Flat adenoma and flat mucosal carcinoma (IIb type)— A new precursor of colorectal carcinoma?

Two flat adenomas and a flat mucosal carcinoma of the colon were reported in patients with synchronous and metachronous colonic carcinomas. These lesions were almost flat and were not detected by preoperative endoscopic examinations. Colonoscopists should be aware of the presence of flat adenomas, which can be easily missed, and recognize them as lesions that play an important role in the "adenoma-carcinoma sequence."     

Improved detection of colorectal neoplasms with selective use of chromoendoscopy in 2005 consecutive patients

Background Colorectal cancer mortality is decreased by endoscopic polypectomy, but conventional colonoscopy may be inadequate for detecting subtle colonic lesions. Methods We selectively performed chromoendoscopy in all patients undergoing colonoscopy between January 1999 and December 2005 at the International Health Union of Rome. Patients with a history of colorectal polyps, inflammatory bowel disease, colorectal surgery or coagulopathy and those with poor bowel preparation were excluded from this analysis. Whenever colonoscopy revealed suspicious mucosal areas, dye-spraying with 0.2% indigo carmine solution was also performed. Findings from conventional and dyespraying views were classified morphologically, and specimens were analyzed histologically. Non-adenomatous lesions were classified as negative findings. Results A total of 2005 patients underwent conventional colonoscopy and in 305 cases (15%) chromoendoscopy was also performed. Conventional colonoscopy identified 508 neoplasms in 381 patients (19%). Selective chromoendoscopy found an additional 244 neoplasms in 212 patients (11%). Thus, chromoendoscopy was positive in 212 (70%) of 305 patients in whom the examination was performed. Overall, 56 large, ulcerated, advanced cancers and 696 non-advanced neoplasms were found. Of the 696 nonadvanced neoplasms, 448 (65%) were polypoid and 248 (35%) were non-polypoid. All but 4 non-polypoid lesions were only detected with chromoendoscopy. Of the 248 non-polypoid lesions, 12 (5%) were depressed and 236 (95%) were flat. Advanced histology was present in 39 non-polypoid lesions (15%) and was more common in depressed lesions than in flat ones (58% vs. 13%; p<0.001). Conclusions Our study confirms the existence of flat and depressed neoplasms in an Italian population. The vast majority of non-polypoid lesions were only detected by chromoendoscopy, and many lesions with advanced histology were missed by conventional colonoscopy. We therefore recommend selectively performing chromoendoscopy when conventional colonoscopy provides clues for non-polypoid lesions. Therefore, endoscopists should be trained in the detection of these subtle mucosal clues, as well as in the use of chromoendoscopy to enhance their detection. An erratum to this article is available at .     

大肠腺瘤细胞癌变过程中差异表达蛋白的研究进展

大肠癌是消化道常见的恶性肿瘤,而大肠腺瘤被认为是大肠癌的癌前病变之一,腺瘤-腺癌序列(正常大肠上皮-腺瘤-腺癌)也被认为是经典的大肠癌发病过程.研究表明,大肠腺瘤恶变的过程中,多种蛋白的表达水平会发生变化,某些蛋白发生结构的变化,这些蛋白涉及许多种如细胞内酶蛋白、骨架相关蛋白、信号蛋白等.其致癌机制也有很大差别,并且还未完全明确.本文就近年来这些差异表达的蛋白质进行综述,并对其可能的致癌机制进行简要描述.近年来蛋白组学技术也得到了快速发展,由于其检测手段先进,高通量而且可以同时检测多种蛋白,已经被逐步应用于差异蛋白的检测和定性,所以本文就大肠腺瘤与腺癌之间的差异蛋白组学也做了简要介绍,有助于早期发现大肠癌的标志物,早期诊断及了解其发病机制.     

A prospective clinicopathological and endoscopic evaluation of flat and depressed colorectal lesions in the United Kingdom

OBJECTIVES: Flat and depressed colorectal lesions are now reported in Western populations. The malignant potential, anatomical distribution, and other clinicopathological features have not been established in this group. This study aimed to assess prospectively the prevalence, clinicopathological, and endoscopic features of flat and depressed colorectal lesions in the United Kingdom. METHODS: A single endoscopist performed colonoscopy on 850 consecutive patients presenting for routine colonoscopy. All endoscopies were performed using a high magnification colonoscope with chromoscopy to facilitate detection of flat and depressed colorectal lesions. RESULTS: A total of 458 flat lesions were identified. Of these, 173 (38%) were hyperplastic and 285 (62%) adenomatous or beyond. Of the 173 hyperplastic flat lesions, 162 (94%) were located in the recto-sigmoid region. Of the 267 adenomas, 66 (25%) had areas of high grade dysplasia (HGD), with 54/66 (82%) being present in the right colon. Flat lesions <8 mm in diameter was more likely to contain HGD than those <8 mm (p<0.001). Nine of the 10 (90%) flat invasive adenoacarcinomas were in the right colon and all had a depressed morphological component. In contrast, HGD was observed in 58/466 (12%) of protuberant (sessile/pedunculated) adenomas of which 95% (55/58) were located in the left colon. In addition, HGD was present in 17% of all sessile adenomas versus 44.6% of flat lesions >8 mm in diameter (p=0.001). Of the 14 protuberant carcinomas, 13/14 (93%) were in the left colon. Synchronous lesions were found in 96/816 (12%) of cases. Of the 816 patients with two or more left-sided protuberant adenomas <8 mm (with or without HGD), 89 (11%) had one or more flat lesions in the right colon with HGD. CONCLUSIONS: Flat adenomas and carcinomas have a high malignant potential compared to protuberant lesions and have a propensity for developing in the right hemi-colon. Total colonoscopy is required to detect such lesions, as only 18% of flat lesions would be in reach of the flexible sigmoidoscope.     

Flat adenomas exist in asymptomatic people: important implications for colorectal cancer screening programmes

BACKGROUND: Flat adenomas are non-exophytic with a flat top or central depression and histologically the depth of dysplastic tissue is never more than twice the mucosal thickness. Flat adenomas frequently contain severely dysplastic tissue, and may progress rapidly through the adenoma-carcinoma sequence. Flat lesions have never been described in a British asymptomatic population. AIMS: To determine whether flat adenomas exist in an asymptomatic population participating in a large randomised controlled trial of flexible sigmoidoscopy screening. PATIENTS: A total of 3000 subjects (aged 55-64 years) underwent screening by flexible sigmoidoscopy. METHODS: All polyps were removed and sent for histology. The number of polyps with endoscopic and histological features of flat adenomas was recorded. RESULTS: Three subjects had a total of four flat lesions--that is, one per 1000 people screened. Three contained severely dysplastic tissue, one a focus of adenocarcinoma. Three of the four lesions were less than 5 mm in size and the fourth was 15 mm in diameter. CONCLUSIONS: Flat lesions with severe dysplasia exist in the asymptomatic population. This has major implications for gastroenterologists who should be trained to identify them. Their existence is of importance to molecular biologists and epidemiologists investigating the aetiology of colorectal cancer.     

Endoscopic submucosal dissection for colonic lesions: Why and how should we do it?

Endoscopic submucosal dissection (ESD) is a safe and effective alternative to surgery for large non-polypoid colonic lesions and early colorectal carcinoma. In this article, we discuss the development, efficacy and safety of ESD. As the incidence of colorectal cancer is rapidly increasing in Asia, we advocate standardization of ESD program, including patient selection, hardware prerequisites, and training of operators.     

Serrated neoplasia of the colorectum

Serrated polyps of the colorectum form a group of related lesions which include aberrant crypt foci （ACF）, conventional hyperplastic polyps, mixed （admixed） polyps, serrated adenomas and sessile serrated adenomas. In recent years the molecular differences between these morphologically similar lesions have been highlighted, and their differing biological potential has been realised. In particular, the sessile serrated adenoma has become recognised as the precursor lesion to a group of sporadic colorectal carcinomas characterised by morphological and molecular features distinct from conventional adenomas. These recent findings have challenged the long held paradigm that all colorectal carcinomas arise via the traditional adenoma-carcinoma sequence. In addition, they present a major challenge for the early detection and management of colorectal cancer, which is no longer regarded as a homogeneous entity.     

DNA aneuploidy in colorectal adenomas. Role in the adenoma-carcinoma sequence.

INTRODUCTION: Aneuploidy has been observed in 6-27% of lesions known to be precursors of colorectal cancer, such as adenomas or ulcerative colitis. It has been suggested that aneuploidy may predispose to malignancy in these cases. However, its role in the adenoma-carcinoma sequence has not been definitely established. The objective of this study was to assess the incidence of aneuploidy in colon adenomas, as well as to study its possible role in the adenoma-carcinoma sequence. MATERIAL AND METHODS: The study was performed on a series of 57 large bowel adenomas measuring 10 mm or more, collected from 54 consecutive patients. All specimens were obtained either by endoscopic or by surgical resection. There were 49 adenomas with low-grade dysplasia, two with high-grade dysplasia, two intramucous carcinomas, and four microinvasive carcinomas. A flow cytometric DNA analysis was performed in fresh specimens following Vindelov's method. RESULTS: Aneuploid DNA was detected in five out of 49 low-grade dysplasia adenomas (10%), in all four high-grade dysplasia adenomas or intramucous carcinomas (100%), and in three out of four microinvasive carcinomas (75%). The association between aneuploidy and high-grade dysplasia adenomas, intramucous, or microinvasive carcinoma was statistically significant (p < 0.001). No association was found between aneuploidy and any of the following features: age, gender, clinical symptoms of patients, and size or location of adenomas. CONCLUSIONS: The incidence of aneuploidy in this series was 10% in low-grade dysplasia adenomas, and 87% in high-grade dysplasia adenomas or carcinomas, and this difference was statistically significant. These findings suggest that aneuploidy may play a role in the adenoma-carcinoma sequence.     

Flat adenoma-adenocarcinoma sequence in the colon of rats

PURPOSE: As there is an increased awareness of the existence of a “flat adenoma-adenocarcinoma sequence” in the colonic mucosa of human subjects, the aims of the study were to assess whether flat colonic adenocarcinomas in rats are also preceded by flat adenomas, as is reported in humans, and to determine the frequency of flat lesions compared with exophytic lesions in the colon of rats. METHOD: The colonotropic carcinogen 1,2-dimethylhydrazine was injected subcutaneously in 300 Sprague-Dawley rats for 27 weeks. RESULTS: A total of 358 tumors developed in 278 of the 300 rats. Of the 60 adenomas found at histology, 25 percent were flat adenomas. Of the 298 adenocarcinomas, 12.7 percent had originated in a fiat adenoma. Of the 180 colonic neoplasias (adenomas or adenocarcinomas), 29.4 percent were flat neoplasias (flat adenomas or adenocarcinomas arising in a flat adenoma), and the remaining 70.6 percent were exophytic neoplasias (tubulo or villous adenomas or adenocarcinomas arising in exophytic adenomas). From the 298 colonic adenocarcinomas, 1 was a intramucosal adenocarcinoma, 87 were overt adenocarcinomas, and 90 were lymphoid-associated carcinomas; in those 298 adenocarcinomas, no preneoplastic lesion could be recorded. In 208 animals, biopsies were taken from macroscopically visible colonic lesions, and, in the remaining 70 animals, the entire colon was processed for histologic examination. Flat adenomas were found in 3.8 percent of the 208 biopsy specimens and in 10 percent of the 70 colectomy specimens. Further, of the 40 adenomas found in biopsy specimens, 20 percent were flat adenomas, and, of the 20 adenomas found in colectomy specimens, 35 percent were flat adenomas. CONCLUSIONS: The study reported herein indicates the existence of a “flat adenomaadenocarcinoma sequence” in the colonic mucosa of Sprague-Dawley rats. The flat lesions of the colon constituted approximately one-third of the total neoplastic lesions seen in the rat following injections of 1,2-dimethylhydrazine. More flat adenomas were detected at histologic examination of the entire colon than in biopsies obtained from the macroscopically visible colonic lesions. Consequently, flat adenomas may be overlooked by naked-eye examination.     

Detection of colorectal adenomas by routine chromoendoscopy with indigocarmine

OBJECTIVES: Nonpolypoid adenomas, which can be important precursors of colorectal cancers, are difficult to find during routine colonoscopy. The aim of this study was to evaluate the usefulness of routine chromoendoscopy in Korea, where the incidence of colorectal cancer is low compared with western countries. METHODS: Colonoscopy with chromoendoscopy was performed in 74 consecutive patients (48 men, 26 women; mean age 53.0 yr). After a careful examination of the whole colon, a defined segment of the sigmoid colon and rectum (0-30 cm from the anal verge) was stained with 20 ml of 0.2% indigocarmine solution with a spraying catheter. Nonpolypoid lesions were classified as flat or depressed types. Biopsies were taken from all lesions detected before or after staining with indigocarmine. RESULTS: Indications for colonoscopy included routine check-up (21 patients), diarrhea or loose stool (14 patients), abdominal pain (12 patients), constipation (7 patients), bleeding (6 patients), and others (14 patients). Before staining, 58 lesions were found in 30 patients (43.2%). Histology showed tubular adenoma in 41 lesions, hyperplastic or inflammatory changes in 14 lesions, adenocarcinoma in 2 lesions, and villous adenoma in 1 lesion. After indigocarmine staining for normal-looking distal 30 cm colorectal mucosa, 176 lesions were found in 46 patients (62.2%). Histologically, 158 lesions were hyperplastic or inflammatory in nature, and 17 lesions (from 11 patients) were tubular adenomas. There was one serrated adenoma. Eighteen adenomas seen only after spraying indigocarmine were 2.6 +/- 0.6 mm in diameter, and all of them were classified as flat adenomas. There was no depressed-type adenoma. No adenoma with high grade dysplasia, villous histology, or cancer was found after staining. Presence of macroscopic adenomatous lesions or carcinoma before staining could not predict the existence of adenoma after staining. CONCLUSIONS: In a large proportion of patients, flat or depressed adenomas could be found after spraying indigocarmine for normal-looking colorectal mucosa in Korea. The clinical significance of these diminutive adenomas that can be found only after spraying contrast agent needs to be further investigated.     

Endoscopic mucosal resection for colonic non-polypoid neoplasms

BACKGROUND: Colonic neoplastic lesions can be classified morphologically into polypoid and non-polypoid types. Non-polypoid lesions have a higher malignant potential than polypoid lesions. Removing these lesions and obtaining integral specimen for histopathology evaluation during colonoscopy examination is an important task. Endoscopic mucosal resection (EMR) is an alternative to surgery for removing of non-polypoid lesions of the GI tract. This study assessed the safety, efficacy, and clinical outcomes of EMR. PATIENTS AND METHODS: From October 2000 to October 2003 during the routine colonoscopy performed at one medical center, identified 152 non-polypoid colonic neoplasms in 149 patients (92 males, 57 females) were found. The mean patient age was 57.8 +/- 15.5 yr (range 32-80 yr). EMR was performed for lesions suspected of being neoplastic tumors via magnification colonoscopy with the indigo carmine dye spray method. The lesions were removed via EMR with pure cutting current after which hemoclips were applied to the resected wounds. RESULTS: The study identified 40 flat type lesions, 106 lateral spreading tumors, and 6 depressed lesions that were completely resected. The mean size of lesions was 19.4 +/- 10.3 mm (range 6-60 mm). Histological findings were 4 adenocarcinomas, 59 with high-grade adenoma/dysplasia, and 89 with low-grade adenoma/dysplasia. Two patients experienced bleeding immediately following EMR, while adequate hemostasis was achieved using hemoclips. Neither delayed bleeding nor perforation developed following EMR. CONCLUSION: EMR by using pure cutting current and hemoclip is a useful method for obtaining integral specimen for accurate pathologic assessment. This method provides a safe and minimally invasive technique managing of colonic non-polypoid lesions.     

New aspects of modern endoscopy

The prognosis for patients with malignancies of the ga-strointestinal-tract is strictly dependent on early detec-tion of premalignant and malignant lesions. However, small, flat or depressed neoplastic lesions remain dif-ficult to detect with these technologies thereby limiting their value for polyp and cancer screening. At the same time computer and chip technologies have undergone major technological changes which have greatly im-proved endoscopic diagnostic investigation. New imag-ing modalities and techniques are very notable aspects of modern endoscopy. Chromoendoscopy or filter-aided colonoscopy(virtual chromoendoscopy) with high defi-nition endoscopes is able to enhance the detection and characterization of lesions. Finally, confocal laser en-domicroscopy provides histological confirmation of the presence of neoplastic changes. The developing tech-niques around colonoscopy such as the retro-viewing colonoscope, the balloon-colonoscope or the 330-de-grees-viewing colonoscope try to enhance the efficacy by reducing the adenoma miss rate in right-sided, non-polypoid lesions. Colon capsule endoscopy is limited to identifying cancer and not necessarily small adenomas. Preliminary attempts have been made to introduce this technique in clinical routine.     

Advanced diagnostic tools: virtual colonoscopy and magnifying chromoendoscopy

Early endoscopic diagnosis of colorectal cancers (CRCs) represents the best tool for the reduction of CRC mortality, but the conventional colonoscopic view seems unable to clarify faint changes of colorectal mucosa. For these reasons, during the last few decades, two new techniques have been developed in order to better define, diagnose and treat colorectal lesions: chromoendoscopy (CE) and magnifying chromoendoscopy (MC). The authors herein highlight the benefits of both and compare the results of conventional endoscopy and CE with 0.2% indigo carmine solution, evaluating 995 consecutive selected patients referred for colonoscopy between January 1999 and March 2003 at the International Health Union of Rome. CE showed new neoplastic patterns not detectable with conventional endoscopy in 102 patients (10.2%). The incidence of high-grade dysplasia and early carcinomas was 9.9% for protruded, 13.1% for flat and 60% for depressed lesions. Our comparative study on 995 consecutive selected patients confirmed the existence of flat and depressed neoplasms in Italy and shows the high accuracy rate of CE over conventional endoscopy for the detection of non-polypoid lesions. CE should be used routinely in order to enhance the early diagnosis of CRCs, while MC in experienced hands represents a significant advance in colonoscopic practice improving the diagnosis of every single lesion, enhancing therapeutic efficacy of colorectal tumours.     

Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features

Thirty-three small "flat adenomas," not more than 1 cm in diameter, were collected from surgically and colonoscopically removed specimens, and their colonoscopic and histologic characteristics were described. There were 14 adenomas with mild atypia, five with moderate atypia, 14 with severe atypia (or focal carcinoma limited to the mucosa). The grade of atypia seems to increase with the size of lesions, and these lesions were assumed to play an important role in the adenoma-carcinoma sequence. The importance of recognizing the presence of these small "flat adenomas" in everyday practice is stressed.     

Flat colonic adenomas in Malaysia: Fact or fancy?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Pathology of early lower GI cancer

Early colorectal cancer can be treated with curative resection if the depth of invasion is limited to the submucosa (pathologic T category pT1 in the TNM classification). Macroscopically early colorectal cancer and its precursor lesions present as elevated polyps or non-polypoid flat lesions. Microscopically, precursor lesions are characterized by intraepithelial neoplasia and present as classic adenomas or serrated adenomas. Precursor lesions may already contain foci of early colorectal cancer. Early colorectal cancer can be treated by endoscopic resection. Careful handling of the specimen is required in order to optimally identify the factors that may predict an adverse outcome. Whenever a favourable tumour grade is found, without vascular invasion and tumour budding, there seems to be a low risk for adverse outcome and laparotomy may thus be avoided.     

Magnification endoscopy,high resolution endoscopy,and chromoscopy; towards a better optical diagnosis

In the past few years, optical magnification endoscopy and chromoscopy have gained renewed interest in the West as a means for the early detection of minute lesions in patients with Barrett's oesophagus and in patients referred for colonic cancer screening. In Barrett's oesophagus, the vast majority of data on the use of chromoscopy deals with the application of methylene blue. Conventional videoendoscopy in combination with methylene blue staining improves the detection of Barrett's mucosa. A correlation has been shown between variation and intensity of staining and histologically verified stages of dysplasia or cancer. Magnification endoscopy and chromoscopy improve the detection of colonic non-polypoid lesions associated with neoplasia and carcinoma. Pitt pattern analysis enables the distinction of non-neoplastic non-polypoid lesions (type I and II) from neoplastic type non-polypoid lesions (type III-V) with great accuracy. It is certain that "old fashioned" chromoscopy combined with advanced endoscopic technology carry a great diagnostic potential and should be further put to the test for use in daily clinical practice.     

The relationship between the histopathological atypia and expression of beta-catenin in colonic neoplasms resected by endoscopy; comparison with that of p53 protein]

Previous studies have reported predominantly nuclear localization of beta-catenin as a role for colorectal carcinogenesis. In this study, we examined the immunohistochemical expression of beta-catenin and p53 protein in 90 colonic neoplasms {33 carcinomas in adenoma (CIA), 28 high grade adenomas and 29 low grade adenomas}, resected by colonic endoscopy. Out of 33 CIAs. 28 (84.8%) cases showed predominantly nuclear localization of beta-catenin, and that was significantly higher than those of both high grade (46.4%) and low grade (13.8%) adenomas. The positiveness of p53 expression in CIAs was 51.5% (17/33), while 17.9% in high grade and 3.4% in low grade adenomas. However, there was no correlation between both protein expressions (p = 0.3472, chi 2 test). The results suggests that nuclear localization and accumulation of beta-catenin is earlier event than that of p53 mutation in adenoma-carcinoma sequence, and is useful as a marker in histopathological diagnosis for malignant conversion as well as p53.