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Colon tumor

Polyps

Adenoma-carcinoma sequence of colon


Reviewers: Shilpa Jain, M.D, New York University (see Reviewers page)
Revised: 2 May 2012, last major update August 2010
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

Definition / General
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● Well characterized series of histopathologic events associated with distinct molecular alterations
● Based upon the genetic background, sporadic colorectal carcinoma (CRCs) can be subclassified into three types:
   (A) chromosomal instability / CIN (abnormal number of chromosomes, not diploid)
   (B) microsatellite instability / MSI (diploid but DNA mismatch repair gene alterations), and
   (C) an additional group with CpG island methylator phenotype / CIMP

(A) Chromosomal instability pathway
● CIN pathway is associated with large genomic alterations including aneuploidy, gain and loss of chromosomal regions
● Carcinomas arise from the accumulation of activation (by mutation) of oncogenes and the inactivation of tumor-suppressor genes that initially cause adenomatous polyps (usually); then some acquire additional mutations and become malignant (4-10 mutations are required to produce malignant phenotype)
● Molecular pathway may vary in each particular tumor
● Earliest event often involves APC gene (germline mutations of APC are responsible for familial adenomatous polyposis (FAP) syndrome, while somatic mutations of APC occur in 50% of sporadic adenomas and 80% of sporadic colon cancer)
DCC (Deleted in colon cancer) gene loss occurs late in carcinogenesis with frequent deletion in carcinoma (73%) and in high grade adenoma (47%)
K-ras mutations (10% of adenomas, 50% of adenomas with severe dysplasia, 35-45% of carcinomas) occur in larger but not smaller polyps
● Ras mutations are point mutations at codons 12, 13 and 61
● As KRAS is the downstream effector of EGFR, and is frequently mutated in colorectal cancer, the mutational status of KRAS has become an important predictive marker for the effectiveness of cetuximab or panitumumab for metastatic colorectal cancers
p53 gene mutation occurs at the point of development of high grade dysplasia, and is found in 50% of adenomas with high grade dysplasia and 70% of sporadic colon cancers
● Loss of the wild type of p53 activity is thought to be a major predictor of falure to respond to radio- and chemotherapy (J Clin Pathol 2008; 61:561)
DPC4/DCC/SMAD4 mutation (18q21, reduced expression in 70% of carcinomas) occurs later in the sequence and indicates an advanced phenotype
● Loss or low level of SMAD4 expression in colorectal carcinomas is associated with poor prognosis following surgery and 5-FU-based adjuvant therapy; however, the predictive value of SMAD4 mutation/inactivation is controversial (Biochem Biophys Res Commun 2003; 306:799, Clin Cancer Res 2005;11:6311)
EGFR, a receptor tyrosine kinase, is overexpressed in up to 80% of colorectal cancers (Acta Oncol 1998;37:285)
● Tumors with a high level of EGFR expression usually have poor prognosis
● Removing adenomas via screening colonoscopy reduces the incidence of colorectal cancer (N Engl J Med 1993;329:1977)
● Polyposis syndrome patients have an increased risk for carcinoma (nearly 100% for familial polyposis and Gardner’s syndrome)
● Villous adenomas have a higher malignant risk than tubular adenomas
Polyps with no malignant risk: solitary hyperplastic polyps, juvenile polyps and Peutz-Jegher polyps

(B) Microsatellite instability pathway
● Associated with inactivation of DNA mismatch repair proteins, which leads to mutation accumulation
● In sporadic colon carcinoma, MSI is usually caused by loss of expression of MLH1, secondary to MLH1 promoter methylation, while in hereditary nonpolyposis colon cancer / HNPCC, the underlying defect is the inherited mutation of a repair gene
● 15–20% of sporadic CRCs have microsatellite instability (MSI-H)
● Sporadic MSI-H cancers are frequently poorly differentiated, mucinous and more proximally located than HNPCC tumors
● In sporadic MSI-H cancer, serrated adenomas are most common, and may transform into carcinoma without a component of adenomatous dysplasia (Am J Clin Path 2006;125:132), but traditional adenomas are usually seen in HNPCC
● Lymphocytic infiltration is common in both type of tumors
● BRAF mutations are associated with the microsatellite instability pathway (Gut 2004;53:1137)

(C) CpG island methylator pathway (CIMP)
● CpG island methylator phenotype underlies microsatellite instability in most cases of sporadic colorectal cancer associated with MLH1 hypermethylation
● It is also strongly associated with BRAF mutation
● However, only one third of CIMP positive tumors are MSI–H; thus CIMP appear to be an independent predictor for microsatellite status

Serrated Adenoma Pathway:
● Historically, hyperplastic polyps were not considered a precursor of carcinoma
● However, more recent studies have demonstrated that certain types of hyperplastic or serrated polyps, those with DNA mismatch repair deficiency, may give rise to cancer
● Sessile serrated adenomas frequently (78%) have BRAF mutations or K-ras mutations (11%), in contrast to hyperplastic polyps, which show frequent K-ras mutations (70%) with less common BRAF mutations (20%)
● MLH1 promoter methylation is frequent in serrated polyps, suggesting that they give rise to sporadic colorectal carcinoma with MSI
● Smoking and estrogen withdrawal may be associated with serrated pathway carcinoma

Diagrams
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End of Colon tumor > Polyps > Adenoma-carcinoma sequence of colon


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