Dr. Leopoldo López Rosés
Hospital Universitario Lucus Augusti. Lugo
Patients with long-standing ulcerative colitis are at a high risk for developing colorectal dysplasia and carcinoma. Evidence suggests that in ulcerative colitis, cancer develops through a progressive sequence of morphological and genetic changes from chronic inflammation to low-grade dysplasia, high-grade dysplasia and, eventually, carcinoma1-4. Moreover, recent data attributes a similar increase in the risk of colon cancer to Crohn’s disease5-7.
Dysplasia in inflammatory bowel disease (IBD) can be classified into two types:
• Flat: undetectable endoscopically.
• Raised: also known as dysplasia-associated lesion or mass (DALM). Depending on its gross endoscopic appearance, the latter type can be divided into:
– Adenoma-like lesions.
– Non-adenoma-like lesions8,9.
Where the patient’s clinical condition allows, the recommended treatment for flat dysplasia is colectomy, even in the case of a low-grade recurrent or multifocal dysplasia, provided that the biopsies were obtained during remission10.
The treatment approach for DALMs, a heterogeneous group of lesions with different morphological and endoscopic manifestations, is not as clear. Non-adenoma-like DALMs consist of irregular plaques, or broad-based, ulcerated or stenosed mass lesions, whereas adenoma-like lesions are well-defined, sessile or pedunculated lesions resembling sporadic adenomatous polyps11,12.
Non-adenoma-like DALMs are associated with an incidence of synchronous or metachronous cancer of up to 80%, which is why colectomy is recommended. This approach has been recommended since 1981, when Blackstone et al. published a series of 112 patients with ulcerative colitis monitored over a four-year period: DALMs (non-adenoma-like, according to current definitions) were detected in 12 of them, and invasive carcinoma in seven13.
However, evidence suggests that adenoma-like DALMS can be managed by endoscopic resection and subsequent monitoring, thus avoiding the need for colectomy. In 1991, Nugent et al. described the endoscopic resection of eight pedunculated polyps, with no dysplasia detected anywhere in the colon; four patients underwent total colectomy, and the other four continued to receive endoscopic follow up. No dysplasia was detected in either group14. Further studies have been published since this initial report, which supports the endoscopic management of such lesions9,15-18. There is some debate as to whether these lesions are true adenomas that develop on inflamed areas, or whether they constitute entities that are distinct from the sporadic adenomas that appear on healthy areas of mucosa located close to the segment affected by colitis. Some immunohistochemical and molecular data support the concept that these are all sporadic adenomas, which in turn would reinforce the role of endoscopic resection as a curative treatment in such cases19,20 (Video 1).
DETECTION OF DYSPLASIA
Gastroenterologists must identify patients with IBD who are at risk of cancer, include them in a monitoring program, examine the entire lining of the rectum and colon in each scheduled exploration, and adjust the treatment individually depending on the findings. They must also ensure that patients adhere firmly to the screening protocol.
Unfortunately, to date there is no scientific evidence that demonstrates that endoscopic follow-up in IBD decreases the risk of developing or dying from colon cancer. However, there does appear to be evidence that screening allows for an earlier diagnosis and that this improves the prognosis, as well as being cost-effective and helping to avoid unnecessary colectomies21.
By consensus, the dysplasia screening technique involves performing biopsies of all four quadrants every 10 cm along the entire length of the rectum and colon, and delivering one test tube for each of the four segments
to the pathologists. In addition, biopsies taken from raised or suspicious lesions should
be sent in separate test tubes22. Due to
the laborious and time-consuming nature of the procedure, there have been attempts to evaluate the efficacy of staining techniques such as chromoendoscopy23. Combined with high-definition endoscopy, this technique can improve the detection of small, hard-to-see lesions, improving the sensitivity of the examination and characterisation of the lesions, thus increasing the specificity of the procedure. In addition, new virtual chromoendoscopy and endomicroscopy techniques have recently been shown to increase the sensitivity of the detection
of intraepithelial neoplasia and high-grade dysplasia. In the future, these may therefore play an important role in screening for cancer in these patients24,25.
The pathologist’s interpretation is an important factor in the process involved
in the diagnosis of dysplasia and cancer in IBD, as the therapeutic approach is determined based on his report. Different categories of dysplasia are currently distinguished: negative, indefinite or positive for dysplasia, the latter of which can be subdivided into high- and low-grade26. Given the therapeutic implications of the pathological diagnosis, an assessment by a second independent pathologist should be requested before making any treatment decisions22,27. (Fig. 1 and Fig. 2)
ENDOSCOPIC TREATMENT OF DYSPLASIA
As previously mentioned, dysplasia may be either flat and not amenable to endoscopic management, or raised (DALM). Within this second group, one can distinguish between the non-adenoma-like type, which is also not amenable to endoscopic management, and the adenoma-like type, which is eligible for endoscopic resection.
Flat high-grade dysplasia carries an associated risk of carcinoma of about 50%, which is why colectomy is recommended in these cases28. Patients with flat low-grade dysplasia have a positive predictive value for cancer of 22% in some studies, meaning that they have a nine-fold higher risk than those without dysplasia; therefore, colectomy appears to be a highly advisable option in this patient group too29.
The choice of treatment should be agreed upon with the patient, and if endoscopic monitoring is chosen, it should be very close.
Regenerative and reparative epithelial changes, especially in situations of active inflammation, can cause atypia and be difficult to differentiate from dysplasia. These cases are classified as indefinite for dysplasia. Recent studies have shown a 9% progression to high-grade dysplasia or carcinoma, which represents an intermediate risk between no dysplasia and low-grade dysplasia30. Annual monitoring is recommended22.
Patients with long-standing ulcerative colitis with no dysplasia have a 1.1% risk of cancer at five years. In these patients, endoscopic monitoring is recommended with biopsies every 1-5 years22.
Treatment of adenoma-like DALMs depends on the size and appearance of the lesion, which can be excised using traditional or advanced techniques (Video 2) with no risk of subsequent malignancy, as long as the presence of dysplasia in the surrounding mucosa and any other part of the colon is ruled out. To ensure healing, it is also essential to resect the entire lesion, as a high rate of progression to carcinoma has been observed in patients with raised dysplasia who undergo only a biopsy, or in whom resection was incomplete31.
The remaining polypoid lesions detected during colonoscopy are either inflammatory polyps or pseudopolyps with no malignant potential, which do not require resection, although the presence of multiple pseudopolyps has been identified as a predictor of subsequent carcinoma, possibly because it is indicative of previous, severe inflammation and hinders endoscopic assessment21.
Morphologically, colorectal adenomas can be divided into two groups: protruded or flat. The latter are more difficult to detect and may thus go unnoticed, leading to a delayed diagnosis at more advanced stages. Flat adenomas are endoscopically defined as having a thickness less than half their diameter, or histologically as having a thickness that is less than twice that of the adjacent healthy mucosa. The Paris classification (Table I) compares the height of the lesion with the closed cups of a pair of biopsy forceps (2.5 mm); polyps measuring more than 2.5 mm in height are considered protruding, whereas shorter ones are classified as flat32. These may preferentially grow horizontally, giving rise to so-called laterally spreading tumours (LST), which are divided into two subtypes: granular, with a nodular surface, and non-granular, with a flat surface33,34. There are differences between the two types in terms of the risk of malignant degeneration and submucosal invasion. Non-granular lesions have a greater risk of malignant submucosal invasion (14%) compared to the granular type (7%). Furthermore, it is known that granular LSTs have a greater risk of deep submucosal invasion under large nodules (>10 mm) and depressed areas, whereas in non-granular LSTs, the risk of submucosal invasion is directly related to size, sclerotic changes and Kudo pit pattern V; it is is also more common under depressed areas. For these reasons, granular LSTs are considered removable via endoscopic mucosal resection in various fragments, while in the case of non-granular LST, en bloc resection of the lesion is required for appropriate histopathological grading35.
In the colon, the risk of lymph node metastasis is low when malignant submucosal invasion is limited to the upper third of the submucosal layer, and its lateral extension is less than 50% of the diameter of the lesion. In contrast, metastases are common when submucosal invasion is massive, both horizontally and vertically, reaching the deeper areas of the submucosa.
The submucosa of the colon is divided into:
• three levels of similar thickness: sm1, sm2 and sm3; in sm1 lesions for instance, invasion reaches no deeper than 1,000 microns.
• three groups: a, b and c, relating to lateral extension; with grades a and b, lateral extension is less than 50% of the diameter of the lesion.
• Limited submucosal invasion corresponds to levels sm1a and sm1b.
• Massive invasion corresponds to levels sm1c, sm2 and sm3.
Thus, a level sm1 malignant infiltration that corresponds to a depth of no more than 1,000 microns is regarded as the limit up to which endoscopic removal can be considered curative, given that irrigation of lymphatic metastases in this case is less than 1%, vs. 6% for sm2 and 14% for sm332,36.
Endoscopic resection techniques
Adenoma-like lesions measuring less than 2 cm can be excised en bloc using conventional polypectomy (Fig. 3). When the implantation pedicle is greater than 2 cm, it is advisable to use advanced techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).
Careful examination of the lesion is required before attempting its removal: its extension must be defined, to which end chromoendoscopy with indigo carmine dye or methylene blue, or virtual chromoendoscopy systems can sometimes be useful. A great
deal of attention should also paid to pit
(Table II) and vascular patterns (Table III)
in order to identify signs of invasive carcinoma that would contraindicate endoscopic treatment. This requires the use of high definition (HD) endoscopes, preferably with magnification, again using dyes. According
to the Kudo classification, there are five kinds of pit patterns: I and II are not neoplastic. IIIS, IIIL and IV correspond to intramucosal neoplasms, and type V, with distorted epithelial crests, represents carcinoma37-39 (Table IV and Table V).
In order to perform EMR and ESD, prior raising of the lesion is required, via the injection of substances underneath in order to separate it from the muscularis propria and reduce the risk of perforation. Although the fluid most commonly used is saline, it has the disadvantage that the cushion thus created is short-lived, calling for repeated injections during the procedure. Other more viscous substances are available that last longer and are thus preferable; these include glycerol (10% glycerine and 5% fructose in saline), hyaluronic acid and hydroxypropyl methylcellulose, among others40. A small amount of epinephrine and indigo carmine or methylene blue can be added to all of the above. It is important to make sure that the polyp is properly and fully lifted, as this is indicates the absence of submucosal neoplastic invasion. Failure to lift can sometimes be due to the presence of fibrosis under the lesion which, according to Japanese experts would indicate the use of ESD rather than EMR. Fibrosis may be induced by biopsy collection, a tattoo very close to the lesion, or a prior attempt at excision. All of this should be taken into account when these lesions are identified in order to try to avoid procedures that might hinder or prevent subsequent endoscopic resection.
In mucosal resection, once the lesion is elevated, one proceeds to a piecemeal removal by means of partial resections with a polypectomy snare, starting from one edge until complete resection is achieved (Fig. 4). Each fragment should not exceed 10-15 mm in size. The first fragment should include a small margin of normal mucosa, and subsequent fragments should include the edge of the previous one. Air aspiration can sometimes be useful during snare closure in order to reduce the risk of said snare slipping over the surface of the polyp without catching any tissue. Before applying electric current, once the fragment is caught, gas insufflation must be repeated in order to confirm safe conduct of the procedure. The endoscope should be positioned in a manner such that the lesion is located at 6 o’clock, in line with the working channel. One can use either pure coagulation current or EndoCut. After capturing each fragment with the snare and before applying current, said fragment must be must drawn away from the wall to reduce the risk of perforation41.
Endoscopic submucosal dissection seeks to remove the lesion in one piece regardless of its size, thereby facilitating histological assessment and improving the rate of curative resections. This method is particularly useful in the case of IBD, since the presence of prolonged inflammatory activity can cause mucosal and submucosal fibrosis; because it hinders proper elevation after fluid injection, this desmoplastic reaction can interfere with mucosal resection42-44. The development of specific instruments has made dissection of fibrotic tissue and en bloc excision possible, ensuring healing. In fact, fibrosis is considered an indication for ESD.
The criteria confirming that ESD can be considered curative are:
• Tumour-free edges of the resected fragment.
• Well-differentiated histopathological type.
• A depth of invasion less than 1,000 microns (up to the superficial submucosal layer or sm1).
• Absence of lymphovascular invasion45.
ESD is superior to EMR in that it allows en bloc resection of the lesion, resulting in a higher percentage of complete resections and a lower incidence of recurrence. By contrast, ESD takes much longer to perform, is technically more difficult and carries a higher risk for complications, especially perforation46.
Endoscopic submucosal dissection is particularly difficult in the rectum and colon, for the following reasons:
• The wall of the colon is very thin and is therefore at a greater risk of perforation than other locations.
• Endoscopic control is more difficult in some parts of the colon because of paradoxical movements.
• Retroflexion of the endoscope may be difficult due to the narrow lumen.
• The lesions to be removed may be located either in or behind the folds of the colon.
• If perforation occurs, there is a high risk of peritonitis, which requires surgical treatment47.
ESD starts with a circumferential cut around a portion of the lesion and, as in EMR, after elevation thereof. This procedure normally makes use of an EndoCut current. Then, using coagulation and with the help of a translucent cap placed on the end of the endoscope, which serves to separate the fragment from the wall, the submucosal plane is carefully dissected, taking care not to reach the muscle layer until total removal is achieved (Fig. 5). A range of accessories are available for this purpose, such as the Dual Knife, Hook Knife, Mucosectomy, Flex Knife,Hybrid Knife and Flush Knife, among others. The latter two are special in that liquid injection can be performed with the instrument itself, achieving a faster dissection. The use of one piece of equipment over another depends on the characteristics of the lesion and the individual preferences of the endoscopist. Moreover, and due to the characteristics of the colon and location of the lesions, it is often preferable to use small calibre endoscopes such as conventional gastroscopes or paediatric colonoscopes, as they are more manoeuvrable and allow easier retroflexion40,47.
Sometimes, a mixed or “hybrid” technique is used, which combines initial submucosal dissection with final en bloc snare resection, with results that are similar to those of traditional ESD.
After surgical excision, it is important to ensure haemostasis of the eschar via electrocoagulation of the visible vessels with specific forceps such as the Coag Grasper or argon gas, thus reducing the risk of delayed bleeding. Also, one can electocoagulate the edges of the eschar and any area suspected of constituting residual adenoma in order to reduce the risk of recurrence41.
The piece must be sent to the pathology laboratory en bloc and spread on a soft surface with the help of pins in order to allow the pathologist to perform a rigorous study and assess the depth of invasion and infiltration of the edges (Fig. 5).
Because these procedures take a long time (often several hours in the case of ESD), it is best to resort to carbon dioxide (as opposed to room air) insufflation during colonoscopy, as CO2 is rapidly absorbed, significantly reducing patient discomfort48. Often, it is also necessary to reposition the patient several times in order to make use of gravity and of the fact that the fragment separates from the intestinal wall during dissection, making the process easier and safer.
1. There are two types of dysplasia:
– If high-grade, colectomy must be indicated.
– If low-grade, colonoscopy should be repeated within 3–6 months and, if confirmed, colectomy should also be indicated.
– In cases described as indefinite for dysplasia, an endoscopic check-up is recommended within one year.
• DALMs. There are two possible types:
– Non-adenoma-like: these are large, ulcerated or stenosing lesions: colectomy is indicated.
– Adenoma-like: these are similar to sporadic adenomas. They may be excised endoscopically, provided there is no dysplasia in the surrounding mucosa nor anywhere else in the colon. Close subsequent endoscopic follow-up is indicated, with initial check-ups at 3–6 months. If no dysplasia is confirmed, a check-up should be conducted after one year, and then every two years, as in colitis without dysplasia.
2.- Endoscopic treatment of adenoma-like DALMs:
• Lesions smaller than 2 cm in diameter: conventional polypectomy.
• Lesions larger than 2 cm: EMR or ESD.
3.- Before deciding whether or not to perform the endoscopic removal of the lesion, thorough exploration is required, making use of, where possible, high-resolution and magnification instruments, and either dyes or virtual chromoendoscopy, in order to rule out the presence of signs suggestive of invasive carcinoma.
4.- Laterally spreading tumours (LST):
• Granular type: may be removed by EMR in fragments.
• No granular type: requires en bloc removal.
5.- Cure criteria after endoscopic excision:
• Complete surgical excision: free side edges and a depth of involvement not exceeding sm1 (1,000 microns).
• Distinct histological lineage.
• Absence of vascular or lymphatic involvement.
1. Lashner BA, Silverstein MD, Hanauer S. Hazard rates for dysplasia and cancer in ulcerative colitis. Dig Dis Sci. 1989; 34: 1536-41.
2. Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centers. Gut. 1988; 29: 206-17.
3. Langholz E, Munkholm P, Davidsen M, M, Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology. 1992; 103: 1444-50.
4. Sharan R, Schoen RE. Cancer in inflammatory bowel disease: an evidenced-based analysis and guide for physicians and patients. Gastrornterol Clin N Am. 2002; 31: 237-54.
5. Gillen CD, Walmsley R, Prior P, Andrews HA, Allan RN. Ulcerative colitis and Crohn´s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut. 1994; 35: 1590-2.
6. Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn´s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut. 1994: 35: 950-4.
7. Canavan C, Abrams KR, Mayberry L. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn´s disease. Aliment Pharmacol Ther. 2006; 23: 1097-104.
8. Odze RD. Adenomas and adenoma-like DALMS in chronic ulcerative colitis: a clinical, pathological and molecular review. Am J Gastroenterol. 1999; 94: 1746-50.
9. Engelsgierd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma –like dysplastic lesions in chronic ulcerative colitis. Gastroenterology. 1999; 117: 1288-94.
10. Friedman S, Odze RD, Farraye FA. Management of neoplastic polyps in inflammatory bowel disease. Inflamm Bowel Dis. 2003; 9(4): 260-66.
11. Tytgat GNJ, Dhir V, Gopinath N. Endoscopic appearance of dysplasia and cancer in inflammatory bowel disease. Eur J cáncer. 1995; 31A: 1174-7.
12. Butt JH, Konishi F, Morson BC,Lennard-Jones JE, Ritchie JK. Macroscopic lesions in dysplasia and carcinoma complicating ulcerative colitis. Dig Dis Sci. 1983; 28: 18-26.
13. Blackstone MO, Riddell RH, Rogers BH, Levin B. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: An indication for colectomy. Gastroenterology. 1981; 80: 366-74.
14. Nugent F, Haggit RC, Gilpin PA. Cancer surveillance in ulcerative colitis. Gastroenterology. 1991; 100: 1241-8.
15. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology. 1994; 107: 934-44.
16. Medlicott, SAC, Jewell LD, Price L, Fedorak RN, Sherbaniuk RW, Urbanski SJ. Conservative management of small adenomata in ulcerative colitis. Am J Gastroenterol. 1997; 92: 2094-8.
17. Rubin PH, Friedman S, Harpaz N, Goldstein E, Weiser J, Schiller J, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology. 1999; 117: 1295-300.
18. Kisiel JB, Loftus EV, Harmsen WS, Zinsmeister AR, Sandborn WJ. Outcome of sporadic adenomas and adenoma-like dysplasia in patients with ulcerative colitis undergoing polypectomy. Inflamm Bowel Dis. 2012; 18(2): 226-34.
19. Walsh SV, Loda M, Torres CM, Antonioli D, Odze RD. P53 and beta catenin expression in chronic ulcerative colitis-associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. Am J Surg Pathol. 1999; 23: 963-9.
20. Odze R, Brown CA, Noffsinger AE,Fogt F. Genetic alterations in chronic ulcerative colitis-associated adenoma-like DALMs are similar to non-colitic sporadic adenomas. Am J Surg Pathol. 2000; 24: 1209-16.
21. Ullman T, Odze R, Farraye FA. Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn´s disease of the colon. Inflamm Bowel Dis. 2009; 15(4): 630-38.
22. Itzkowitz SH, Present DH. Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis. 2005; 11: 314-21.
23. Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut. 2004; 53: 256-60.
24. Dekker E, van den Broek FJ, Reitsma JB, Hardwick JC, Offerhaus GJ, van Deventer SJ et al . Narrow-band imaging comparedwith conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy. 2007; 39: 216-21.
25. Hurlstone DP, Kiesslich R, Thomson M, Atkinson R, Cross SS. Confocal chromoscopic endomicroscopy is superior to chromoscopy alone for the detection and characterization of intraepithelial neoplasia in chronic ulcerative colitis. Gut. 2008; 57: 196-204.
26. Riddell RH, Goldman H, Ransohoff M. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983; 14: 931-68.
27. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology. 2003; 124: 544-60.
28. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet. 1994; 343: 71-4.
29. Thomas T, Abrams KA, Robinson RJ, Mayberry JF. Meta-analysis: cancer risk of low grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther. 2007; 25: 657-68.
30. Levine JS, Burakoff R. Chemoprophylaxis of colorectal cancer in inflammatorybowel disease. Inflamm Bowel Dis. 2007; 13: 1293-8.
31. Vieth M, Behrens H, Stolte M. Sporadic adenoma in ulcerative colitis: endoscopic resection is an adequate treatment. Gut. 2006; 55: 1151-5.
32. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc. 2003; 58(6): S3-S43.
33. Kudo S. Early colorectal cancer. Tokyo: Igaku-shoin; 1996.
34. Kudo S, Lambert R, Allen JI, Fujii H, Fujii T, Kashida H, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. A workshop held in Kyoto on February 10-11, 2008. Gastrointest Endosc. 2008; 68(suppl 84): S1-S47.
35. Uraoka T, Saito Y, Matsuda T, Ikehara H, Gotoda T, Saito D, et al. Endoscopic indications for endoscopic mucosal resection of laterally spreading tumours in the colorectum. Gut. 2006; 55: 1592-7.
36. Yokoyama J, Ajioka Y, Watanabe H, Asakura H. Lymph node metastasis and micrometastasis of submucosal invasive colorectal carcinoma: an indicator of the curative potential of endoscopic treatment. Acta Medica Biologica. 2002; 50: 1-8.
37. Kudo S, Hirota S, Nakajima T, Hosobe S, Kusaka H, Kobayashi T, et al. Colorectal tumours and pit pattern. J Clin Pathol. 1994; 47: 880-5.
38. Liu HH, Kudo SE, Juch JP. Pit pattern analysis by magnifying chromoendoscopy for the diagnosis of colorectal polyps. J Formos Med Assoc. 2003; 102: 178-82.
39. Tanaka S, Hamura H, Nagaca S. Diagnostic of invasion depth in early colorectal carcinoma by pit pattern analysis with magnifying endoscopy. Dig Endosc. 2001; 13( suppl ): S2-5.
40. Uraoka T, Parra-Blanco A, Yahagi N. Colorectal endoscopic submucosal dissection in Japan and western countries. Dig Endosc. 2012; 24(suppl): 1-4.
41. Pachlewski J, Regula J. Endoscopic mucosal resection for colorectal polyps. In Monckemüller K, Wilcox CM, Muñoz M. Interventional and therapeutic Gastrointestinal Endoscopy. Basel: Karger; 2010. pp. 269-86.
42. Smith LA, Baraza W, Tiffin N, Cros SS, Path FRC, Hurlstone DP. Endoscopic resection of a adenoma-like mass in chronic ulcerative colitis using a combined endoscopic mucosal resection and cap assisted submucosal dissection technique. Inflamm Bowel Dis. 2008; 14(10): 1380-86.
43. Hurlstone DP, Shorthouse AJK, Brown SR, Tiffin N, Cross SS. Salvage endoscopic submucosal dissection for residual or local recurrent intraepithelial neoplasia in the colorectum: a prospective analysis. Colorectal Dis. 2008; 10(9): 891-7.
44. Fujishiro M, Yahagi N, Nakamura M, Kakushima N, Kodashima S, Ono S, et al. Endoscopic submucosal dissection for rectal epithelial neoplasia. Endoscopy. 2006; 38: 493-7.
45. Kitajima K, Fujimori T, Fujii S, Takeda J, Ohkura Y, Kawamata H, et al. Correlations between lymph node metastasis and the depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol. 2004; 39: 534-43.
46. Saito Y, Fukuzawa M, Matsuda T, Fukunaga S, Sakamoto T, Uraoka T, et al. Clinical outcome of endoscopic submucosal dissection versus endoscopic mucosal resection or large colorectal tumors as determined by curative resection. Surg Endosc. 2010; 24(2): 343-52.
47. Yamamoto H. Endoscopic submucosal dissection for colorectal tumors. In Monckemüller K, Wilcox CM, Muñoz Navas M. Interventional and therapeutic Gastrointestinal Endoscopy Basel: Karger; 2010. pp. 287-95.
48. Bassan MS, Holt B, Moss A, Williams SJ, Sonson R, Bourke MJ. Carbon dioxide insufflation reduces number of postprocedure admissions after endoscopic resection of large colonic lesions: a prospective cohort study. Gastrointest Endosc. 2013; 77(1): 90-5.