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01-07-2020 | Original Article

How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression

Authors: Yuko Omori, Yusuke Ono, Toshikazu Kobayashi, Fuyuhiko Motoi, Hidenori Karasaki, Yusuke Mizukami, Naohiko Makino, Yoshiyuki Ueno, Michiaki Unno, Toru Furukawa

Published in: Virchows Archiv | Issue 1/2020

Abstract

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.

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Title: How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression
Authors: Yuko Omori
Yusuke Ono
Toshikazu Kobayashi
Fuyuhiko Motoi
Hidenori Karasaki
Yusuke Mizukami
Naohiko Makino
Yoshiyuki Ueno
Michiaki Unno
Toru Furukawa
Publication date: 01-07-2020
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 1/2020
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-020-02806-8

At a glance: The STEP trials

Springer Medicine

How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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