Two colons‐two cancers: Paradigm shift and clinical implications

Abstract

Embryological and physiological data suggest that proximal (in relation to the splenic flexure) and distal parts of the colon represent distinct anatomical and functional entities. Since 1990, molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in the pathogenesis of colon cancer (CC). Thus, a new paradigm has emerged with the discovery that CC is a heterogeneous disease; furthermore recent data have demonstrated that these two distinct pathways in colorectal carcinogenesis are characterized by a different clinical outcome. The implications for the clinicians are twofold; (1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI-positive lesions; and (2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in ongoing trials of adjuvant chemotherapy for CC. In the future, clinical decision-making regarding adjuvant chemotherapy might be stratified according to the MSI status of cancers located proximally to the splenic flexure.

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…These findings further support previous evidence suggesting that proximal and distal CRC may represent different epidemiological, pathological, genetic, and clinical entities. 23 , 24 Right-sided tumours, often defined as proximal to the splenic flexure, are generally poorly differentiated, diagnosed in more advanced tumour stages, displaying different molecular patterns, and carrying a poorer prognosis than left-sided tumours. 24 , 25 Several studies also demonstrate the importance of taking PTL into account when evaluating treatment response, 26-28 and retrospective analyses from large phase III trials have demonstrated that patients with right-sided tumours have less benefit from the addition of EGFR-targeted therapy.…”

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

“…55 Two different pathways, microsatellite instability (MSI) and chromosomal instability (CIN), are involved in the pathogenesis of CRC. Tumors originating in the proximal part of the colon carry a better patient prognosis due to a high percentage of MSI-positive lesions, 56,57 whereas distal cancers are more often initiated through the CIN pathway 58 with a potentially worse prognosis. MMP-2, TIMP-3 and TIMP-4 may be of future clinical value.…”

Selective expression of gastric mucin MUC6 in colonic sessile serrated adenoma but not in hyperplastic polyp aids in morphological diagnosis of serrated polyps

“…Indeed, there is accumulating evidence suggesting that the right and left colon may be considered as two distinct 'organs' with different embryology, biochemical metabolism and carcinogenesis. 31,32 Although it does not appear simply to be a marker of the right colon itself (as it was negative in flat mucosa regardless of site), it is difficult to address the possibility that MUC6 may highlight right colon polyps regardless of their pathogenesis, because of the distinct segregation of sessile serrated adenomas and hyperplastic polyps in the right and left colon, respectively. However, our series did include five left colonic sessile serrated adenomas that were MUC6-positive, and one right colonic hyperplastic polyp that was MUC6-negative.…”