Endoscopic submucosal dissection for early

doi:10.1111/j.1744-1633.2007.00366.x

Review article

Endoscopic submucosal dissection for early neoplasia of foregut: Current development Philip Wai-Yan Chiu,1* Enders Kwok-Wai Ng1 and Haruhiro Inoue2 1 Institute of Digestive Disease, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong; and 2Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan.

In the past, conventional techniques of endoscopic resection, including endoscopic mucosal resection, were limited by the size of the specimen obtained, the obscurity of the resection and the uncertainty of the resection margins in piecemeal resection for early cancer of the foregut. Endoscopic submucosal dissection emerged as a novel technique of mucosal resection which can achieve a curative resection for early cancer of the foregut with a wide margin. The current article focused on a review of the application of endoscopic submucosal dissection in treating early cancer of the upper gastrointestinal tract. Key words: early gastric cancer, endoscopic submucosal dissection, superficial oesophageal neoplasia.

Introduction Carcinoma of the foregut remains a major health issue in Asia. While gastric cancer persists as the second leading cause of death in the Asia–Pacific region, oesophageal squamous cell carcinoma (ESCC) frequently occurs in the Asian Cancer Belt, including Eastern Turkey, Iraq, Iran, Northern China, Hong Kong and Japan.1–3 Carcinoma of the foregut, however, is notoriously difficult to treat. The 5-year survival for advanced carcinoma of the stomach is around 20–30%, whereas that for ESCC is only 10–20%.4–6 One of the reasons for such a poor result is that these cancers are diagnosed at an advanced stage. Everett and Axon, however, showed that, worldwide, early gastric cancer has an excellent survival prognosis, with a 5-year survival of more than 90%.7 This is attributed to the fact that intramucosal early neoplasia of the foregut seldom metastasizes. This has allowed the application of local mucosal resection for early gastric or superficial oesophageal neoplasia limited to the mucosa or upper submucosa. The present review will focus on endoscopic submucosal dissection (ESD), which is a recently emerged technique of endoscopic resection in the treatment of early gastric and oesophageal cancer.

*Author to whom all correspondence should be addressed. Email: [email protected] Received 15 November 2006; accepted 22 January 2007.

Vienna and Paris Classification: Speaking the same language Before the consideration of treatment for early gastrointestinal (GI) neoplasia, we must first have a classification and description system for suitable lesions. There has been discrepancy in the pathological definition and classification of early GI neoplasia between Japanese and Western pathologists. Since the recognition of the existence of early GI neoplasia, several nomenclature systems were developed to describe such a lesion.8–12 Western pathologists rely on the invasive nature of the neoplastic lesion to make a diagnosis of carcinoma, whereas Japanese pathologists focus on the cellular changes.13 The hot debate on the nomenclature system led to a thorough discussion of the definition of terms to describe early GI cancers. The Vienna classification in 2000 started a conjoint classification on gastric dysplasia (Table 1).14,15 This classification standardized the terminology for describing early gastric neoplasia, which allowed a common platform for gastroenterologists and surgeons to discuss the appropriate treatment. For Type 4 and Type 5 lesions, a resection is indicated. There is still controversy in the management of Type 3 lesions, especially when the lesion is low-grade dysplasia. Most endoscopists, however, would favour a formal histopathological examination of such a lesion. As the technique of endoscopic resection is quite mature, endoscopic mucosal resection (EMR) or ESD could be applied to resect such a lesion for histopathology.

Surgical Practice (2007) 11, 106–114 © 2007 The Authors Journal compilation © 2007 College of Surgeons of Hong Kong

ESD for early neoplasia of foregut

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Table 1. Revised Vienna classification of gastrointestinal epithelial neoplasia and recommended management Category 1 2 3

4 4.1 4.2 4.3 4.4 5

Diagnosis Negative for dysplasia Indefinite for dysplasia Mucosal low-grade neoplasia Low-grade adenoma Low-grade dysplasia Mucosal high-grade neoplasia High-grade adenoma/dysplasia Non-invasive carcinoma (carcinoma in situ) Suspicious for invasive carcinoma Intramucosal carcinoma Submucosal or deeper invasion by carcinoma

Management Optional follow up Follow up Endoscopic resection or follow up

Endoscopic or surgical local resection

Surgical resection

The nomenclature of early neoplasia of the GI tract is further refined in the Paris classification.16,17 The Paris classification unified the endoscopic description of early GI neoplasia. Type 0 was assigned to define superficial neoplastic lesions to distinguish from those lesions classified by the Borrmann classification of gastric cancer in 1926.18 Morphologically, Type 0 early GI neoplasia can be classified into: Type 0 I: polypoid; Type 0 II: non-polypoid and non-excavated; and Type 0 III: non-polypoid with a frank ulcer. Type 0 II can be further classified into: Type 0 IIa: elevated; Type 0 IIb: flat; and Type 0 IIc: depressed (Fig. 1). If the superficial neoplasic lesion has elements of elevation and depression, the classification can be a combination of IIa and IIc depending on which proportion dominates. This classification facilitated a communication between endoscopists on the appearance and subsequent management of the superficial neoplastic lesion. Moreover, the macroscopic appearance has a predictive value on the depth of invasion.

How to recognize early neoplasm of the foregut Early GI neoplasia is notoriously difficult to diagnose, as they are usually asymptomatic. The diagnosis of an early GI neoplasia requires a high index of suspicion upon endoscopy, and a meticulous technique. Moreover, ample time and careful examination throughout the procedure is a prerequisite to successful diagnosis. Recently, novel developments in endoscopy including chromoendoscopy, magnifying endoscopy and narrow band imaging have assisted in the recognition of these early tumours.19

Chromoendoscopy Chromoendoscopy involves the use of dye spray onto the mucosa to assist in the recognition of abnormal

Fig. 1. Morphological classification of superficial neoplastic lesions of the gastrointestinal tract.

mucosal lesions. For the oesophagus, the commonest dye used is the Lugol iodine20 (Fig. 2). This is a vital staining which reacts with the squamous oesophageal mucosa. Normal squamous oesophageal cells with adequate glycogen storage will take up the iodine and become brownish. Neoplastic cells and inflammatory conditions are depleted of glycogen. Hence, these lesions will be under- or unstained upon Lugol chromoendoscopy. A recent large-scale multicentre trial


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(a)

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Fig. 2. (a) Superficial oesophageal carcinoma on white light endoscopy. (b) Superficial oesophageal carcinoma enhanced after Lugol chromoendoscopy. (c) Type V1 intracapillary capillary loops patterns on magnifying endoscopy for superficial oesophageal carcinoma. 䉳

confirmed that Lugol chromoendoscopy improved the sensitivity in detecting early oesophageal squamous neoplasia in high-risk patients with head and neck or tracheobronchial cancer.21 Chromoendoscopy for stomach uses a non-vital staining technique, and the commonest dye used is indigocarmine.22 Indigocarmine is not taken up by the gastric mucosal cells. However, it will enhance the mucosal pit pattern and outline the abnormal lesion (Fig. 3).

(b)

(c)

Magnifying endoscopy Magnifying endoscopy can achieve a magnification of 80 times on a 14 inch monitor. Mucosal vascular and pit patterns can thus be observed. The diagnosis of early oesophageal cancer relies on the recognition of abnormal vascular patterns named intracapillary capillary loops (IPCL).23 These are normal capillary loops which are distributed within the mucosal level between papillary strictures of the squamous mucosa. In superficial oesophageal neoplasia involving the mucosa, these IPCL will become dilated and torturous (IPCL Types IV, V1 and V2). If the neoplasia invades the submucosa, there will be abnormal neovascularization (IPCL Type Vn). The correlation between the IPCL pattern and the depth of invasion of superficial oesophageal neoplasia can be more than 80%.24 Magnifying endoscopy allows the observation of the gastric pit pattern which will become irregular with various shapes in early gastric cancer. Although the definition of abnormal pit pattern for early gastric cancer is not yet definite, a non-structural pit pattern is recognized as a good indicator of submucosal invasion.25

Endoscopic resection: Indications and contraindications Endoscopic mucosal resection emerged as a radical local resection more than 10 years ago. EMR can be classified into mucosectomies with or without suction, and commonly practiced techniques include strip biopsy technique, cap EMR technique, tube method, and four-step mucosal resection.26–30 The aim of these techniques is to remove the mucosa together with the carcinoma with adequate circumferential margin. The techniques of EMR, however, can only remove a limited size of mucosa. In the past, the Japanese Surgical Practice (2007) 11, 106–114 © 2007 The Authors Journal compilation © 2007 College of Surgeons of Hong Kong


(a)

(b)

(c)

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Fig. 3. (a) Early gastric cancer Type 0 IIa lesion on ordinary white light endoscopy. (b) Same lesion after indigocarmine chromoendoscopy. (c) Irregular gastric pits without non-structural pattern upon magnifying endoscopy representing an early gastric cancer limited to the mucosa. 䉳

Gastric Cancer Association recommended that endoscopic resection should be applied only to treat differentiated intestinal-type early gastric cancer limited to mucosa of less than 2 cm and without ulceration.31 One of the reasons for this recommendation is related to the limitation of the technique available for endoscopic resection. The maximal size of a one-piece mucosectomy specimen obtained from conventional EMR is only around 20 mm.27 For the strip biopsy technique, the size of the specimen is limited by the degree of lifting and the area of the snare, whereas for the cap technique, the size of the specimen is limited by the size of the cap used. Gotoda et al. conducted a large-scale study on the possibility of lymph node metastasis in early gastric cancer. From a review of 1230 intramucosal welldifferentiated carcinomas less than 3 cm and 929 intramucosal well-differentiated carcinomas of any size, they found that none of these had lymph node metastasis.32 The recommendation of endoscopic resection for early gastric cancer was thus extended (Table 2).32,33 Currently, endoscopic resection for early gastric cancer is recommended for well-differentiated intramucosal adenocarcinoma intestinal type of any size without ulceration, and those less than 3 cm with ulceration. The risk of lymphovascular spread is, however, much higher if the tumour is diffuse-type adenocarcinoma on Lauren’s classification. Although the conventional technique of endoscopic resection is limited by the size of the specimen, a complete resection for early GI neoplasia can be achieved by piecemeal resection. Piecemeal resection, however, renders examination of the resection margins difficult. The confirmation of clearance at the deep margin is especially tough at the resection margins of the pieces. The emergence of a novel technique of endoscopic resection, ESD, enhanced the adequacy of circumferential resection margins by achieving an en-bloc resection of the entire neoplasia.

Endoscopic submucosal dissection Endoscopic submucosal dissection is carried out through the use of various novel endoscopic dissection knives. These can be classified into insulated and non-insulated types. The Insulated tip (IT) knife was among the first developed devices used for ESD.34 The dissection at the submucosal plane was Surgical Practice (2007) 11, 106–114 © 2007 The Authors Journal compilation © 2007 College of Surgeons of Hong Kong

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Table 2.

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Expanded indications for endoscopic resection for early gastric cancer

Ulceration Size

Mucosal cancer No ulceration

Intestinal Diffuse

Submucosal cancer Ulceration

ⱕ SM1

ⱖ SM1

ⱕ 20 mm

> 20 mm

ⱕ 30 mm

> 30 mm

ⱕ 30 mm

Any size

ER (traditional indication) Radical surgery

ER (extended indication) Radical surgery

ER (expanded indication) Radical surgery

Radical surgery

ER (expanded indication) Radical surgery

Radical surgery

Radical surgery

Radical surgery

ER, endoscopic resection.

enhanced by the insulated nature of this end, which served to prevent perforation. However, this ceramic tip hinders sharp dissection. Recently, the Hook knife and the Triangular tip (TT) knife emerged as newly designed devices for ESD.35,36 These devices are not insulated at the tip. They are sharp in action, and allow a faster dissection within the submucosal plane. These devices are, however, technically more demanding and a higher level of precision is needed. Flex knife uses a wire snare insulated with a plastic sheath.37 This allows a larger flexibility of the knife and a better manipulation especially around curvatures of the GI tract. This is particularly used for gastric and colorectal ESD. There have been reports on the use of the needle knife alone in performing ESD. The mucosa is elevated by the cap attached to the end of the endoscope while submucosal dissection is carried out by lateral movement of the needle.38 A novel device named Flush knife serves a similar function to an ordinary needle knife, with an additional ability of injection. This facilitates a simultaneous submucosal injection with the dissection, eliminating the necessity of exchanging devices. The fundamental steps in ESD include an initial identification of the early GI neoplasia and marking of the lesion with an adequate resection margin. The recommended margin is at least 2–3 mm. The marking is performed by electrocautery using the snare wire, needle knife, TT knife, Hook knife or Flex knife (Fig. 4). Submucosal injection is then done to achieve adequate lifting and facilitate dissection at the submucosal plane. Conventionally, the agent used for submucosal injection included normal saline mixed with epinephrine and indigocarmine. Recently, sodium hyaluronate is increasingly used for submucosal injection.39 Sodium hyaluronate is a high molecular weight particle with dense viscosity. It remains in the submucosal plane for a significantly longer period of time, and it allows a persistent elevation of the mucosa for prolonged dissection. This is useful when a prolonged period of ESD is expected, as saline tends to diffuse away after initial submucosal dissection. Submucosal

(a)

(b)

Fig. 4. (a) Type 0 IIa + IIc early gastric cancer. (b) Electrocautery markings around the early gastric cancer.

dissection is subsequently carried out using various instruments (Fig. 5). Commonly, there are numerous penetrating vessels between the mucosa and submucosa. These vessels can be effectively cauterized by the IT knife, TT knife, Hook knife, Flex knife or the



Chiu et al.52

Fujishiro et al.39

Watanabe et al.44

Toyonaga et al.38

Oda et al.51

ESD, endoscopic submucosal dissection; Hook, Hook knife; IT, Insulated tip knife; N/A, not available; No. number of patients; TT, Triangular tip knife.

0% 18 months 0% 4% 30 IT/TT/Hook

26 Flex knife

120 IT/Hook

Needle knife

20

–

83

100%

100%

0%

3.8%

0%

0%

N/A 4% 6% 93% 60 (10–540) 1033 IT

100%

0% 12 months

– – 3.7% 0% 37% – 27 Hook

10% 6 months 0.8% 0% 54% Miyamoto et al.40

Gastrointestinal Endoscopy 2002 Digestive Endoscopy 2004 Digestive Endoscopy 2005 Digestive Endoscopy 2005 Gastrointestinal Endoscopy 2006 Gastrointestinal Endoscopy 2006 Surgical Endoscopy (in press)

IT

111

Fujisaki et al.50

Time (min) No. ESD Journal/year Author [ref]

coagulation grasper. After ESD, the specimen obtained should be examined carefully. All the markings should be resected within the specimen and the mucosa should be spread and pinned onto a plate before formalin fixation, as the specimen will shrink after processing. The mucosal defect should be re-examined for haemostasis. The commonly reported complications of ESD occur at the early and late phase. Early complications include bleeding and perforation. Bleeding is very common during ESD. Most of the bleeding can be stopped with the use of various endoscopic techniques including injection, heater probe or haemoclips. Most endoscopists, however, will choose to use coagrasper using electrocautery for haemostasis, as the application of clips may hinder further

Table 3.

Fig. 5. (a) Endoscopic submucosal dissection (ESD) performed with Insulated tip knife. (b) Defect of the gastric mucosa after ESD.

Endoscopic submucosal dissection for treatment of early gastric cancer

Complete resection (R0)

(b)

–

Delayed bleeding

Perforation

Follow up

(a)

123

Local recurrence


ESD, endoscopic submucosal dissection; No. number of patients.

180

100%

0%

0%

14.6 months 3.3% 0% 97% 70

30 5 20 Flex knife Needle knife Endoscopy 2006 Surgical Endoscopy 2006 Digestive Endsocopy 2005 Kakushima et al.53 Shimoyama et al.54 Toyonaga et al.55

Follow up Perforation Delayed bleeding Complete resection (R0) Time (min) No. ESD Journal/year Author [ref]

Endoscopic submucosal dissection for treatment of superficial oesophageal neoplasia Table 4.

0% 0% 0%

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Local recurrence

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submucosal dissection, while heater probe could lead to perforation. Ono et al. reported a 5% risk of bleeding and perforation, while the rate of bleeding after ESD can be up to 38%.34,40 Most of the delayed bleeding occurs within the first 12 h after ESD, which is usually allayed by endoscopic therapy. There are diverse management techniques after ESD to prevent delay bleeding. Most endoscopists would prescribe acid-reducing agents after ESD. A randomized trial conducted in Japan on 57 patients showed that both adjuvant intravenous famotidine and omeprazole resulted in a similar bleeding rate after EMR.41 The important predictor to bleeding after EMR is the occurrence of bleeding during the procedure.42 From the experience of managing bleeding peptic ulcers, we prefer to use high-dose intravenous omeprazole infusion after ESD to prevent rebleeding.43 Watanabe et al. reported that there is no significant difference in the rate of perforation between ESD and EMR (4.2% vs 3.2%).44 However, the en-bloc resection rate of ESD is significantly higher than EMR if the lesion is greater than 10 mm. Most prospective series showed an ESD-related perforation rate ranging from 0 to 4%, which is higher than that reported for EMR. The majority of reports confirmed that endoscopic closure using metallic clips is successful in managing perforation during ESD.45 The higher risk of perforation with ESD as compared to EMR may be related to the handling of the instruments for submucosal dissection, as they are technically demanding. Each dissecting knife requires a particular dissection motion in order to achieve submucosal dissection. Inoue et al. suggested that a larger volume of submucosal injection can prevent EMR-related perforation.46 Another important step to avoid ESD-related perforation is to have an adequate view of the submucosal plane, with a good separation between the mucosa and the muscularis propria. This can be achieved by an appropriate solution that can stay adequately long in the submucosal plane to enhance the dissection. Fujishiro et al. reported that the use of hyaluronic acid mixed with glycerin and sugar can achieve a 94% en-bloc resection rate with minimal rate of bleeding and perforation. The authors showed that high molecular weight solution can stay in the submucosal plane for a significantly longer period of time as compared to saline alone.47 High molecular weight solution should be recommended for enhancing the performance of ESD in difficult situations like oesophageal or colonic ESD, or ESD for local recurrence or with dense scarring. The most important late complication is tumour recurrence. Oka et al. reported a large series of retrospective comparisons between EMR and ESD, and found that en-bloc resection with large piece mucosectomy is Surgical Practice (2007) 11, 106–114 © 2007 The Authors Journal compilation © 2007 College of Surgeons of Hong Kong


associated with a lower rate of local recurrence.48,49 Currently, there is limited prospective study addressing the issue of long-term oncological clearance for early cancer of the foregut treated with ESD. With an average follow-up period of only 12 months, the local recurrence rate is mostly reported as 0% in most of the prospective series (Tables 3,4). Longer term follow up is necessary to investigate the rate of local recurrences and the occurrence of metachronous tumour.

Conclusions Endoscopic submucosal dissection has emerged as a novel technique to achieve en-bloc resection of early gastric and superficial oesophageal neoplasia. With ESD, a curative resection can be achieved with a low rate of complications and recurrence. The key to success lies in the endoscopic detection of early GI neoplasia, and stringent selection criteria of suitable cases to be treated with this seamless radical surgery.

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