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LGS-II
Interval Colorectal Cancer: Don’t Distress Yourself Any Longer
Clinical and Biological Features of Interval
Colorectal Cancer
Yu Mi Lee, M.D., Kyu Chan Huh, M.D., Ph.D.
Konyang University School of Medicine, Daejeon, Korea
Introduction
Colorectal cancer (CRC) is the third most common malignancy worldwide, with a 6% lifetime risk of developing this cancer.1 Most CRCs develop from adenomatous polyp with a mean observed sojourn time of 3 - 6
2
years. Screening colonoscopy with polypectomy can reduce the incidence and mortality associated with colon
cancer.3 However CRC develops even though previous colonoscopy was normal or polyp was completely removed, colon cancer developed during unexpected short time period. Like this case, colon cancer is called as interval cancer
Clinical features of interval colorectal cancer
Interval CRC is CRC that is found before the next recommended screening or surveillance interval within 5
years after a negative colonoscopy or within 3 years after a polypectomy for advanced adenoma.
The overall prevalence of interval CRC ranged from 1.8 to 9.0% from Singh’s meta-analysis study of interval
CRC.4 On pooled analysis, the prevalence of interval CRCs was 3.7% within 6 - 36 months of previous
colonoscopy. But when they defined interval CRCs as those diagnosed within 6 - 60 months, the pooled preva5
lence of interval CRCs was 6%.
Regarding location, the prevalence of proximal interval CRCs was 6.5%. This corresponds to 1 in 15 proximal CRCs being interval CRCs. the prevalence of distal interval CRCs was 2.9%. This corresponds to 1 in 34
distal CRCs being interval CRCs. As compared with detected CRCs, interval CRCs were 2.4 times more likely to
be proximal CRC than distal CRCs.4
Although meta-analysis study reported females were no more likely than males to develop interval CRCs,5
6,7
several studies individually reported a higher prevalence of interval CRCs in females as compared with males.
Generally, interval CRCs are classified as missed lesions, incomplete colonoscopy, incomplete resection of
polyps and newly developed cancers or rapid tumor progression (de novo I-CRCs). Among them, the most colon etiology is missed lesion
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LGS-II: Interval Colorectal Cancer: Don’t Distress Yourself Any Longer
Biological features of interval colorectal cancer
Many studies have primarily focused on the proportion of I-CRCs due to false-negative colonoscopies. Rapid
growing features of I-CRC could be another cause of I-CRCs that is specific aberrant biology that drives their
de novo and rapid growth.
The characteristics of SSA/Ps are pale, flat lesion or covered with mucus, which cause missing the lesion or
incomplete resection and they was located predominantly within the proximal colon. Serrated pathway of colorectal cancer carcinogenesis has BRAF, CIMP and MSI mutations and MLH1 methylation. Sessile serrated adenomas/polyps (SSA/Ps) share many genomic and colonic site characteristics with I-CRCs, and consequently
have been suggested to be a precursor lesion for I-CRCs
The reason why SSAPs have been suggested to be a precursor lesion for I-CRCs as follow First, I-CRCs were
almost 4 times as likely as non-interval colon cancers to be associated with mismatch repair gene dysfunction,
8
and hence demonstrate microsatellite instability (MSI). Second, the risk of I-CRCs is high in patients with a
9
proximal mucinous cancer. And synchronous colorectal cancers had more frequent mutations in BRAF, were
more frequently (CpG island methylation phenotype (CIMP)-high and MSI-high. These suggest that biologic
characteristics of I-CRCs are associated with serrated neoplastic pathway.
Conclusion
The prevalence of interval CRCs ranges from 2.8 to 9.0% of all sporadic CRCs. As compared with sporadic
CRCs, interval CRCs was 2.4 times more likely to be proximal CRC than distal CRCs. And higher prevalence of
interval CRCs in females as compared with males. While I-CRCs may arise due to false negative colonoscopies,
a portion is also likely attributed to aberrant molecular biology. Due to the physical and molecular similarities
shared between sessile serrated adenoma (SSA/Ps) and I-CRCs. Since SSA/Ps possess the CIMP, this could explain the increased prevalence of CIMP and MSI-High observed in I-CRCs. And hypermethylation and/or mutation of other genes (i.e., p16INK4a, IGFBP7, Wnt pathway) may occur concurrently and effectively synergize
to produce a tumorigenic phenotype conferring rapid development.
References
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N Engl J Med 2012 Feb 23;366(8):687-96.
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