Third, loss of CDX2 is specifically enriched in certain CRC subtypes coming from both ends of the spectrum of biological aggressiveness, ranging from indolent variants such as medullary carcinomas to highly aggressive subtypes such as MANEC/NECs, arguing that both MSI-status, as well as the histomorphologic subtype of CRC, have to be considered before CDX2 might be used for clinical decision-making. This evidence concerns the gene CDX2 and digestive system mixed adenoneuroendocrine carcinoma.