Early colorectal cancer -concept, diagnosis, and management

REVIEW ARTICLE Int J Clin Oncol (2006) 11:1–8 © The Japan Society of Clinical Oncology 2006 DOI 10.1007/s10147-005-0550-5 Hiroshi Kashida · Shin-ei Kudo Early colorectal cancer: concept, diagnosis, and management Received: November 21, 2005 Abstract In colorectal cancers, although flat and depressed- type lesions are found by regular endoscopic view, magnifi- cation and pit-pattern observation are vital parts of the precise diagnosis of the lesion. The depressed-type lesions appear to have a prominent tendency to show malignant characteristics, and the recognition and timely treatment of such lesions is important for improving the morbidity and mortality of colorectal cancer. Chromoscopy is mandatory for an accurate diagnosis of these lesions. The pit-pattern classification correlates well with actual histological findings and can provide important additional information prior to endoscopic treatment of the lesion. Key word word文档格式规范word作业纸小票打印word模板word简历模板免费word简历 s Depressed colorectal cancer · Chromoscopy · Magnifying colonoscopy · Pit pattern · Endoscopic mucosal resection Introduction Colorectal cancer is increasing and is expected to become the first cause of death from diseases of the digestive system in Japan within 10 years. Therefore it is important to pre- vent, to detect, and to treat colorectal cancer early enough. In this article, the present concept, diagnosis, and manage- ment of early colorectal cancer are reviewed. H. Kashida (*) · S. Kudo Digestive Disease Center, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-chuo, Tsuzuki-ku, Yokohama 224-8503, Japan Tel. +81-45-949-7833; Fax +81-45-949-7735 e-mail: kashi-md@xf6.so-net.ne.jp Concept of early colorectal cancer In carcinogenesis, a single cell transforms into a cancer, proliferates through frequent mitoses, and gradually forms a mass. It takes a certain time for a cancer to be diagnosed as such after its birth. Early colorectal cancer is defined by the Japanese rule1 as being limited to the mucosa or invad- ing only to the submucosa, regardless of the presence or absence of lymph node metastases. The term “early” does not always imply that the lesion is detected right after its birth, but only means that it is early enough for the tumor to be completely cured. Thus, the term does not reflect the time course of the tumor, nor does it fully represent its biological nature. According to the classification published by The World Health Organization (WHO),2 only epithelial tumors that have penetrated through the muscularis mucosae into the submucosa are considered malignant in the colon or rec- tum. Japanese pathologists do not agree with this defini- tion.3 Western and Japanese pathologists have discussed the matter and have published a new classification in the hope that it would be accepted universally.4 The Japanese rule5 divides the gross appearance of early colorectal cancers into: type I, protruded (Ip, Isp, Is); type II, superficial (IIa, IIb, IIc); and type III, excavated. The Paris endoscopic classification of superficial gastrointestinal neoplasms6 is largely based on the Japanese classification. Colorectal adenomas and early carcinomas can be grossly divided into three groups; protruded or polypoid, flat- elevated, and depressed.7 The depressed-type colorectal cancers can be absolutely depressed or can be accompanied by a slightly elevated margin. Some flat-elevated adenomas spread extensively and circumferentially along the colonic wall although they are very short in height. These large flat- elevated adenomas are sometimes malignant, but not so advanced in spite of their large diameter. We8 advocated a category “laterally spreading tumor (LST)”, which is de- fined as lesions larger than 10mm in diameter but extending circumferentially rather than vertically. This category is fur- ther divided into a granular type, which is composed of fine Used Mac Distiller 5.0.x Job Options This report was created automatically with help of the Adobe Acrobat Distiller addition "Distiller Secrets v1.0.5" from IMPRESSED GmbH. You can download this startup file for Distiller versions 4.0.5 and 5.0.x for free from http://www.impressed.de. 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Staging of early colorectal cancer The degree of submucosal invasion (Fig. 1)8 is classified into three stages, based on the depth of invasion; sm1, sm2, and sm3. Stage sm1 is subclassified into 1a, 1b, and 1c, according to the horizontal extension of the invaded area. Sm 1a or 1b cancers (slightly or minimally invasive cancers) without ves- sel permeation never metastasize to the lymph nodes, liver, or other organs. In contrast, sm1c and sm2 or sm3 lesions (massively invasive submucosal cancers) show a substantial proportion (around 10%) of nodal metastasis. Biological behavior of colorectal neoplasia The invasive rates (Table 1) in depressed types of tumors were 7.9% in lesions not exceeding 5mm, 44.9% in those of 6–10mm, and 69.9% in those of 11–15mm. Depressed le- sions are invasive even when they are very small, strongly suggesting that they grow rather rapidly at an early stage,9–14 to become advanced cancer. In contrast, invasive rates in flat-elevated adenomas were 0.03% for those less sm3 sm2 sm1a sm1b sm1c A B massively invasive slightly invasive Fig. 1. Degrees of submucosal invasion. sm1, upper 1/3; sm1a, B/A, �1/4; sm1b, B/A, 1/4–1/2; sm1c, B/A, �1/2; sm2, middle 1/3; sm3, lower 1/3 Table 1. Rates of submucosal cancer in colorectal neoplasms, excluding advanced cancers (April 1985–June 2005) Gross Size (mm) Total appearance �5 6–10 11–15 16–20 �21 Depressed 20/253 70/156 51/73 21/24 15/17 177/523 7.9% 44.9% 69.9% 87.5% 88.2% 33.8% Flat-elevated 2/6848 3/1197 14/550 22/201 65/307 106/9103 0.03% 0.25% 2.5% 10.9% 21.2% 1.2% Protruded 0/6234 62/4732 89/1163 68/414 68/233 287/12 776 0% 1.3% 7.7% 16.4% 29.2% 2.2% Total 22/13335 135/6085 154/1786 111/639 148/557 570/22 402 0.16% 2.2% 8.6% 17.4% 26.6% 2.5% 3 than 5mm, 0.25% for those of 6–10mm, and 2.5% for those of 11–15mm, with these rates being even lower than those for protruded polyps. Therefore, flat lesions are usually benign or only focally malignant and grow very slowly, not becoming invasive until they are rather large. Some stud- ies15 have suggested that, on following, many small ad- enomas either do not grow, or sometimes diminish in size. Development of colorectal cancer Concerning the development of colorectal carcinoma, two main doctrines have been advocated; one, called the “adenoma-carcinoma sequence” theory,16 maintains that a cancer develops from normal mucosa through a stage of adenoma, while the other, called the “de-novo” theory,17 claims that a carcinoma emerges directly from normal epi- thelium without going through a stage of adenoma. The majority of advanced colon cancers are depressed rather than protruded. Few researchers have witnessed an intermediate-stage colon cancer between a benign polyp and an advanced depressed carcinoma, while a significant number of small colonic cancers without any adenomatous remnant have been reported,18–20 and benign adenomatous tissue is seen in only about 20% of advanced colorectal carcinomas.21,22 The periphery is usually covered with the normal mucosa and is elevated because of compression by the carcinoma or because of the submucosal proliferation of the tumor cells. The transition from the carcinoma to the adjacent normal colonic mucosa is abrupt and there is no evidence of “residual” adenoma. Occasionally, there can be a few glands which show adenoma-like changes, but these charges could be reactive to the tumor and not related to carcinogenesis. The supporters of the adenoma-carcinoma theory assert that the adenomatous polyp has been ulcerated or sloughed away during the development. But this may not be the case, because most small early cancers without an adenomatous remnant are not ulcerated. There is speculation that a carci- noma may overgrow a polyp, destroying the evidence of a precursor adenomatous polyp. Shimoda et al.21 described that, in early colorectal cancers which showed polypoid growth, about 90% contained an adenomatous element; while in those which showed nonpolypoid growth, none contained any adenomatous remnants, although they were significantly smaller (average diameter, 8.7mm) than those with polypoid growth (average diameter, 16.8mm). If an adenomatous precursor is to be gradually replaced by a carcinoma, a higher incidence of adenomatous remnants should be recognized in smaller lesions. Meanwhile, there is no evidence, either, that colon can- cers without an adenomatous component really arise de novo from an absolutely normal mucosa. An alternative explanation may be that these lesions arise from very small microadenomas, which are rapidly replaced by the expand- ing carcinoma. It is difficult to prove which is true – whether a cancer arises from a microadenoma that is replaced rap- idly by carcinomatous tissue, or whether it arises strictly de novo from an isolated dysplastic cell that degenerates readily without going through an adenomatous step. In any case, such a rapid development of cancer looks quite differ- ent from the conventional polyp-cancer concept. It would be natural to believe that there is a de-novo pathway also in colorectal cancer development. De-novo carcinogenesis from flat mucosa, without going through an adenomatous stage, is not rare in the gastrointestinal tract, other than the colorectum. Studies of chemically induced colonic carcino- mas in experimental animals23,24 have shown evidence in support of de-novo carcinogenesis. It is only in the human colorectum that the adenoma-carcinoma sequence is re- garded as the main pathway of carcinogenesis. Genetic alterations in colorectal neoplasia Genetic studies also seem to support the idea that there are at least two ways of colonic cancer development. The adenoma-carcinoma sequence theory in the colorectum was supported by Vogelstein et al.25 Multistep carcinogenesis had been assumed in other organs as well, but the study by Vogelstein’s group was epoch-making, in that they con- nected the genetic alterations to morphological changes in colorectal tumors. The first genetic alteration to be recog- nized in colorectal tumorigenesis is that of the APC (adenomatous polyposis coli) gene. Mutational activation of the K-ras oncogene is considered to play a role in the progression of the size and grade of atypia in the adenoma- carcinoma sequence. In studies comparing the K-ras mutation and the configuration of colorectal tumors, K-ras mutations were detected in as many as 70% of protruded adenomas, whereas they were rare in superficial ad- enomas.26 Superficial colorectal tumors are regarded as candidates for de-novo carcinogenesis and seem to be asso- ciated with specific genetic alterations different from those in the adenoma-carcinoma sequence. It is speculated that, once a lesion becomes overt carcinoma, the consecutive changes are similar regardless of the lesion’s initial form or whichever pathway it has followed. P53 alteration is not only frequently witnessed in the development of carcinoma through the adenoma-carcinoma sequence but has also been shown to be a frequent event in de-novo carcinogen- esis. It would be important to determine the genetic profiles of early colorectal cancers and precancerous lesions classified by their gross configuration. Detection of colorectal adenomas and early cancers The immunological fecal occult blood test (FOB) is used in Japan as a method of screening for colorectal cancers. In actuality, however, subjects positive for FOB turn out to have polyps more often than cancers. It is not rare that a flat adenoma or a depressed lesion is found in FOB-negative subjects. These lesions are also notoriously difficult to detect with a barium enema study. Therefore, total colono- 4 scopy is important for the diagnosis of early colorectal cancers. To detect a protruded polypoid lesion is not so difficult. In order to detect a depressed or a flat-elevated lesion, finding a small area with slight color change is important.27 Some lesions look faintly red; others are slightly pale. A minimal deformation of the bowel wall, interruption of the mucosal capillary network pattern, or spontaneous bleeding suggests the existence of a depressed lesion. It is also impor- tant to observe the suspected lesion with air inflation and deflation. In benign lesions, both the lesion and the sur- rounding normal mucosa are elevated after the deflation of air, and so no significant shape change occurs. In intramucosal or minimally invasive cancers, the surround- ing mucosa becomes elevated when the air is deflated, em- phasizing the depression. The sign is not observable in more invasive lesions, as they are hard, and fixed to the colonic wall. Chromoendoscopy is very useful for clarifying the de- pression within a lesion. But you should bear in mind that lesions should be detected with ordinary views and the dye be sprayed only after the detection of a lesion. Kariya et al.28 reported the first case of depressed early colon carcinoma in the Japanese language in 1977. Kudo and Muto29 reported their own cases, in Japanese, in 1986, and Kudo made a report in English in 1993.30 Depressed-type early colorectal cancers, as well as flat adenomas, were first thought to be unique to a localized area in Japan or the East, but, re- cently, an increasing number of similar lesions has also been witnessed in Western countries.31–34 Though depressed early IIILIIIS IV IV NV I II Fig. 2. Classification of pit patterns. I, II, IIIs, small; IIIL, large; IV, VI, irregular; VN, nonstructural 5 colonic cancers are still found only rarely, taking into ac- count the difficulty of endoscopic detection of such tumors and their rapid growth, there could be still far more that are being overlooked than detected. So-called flat adenomas are not perfectly flat, but are usually slightly elevated. Their color is often faintly reddish, which helps to detect them. Chromoendoscopy is useful for clarifying the lesion, but sometimes, with this modality, flat lesions resemble depressed lesions, because they appear to have a depression. The depression in a depressed lesion is Table 2. Pit patterns and histology of lesions (April 2001–June 2005) Pit pattern Adenoma (dysplasia)