Classification of colorectal cancer based on correlation of clinical, morphological and molecular features

Histopathology. 2007 Jan;50(1):113-30. doi: 10.1111/j.1365-2559.2006.02549.x.


Over the last 20 years it has become clear that colorectal cancer (CRC) evolves through multiple pathways. These pathways may be defined on the basis of two molecular features: (i) DNA microsatellite instability (MSI) status stratified as MSI-high (MSI-H), MSI-low (MSI-L) and MS stable (MSS), and (ii) CpG island methylator phenotype (CIMP) stratified as CIMP-high, CIMP-low and CIMP-negative (CIMP-neg). In this review the morphological correlates of five molecular subtypes are outlined: Type 1 (CIMP-high/MSI-H/BRAF mutation), Type 2 (CIMP-high/MSI-L or MSS/BRAF mutation), Type 3 (CIMP-low/MSS or MSI-L/KRAS mutation), Type 4 (CIMP-neg/MSS) and Type 5 or Lynch syndrome (CIMP-neg/MSI-H). The molecular pathways are determined at an early evolutionary stage and are fully established within precancerous lesions. Serrated polyps are the precursors of Types 1 and 2 CRC, whereas Types 4 and 5 evolve through the adenoma-carcinoma sequence. Type 3 CRC may arise within either type of polyp. Types 1 and 4 are conceived as having few, if any, molecular overlaps with each other, whereas Types 2, 3 and 5 combine the molecular features of Types 1 and 4 in different ways. This approach to the classification of CRC should accelerate understanding of causation and will impact on clinical management in the areas of both prevention and treatment.

Publication types

  • Review

MeSH terms

  • Adenocarcinoma / classification*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Colorectal Neoplasms / classification*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • CpG Islands / genetics
  • DNA Methylation
  • DNA, Neoplasm / analysis
  • Humans
  • Microsatellite Instability
  • Mutation
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology


  • DNA, Neoplasm