Endoscopic Mucosal Resection (EMR)

Endoscopic mucosal resection

Endoscopic mucosal resection can be performed in the oesophagus, stomach, small bowel and colon. It is an excellent technique for the treatment of early gastrointestinal neoplasia. The following pages illustrate the assessment and resection of lesions from all of these areas.

Upper gastrointestinal EMR

Endoscopic mucosal resection has an important role to play in the treatment of early gastrointestinal neoplasia in the upper GI tract. Over the last 10 years the evidence base for the benefits of the techniques has grown

The oesophagus

Barrett's oesophagus is an important condition with a high incidence in Western Europe. The development of high grade dysplasia carries a high risk of malignant transformation. Traditionally the only approach has been oesophagectomy. This is a major operation with a significant mortality and morbidity. With the advent of effective strategies for localising dysplasia, EMR has emerged as an effective treatment for dysplasia and intramucosal cancer within Barrett's oesophagus. Initial studies have suggest equivelant 5 year survival to oesophagectomy.

The key to the endoscopic treatment of Barrett's neoplasia is identification of the dysplastic areas. The two main methods are:

1) Dye spray

2) Electronic imaging

The main dye sprays used are acetic acid and methylene blue.

Electronic imaging utilises the image enhancement facilities of the modern endoscopes. Both Narrow Band Imaging on olympus systems and FICE on Fujinon equipment has been shown in studies to be effective in localising dysplasia.

Oesophageal EMR can be performed in two ways:

1) Cap and snare

The dysplastic area is first lifted by injecting a lifting solution into the sub-mucosal space under the dysplasia. A specially designed plastic cap is then fitted to the end of the gastroscope. A snare is inserted into the cap and a loop formed by sucking an area of healthy tissue into the cap. The lifted dysplastic area is then sucked into the cap and the snare tightened around the base of the tissue. This is then snared off using a cutting current.

2) Duette cap

This is similar to a variceal banding device. The dysplastic tissue is sucked into the cap and a band fixed around its base. The banded tissue is then snared off. Lifting is not necessary with the duette cap. It cannot however take as large a pieces as the cap and snare.

EMR is not the only method for treating Barrett's neoplasia. Radio-frequency ablation (HALO) has been shown to be effective in treating high grade dysplasia within Barrett's. Radiofrequency electrodes deliver thermal energy through a balloon (HALO 360) which is inflated to make contact with the oesophageal wall. Missed areas can be ablated using a focal probe (HALO 90). The burnt tissus is removed by use of a soft plastic cap on the gastroscope and a further application applied during the same treatment session. If further Barrett's mucosa remains at follow up endoscopy this can be repeated if required.

HALO cannot be used to treat nodular dysplasia. This is very important. Such areas should be removed by EMR first. It should also be remembered that HALO does not provide a tissue sample. Therefore after treatment it will not be known if the lesion was actually invasive cancer. Therefore accurate endoscopic assessment prior to treatment is vital.

A key requirement for successful endoscopic therapy for Barrett's neoplasia is effective follow up. The possibility for developing metachronous lesions exists, and as such all patients receiving EMR or HALO ablation should receive 3 monthly chromoendoscopy for the first year with regular review thereafter.

Squamous neoplasia of the oesophagus

In the western world adenocarcinoma is the most common oesophageal malignancy. However, this is not the case worldwide. In the far East squamous cell cancer is a common condition.

It would however be wrong to assume that squamous cell cancer does not occur in the west. It is difficult to identify in early stages and different endoscopic techniques are required to localise the neoplasia.

Lugol's iodine is a very important stain for identifing squamous neoplasia. When sprayed onto the oesophagus the tissues turn black. Where there is squamous neoplasia there is charactistic voiding areas. These then subsequently turn pink over time. Unlike acetic acid, patients can find the application of Lugols iodine an uncomfortable process, and this should be explained before the procedure.

The following video demonstrates the application of Lugols iodine in the localisation of neoplasia.

Squamous neoplasia can be seen with acetic acid. However, it is different to the appearances seen with Barrett's neoplasia. Rather than a disappearance of the acetowhitening relative to the surrounding tissues there is a snowstorm effect with the neoplastic tissue turning white with the surrounding healthy squamous tissue failing to change at all.

This is demonstrated in the next video.

Squamous neoplasia can be treated endoscopically. However, there are a number of important considerations. The risk of lymph node metastasis is much higher in squamous cell cancer. Therefore, whereas SM-1 cancer can be endoscopically resected with low risk for positive lymph nodes in Barrett's ascoiated adenocarcinoma, the risk is in the region of 8-10% with squamous cell cancer.Therefore the presence of SM-1 invasion is an indication for oesophagectomy.

There has been some data from China suggesting that HALO ablation can be used to successfully treat squamous dysplasia. It is important to note however that this will not provide any information regarding depth of invasion and there is a need for further data regarding the efficacy of this treatment in this setting.

Sub-mucosal lesions

Submucosal tumours are challenging to remove endoscopically. They all need assessment with endoscopic ultrasound (EUS) to establish which layer they originate from.

Submucosal tumours need resection by ESD technique. Although some carcinoids have been removed by EMR technique we would be unhappy about this in the majority of cases as the risk of a positive deep margin is much higher and in the majority of cases would simply not be possible at all. It is important that if submucosal resections are to be attempted that they are undertaken in an environment with comprehensive surgical support as the risk of perforation is significant.

Carcinoids

When less than 2cm in size it is possible to resect carcinoid tumours endoscopically. These should be low risk tumours with a low proliferation index. They typically arise in the mucosal layer from entericromaffin cells and spread deeper as they grow. They are classified as type 1-3. Type 1 lesions are associated with hypergastrinaemia secondary to chronic atrophic gastritis, type 2 occur in association with zollinger ellison syndrome and type 3 are sporadic. Type 1 and 2 are the safest to remove endoscopically.

Synchronous and metanchronous lesions are common with carcinoids. Therefore careful assessment and follow up is required.

This next video shows the difficulty which can be encountered when a carcinoid tumour is located in an inaccessable place. Note that this procedure was time consuming and technically very challenging. Again a general anaesthetic was required.

GISTS

Gastrointsetinal stromal tumours originate from the 4th layer or, less commonly, the 2nd layer. They stain positive for CD117. 10-30% harbour underlying malignancy, especially those over 3cm in size.

Below is a video of a gastric GIST being removed by ESD technique. Note the laparoscope outside of the stomach. This is seen as the light illuminating the stomach from outside. The patient also required a cholecystectomy for an unrelated condition and by performing both procedures under the same anaesthetic we enjoyed an extra sense of security when performing the resection. We could have proceed to a laparoscopic resection if we perforated the stomach.

The next video demonstrates resection of an oesophageal GIST. Again we performed this in theatres under general anaesthetic with full surgical support. Note a microperforation occured which was easily treated endoscopically with a clip. We kept the patient in hospital for a few ways and performed a CT scan which confirmed some air in the mediastinum. The patient was asymptomatic throughout and went home without any discomfort or other issues.

Lipomas

These are yellow lesions which indent with pressure from the biopsy forcips (pillow sign). They arise from the third layer and do not require removal.

Glomus tumours

These arise from the 4th layer. UnLike GISTs they are almost always benign and CD117 negative. They are vimenten positive.

Principles of colonic EMR

Endoscopic mucosal resection (EMR) is an important technique for removing adenomas from the colon. The principle behind the technique is simple; resectable lesions are confined to the mucosa. By injecting a cushion of fluid into the submucosal space the epithelium is separated from the underlying tissues, lifting th elesion up. This makes it safer to remove using a snare and diathermy

Lesion assessment skills

To perform safe colonic EMR requires a combination of knowledge and practical skills. Before attempting to resect any lesion it is first necessary to assess it carefully to ensure that it is not an invasive cancer, or in the case of large lesions contains an invasive component. To do this effectively requires an understanding of Kudo pit patterns and the principles of vascular pattern assessment.

The following video illustrates a Paris type IIa+IIc lesion with an area of Kudo type V pits which represents a cancer. This is unsuitable for endoscopic resection.

Lifting solutions

To perform EMR a fluid is injected beneath the lesion to produce a sub-mucosal lift. A wide range of lifting solutions have been used. The ideal solution should produce:

1) a long lasting high elevation

2) an avascular field

3) good delineation of tissue planes

Furthermore, it needs to be cheap and safe. Numerous combinations have been used. Most units use a mix of either normal saline or gelofusine with adrenaline and a blue dye, either methylene blue or indigo-carmine. Hyaluronic acid produces a good lift but is very expensive.

Assessment of lesions

When assessing lesions for endoscopic resection the difficulty of a resection should be estimated before starting the procedure. The main factors which increase difficulty are:

1) Size: Greater than 1/3 of the circumference of the lumen

2) Crossing more than one haustral fold

3) Presence of diverticular disease

4) Extending to the dentate line

5) Previous EMR attempts or scarring

An important question the endoscopist needs to ask is whether there is enough time on a given list to completely resect the lesion. Scarred lesions from previous aborted EMR attempts are much harder to remove and therefore it is better not to start a resection if there is not time to finish it. Furthermore, as large lesions can take several hours to remove patients need prior warning and consent before beginning such a procedure.

The following video illustrates a scarred lesion extending down to the dentate line. This lesion is a challenge on three accounts; it is large, low and scarred.

Right sided lesions are more challenging to remove. The right colon is thin walled and as such the risk of perforation is higher. However, good results can still be obtained, as this following video demonstrates.

Endoscopy equipment

When attempting EMR it is very important that the endoscopist understands the equipment that they are using.

Diathermy

An understanding of the diathermy unit is particularly important. The difference between the settings can make the difference between a safe proedure and one that results in bleeding or perforation.

Blue pedal

Provides a coagulation current

Forced will remove lesions with coagulation of small vesels. Good for reducing risk of bleeding. The energy delivered will penetrate deep into the tissues, therefore there is a greater risk of perforation

Soft will stop bleeding. Not for removal of lesions

Yellow pedal

Provides a cutting current

Will cut through tissue but higher risk of bleeding. Not so deep so lower risk of perforation. The effect provides coagulation between the bursts of cutting current. The higher the effect the more coagulation is provided.

There are many different diathermy units on the market, all with different settings. The endoscopist should know their unit and how it behaves in a given situation. If a new diathermy unit is installed staff should become familiar with it before beginning the procedure.

Argon photo coagulation (APC)

APC is useful for ablation of small areas of potentially residual tissue. It is an especially impirtant technique when a resection is performed on a scarred lesion where residual tissue may be difficult to remove. However, it should not be seen as a quick fix to an inadequate resection.

The following video demonstrates APC after a multipiece EMR in the caecum. Note how the lesion surrounds the appendiceal orifice making this a challenging resection.

Clips

Endo-clips can perform two functions:

1) Clip bleeding polyp stalks

2) Close mucosal defecits.

If muscle fibres become exposed in a sensitive area at high risk of perforation endo clips can be used to close the mucosa and reduce the risk of complications.

The nursing team

Probably the most important component to safe EMR. To perform large resections safely does not require just an experienced endoscopist. Nursing staff who perform EMR regularly and are familiar with the procedures are essential. A training programme within the unit is highly recommended for developing the skills of the whole team. In particular, the nurses need to be familiar with all the equipment being used, and if they close the snare should be confortable with this skill. Note that it is not the same as snaring stalked polyps. Snare markers will provide much less in the way of a guide and the process works much more by feel. Clear instructions between the endoscopist and assisting nurse are crucial, and should be rehearsed before starting the procedure.

Relationship with the surgeons

EMR can result in perforation. Therefore a close working relationship with the surgeons is very important. MDT discussion is very important and it is necessary for a co-ordinated unified approach to be adopted. Furthermore, there are rare cases where combined endoscopic/laparoscopic approaches can yield benefits. This can only be achieved if all parties understand the benefits and limitations of what is being attempted.

Endoscopic submucosal dissection (ESD)

Resections of Large Laterally Spreading Tumours of Granular Type (LST-G)

LST resections are complex and time consuming. It is important when undertaking this kind of resection that enough time is allocated, as many will take several hours to remove. If a lesion is only partially resected it will be much harder to remove on subsequent occasions due to scarring.

ESD Technique in a Rectal Laterally Spreading Tumour

This video illustrates ESD technique using dual and IT knife combination on a rectal laterally spreading tumour. Combining knives makes the technique easier to perform

ESD can be useful in managing the problems encountered by scarred lesions. Whenever an EMR is performed scar tissue is formed. If a further attempt at resection is performed it is then often not possible to get into the tissue plane adequately to lift the lesion. In these cases a 'hybrid knife' technique can be useful for identifing a tissue plane for subsequent piece-meal resection.

The next video shows a conventional multi-piece EMR. Not how it lifts more effectively than the previous lesion. Also note its location in the caecum. This area of the colon is thin walled, being around 1mm thick. Therefore caution is required to avoid perforating the bowel. Therefore EMR is a safer technique in this area than ESD.

The following videos are of a lecture from the Portsmouth EMR symposium 2008. It investigates the benefits and difficulties in performing ESD in a western setting.

Pathological Examination of Endoscopic Resection Specimens from the Oesophagus and Cardia

David Poller and Michael Vieth

Introduction

Endoscopic mucosal/submucosal resection or dissection (EMSRD) is also referred to as ‘endoscopic mucosal resection’ ( EMR). EMSRD techniques involve the endoscopic removal of the endoscopically abnormal area(s) of tissue by snaring or suction of mucosa, aiming to include as much of the submucosal layer as possible which are then submitted for histopathological examination. EMSRD pathology specimens are used for pathological diagnosis, tumour staging, and therapeutic removal of lesions or abnormal mucosa. EMSRD is now frequently applied in conjunction with other endoscopic ablation techniques such as photodynamic therapy (PDT), or radiofrequency ablation for treatment of Barrett’s mucosa and Barrett’s neoplasia . A few centres outside of Japan undertake endoscopic submucosal dissection (ESD) in the upper gastrointestinal tract, mainly for gastric lesions but also increasingly in oesophageal lesions.

How To Do It

EMSRD specimens should be photographed and if necessary orientated for endoscopic/pathological correlation
The specimen is submitted whole to the pathology department and fixed for at least 24 hours in 10% aqueous formaldeyde.
The EMSRD specimen should be handled very carefully and kept flat so that it does not curl up or become distorted

Larger EMSRD specimens can be very carefully pinned out onto corkboard without tension (see above)

Smaller specimens can be laid flat and submitted on tissue paper or wedged

gently between sponges in a tissue cassette (see above)

After receipt in the laboratory the tissue is unpinned from the corkboard or gently removed from the tissue cassette or filter paper
The deep margin of the specimen is carefully marked with a coloured dye or gelatine, and the lateral margins also
The number and size of all the portions of tissue received in the laboratory should be documented in mm
Specimens can be photographed or described and the blocks can be orientated on the specimen photographs or drawings if this is thought to be helpful in order to identify the closest margin to a neoplastic lesion
Dissecting microscope orientation of lesions may be helpful if there is no macroscopically visible lesion
Blocks are then taken very carefully at 1.0-1.5 mm intervals and embedded on edge in a tissue cassette

The whole specimen is processed for pathological examination with no more

than 2 slices per block (see above)

Haematoxylin and eosin stained sections are examined with 2 additional levels cut and stained from each block at 50mm

Reporting of Specimens

Assess all benign and/or neoplastic lesions present, e.g. Barrett’s mucosa without dysplasia, low or high grade dysplasia, or adenocarcinoma.
Report cases using a modified Riddell system or the Vienna classification for reporting of dysplasias, eg with Riddell negative for dysplasia, indeterminate for dysplasia, low grade dysplasia, high grade dysplasia, adenocarcinoma (mucosal and submucosal).
If adenocarcinoma is present the grade should be stated.
If there is evidence of signet ring change this should be stated.
If there is suspected or definite tumour lymphovascular or perineural invasion this should be noted
The distinction of high grade Barrett’s dysplasia from intramucosal adenocarcinoma may be difficult
Where there is clear and unequivocal cellular infiltration of mucosa, particularly in the case of poorly differentiated/diffuse or signet ring adenocarcinoma this should be stated with certainty but often there is some uncertainty as to the presence or absence of definite mucosal invasion
In some institutions the frequency of the diagnosis of high grade dysplasia is very low and pathologists are increasingly basing their adenocarcinoma diagnosis on certain signs of early invasion such as lateral expansion / intertubular fusion
Depth of invasion may also be difficult to assess, particularly as many specimens may have cautery or thermal artefact which is usually more marked at specimen margins

Problems and Points To Watch Out For

The majority of patients with Barrett’s dysplasia also have reduplication of the muscularis mucosae (MM) of the lower oesophagus so that neoplastic Barrett’s glands are often seen to infiltrate muscle of the muscularis mucosae. This reduplicated muscle is derived from muscularis mucosae and not from muscularis propria.

Staging

Vieth and Stolte from Bayreuth have proposed that depth of invasion of mucosa can be subdivided into 4 groups,

m1=invasion of lamina propria,

m2=invasion of superficial muscularis mucosae

m3=invasion of space between duplicated layers of muscularis mucosae

m4=infiltration of deeper muscularis mucosae

sm1=superficial third submucosal invasion

sm2=middle third submucosal invasion

sm3=deep third submucosal invasion

Westerterp et al. from Amsterdam stage depth of invasion differently

m1=HGD or carcinoma in situ

m2=invasion of lamina propria,

m3=invasion of upper and lower muscularis mucosae and space in between.

sm1=superficial submucosal invasion

sm2=middle third submucosal invasion

sm3=deep submucosal invasion

In our experience it is unusual to see invasion beyond the level of sm1 in EMSRD specimens of the oesophagus although assessment of depth of invasion beyond muscularis mucosae to sm1 or sm2 can be quite subjective as the full thickness of the oesophageal submucosal layer is not present in oesophageal EMSRD specimens. Some centres now aim to completely remove early sm1 tumours by EMSRD. An attempt at assessment of the maximum vertical depth of vertical invasion of carcinoma beyond the muscularis mucosae should be made but in view of the difficulty in determining what proportion of the total depth of the submucosa is involved by adenocarcinoma an alternative approach may be provide an absolute measurement of the depth of invasion from the mucosal or lesion surface to the deepest area of invasion of the lesion, in a manner similar to that of assessment of Breslow thickness in cutaneous melanomas. The tumour free margin thickness at the deepest level of invasion can also be measured, provided that the specimen is correctly orientated at the time of specimen cut up. The results of several large series of Barretts dysplasia or adenocarcinoma managed by EMSRD have confirmed that involvement of deep resection margins of pathology specimens appears to predict for recurrence of dysplasia or adenocarcinoma after EMSRD.

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