Theoretical And Practical Considerations For Endoscopic Mucosal Ablation

There are important considerations in the choice of endoscopic mucosal ablation. The most important being the depth of destruction that can be obtained to destroy both Barrett's mucosa and neoplastic tissue and, at the same time, allow safe healing. The mean thickness of nondys-plastic Barrett's mucosa is about 0.6 mm. This figure has been derived by measurement in various ways. Histopathology measured Barrett's mucosa to be 0.5 mm (range 0.39-0.59 mm) compared with a normal squamous epithelium of 0.49 (range 0.42-0.58 mm) (36). It was assumed that fixation produces a 10% shrinkage with a further 10% reduction which was caused by processing—producing a shrinkage of 20%. Thus, the mean thickness of Barrett's mucosa is approximately 0.6 mm. Optical coherence tomography (OCT) of excised unfixed specimens has recorded a depth of between 0.45 mm and 0.5 mm (37). Dysplasia and mucosal cancer are thicker and in OCT appear optically denser. This represents approximately 15% of the thickness of the distal esophageal wall, which is approximately 4 mm, as measured by endoscopic ultrasound (38). It is important to understand that the technique of ablation must not produce full-thickness necrosis and risk perforation, particularly in the distended esophagus.

Glycine + Succinyl CoA <

Heme

Negative feedback control

5-aminolaevulinic acid

(excess will result in accumulation of PpIX)

Mitochondria

Protoporphyrin IX Photosensitiser (PpIX)

Porphobilinogen-^ Protoporphyrinogen

FIGURE 2 Diagram to illustrate the pathway of endogenous photosensitization with 5-aminolaevulinic acid to generate the photosensitizer protoporphyrin IX.

The conditions for safe healing are of crucial importance. In a canine model of gastroesophageal reflux, columnar-lined esophagus could be induced and was thought to be associated with regrowth from the proximal columnar-lined portion of the deep esophageal glands (39). After full reflux control, an acute injury to the esophageal mucosa was still associated with some regeneration by columnar cells, as well as squamous islands from the distal squamous part of the esophageal gland ducts. It was postulated that stems cells, possibly in the esophageal gland duct have multipotential for cell differentiation and could produce columnar or squamous cells depending on environmental conditions. Squamous re-epithelialization could be encouraged by full reflux control. Recent detailed, human morphological studies have confirmed that squamous regeneration is universally associated with esophageal ducts (40).

However, studies of a rodent model (does not have esophageal glands) of Barrett's-like esophagus have suggested that the ductal epithelium may not be so crucial (41). The multipotential stem cells may not be exclusively located in the duct epithelium but reside in the basal layer of the squamous and the regenerative columnar villi epithelium. The depth of the mucosal injury appears to be crucial to the type of regeneration. It has been suggested, but not established, that for squamous cells to predominate, as well as environmental control of reflux being essential, some part of the distal squamous-lined-esophageal-gland duct must survive. As this duct is the most distal portion, and thus the part most likely to destroyed by ablation techniques, the empirical evidence does not support this hypothesis. Certainly, multipotential stem cells must survive to regenerate the epithelium, but, at present, the site and source of these cells are unknown, and they may reside deeper in the esophageal duct. It is very important that reflux control is adequate. Patients with long segments of Barrett's esophagus ablated, who have persistent acid and bile reflux, are more prone to recurrence at 1-year follow-up (42).

METHODS OF ENDOSCOPIC ABLATION: PHOTODYNAMIC THERAPY Exogenous Photosensitization

Exogenous photodynamic therapy with an administered photosensitizer will destroy sufficient depth to eradicate early T1 and some T2 cancers (43). Up to 30% of patients may develop esoph-ageal strictures, and cutaneous photosensitivity is a problem. This form of therapy is ideal if there is nodularity and possible early occult cancer is present. The depth of necrosis may be approximately 6 mm (44,45), which clearly implies full-thickness damage to the esophagus. Perforation does not occur because the damage spares the tissue architecture, with collagen remaining intact and the bursting strength of the intestine maintained (46). There is, however, an increased risk of stricture formation. The patient receives light irradiation for 48 hours after the administration of 2 mg/kg of Photofrin (porfimer sodium) by slow intravenous injection (47).

The clinical protocol for tetra(m-hydroxyphenyl)chlorine (mTHPC) proposes a drug dose of 0.15 mg/kg administered intravenously four days before irradiation (48).

Endogenous Photosensitization

Endogenous photodynamic therapy (PDT) with orally administered 5-aminolaevulinic acid (ALA) is ideal if there is no visible lesion. The mechanism for the generation of the endogenous photosensitizer is shown in Figure 2. There is a much-reduced risk of stricture or cutaneous photosensitivity. The depth of tissue necrosis is limited to 2 mm. The patient receives 30 mg/kg to 75 mg/kg ALA dissolved in orange juice or lemonade, and the maximum dosage used is 75 mg/kg (49-52). The prodrug is administered three to six hours prior to endoscopic light irradiation. The dose may be fractionated into two aliquots of 30 mg/kg each ingested four hours and three hours prior to PDT.

Endoscopic Technique of Photodynamic Therapy

Endoscopy is usually performed with topical anesthesia and intravenous sedation of between

1 and 10 mg of midazolam. In our practice, we have found that analgesia is occasionally administered (pethidine 50-100 mg intravenously). Patients photosensitized using 5-ALA often require a prolonged endoscopy (20-40 minutes) and notice local discomfort and irritation during light irradiation. Throughout treatment, oxygen is delivered via a nasal sponge at a rate of 4 to 5 L/min. Repeat sedation may be necessary. The treatment times are considerably shorter for Photofrin (8-10 minutes) and tetra(m-hydroxyphenyl)chlorine (mTHPC) (2 minutes) photosensitization than for ALA, and there appears no problem of discomfort. It is very important to pay close attention to light dosimetry and use an appropriate light-centering device (53). The aim is to deliver an even light dose to a defined circumferential area of the esophagus; treating long areas and repeated sequential areas are irradiated in 5 to 7 cm lengths. Usually windowed balloons are the easiest to use. These inflatable, transparent polyurethrane balloons can be passed over a guide wire, or through the biopsy channel of the endoscope. A small video endoscope is passed down beside the device to ensure positional stability throughout treatment. Light is usually delivered by a laser fiber, which is inserted and the correct wavelength of light chosen PpIX-630 nm, Photofrin-630 nm, and mTHPC-652 nm. Nonlaser light devices are also highly effective.

Thermal, Photothermal (Laser), Cryotherapy, and Mechanical Ablation

Thermal and photothermal methods often require repeated application and endoscopic therapy. They are usually cheaper, more readily available and may be as effective as PDT. In areas of large field change, PDT offers some advantages as a large surface area can be treated. The potassium titanyl phosphate (KTP) laser has tissue penetration characteristics that should allow safe thermal treatment of mucosal disease. Irradiation with the KTP laser with a power of 15 to 20 W for a 1-second pulse produces mucosal temperatures of greater than 65°C with a temperature of 21°C on the outer surface of the esophagus. It was extremely difficult to generate high temperatures on the external surface of the esophagus, using this laser. The diode laser (25 W for 5 seconds) could produce surface temperatures of 90°C but with external temperature of 38°C. The Nd:YAG laser tended to produce worrying temperatures through to the external surface at energy levels that were sufficient to produce thermal destruction on the mucosa (54). It has proved to be highly effective for the treatment of dysplasia and early cancer (55). The Nd: YAG laser has been used very effectively, but the risk of perforation and full-thickness damage is greater.

There are two other widely used method of thermal ablation. The most commonly used is argon beam plasma coagulation (APC). This transfers electrical energy to the tissue by means of an ionized, electrically conducting plasma of argon gas, delivered at between 1 L/min and

2 L/min. The APC has certain theoretical safety advantages. The current causing very high temperatures on the surface produce a zone of devitalization, surrounded by zones of coagulation, desiccation, and tissue shrinkage. As soon as the area on the surface loses electrical conductivity as a result of this desiccation, the plasma beam has to change direction in order to remain electrically conductive. Therefore, the depth effect is limited, and full-thickness necrosis and perforation are unlikely to occur. Five perforations have been reported, two resolved with conservative medical therapy, and three had operations following which two patients died. Strictures are reported in 0% to 9% of patients, and fever may also occur (56-59). Another important method is multipolar electrocoagulation (MPEC). This device depends on the heat of a current passing between electrodes in contact with the tissue. An endoscopic probe is used to produce a surface white coagulum over the entire circumferential area of Barrett's esophagus. Strictures requiring dilatation have occurred in less than 1% of patients. Residual areas of Barrett's occur in 8% (0-28%), and the other complications of pain and fever are transient and mild (60,61).

Endoscopic Mucosal Resection

Endoscopic mucosal resection is an excellent method for the eradication of focal lesions in the esophagus and does allow accurate pathological assessment and staging. The ideal lesions are (i) less than 20 mm in diameter; (ii) well- or moderately differentiated carcinomas (grading G1/G2); (iii) areas of focal high-grade dysplasia; (iv) endoscopic macroscopic appearance types I (polypoid), Ila (flat raised), lib (flat at mucosal level), and ilc (slightly depressed). Larger areas that are ulcerated (type III); poorly differentiated; or infiltrating the mucosa can be treated but there is an increased risk of recurrence (62,63). In addition, the management of multifocal areas of highgrade dysplasia may be technically difficult, requiring multiple interventions, although with experience very substantial areas can be removed (64). There are essentially two standard methods—the "lift-and-cut" and the "suck-and-cut" technique (Figs. 3-5).

A standard forward-viewing endoscope is fitted with a transparent guttered cap. The cap, holding open snare within the gutter, is used to aspirate the tissue to form a polyp. It is usual to form a pseudopolyp by submucosal injection. This has the benefit of allowing the area to be assessed for invasion and reduces the chance of inadvertent perforation. If the area fails to lift then there is a definite possibility of submucosal invasion. The area of tissue is then removed with the snare. An alternative method is to use a variceal banding initially to ligate the base and form the pseudopolyp. Resections of esophageal lesions can be with a double channel endoscopy. A grasping forceps is used to pull the lesion into the loop of the snare, following elevation with a submucosal injection. Recently, a ceramic tip resection device, predominantly developed for use in the treatment of early gastric cancer, has been used in the esophagus.

Chromoendoscopy may be useful to identify early cancer and dysplasia. The dyes that may be used are methylene blue, which has proved useful in the identification of dysplasia and cancer, which stain less than the surrounding intestinal metaplasia. Lugol's solution can be used to identify residual columnar epithelium with squamous mucosa. Toludine blue will stain columnar mucosa and indigo carmine can be used as a nonabsorbed stain to enhance magnification endoscopic discrimination of suspect lesions.

FIGURE 3 A nodule of intramucosal carcinoma in a segment of Barrett's esophagus viewed at endoscopy through the transparent endoscopic mucosal resection cap prior to resection.

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