respectively.40,88,108110

Prevention and management of perforationAs the colonic wall is thinner than that of the stomach, therisk of perforation during the procedure is higher in the colonthan in the stomach. Before the procedure, sufficient pre-treatment is required to prepare for the possibility of perfo-ration. During the procedure, it is essential to ensure goodmaneuverability of the scope. It is important to select a scopeaccording to the location and morphology of the tumor, andit is necessary to use appropriate devices, local injectionagents, and a carbon dioxide insufflator for a successfulprocedure.85,111 When perforation occurs during the proce-dure, clipping should be carried out as far as possible,regardless of the location (level of evidence: IVb, grade ofrecommendation: B). When closure of the perforation iscomplete, surgical rescue can usually be avoided by giving

i.v. antibiotics and fasting.108,112,113 The presence of free airwithin the abdominal cavity after perforation on computedtomography (CT) evaluation cannot be used to guide thedecision for emergency surgery.113 It is necessary to decidethe timing of the emergency surgery carefully in cooperationwith surgeons. Nevertheless, in cases of incomplete closureof the perforation, emergency surgery should be carried outas soon as possible as the risk of pan-peritonitis is extremelyhigh in this situation.

In cases of rectal lesion below the peritoneal reflection,perforation into the abdominal cavity would not occur as aresult of anatomical features; however, penetration into theretroperitoneum occurs and, consequently, mediastinalemphysema or subcutaneous emphysema may occur.114

Prevention and management of bleedingFor bleeding associated with endoscopic resection, clippingor coagulation is appropriate. In case of minor bleeding froma small vessel, contact coagulation with the tip of a knife orcoagulation with hemostatic forceps is usually used forhemostasis. In cases of severe bleeding from a large vessel orartery, hemostatic forceps are indispensable. To avoiddelayed perforation caused by thermal damage, the bleedingpoint should be grasped precisely with hemostatic forceps,and application of electrocoagulation should be minimized.Generally, severe bleeding seldom occurs in the colon incomparison with the stomach. However, in the rectum, espe-cially below the peritoneal reflection, a pulsating largeexposed vessel is sometimes present within the resectionwound. Therefore, clipping is sometimes used in such casesto prevent delayed bleeding. Serious delayed bleeding thatrequires blood transfusion seldom occurs in the colon. Emer-gency endoscopy is usually required to treat exposed bloodvessels in the case of continuous bloody stool.

A randomized controlled trial reported that preventiveclipping after endoscopic resection did not decrease thedelayed bleeding rate (0.98% with clipping and 0.96%without clipping).115 However, target lesions included in thattrial were relatively small (mean size, 7.8 mm). A retrospec-tive analysis reported that preventive clipping was useful forlesions >2 cm in size (1.8% with clipping and 9.7% withoutclipping).116 Another retrospective analysis also suggestedthe potential usefulness of preventive clipping for patientsundergoing endoscopic resection at an outpatient clinic.117

However, at present, no firm evidence has been obtained byrandomized controlled trials for the efficacy of suturing theESD/EMR wound to prevent delayed bleeding. In addition,one report showed that preventive clipping after polypec-tomy is poorly cost-effective in subjects who are not takingantithrombotic medication.118 Therefore, prophylactic clip-ping in EMR seems to be effective to some extent for high-



risk patients and may be effective for patients with largelesions or for those undergoing antithrombotic therapy (levelof evidence: IVb, grade of recommendation: B).

PERIOPERATIVE CARE BEFORE AND AFTERENDOSCOPIC TREATMENT

DURING PERIOPERATIVE CARE after endoscopictreatment, attention should be given to delayed perfo-ration and delayed bleeding, and patients should be hospital-ized if necessary (level of evidence: IVb, grade ofrecommendation: B). Perioperative care should be consid-ered during the clinical practice of ESD/EMR, including thehospitalization period.119 For patients using antithromboticdrugs who will undergo ESD/EMR, the reader is referred tothe Guidelines for Gastroenterological Endoscopy inPatients Undergoing Antithrombotic Treatment publishedby the JGES.2

Antithrombotic drugsThe guidelines mentioned above propose a strategy in whichpatients who undergo ESD/EMR are divided into high- andlow-risk groups according to the predicted risk of thrombo-embolism. The way in which antithrombotic drugs arehandled in pre-/post-ESD/EMR procedures is dependent onthe risk for thromboembolism in subjects, and publishedJGES guidelines should be referred to for further details. Inbrief, withdrawal of aspirin monotherapy even in subjectswho undergo ESD/EMR is not required when those subjectsare deemed at high risk for thromboembolism, whereas itcan be withdrawn for 35 days in low-risk patients. Thieno-pyridine derivatives are recommended to be replaced withaspirin or cilostazol for 57 days in high-risk subjects whoundergo ESD/EMR procedures. However, in low-risk sub-jects, thienopyridine derivatives can be withdrawn for 57days for the procedures. The procedures planned in patientstaking aspirin in combination with warfarin or dabigatranshould be postponed until the antithrombotics can be with-drawn. The procedures can be carried out in patients takingaspirin or cilostazol if warfarin or dabigatran is replaced withheparin. After the withdrawal of an antithrombotic drug, thedrug can be given again when hemostasis is endoscopicallyconfirmed. Careful observation against post-procedure hem-orrhage must be taken after antithrombotic drugs areresumed.

Bowel preparationAfter confirming that no stenosis of the digestive tract ispresent, a diet preparation for colonoscopy (or food in accor-dance with the diet) and a laxative are given at bedtime onthe night before the procedure. On the day of colonoscopy,

2 L of an intestinal lavage solution is given. In cases wherepretreatment is incomplete, an additional intestinal lavageshould be considered.

With regard to premedication and sedation, as intestinalperistalsis may hinder the treatment, if possible, a spasmo-lytic (scopolamine Buscopan, Boehringer Ingelheim,Tokyo, Japan) is i.v. or i.m. injected after confirming that nocontraindication (glaucoma, prostatic hypertrophy, andarrhythmia) is present. The use of a sedative/analgesic isdetermined according to the endoscopists judgment and thepatients wishes. However, excessive sedation should beavoided in colorectal ESD/EMR because position changesare often required. Abdominal fullness can be reducedthrough carbon dioxide insufflation, decreasing the amountof sedatives required.85,111

Instruments and drugs to be preparedWhen a sedative is used during the procedure or whentreatment is predicted to take a considerable time, it isdesirable to monitor the patients oxygen saturation andelectrocardiogram.

Postoperative managementIn the Japanese situation, EMR for lesions 2 cm in size should be done after the patient is hospitalized.However, no recommendations are provided in these guide-lines for the length of hospitalization and the timing of oralingestion after endoscopic procedures. One report regardingESD found that no adverse event occurred in a clinicalpathway where the length of hospitalization was 4 nights and5 days with oral ingestion starting 2 days after the opera-tion.119 A meal is given after confirming the absence ofinflammatory findings, such as level of serum C-reactiveprotein (CRP), abdominal pain, and fever, while checkingfor delayed perforation and delayed bleeding. Both thelength of hospitalization and the fasting period should beconsidered with regard to each specific situation.

Post-polypectomy electrocoagulationsyndromeEven in cases where no perforation has developed, abdomi-nal pain or fever may occur if the muscular layer is rupturedor thermally denatured. Pain and fever may be caused byinflammation of the peritoneum, which sometimes occursafter electrocoagulation, even when no subsequent perfora-tion occurs.120 Although for most patients conservative treat-ment can generally be carried out, it is important to adoptcareful measures such as prolongation of the fasting periodwhile considering the possibility of delayed perforation.



Delayed perforationDelayed perforation is an intestinal perforation that develops acertain period of time after the operation (i.e. intestinal perfo-ration that is detected after the scope has been withdrawnfollowing completion of ESD/EMR during which perforationdid not occur). Delayed perforation is diagnosed on the basis ofabdominal pain, abdominal findings, presence of fever, andinflammatory response. Most cases of delayed perforationoccur within 14 h after the operation. However, approximatelyone-third of delayed perforation cases are confirmed 24 h afterthe treatment. Free air, which cannot be detected by simpleX-ray imaging, is sometimes found on abdominal CT. There-fore, in caseswhere delayedperforation is suspected, abdominalCT should be carried out. Surgeons must be called for emer-gency surgery,which is essential in casesof delayedperforation.The incidence of delayed perforation is 0% in EMR (no datahave been reported) and 0.10.4% in ESD (i.e. indicating thatdelayed perforation seldom occurs).37,88,121

Delayed bleedingDelayed bleeding is defined as a decrease in hemoglobin by>2 g/dLor confirmation ofmarked hemorrhage a certain periodof timeafter endoscopic treatment.122Delayedbleedingdoesnotinclude small amounts of bleeding such as the presence of traceamounts of blood in the stool.The incidenceof delayedbleedingis reported to be 1.41.7% in EMR88,97 and 1.52.8% inESD.37,88,97,121 Delayed bleeding is mainly observed during theperiod between 2 and 7 days after the operation, and a hemor-rhage observed within 10 days after the operation may beconsidered delayed bleeding. The effect of application of aprophylactic clip on delayed bleeding has been discussed pre-viously.A study reported that prophylactic clip application waseffective for lesions >20 mm in size.123 However, the effective-ness of prophylactic clip application for high-risk lesions mustbe evaluated through prospective studies.

Fourniers syndrome (fulminantnecrotizing fasciitis)In cases where the rectum is below the peritoneal reflection,perforation into the abdominal cavity does not occur becauseof anatomical features; however, penetration into the retro-peritoneum occurs and, consequently, mediastinal emphy-sema or subcutaneous emphysema may occur.114 Moreover,the possibility of fulminant necrotizing fasciitis (Fournierssyndrome) cannot be dismissed, although it is extremelyrare, and no study has reported its development after endo-scopic resection.124 However, when fulminant necrotizingfasciitis develops, it causes septicemia and disseminatedintravascular coagulation, and the associated mortality isreported to be 2040%. Therefore, broad-spectrum antibiot-ics and immediate surgical treatment are required.125

ASSESSMENT OF CURABILITY

CURABILITY IS EVALUATED based on the tumormargin of the resected specimen and risk factors forlymph node/distant metastasis (level of evidence: IVb, gradeof recommendation: B).

Tis (M) carcinomaWith regard to colorectal tumors, Tis (M) carcinomas gen-erally do not metastasize to lymph nodes or other organs.These lesions can be radically cured by endoscopic localresection. However, in cases with positive lateral tumormargin or piecemeal resection, local recurrence has beenreported.42,124,126 Previous reports have compared the rates ofen bloc resection in EMR (piecemeal EMR) with those inESD for mucosal lesions with tumor sizes 20 mm. Consequently, the rates of en bloc resection weredetermined to be as high as 66.580% in EMR when thetumor sizes were

recurrence is extremely rare (level of evidence: IVb, grade ofrecommendation: B). In cases in which only the SM invasiondepth does not satisfy the criteria for a radical cure, andwhere no other risk factors for metastasis are observed, thelymph node metastasis rate has been reported to beextremely low.130134 At present, a research project of JSCCRconcerning the stratification of risk factors for the metastasisof pT1b SM cancer (SM invasion depth >1000 m) to otherorgans is ongoing.

POSTOPERATIVE FOLLOW UP

THE AIM OF follow up after colorectal ESD/EMR isearly detection of local residual/recurrence, metastasis,and metachronous lesions.133,134 Some studies have reportedthat endoscopic treatment for colorectal tumors decreasedthe incidence of colorectal carcinoma and the risk of mor-tality.135,136 Surveillance after surgical resection for colorectalcarcinoma was reported to improve prognosis.137,138 Althoughno evidence-based consensus on the actual follow-upmethods after endoscopic treatment is available in Japan, theJSGE Evidence-Based Clinical Guidelines for Managementof Colorectal Polyps (in press) guidelines recommend thatfollow-up colonoscopy should be done within 3 years afterpolypectomy.139 The follow-up plan should be establishedwith regard to therapeutic techniques such as en bloc resec-tion and piecemeal resection, curability evaluation based onpathological examination of the resected specimens, riskfactors for multiple lesions and carcinomas, and underlyingdisease. In essence, the plan must give importance to thebackground of each patient.

Local residual/recurrenceFor early detection of local residual/recurrence, periodicobservation with colonoscopy is desirable, and endoscopicmeasures are applicable to many early detection cases. Inadenoma or pTis (M) carcinoma, when piecemeal resection isused or the tumor margin after resection is unclear and thecurability cannot be accurately evaluated, colonoscopyshould be done approximately 6 months after the endoscopictreatment (level of evidence: IVb, grade of recommendation:B). Compared with complete en bloc resection, histologicalevaluation is more difficult and the local residual/recurrencerate is higher in piecemeal resection.42,92,96,140,141 The recur-rence rates were reported to be 18.4%, 23.1%, and 30.7% at 5,12, and 24 months after piecemeal resection, respectively.96

When the horizontal tumor margin is difficult to evaluate orwhen piecemeal resection is carried out, it is recommended tocarry out colonoscopy within 612 months.49,142

No local residual/recurrence was detected in the case ofadenoma or pTis (M) carcinoma for which complete en bloc

resection had been carried out and for which curative resectionwas concluded based on histological examination.49,129

However, in the case of pT1a (SM) carcinoma (SM invasiondepth 3) colorectal adenomas with lesions >10 mm insize and a history of colorectal carcinoma.146,150152 Afollow-up schedule must be established on the basis of eachpatients background, including risk factors, age, and comor-bidities. In the USA, follow up after endoscopic resection isstratified according to risk, and colonoscopy is recommendedto be carried out for multiple (310) adenomas, adenomas>10 mm in size, villous adenomas, and high-grade dysplasia3 years after endoscopic treatment. Moreover, colonoscopy isrecommended to be carried out for multiple (>10) adenomaswithin 3 years after endoscopic treatment.142



PATHOLOGY

Handling of specimens

TO JUDGE THE curability of a lesion and the necessityfor additional treatment, accurate histological diagnosisis critical, and resected specimens must be appropriatelyhandled (level of evidence: VI, grade of recommendations:C1). The resected specimen is pinned on a rubber or corksheet so that the mucous membrane surrounding the lesion isevenly flattened and the mucous membrane surface can beobserved (Figs 2,3). Subsequently, the specimen is fixed witha 1020% formaldehyde solution for 2448 h at roomtemperature.153

As a specimen rapidly autolyzes after resection, it mustbe fixed as quickly as possible. To prevent drying of the

specimen, it should be soaked in a physiological salinesolution. Thereafter, the endoscopist is required to appro-priately display the specimen so that the difference betweenthe specimen and the clinical images is minimized and thetumor margin of the specimen can be judged. Specimensobtained from piecemeal resection must be reconstructed tothe greatest extent possible so that the tumor margin can bejudged.

To carry out histological diagnosis precisely and indetail, specimens must be appropriately cut (level of evi-dence: VI, grade of recommendation: C1). An endoscopistmust provide documentation (an explanatory text or anillustration) to a pathologist so that the basic informationon preoperative diagnosis (including the result of biopsy),the site and morphology of the lesion, and the tumor sizeas well as the clinical evaluation can be accurately con-veyed. It is helpful to indicate the location that most clearlyexhibits the malignancy of the lesion in clinical andimaging findings in the above documentation.

After fixation, the entire specimen is sectioned intopieces at intervals of 23 mm, and all slides are preparedfor histological diagnosis. Procedure of the actual cutting isas follows: (i) a tangent that touches the focus closest tothe horizontal tumor margin is assumed, as shown in

Figure 2 Fixed endoscopic mucosal resection specimen.

Figure 3 Fixed endoscopic submucosal dissection specimen.



Figure 4; (ii) the first shallow cut is carried out in thedirectionperpendicular to the tangent; (iii) shallow cutsparallel to the first cut are carried out so that all slicesare not completely separated from each other, after whichthe specimen is photographed; and (iv) deep cuts arecarried out to completely separate all the slices for thepreparation of slides. When a region of the lesion isunclear, observation with a stereoscopic microscope isrecommended.44

Description of pathological ndingsHistological diagnosis of tumors is carried out in accordancewith the Japanese Classification of Colorectal Carcinoma(8th edition).44 The histological type, depth of wall invasion,vascular invasion (ly, v), and resection tumor margins (hori-zontal, vertical) of the carcinoma are judged. In the case ofpT1 (SM) carcinoma, the invasion depth (pT1a: pap>por2). The depth of wall invasion is repre-sented based on the deepest layer of carcinoma invasion. Inthe case of pT1 (SM) carcinoma, the invasion depths ofpedunculated and non-pedunculated lesions are evaluatedseparately.

Usefulness of special stainingand immunostainingIn histological diagnosis, diagnosis of types with specia-lized histology, measurement of invasion depth, and specialstaining and immunostaining of vascular invasion are

informative. With regard to types with specialized histology,endocrine cell carcinoma with a high grade of malig-nancy and carcinoid tumor with a low grade of malignancy/neuroendocrine tumor must be discriminated from adeno-carcinoma. For this discrimination, immunostaining (chro-mogranin A, synaptophysin, and CD56) is effective. Inthe case of conventional adenocarcinoma, the grade ofbudding is assessed using hematoxylin-eosin (HE)-stained specimens. Cytokeratin is useful for histologicalevaluation because cancer cells become distinctive afterimmunostaining.154,155 When measuring the invasion depth,immunostaining with desmin helps to identify the muscula-ris mucosae.156,157 Elastica van Gieson staining or Victoriablue/HE double staining can be used to confirm venousinvasion. To verify lymphatic vessel invasion, immuno-staining with anti-lymphatic vessel endothelial antibody(D2-40) in combination with other staining methods ispreferred.154160

ACKNOWLEDGMENTS

WE GREATLY APPRECIATE the affiliated congressand the secretary of the JGES for their cooperation.The guidelines committee was formed as shown in the tablebelow. The JGES entrusted the creation of the Guidelines toseven gastroenterological endoscopists, one colorectalsurgeon, one gastroenterological pathologist, and one clini-cal oncologist (a total of 10) as members of the GuidelinesCommittee. Moreover, five gastroenterological endoscopists,two colorectal surgeons, and one gastroenterologicalpathologist (a total of eight) were in charge of evaluating theGuidelines as members of the Evaluation Committee, asfollows.

Figure 4 Cut-out of a resected speci-men. , mucosal cancer region; ,submucosal cancer region.



Guidelines Committee, Japan Gastroenterological EndoscopySociety

Responsible Director:Kazuma Fujimoto (Department of Internal Medicine, Saga

University Faculty of Medicine)Chairman:Kazuma Fujimoto (Department of Internal Medicine, Saga

University Faculty of Medicine)Working CommitteeChairman:Shinji Tanaka (Endoscopy and Medicine, Hiroshima University)Chairman in charge of Guidelines creation:Shinji Tanaka (Endoscopy and Medicine, Hiroshima University)Deputy Chairman:Hiroshi Kashida (Department of Gastroenterology and

Hepatology, Kinki University Faculty of Medicine)Members:Yutaka Saito (Endoscopy Division, National Cancer Center

Hospital)Naohisa Yahagi (Tumor Center, Keio University Hospital)Hiroo Yamano (Digestive Disease Center, Akita Red Cross

Hospital)Shoichi Saito (Department of Endoscopy, The Jikei University

School of Medicine)Takashi Hisabe (Department of Gastroenterology, Fukuoka

University Chikushi Hospital)Takashi Yao (Department of Pathology, Juntendo University)Masahiko Watanabe (Department of Surgery, Kitazato

University)External member: Masahiro Yoshida (Chemotherapy Institute,

Kaken Hospital)Chairman of the Evaluation Committee:Shin-ei Kudo (Digestive Disease Center, Showa University

Northern Yokohama Hospital)Deputy Chairman:Osamu Tsuruta (Digestive Disease Center, Kurume University

School of Medicine)Members:Ken-ichi Sugihara (Department of Surgical Oncology, Tokyo

Medical and Dental University)Toshiaki Watanabe (Department of Surgical Oncology, The

University of Tokyo)Yusuke Saitoh (Department of Gastroenterology, Asahikawa City

Hospital)Masahiro Igarashi (Department of Endoscopy, Cancer Institute

Ariake Hospital)Takashi Toyonaga (Division of Endoscopy, Kobe University

Hospital)Yoichi Ajioka (Division of Molecular and Diagnostic Pathology,

Niigata University)

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1 esd vs emr

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