The serrated pathway to colorectal carcinoma: current concepts and challenges

<jats:p>Approximately 30% of colorectal carcinomas develop via a serrated neoplasia pathway, named for the pattern of crypts in the precursor polyps. Molecular abnormalities consistently involve methylation of <jats:styled-content style="fixed-case">C</jats:styled-content>p<jats:styled-content style="fixed-case">G</jats:styled-content> islands [<jats:styled-content style="fixed-case">C</jats:styled-content>p<jats:styled-content style="fixed-case">G</jats:styled-content> island methylator phenotype (<jats:styled-content style="fixed-case">CIMP</jats:styled-content>)] of low degree (<jats:styled-content style="fixed-case">CIMP</jats:styled-content>‐<jats:styled-content style="fixed-case">L</jats:styled-content>) or high degree (<jats:styled-content style="fixed-case">CIMP</jats:styled-content>‐<jats:styled-content style="fixed-case">H</jats:styled-content>), and activating mutations of the mitogen‐activated protein kinase pathway components <jats:italic><jats:styled-content style="fixed-case">BRAF</jats:styled-content></jats:italic> or <jats:italic><jats:styled-content style="fixed-case">KRAS</jats:styled-content></jats:italic>. Microsatellite instability (<jats:styled-content style="fixed-case">MSI</jats:styled-content>) of a high level (<jats:styled-content style="fixed-case">MSI</jats:styled-content>‐<jats:styled-content style="fixed-case">H</jats:styled-content>) is often present, allowing for a molecular classification of serrated pathway carcinoma as: (i) <jats:italic><jats:styled-content style="fixed-case">BRAF</jats:styled-content></jats:italic> mutant/<jats:styled-content style="fixed-case">CIMP</jats:styled-content>‐<jats:styled-content style="fixed-case">H</jats:styled-content> with either a) <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐<jats:styled-content style="fixed-case">H</jats:styled-content> or b) microsatellite stable (<jats:styled-content style="fixed-case">MSS</jats:styled-content>); and (ii) <jats:italic><jats:styled-content style="fixed-case">KRAS</jats:styled-content></jats:italic> mutant/<jats:styled-content style="fixed-case">CIMP</jats:styled-content>‐<jats:styled-content style="fixed-case">L</jats:styled-content>/<jats:styled-content style="fixed-case">MSS</jats:styled-content>. Precursor polyps include sessile serrated adenoma (<jats:styled-content style="fixed-case">SSA</jats:styled-content>), characterized by proximal location, crypt architectural disturbance, and <jats:italic><jats:styled-content style="fixed-case">BRAF</jats:styled-content></jats:italic> mutation. Microvesicular hyperplasic polyp (<jats:styled-content style="fixed-case">MVHP</jats:styled-content>) probably precedes the development of <jats:styled-content style="fixed-case">SSA</jats:styled-content>, and borderline lesions between <jats:styled-content style="fixed-case">MVHP</jats:styled-content> and <jats:styled-content style="fixed-case">SSA</jats:styled-content> occur. Cytological dysplasia in <jats:styled-content style="fixed-case">SSA</jats:styled-content> portends advanced genetic abnormality and a high risk of progression to carcinoma. The traditional serrated adenoma has a predilection for the left colon, tubulovillous architecture, eosinophilic cytoplasm, and frequent <jats:italic><jats:styled-content style="fixed-case">KRAS</jats:styled-content></jats:italic> mutation. Serrated morphology carcinoma is a new <jats:styled-content style="fixed-case">W</jats:styled-content>orld <jats:styled-content style="fixed-case">H</jats:styled-content>ealth <jats:styled-content style="fixed-case">O</jats:styled-content>rganization subtype with well‐differentiated, mucinous or trabecular patterns. It has frequent <jats:italic><jats:styled-content style="fixed-case">KRAS</jats:styled-content></jats:italic> or <jats:italic><jats:styled-content style="fixed-case">BRAF</jats:styled-content></jats:italic> mutations and a poor prognosis. This review provides an insight into the histology and molecular mechanisms driving these serrated pathway lesions.</jats:p>