Precancer in ulcerative colitis: the role of the field effect and its clinical implications

Abstract

Cumulative evidence indicates that a significant proportion of cancer evolution may occur before the development of histological abnormalities. While recent improvements in DNA sequencing technology have begun to reveal the presence of these early preneoplastic clones, the concept of 'premalignant field' was already introduced by Slaughter more than half a century ago. Also referred to as 'field effect', 'field defect' or 'field cancerization', these terms describe the phenomenon by which molecular alterations develop in normal-appearing tissue and expand to form premalignant patches with the potential to progress to dysplasia and cancer. Field effects have been well-characterized in ulcerative colitis, an inflammatory bowel disease that increases the risk of colorectal cancer. The study of the molecular alterations that define these fields is informative of mechanisms of tumor initiation and progression and has provided potential targets for early cancer detection. Herein, we summarize the current knowledge about the molecular alterations that comprise the field effect in ulcerative colitis and the clinical utility of these fields for cancer screening and prevention.

Figure 1.

Proposed model of carcinogenesis in UC. This model integrates the etiological, molecular and dysplastic field effects with known cellular and molecular events that contribute to the different stages of carcinogenesis in UC. The arrow indicates the temporal direction of dysplastic progression and the color gradient reflects the increasing risk of cancer at the different stages of the process. Cancer arises within dysplastic and/or molecular fields. Molecular fields precede dysplastic fields and are more extensive, thus offering an excellent opportunity for precancer detection.

Figure 2.

Implications of the field effect on UC colonoscopic surveillance. By analyzing several screening biopsies procured along the colon, field effects can be identified and could possibly be used to predict cancer progression risk. The colon diagrams represent four clinical scenarios in which dysplasia may not be detected by chromoendoscopy but in which screening biopsies could identify molecular fields: (A) pancolonic field, (B) multifocal fields, (C) extensive field and (D) localized field. Cancer is a probabilistic process that depends on the rate of mutation and the number of cells at risk. Thus, we postulate that large, multifocal fields are likely to be associated with higher risk of cancer progression compared to small, unifocal fields. Studies with large numbers of patients are needed to validate this model, quantify the progression risk accordingly, and integrate it with other known cancer risk factors in UC. If such approach was developed, it would facilitate tailoring the time interval between colonoscopies to the level of risk for each patient.