In Lynch syndrome, flat and diminutive adenomas are particularly prone to malignant transformation, but they can be missed by standard colonoscopy. It is not known whether chromocolonoscopy is able to detect more adenomas than standard colonoscopy in patients with Lynch syndrome.

We conducted a prospective, multicenter, randomized trial to compare standard colonoscopy with standard colonoscopy followed by pancolonic chromoscopy with indigo carmine in patients with a proven germline mutation in a mismatch-repair gene related to Lynch syndrome and who were undergoing screening or surveillance colonoscopy. Standard colonoscopy was used first to detect visible lesions. Colonoscopy with chromoscopy was then performed by a second gastroenterologist (blinded to the findings of the first colonoscopy) to detect additional lesions. The primary end point was the number of patients in whom at least one adenoma was detected.

A total of 78 eligible patients (median age, 45 years) were enrolled at 10 centers from July 2008 to August 2009. Significantly more patients with at least one adenoma were identified by chromocolonoscopy (32/78 (41%)) than by standard colonoscopy (18/78 (23%); P<0.001). The percentage of patients in whom at least one additional adenoma was detected during the chromoscopy was 31% (24/78). Overall, chromocolonoscopy plus colonoscopy detected a total of 55 adenomas in 32 patients (mean number of adenomas detected per patient: 0.7 vs. standard colonoscopy alone: 0.3; P<0.001).

The results support the proposition that chromocolonoscopy may significantly improve the detection rate of colorectal adenomas in patients undergoing screening or surveillance colonoscopy for Lynch syndrome.

Colorectal flat adenomas have been associated with a higher risk of colorectal malignancy. We describe demographic characteristics and endoscopic findings in patients with colorectal flat adenomas.

In total, 1934 consecutive patients undergoing colonoscopy were prospectively included. Polyp shape was classified according to the Japanese classification. Chromoendoscopy was applied whenever a flat lesion was suspected. Indications for colonoscopy, demographic data, and characteristics of neoplastic lesions were recorded. Patients were classified as follows: group 1, no adenomas (n=1250); group 2, only protruding adenomas (n=427); group 3, protruding and flat adenomas (n=118); and group 4, only flat adenomas (n=139).

Approximately one in every 10 patients (13.2%) had flat adenomas. Among them, concomitant protruding adenomas were identified in approximately half of the cases. In multivariate analysis, age older than 50 years [odds ratio (OR)=1.62; 95% confidence interval (CI)=1.08-2.43, P=0.02], protruding adenomas (OR=2.17; 95% CI=1.65-2.87, P<0.001), follow-up colonoscopy for polyps or cancer (OR=2.22; 95% CI=1.59-3.10, P<0.001), screening colonoscopy (OR=1.60, 95% CI=1.15-2.22, P=0.005), and specifically trained endoscopist (OR=2.02, 95% CI=1.53-2.68, P<0.001) were associated independently with flat adenoma detection.

Flat adenomas have specific demographic factors that might help to improve detection. Particularly, age older than 50 years, colorectal neoplasia surveillance, and the presence of protruding adenomas should alert endoscopists to the possible presence of these lesions. Trained endoscopists may offer a greater chance of detecting these lesions.

Computed tomographic colonography (CTC) has been reported to be as effective as optical colonoscopy in the detection of significant adenomas. However, there are widely conflicting performance data in relation to detection of flat neoplasia. This article describes the potential and limitations of CTC and computer-aided diagnosis in the detection of flat neoplasms.

(i) To determine the prevalence of nonpolypoid colorectal neoplasms (NP-CRNs) in a prospective cohort of patients of a Mediterranean area; (ii) to compare the characteristics of NP-CRNs with those of polypoid adenomas, focusing on the rate of high-grade dysplasia (HGD) and carcinoma; (iii) to evaluate the characteristics of patients harboring NP-CRNs versus patients with protruding adenomas (P-CRNs).

A prospective, cross-sectional observational study was made in which consecutive unselected patients were scheduled for colonoscopy and pancolonic chromoendoscopy. The Paris Classification of Superficial Neoplastic Lesions was used to classify the detected lesions, and the revised Vienna criteria were applied to describe the grade of dysplasia. All examinations were performed by the same endoscopist, and all samples were reviewed by the same pathologist.

A total of 290 patients were included, and 613 neoplasms were detected-26% of them being NP-CRNs. The prevalence of NP-CRNs was 34.1% [95% confidence interval (CI): 28.8%-39.7%]. The proportion of HGD or carcinoma in NP-CRNs was 2.5% (95% CI: 0.8%-5.9%), versus 2.9% in P-CRNs (95% CI: 1.6%-4.7%). Size larger than 10 mm [odds ratio: 22.7 (95% CI: 5.2-99.2)] and a pedunculated morphology [odds ratio: 5.7 (95% CI: 1.3-24.3)] were related to the presence of HGD or carcinoma. A relationship between increased size and HGD or carcinoma was found for all morphologies. Patients harboring only NP-CRNs and patients harboring only P-CRNs were similar for all the variables collected.

NP-CRNs have a high prevalence in our region, but show a proportion of HGD and carcinoma similar to that seen in P-CRNs. No patient variable is predictive of the presence of a NP-CRN.

Flat lesions in the colon may result in false-negative computed tomography colonography interpretations. It is unknown whether flat lesions are better measured on two-dimensional (2D) or three-dimensional (3D) images and which settings are optimal for enhanced reproducibility and decreased variability. We evaluated these factors to determine whether 2D or 3D is best for flat lesion measurements.

Eighty-eight lesions in 66 patients from a previously published clinical trial were analyzed. Lesions were viewed with four methods including 2D at three window/level settings and 3D endoluminal view. Lesions in either supine or prone were counted as one dataset. Long axis and height were measured. Criteria of "height" (<or=3 mm high) or "ratio" (height <or=half the long axis) were applied. A subset of lesions was subject to inter- and intra-observer variability analysis.

With the "height" criterion, more datasets were classified as flat in 2D flat (n = 76), 2D soft tissue (n = 82), and 3D (n = 73) views than in the 2D lung (n = 49) view. If long axis is used as the key metric, endoluminal 3D (12.1%) views significantly showed the least inter-observer variability compared to lung (18.9%) or soft tissue (20.2%) views. Intra-observer variability was low overall for all methods.

When characterizing lesions as flat, a consistent viewing method should be used. To minimize inter-observer variability (such as when following a patient over time), it is best to use the ratio criterion for flat lesion definition incorporating the single longest dimension on 3D views as the key metric.

Flat lesions have been a source of controversy because of concerns that CT colonography (CTC) is insensitive in detecting these lesions, yet they may harbor a high incidence of advanced neoplasia. The wide variation in the reported incidence of flat lesions may in part be due to the lack of a uniform definition of "flat", and in fact in many prior reports the inclusion criteria for flat are not even clearly specified. Emphasis on the more recent CTC literature suggests that when limited the target lesion to neoplasia (adenomas or adenocarcinoma), the incidence of flat lesions is low and most can be detected by CTC. Using fecal tagging and careful attention to the proper methods of searching for flat lesions with both 3D and 2D techniques can maximize the detection of flat lesions at CTC. Computer-aided detection may be helpful.

Nonpolypoid (flat and depressed) colorectal lesions are increasingly recognized. Their endoscopic removal requires specialized EMR techniques, which are more complex to perform. Outcomes data on EMR of nonpolypoid neoplasms in the United States is needed.

To determine the safety and efficacy of EMR in the resection of nonpolypoid colorectal neoplasms > or = 1 cm.

Retrospective analysis.

Veterans Affairs Palo Alto Health Care System.

Over a 5-year period, patients who underwent EMR for nonpolypoid colorectal lesions > or = 1 cm.

A standardized approach that included lesion assessment, classification, inject-and-cut EMR technique, reassessment, and treatment of residual tissue.

Complete resection, bleeding, perforation, development of advanced cancer, and death.

A total of 100 patients (125 lesions: 117 flat and 8 depressed) met inclusion criteria. Mean size was 16.7 +/- 7 mm (range, 10-50 mm). Histology included 5 submucosal invasive cancers, 5 carcinomas in situ, and 91 adenomas. Thirty-eight patients (48 lesions) did not receive surveillance colonoscopy: 8 had surgery, 16 had hyperplastic pathology, and 14 did not undergo repeat examination. Surveillance colonoscopy was performed on 62 patients (77 lesions). Complete resection was achieved in 100% of these patients after 1 to 3 surveillance colonoscopies. All patients received follow-up (mean [standard deviation] = 4.5 +/- 1.4 years); none developed colorectal cancer or metastasis.

Single endoscopist, retrospective study.

A standardized EMR (inject-and-cut) technique is a safe and curative treatment option in nonpolypoid colorectal neoplasms (> or = 1 cm) in the United States.

to determine the frequency and malignancy risk of colonic flat adenomas among patients with colorectal polyps in a Spanish population.

1300 consecutive colonoscopic examinations were reviewed; 640 polyps were detected and removed endoscopically in 298 patients. Chromoendoscopy with 0.2% indigo carmine was applied to clarify the macroscopical appearance of flat lesions. The following data was collected for flat and protruding polyps: size, location (proximal or distal to splenic flexure), histology (neoplastic or non neoplastic), high grade dysplasia (HGD) and submucosal invasive carcinoma (SIC) or beyond.

490 polyps (76.6%) were adenomas and 150 (23.4%) hyperplastic; 114 (23.3%) adenomas were flat (3 flat-depressed) whereas 376 (76.7%) were protruding. The diameter of flat and protruding adenomas was 9.2 +/- 7.9. mm and 7.0 +/- 5.9 mm, respectively (p < 0.001). A proximal location was more frequent for flat (63.1%) than for protruding adenomas (48.7%) (p = 0.003). The rate of HGD or SIC was significantly higher in flat than in protruding adenomas (7.0 vs 2.6%; p < 0.04). Two of the 3 flat-depressed lesions (both

CONCLUSIONS

In a Spanish population, flat adenomas represent nearly one quarter of all colorectal neoplastic polyps, their most frequent location being the right colon and they bear a higher risk of malignancy than protruding adenomas, especially for the flat depressed type.

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To compare the cleansing quality of polyethylene glycol electrolyte solution and sodium phosphate with different schedules of administration, and to evaluate whether the timing of the administration of bowel preparation affects the detection of polyps.

One hundred and seventy-seven consecutive outpatients scheduled for colonoscopy were randomized in one of four groups to receive polyethylene glycol electrolyte solution or oral sodium phosphate with two different timing schedules. Quality of cleansing, polyp detection, and tolerance were evaluated.

Patients receiving polyethylene glycol or sodium phosphate on the same day as the colonoscopy, obtained good to excellent global cleansing scores more frequently than patients who received polyethylene glycol or sodium phosphate on the day prior to the procedure (P < 0.001). Flat lesions, but not flat adenomas, were more frequent in patients prepared on the same day (P = 0.02).

The quality of colonic cleansing and the detection of flat lesions are significantly improved when the preparation is taken on the day of the colonoscopy.

Gelatinase activity has been associated with colorectal cancer (CRC) invasion and metastasis. However, it remains unresolved whether these proteases participate in early colorectal carcinogenesis. The activity of metalloproteinases (MMP) 2 and 9 were measured by zymography in 122 colorectal adenomas, 22 CRC samples, 12 hyperplasic polyps and in 114 matched normal mucosal samples from 114 patients undergoing colonoscopy. There was a progressive and significant increase of pro-MMP-9 activity from adenoma to CRC tissue, whereas the activity of the latent and active forms of MMP-2 was exclusively up-regulated in CRC samples. Among neoplastic polyps, pro-MMP-9 activity was significantly higher in advanced versus non-advanced adenomas and in those harbouring high grade dysplasia. In addition, a positive correlation was observed between MMP-9 activity and the size of the adenomas. The present study demonstrates that MMP-9 is markedly up-regulated in the adenomatous tissue and suggests that this gelatinase might be a marker for early colorectal carcinogenesis.

Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported.

A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (F-LST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed.

Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P = .002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P < .0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%).

High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway.

Focal submucosal invasive colorectal cancers (submucosa-sm1) can be managed by endoscopic mucosal resection (EMR) as local lymph node metastasis (LNM) are rare. Lesions are usually flat, depressed or mixed. In deeper vertical submucosal invasion (sm2-3) LNM rates exceed 10-15%. EMR within this group can be complicated by perforation, noncurative resection and may leave LNM untreated. It is therefore essential to differentiate accurately focal sm1 disease from submucosal sm2/3 disease. The aim of this study was to evaluate the relationship between the invasive type V pit pattern using high-magnification-chromoscopic-colonoscopy (HMCC) and submucosal invasive depth for flat and depressed colorectal lesions.

Total colonoscopy was performed by a highly selected single endoscopist using the Olympus C240Z on 850 patients between January 2001 and July 2003. Kudo type V pits were identified using 0.05% crystal violet (CV) applied directly to the lesion using a steel tipped catheter. Type V pits were graded into class V(n)A-C as described by Nagata. Morphology was documented using the Japanese Research Society classification (JRSC). Histological sections, with reference to mucosal invasive characteristics, acquired using EMR or surgical excision were then compared with the pit pattern.

Fifty-one lesions showed a type V pit pattern. The kappa coefficient of agreement between pit the type V pit pattern and histologically confirmed submucosal invasion was 0.51 (95% CI). Following resection, 97% of lesions were correctly anticipated to have sm2 + invasion using pit type Vn(B) and Vn(C) as clinical indicators of invasive disease. Specificity was low at 50% with an accuracy of 78%.

The type V pit pattern is useful for the in vivo staging of submucosal invasive depth in flat and depressed colorectal lesions and is as sensitive as conventional 7.5 MHz EUS. There was a tendency to over-stage lesions and hence the technique is limited by its low overall specificity.

High-magnification chromoscopic endoscopy is a new technique which has been recently introduced to the UK. This technology, initially pioneered by the Japanese in the 1980s, has changed our understanding of the pathogenesis of colorectal cancer and our subsequent therapeutic strategies aimed at the secondary prevention of cancer. Magnification colonoscopic techniques when combined with colonic chromoscopy (dye spraying of the colon) permit in vivo assessments of lesions at a magnification and resolution similar to a stereomicroscope. Furthermore, flat/depressed adenomas and cancers can be diagnosed with increasing frequency and new resection practices performed. This technique is known as endoscopic mucosal resection. As gastrointestinal endoscopists adopt these new techniques, close liaison with histopathologists is essential to provide the highest standards of diagnostic accuracy. The histopathologist also needs to be aware of the endoscopic findings when interpreting specimens and hence must understand new endoscopic terminologies and classification systems that accompany the introduction of new technologies and therapeutic techniques. This article describes the controversies relating to the flat and depressed colorectal lesion, where these new endoscopic technologies are ideally suited. It then provides a working description of high-magnification chromoscopic colonoscopy including the Japanese 'pit pattern' and morphological classification system-information which will be provided to histopathologists with specimens obtained by these new techniques. Finally, we describe the procedure of endoscopic mucosal resection, as the type and quality of specimens received for histopathological analysis will be highly influenced by these techniques.

Some two-thirds of colorectal carcinomas arise from adenomatous polyps, and as such, screening by colonoscopy and polyp removal should significantly reduce colorectal cancer. This has not been the case, as evidenced by recent studies, which revealed that endoscopy failed to prevent up to 50% of all subsequent carcinomas. Flat or depressed adenomas, frequently reported from Japan but rarely elsewhere, might explain the 'missed carcinomas.' Detection of flat adenomas has not been previously reported from Malaysia.

In the present prospective study, 426 consecutive patients underwent colonoscopic examination between March 1997 and January 2000, for a variety of bowel symptoms. The examinations were performed by an experienced endoscopist using a standard colonoscope and methylene blue dye spraying technique. Macroscopically, flat adenomas were defined using the criteria proposed by Sawada.

Twenty-nine adenomas were identified in 12 patients, of which 15 were polypoid and 14 were flat, with no depressed lesions. Eight polypoidal lesions and all the flat adenomas contained mild or moderate areas of epithelial dysplasia. Seven severely dysplastic polyps were identified. One Duke's A polypoidal cancer and two advanced carcinomas were also found. All the severely dysplastic lesions and Duke's A carcinomas were found in polyps greater than 10 mm in mean size. The flat adenomas were all less than 5 mm in size.

A significant proportion of colonic adenomas in Malaysian patients appear as small flat lesions, which could easily be missed during endoscopy. Increased recognition and treatment of flat adenomas among colonoscopists is warranted.

An increasing body of literature is available showing the existence of flat and depressed colorectal neoplasms in Western countries. The appreciation that colorectal neoplasms may present as flat or depressed lesions has important implications, as the risk of adenocarcinoma in depressed lesions has been found to be markedly higher than in flat or protruding lesions of similar size. There is concern that flat or depressed colorectal neoplasms might be easily missed during a colonoscopy and subsequently diagnosed as cancer within a few years after a clearing examination. In this review, we appraise advances in the study of flat and depressed colorectal cancers based on the English literature published in 2000 and subsequently, with emphasis on their epidemiology, diagnosis, and therapy.

Discrimination between neoplastic and non-neoplastic colorectal polyps is essential for determining appropriate treatment. The mucosal crypt pattern of polyps can be observed with a nonmagnifying colonoscope; however, mucosal crypt patterns are better seen by magnifying colonoscopy, which can also be a noninvasive means for predicting histopathology. This study prospectively compared the ability to distinguish between neoplastic and non-neoplastic lesions by magnifying and nonmagnifying colonoscopy.

Six hundred sixty patients were randomly assigned to undergo magnifying or nonmagnifying colonoscopy (2 groups each of 330 patients). The mucosal crypt pattern of colorectal lesions was classified into types I through V after spraying with 0.2% Indigo carmine dye. The histopathology of all lesions was confirmed by evaluation of endoscopic resection specimens or biopsy specimens. Only lesions 10 mm or less in diameter were included in the study.

The accuracy of magnifying colonoscopy in distinguishing neoplastic from non-neoplastic lesions (92%, 372/405) was significantly higher than for nonmagnifying colonoscopy (68%, 278/407). Insertion of magnifying and nonmagnifying colonoscopes to the cecum was successful in, respectively, 321 patients (97%) and 317 patients (96%), with no significant differences in the average time to reach the cecum or average total procedure time. No serious complication was observed during or immediately after the examinations.

Observation of mucosal crypt pattern with magnifying colonoscopy is superior to nonmagnifying colonoscopy for distinguishing between neoplastic and non-neoplastic colorectal lesions.

As the prognosis of both gastric and colonic cancer remains poor, the challenge is to detect lesions at an early and treatable stage. The benefit of early detection is not only improved survival, but also that patients may be treated with endoscopic mucosal resection, a low-cost, low-morbidity and low-mortality alternative to surgery. In spite of the increasing use of endoscopy in the West, we are not detecting as many early cancers as in Japan. This chapter will discuss the possible reasons for this discrepancy and give a practical guide to 'Japanese endoscopy techniques'. Finally, we have compiled a comprehensive review of the indications, techniques and complications of endoscopic mucosal resection. Throughout the chapter, controversies have been highlighted to give an insight into the limits of our knowledge and stimulate future research.

Flat and depressed colorectal tumours were originally thought to be unique to the Japanese population. Recently there have been reports of flat and depressed lesions in western countries but they have been thought to be uncommon.

In this prospective study, 1000 consecutive patients attending for routine colonoscopy were examined for flat or depressed lesions. The examinations were done by one European colonoscopist using methods developed in Japan.

321 adenomas were found: 202 (63%) were polypoid, 36% (117) were flat and 2 (0.6%) appeared depressed. Most adenomas contained areas of mild or moderate dysplasia but 10% (31) were severely dysplastic. Six Dukes' A adenocarcinomas were identified together with 25 more advanced adenocarcinomas. The likelihood of Dukes' A cancer or severe dysplasia increased from 4% (3/70) in small flat lesions, to 6% (9/154) in small polyps, 16% (8/50) in larger polyps, 29% (14/49) in large flat lesions, and 75% (3/4) in depressed lesions. 54% (20/37) lesions containing severe dysplasia or Dukes' A carcinoma were flat or depressed.

The polyp-carcinoma hypothesis prompts colonoscopists to search only for polypoid lesions when screening for cancer, and many early colorectal neoplasms may therefore be missed. Colonoscopists require training in the recognition of flat and depressed lesions to detect colorectal tumours in the early stages.

In view of the many studies of early stage colorectal carcinoma from Japan, it is essential to know whether the criteria for the histologic diagnosis of colorectal carcinoma are similar in Japan and Western countries.

Eight expert pathologists from Japan (4), North America (2), and Europe (2) individually reviewed microscope slides of 20 colorectal lesions from Japanese patients who had undergone endoscopic mucosal resection or surgery because early stage carcinoma and/or adenoma was suspected. The pathologists indicated the pathologic findings on which they based each diagnosis.

For 11 slides that showed adenoma according to the Western pathologists with low grade dysplasia according to at least half of them, the Japanese diagnosed definite carcinoma with or without adenoma in 4 cases and adenoma in 5, and in 2 cases they were equally divided between a diagnosis of adenoma and carcinoma. For five slides showing adenoma with high grade dysplasia according to the Western pathologists, the Japanese diagnosed definite carcinoma with adenoma in three cases and adenoma in one, and in one case they were equally divided between a diagnosis of adenoma and carcinoma. For one case in which the Western pathologists were equally divided between a diagnosis of carcinoma and adenoma with high grade dysplasia, all the Japanese pathologists diagnosed definite carcinoma with or without adenoma. Three slides showed definite carcinoma with or without adenoma, according to both the Western and the Japanese pathologists. The presence of invasion was the most important diagnostic criterion of colorectal carcinoma for the Western pathologists, whereas for the Japanese the nuclear features and glandular structures were more important.

In Japan, colorectal carcinoma is diagnosed on the basis of nuclear and structural criteria, even in cases considered by Western pathologists to be noninvasive lesions with low grade dysplasia. This diagnostic practice may contribute to the relatively high incidence of early stage colorectal carcinoma reported in Japan as compared with Western countries.