Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management

Abstract

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.

Figure 1.

Molecular pathogenesis of colitis-associated colorectal cancer (CRC) compared with sporadic CRC. (A) Sporadic CRC arises from adenoma (and sessile serrated polyp) precursors that progress through various stages until carcinoma. Loss of APC function is considered an early event and P53 mutations/loss are late. (B) In contrast, colitis-associated CRC also progresses through dysplastic precursor lesions, which tend to have a flatter morphology and demonstrate reversal of the APC and P53 sequence of molecular alterations, with P53 changes being very early, even before dysplasia. The molecular alterations associated with both sporadic and colitis-associated carcinogenesis are influenced by environmental factors, including general and specific components of the microbiome. COX-2, cyclooxygenase-2; DCC, deleted in colon cancer; DPC4, deleted in pancreatic cancer; Kras, Kirsten rat sarcoma viral oncogene homolog; LOH, loss of heterozygosity; miRNA, microRNA. Adapted from: Beaugerie and Itzkowitz20 with permission.

Figure 2.

Molecular and immunologic classification of colorectal cancers (CRCs). Categorization is predominantly based on observations from sporadic CRC (sCRC). Microsatellite instability (MSI) is highly correlated with hypermutation, hypermethylation, adaptive immune cell infiltration, activation of Kras and Braf, and proximal colon location. Tumors manifesting chromosomal instability (CIN) are more heterogeneous but are typically microsatellite stable. In general, sCRCs manifest epithelial canonic genetic pathways involving Wnt and Myc activation. In CAC, the proportion of MSI-positive tumors is approximately similar to that in sCRC. However, CACs demonstrate a shift from the epithelial consensus molecular subtype (CMS) 2 toward the more mesenchymal CMS4 phenotype (epithelial-mesenchymal transition), with dysregulation of Wnt signaling in favor of TGF-β activation, and an “immune-inflamed” immuosuppressive micro-environment enriched in CD4+ cells.17 EGFR, epidermal growth factor receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; VEGF, vascular endothelial growth factor. Adapted from: Nature Reviews Cancer 17:79, 2017, with permission.

Figure 3.

Histologic examples of conventional dysplasia. (A) Sporadic adenoma demonstrating dysplastic crypts at the surface of the polyp (“top-down”). (B) Colitis-associated dysplastic lesion demonstrating dysplastic cells occupying the full height of the crypts. Both are examples of low-grade dysplasia. Courtesy of Noam Harpaz, MD, PhD.