Molecular Validation of the Modified Vienna Classification of Colorectal Tumors

Abstract

Although the Vienna classification has been introduced to resolve discrepancies in histological diagnoses of colorectal tumors between Western and Japanese pathologists, practical applications of this classification scheme have been problematic because invasion of the lamina propria of tumor cells is often difficult to recognize. Therefore, the following refinements of the classification criteria are needed: category 3, low-grade adenoma/dysplasia; category 4, intramucosal borderline neoplasia; 4-a, high-grade adenoma/dysplasia; 4-b, well-differentiated adenocarcinoma; category 5, definite carcinoma; 5-a, intramucosal moderately-differentiated adenocarcinoma; and 5-b, submucosal carcinoma. We attempted to test whether molecular genetic alterations are related to the modified classification scheme and whether they may help to further categorize the various intramucosal neoplasia grades of colorectal tumors. Two-hundred-thirty-two colorectal tumors were examined using flow cytometric analysis of DNA content, polymerase chain reaction microsatellite assays, and single-strand conformational polymorphism assays to detect abnormalities of DNA content, chromosomal allelic loss, and Ki-ras and p53 gene mutations. Microsatellite instability (MSI) was also examined.

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

“…The TP53 gene is one of the most frequently mutated genes in human cancers 4, 5, 23, 24. Approximately half of all cancers have mutated TP53 4, 5.…”

“…In addition, mutation of the TP53 gene is found in 60–80% of CRCs 4, 5, 7. Mutation of the TP53 gene is a representative event during the progression of CRC 4, 5, 23, 24. Recent studies have shown that mutation of TP53 is observed more frequently in LC than in RC 9, 25.…”

“…Therefore, mutation of KRAS is thought to be a critical genetic event in colorectal carcinogenesis 4, 6, 7, 2326.…”

“…The EGF ligand activates a signaling cascade via 2 pathways, that is, the RAS‐RAF‐mitogen‐activated protein kinase (MAPK) and phosphoinositide 3‐kinase (PI3K)‐AKT pathways, suggesting that KRAS mutations may be a key molecular factor mediating the efficacy of EGFR monoclonal antibody therapy in CRC 26, 27. Approximately 30–50% of colorectal tumors are known to harbor mutated KRAS , indicating that up to 50% of patients with CRC may benefit from specific treatment strategies based on KRAS status 23, 26, 27. In the present study, the frequency of KRAS mutations was found to be significantly higher in RC than in LC.…”

Analysis of allelic imbalances at multiple cancer‐related chromosomal loci and microsatellite instability within the same tumor using a single tumor gland from colorectal carcinomas

“…[22][23][24] Samples were processed for 25-30 cycles, with each cycle consisting of 30 sec at 94°C, 1 min at 55-58°C and 2 min at 72°C, followed by a final 10 min extension at 72°C. For quantitative detection of the allelic imbalance at each locus, the size of the 2 alleles (q-value) in a heterozygous sample was determined by comparison with the 2 highest peaks in the normal sample as described previously.…”