GRCh38 · COSMIC v94


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How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression.
Paper ID
Omori Y, Ono Y, Kobayashi T, Motoi F, Karasaki H, Mizukami Y, Makino N, Ueno Y, Unno M and Furukawa T
Department of Investigative Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai, 980-8575, Japan.
Virchows Archiv : an international journal of pathology, 2020
ISSN: 1432-2307
PMID: 32291497 (view at PubMed or Europe PMC)
Intestinal-type intraductal papillary mucinous neoplasm (IPMN) of the pancreas is clinicopathologically distinctive. Our research aimed to elucidate the molecular mechanism of the development and progression of the intestinal-type IPMN. In 60 intestinal-type IPMN specimens, histological transitions from gastric-type epithelia to intestinal-type epithelia were observed in 48 cases (80%). CDX2/MUC2/alcian blue triple staining indicated that CDX2 appeared to precede MUC2 expression and subsequent alcian blue-positive mucin production. Expression of p21 and Ki-67 seemed to be accelerated by CDX2 expression (p = 6.02e-13 and p = 3.1e-09, respectively). p21/Ki-67 double staining revealed that p21 was mostly expressed in differentiated cells in the apex of papillae, while Ki-67 was expressed in proliferative cells in the base of papillae. This clear cellular arrangement seemed to break down with the progression of atypical grade and development of invasion (p = 0.00197). Intestinal-type IPMNs harbored frequent GNAS mutations (100%, 25/25) and RNF43 mutations (57%, 8/14) and shared identical GNAS and KRAS mutations with concurrent gastric-type IPMNs or incipient gastric-type neoplasia (100%, 25/25). RNF43 mutations showed emerging or being selected in intestinal-type neoplasms along with ß-catenin aberration. Activation of protein kinase A and extracellular-regulated kinase was observed in CDX2-positive intestinal-type neoplasm. These results suggest that gastric-type epithelia that acquire GNAS mutations together with induction of intrinsic CDX2 expression may evolve with clonal selection and additional molecular aberrations including RNF43 and ß-catenin into intestinal-type IPMNs, which may further progress with complex villous growth due to disoriented cell cycle regulation, acceleration of atypical grade, and advance to show an invasive phenotype.
Paper Status