41
Endomucosal resection

Mike Thomson and Paul Hurlstone

Introduction

Colonoscopic resection methods have traditionally aimed towards biopsy and polypectomy. Endoscopic mucosal resection (EMR) is in its infancy, but it allows early and effective treatment of selected superficial neoplasms and obviates the need for major surgery in these patients. The safety and efficacy of new endoscopic interventional therapeutics in the form of EMR require further evaluation.

It is important to remember that the inflammation–metaplasia–dysplasia–adenocarcinoma sequence is a concept not exclusive to adult patients, and that children and adolescents have a part to play in this evolutionary pathology. The atypia of lesions needs to be carefully evaluated and is made easier with more modern imaging techniques and hardware.

High‐magnification chromoscopic colonoscopy

High‐magnification colonoscopes enable the magnification of colonic mucosa up to 150 times and also offer higher resolution than older colonoscopes. Their use is maximized in conjunction with chromoscopy and this represents the most common mode of visual enhancement used by endoscopists presently. Using this technique, clear lesion delineation and pit patterns (see Tables 41.1a and 41.1b) can be observed.

icon1 — **Table 41.1a** Paris classification of endoscopic lesion morphology

Endoscopic appearance	Paris class		Description
Protruded lesions	Ip		Pedunculated polyps
Ips		Subpedunculated polyps
Is		Sessile polyps
Flat elevated lesions	IIa		Flat elevation of mucosa
IIa/IIc		Flat elevation with central depression
Flat lesions	IIb		Flat mucosal change
IIc		Mucosal depression
IIc/IIa		Mucosal depression with raised edge

Pit type	Characteristics	Pit size (mm)
I	Normal round pits	0.07 +/− 0.02 mm
II	Stella or papillary	0.09 +/− 0.02 mm
IIIs	Tubular/round pits Smaller than pit type I	0.03 +/− 0.01 mm
IIIL	Tubular/large	0.22 +/− 0.09 mm
IV	Sulcus/gyrus	0.93 +/− 0.32 mm
V(a)	Irregular arrangement and sizes of IIIL, IIIs, IV type pit	N/A

The technique involves initial visualization of the colon with conventional video‐colonoscopy, looking out for the following mucosal signs, which may be subtle.

Focal pallor or erythema
Hemorrhagic spots
Fold convergence

Disruption of mucosal vascular net pattern

Table 41.2 Classification of common chromoscopic dyes

Type of dye	Preparation	Application	Advantages	Side effects
Contrast
Indigo carmine Most commonly used Acetic acid	Standard mucosal toilet	Dye spraying via scope or diffusion catheter		None
Reactive
Crystal violet Kudo type V pit differentiation	Mucosal toilet with proteinase solution	Specialized catheter; 2–3 min wait for fixation		Possible long‐term toxicity
Cresyl violet
Absorptive
Methylene blue	Standard mucosal toilet	Dye spraying via scope or diffusion catheter	Longer staining pattern	Potentially mutagenic

Mucosal unevenness or discrete mucosal deformity
Air‐induced deformation

Once identified, the suspicious areas are washed down with the appropriate mucosal toilet and the dye applied. Lesions are then sized using an open biopsy forceps whose width is known. Morphological classification is then undertaken by activating the colonoscope’s magnification lever and characterizing its appearances.

Pit patterns

Pit patterns have been shown to correlate strongly with their associated histopathological diagnoses and as a result this method of classification is widely used. Types I and II are associated with normal and hyperplastic mucosa. Type III is seen more often in depressed lesions and are associated with carcinomatous change. Type IIIL is associated with adenomas in protuberant lesions. Types IV and V are associated with adenomas with atypical cellularity whereas type V or nonpit patterns are indicative of adenocarcinoma.

A summary of common dyes used in high‐magnification chromoscopic colonoscopy (HMCC) is shown in Table 41.2. Indigo carmine (IC) 0.2–1% is the most frequently used agent. It is a contrast enhancer that pools in recesses, aiding the visualization of abnormal mucosa. As there is no actual reaction with the tissues, it washes off easily which makes it unsuitable for prolonged procedures. IC has been shown to be sufficient in the visualization of type I–IV pits but if further visualization is required, crystal violet (CV) can be used to stain the mucosa. This compound is a potentially toxic reactive dye and should only be used sparingly when type V pits are suspected. Methylene blue stains for a longer period of time and is commonly used in ulcerative colitis cancer surveillance.

The introduction of high‐frequency “miniprobe” ultrasound has now been reported to have a high overall accuracy when used to determine submucosal invasion Paris class II lesions. However, ultrasound imaging requires further training, has significant expense, and may prolong the procedure.

HMCC in the detection of intraepithelial neoplasia and colitis‐associated cancer

Although many pediatric gastroenterologists will see this concept as a theoretical one for their patients, there is no doubt that knowledge of this area is an important corollary of our conception of inflammatory bowel disease (IBD) evolution – this is especially true when counseling adolescents not keen on following treatment regiemes. For instance, azathioprine is now strongly associated with the diminution of colorectal cancer (CRC) risk in long‐term IBD. The management and clinical interpretation of dysplasia in the context of chronic ulcerative colitis are radically different from those of sporadic dysplastic lesions in the “normal” population. These patients have an increased risk of interval cancers, especially those with long‐standing disease. The morphology of precancerous lesions may be flat and multifocal, making HMCC a useful adjunct in their detection. At the current time, dysplasia is the most reliable biomarker of malignant change, being present in >70% of ulcerative colitis patients with CRC.

The ability to differentiate intraepithelial neoplasia from hyperplastic or inflammatory mucosal change using HMCC in ulcerative colitis offers a sensitive and specific tool. There are, however, indistinct mucosal appearances seen in the presence of acute inflammation which may result in equivocal histological diagnoses. It has therefore been recommended that HMCC targeted biopsies be used only when the disease is quiescent and even then only in clearly demarcated lesions.

Summary of limitations of current imaging technology

High sensitivity/specificity for the differentiation of nonneoplastic from neoplastic disease but low overall sensitivity for the anticipation of high‐grade dysplasia.
Effective overstaging of submucosal layer 3/T1 neoplasia.
Operator‐dependent error.
Surface topographical imaging only.
No ability to image surface/subsurface lymphovascular architecture, except with confocal endomicroscopy which is not widely available to date.

Endoscopic mucosal resection

The benefits or early CRC detection are not exclusively those of increased survival as many patients can be treated curatively using novel resection techniques such as EMR. Such a procedure has a low cost and low associated morbidity and mortality when compared to conventional surgery. As mentioned above, new endoscopic imaging techniques such as chromoscopic colonoscopy and HMCC have highlighted the clinical importance of flat and depressed nonpolypoid colorectal lesions.

Simple snare resection is sufficient for pedunculated lesions. EMR permits the resection of flat and sessile lesions by longitudinal section through the submucosal layer. In the colorectum, EMR may provide curative resection for flat and sessile adenomas in addition to early colorectal cancer. EMR facilitates complete histological analysis of the resected lesion and makes it possible to determine precisely the completeness of excision in both the horizontal and vertical resection planes. This makes it advantageous compared to primary tissue ablative techniques such as argon plasma coagulation and electrocoagulation. Numerous EMR techniques have now been described using transparent caps fitted to the proximal aspect of the endoscope and that using an insulation‐tipped cutting knife. With the exception of submucosal posterior rectal tumors, these techniques are reserved for esophageal and gastric resection with the strip biopsy technique used routinely in the colorectum.

Basic EMR technique

The technique of EMR comprises four stages.

Diagnosis and localization of the lesion.
Evaluation of invasive depth to exclude lesions invading the deep submucosal layer 3 or beyond (i.e., T2 disease) using HMCC or ultrasound techniques.
Excision procedure.
Postresection evaluation.

Flat and sessile lesions up to 20 mm in diameter can be resected by en bloc or “single pass” resection with larger lesions requiring a piecemeal approach. A needle catheter is then inserted through the side port of the colonoscope with sterile saline injected around the lesion and surrounding mucosa. A cleavage of the submucosa (having the effect of raising the lesion) then permits simple snare resection. A single cannulation can be used for small lesions (<10 mm) diameter with multiple cannulations usually required for lesions of 20 mm or larger. Adrenaline (1/100 000) mixed with saline or a tissue expander as used in IV resuscitation plus a 1:10 dye such as methylene blue is injected into the submucosal plane, allowing for elevation of the lesion and creation of an artificial tissue plane which facilitates resection. Whatever injection medium is used, it is essential to maintain sufficient mucosal lift or detachment throughout the EMR, which minimizes the risk of muscularis propria entrapment and subsequent perforation.

Peripheral margin tattoos can be used prior to saline submucosal injection to delineate the normal mucosal boundaries around the lesion prior to snaring. This is a helpful technique, as at submucosal lift, the lesion can become distorted and indistinct from the surrounding normal mucosa. If the lesion fails to lift (the nonlifting sign of Uno) or has an asymmetrical appearance then the resection should be abandoned as this indicates tethering to the underlying muscularis mucosa. Perforation and risk of noncurative resection can occur in this scenario.

Following successful submucosal lift, a spiked or “barbed” snare is applied over the lesion and slowly closed under gentle suction. This permits the lesion to be retained within the snare boundaries before final resection. Prior to final cutting (usually using a 25 W coagulation current), the snare should be relaxed slightly to allow any entrapped muscularis mucosa to retract. Following resection, the lesion is retrieved using a pronged grasping forcep or Roth net, followed by immediate fixation in 10% formalin solution. Some endoscopists “pin out” the lesion onto a solid cork or polystyrene plate prior to fixation that limits shrinkage of the resection specimen and permits easier and more accurate histopathological sectioning.

Postresection management

Following resection, it is important to reevaluate the cut margin of the mucosa. High rates of adenoma recurrence may occur, despite reported complete excision by the endoscopist. Performing EMR may therefore be considered a hazardous procedure if this is apparent, where remnant adenomatous tissue continues to assume a risk for carcinomatous transformation. Should a further EMR be unsuccessful, argon plasma coagulation (APC) of any remnant tissue, including application to the entire circumference of the cut margin, should be applied. All lesions should have an adjacent submucosal tattoo using Indian ink to facilitate localization at follow‐up colonoscopy.

Complications of EMR

The main complications of EMR are hemorrhage, perforation, and stenosis. The immediate and early complications (10% of cases) described in the first 12 hours post resection are principally hemorrhage and rarely perforation. EMR may therefore be a safe and effective endoscopic therapy that may enhance our current strategies aimed at the secondary prevention of colorectal cancer. Accurate in vivo staging is essential at colonoscopy prior to consideration of local endoluminal resection. Flat focal submucosal invasive CRCs which are limited to submucosal layer 1 can be managed by EMR as the risk of lymphovenous invasion and nodal metastasis is low (<5%). For lesions with deeper vertical invasion into submucosal layer 3 or beyond (stage T2), the risk of nodal disease increases to 10–15%. EMR in this group is therefore undesirable due to a higher risk of perforation, noncurative excision and untreated nodal disease. Surgical excision is recommended in this group.

Clinical recommendations and conclusions

Colonic chromoscopy and HMCC have been shown to be useful in discriminating between neoplastic and nonneoplastic Paris 0–II colorectal lesions. The decision to target biopsies or progress to therapeutic intervention using EMR can be guided using this technology and avoid inappropriate biopsy or attempted endoscopic resection of lesions without a malignant potential or those which should be referred for surgical excision.