Karel Geboes, Dept of Pathology, University Hospital, KULeuven
Although colorectal cancer complicating chronic inflammatory bowel diseases (IBD) only accounts for 1-2% of all cases of colorectal cancer in the general population, it is considered to be a serious risk. In ulcerative colitis, the increased risk depends mainly on the (early) age at diagnosis, the duration of the disease, the diffuse nature of the condition (pancolitis) and disease activity. A comparable risk appears to exist for patients with Crohn’s disease. In Crohn’s disease, it is however more difficult to assess the risk. Overall, the duration of the disease and an early age at onset appear to be two important risk factors. Cancer development in the colon is characterised by a sequence of inflammation – dysplasia – and adenocarcinoma. It has been established that the presence of dysplasia indicates either the presence of a colorectal cancer or predicts its development.
Dysplastic lesions in IBD are characterised by specific macroscopic appearances, described as DALM (dysplasia associated lesion or mass). In the present review, the different macroscopic types of dysplasia are described and the diagnostic features and classification are reviewed. Furthermore, the impact of molecular techniques and the influence of the better understanding of the genetic abnormalities for the diagnosis are discussed.
Definition of dysplasia
In 1983, Riddeli et al. proposed a precise definition of "dysplasia" for lesions observed in patients with IBD. According to this definition, which is now generally accepted, dysplasia is used only for lesions showing "Unequivocal, non-invasive (confined within the basement membrane), neoplastic transformation of the epithelium excluding all reactive changes" (1). Dysplasia is a non-invasive lesion characterised by architectural and cytological abnormalities of the epithelium, including maturation and differentiation abnormalities of the cells, variabilities in size and shape of the nuclei (anisokaryosis) and cells (anisocytosis) together with a disturbed proliferation with abnormal extension of the proliferative compartment and a a variable number of mitotic figures (2). Because dysplasia is non-invasive, “intra-epithelial neoplasia” has been proposed as an alternative and less confusing term (3).
Endoscopy and macroscopic examination of surgical specimens from patients with ulcerative colitis allow three different types of dysplastic lesions to be distinguished. In 28% of the patients, conventional endoscopy does not show any abnormalities of the mucosa or dysplasia appears as a flat lesion. Flat dysplasia, which is the most common lesion, can appear as warty mucosal excrescences. In the other cases, dysplasia is an elevated lesion. It can appear as slightly elevated nodules or plaques or it may form a polypoid elevated lesion. The polypoid lesions are a heterogeneous group known as dysplasia associated lesion or mass (DALM), sporadic adenomas and adenoma-like lesions (ALM). DALM lesions can either appear as large irregular plaques, masses and large sessile polypoid lesions or even as localized strictures. Polypoid dysplastic lesions must be differentiated from inflammatory pseudopolyps and hyperplastic polyps.
Adenoma-like lesions (ALM) are usually well-circumscribed and small lesions, sometimes with a sessile configuration although a stalk can be present. They appear also in areas involved by inflammation in either ulcerative colitis or Crohn’s disease. They may resemble sporadic adenomas, even in some molecular features (4).
Overall, the identification of dysplasia during routine conventional endoscopy is difficult and the detection rate is poor. Methylene-blue aided chromoendoscopy and high-magnification-chromoscopic-colonoscopy (HMCC) permit a better differentiation of neoplastic from non-neoplastic tissue and improve the diagnostic yield, especially for flat dysplastic lesions. Pit pattern diagnosis, frequently used in Japan could also be helpful (5).
Microscopic features of dysplasia
Generally, the histological features of dysplasia in IBD are comparable with those seen in colonic adenomas in non-colitic patients and include cytological abnormalities such as variations in nuclear position, size and chromatin pattern allied to architectural distortion. In the eighties, an international "Inflammatory Bowel Disease-Dysplasia Morphology study group" established the morphological criteria which allow the distinction between dysplasia in IBD and reactive changes due to inflammation. They also developed a system of grading and classification. Although the morphological spectrum forms a continuum, dysplasia is divided into two grades according to the severity of the alterations, because of different implications for patient management. The recent Vienna classification, based upon the original classification of the International group, proposes three classes: a) non-dysplastic mucosa showing either a normal appearance or quiescent or active colitis; b) lesions which are indefinite for dysplasia, showing a mucosa with cytological and nuclear atypia, but without clear distinction between lesions due to epithelial injury and repair and lesions due to neoplasia; c) genuine dysplasia. Reparative phenomena can appear both in actively inflamed mucosa and in less actively inflamed tissue. During repair, epithelial cells may show features which mimic neoplasia, such as loss of polarity, the presence of large nucleoli and hyperchromatism. This can make a precise diagnosis difficult. In the presence of inflammation it may therefore be difficult to make an unequivocal diagnosis of dysplasia (intra-epithelial neoplasia). Control colonoscopy with extensive sampling may therefore be indicated, because reparative lesions will disappear under treatment.
Because of diagnostic problems, including the differential diagnosis between dysplasia and repair and poor inter-observer agreement for low-grade dysplasia, it is current practice to ask for a second opinion from another expert pathologist. A diagnosis of dysplasia has indeed important therapeutic consequences and therefore should not be proposed lightly. For these reasons, continuous research, especially in the field of molecular biology, is going on to find better tools for the diagnosis (1, 2).
What can we expect from molecular biology?
Because it is an "unequivocally neoplastic" lesion, dysplasia can be considered as one of the phases in the carcinogenesis, the multistep process associated with defects in genes in control of cell proliferation, cell death and cell and tissue structure. The pathogenesis of dysplasia in IBD is not precisely known. However, evidence from epidemiological studies and experimental data suggest a strong relation between inflammation and disease activity on the one hand, and the development of the neoplasia on the other. The magnitude of colorectal cancer risk increases with the extent of disease, and with pancolitis having a more severe inflammation burden. IBD is associated with epithelial cell injury and rapid epithelial cell turnover. The epithelial cell injury can partly be explained by the production of reactive oxygen species such as superoxide radicals through inflammatory cells. It has been shown experimentally that exposure of DNA to reactive oxygen species results in DNA damage when it is replicated in E. coli. Using quantitative fluorescence in situ hybridisation, chromosomal alterations have been detected in ulcerative colitis in both dysplastic and non-dysplastic epithelial cells. The instability appears to be related to telomere shortening. Such a shortening could increase the potential of chromosomal ends to fuse, resulting in cycles of chromatin bridge breakage and fusion and chromosomal instability. The latter hypothesis is supported by the higher frequency of anaphase bridges in samples from patients with ulcerative colitis either with dysplasia or cancer. Anti-inflammatory treatment reduces the cancer risk. Treatment with 5-ASA is indeed associated with an increase in apoptosis, a decrease of proliferation of colorectal mucosa and has been shown to lower the rate of spontaneous mutation (6).
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3 : SCHLEMPER RJ, RIDDEL RH, KATO Y, BORCHARD F, COOPER HS, DAWSEY SM, et al - The Vienna classification of gastrointestinal epithelial neoplasia. Gut, 2000, 47, 251-255.
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5 : KIESSLICH R, FRITSCH J, HOLTMANN M, KOEHLER HH, STOLTE M, KANZLER S, NAFE B, JUNG M, GALLE PR, NEURATH MF. Methylene-blue aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003, 124, 880-888
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