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.

胰腺的肠型导管内乳头状黏液性肿瘤（IPMN）在临床病理上是独特的。我们的研究旨在阐明肠型IPMN发生和发展的分子机制。在60例肠型IPMN标本中，有48例（80％）观察到了从胃型上皮向肠型上皮的组织学转变。CDX2 / MUC2 /阿尔辛蓝三重染色表明CDX2似乎先于MUC2表达和随后的阿尔辛蓝阳性粘蛋白生产。 CD21表达似乎促进了p21和Ki-67的表达（p = 6.02e-13和p 分别为3.1e-09）。p21 / Ki-67双重染色显示，p21主要在乳头顶部的分化细胞中表达，而Ki-67在乳头底部的增殖细胞中表达。这种明显的细胞排列似乎随着非典型等级的发展和侵袭的发展而破裂（p  = 0.00197）。肠道型IPMN具有频繁的GNAS突变（100％，25/25）和RNF43突变（57％，8/14），并且与并发的胃型IPMN或初期胃型瘤形成共享相同的GNAS和KRAS突变（100％， 25/25）。RNF43突变表明在肠道型肿瘤中出现或被选择，以及β-catenin畸变。在CDX2阳性肠型肿瘤中观察到蛋白激酶A和细胞外调节激酶的激活。这些结果表明，获得GNAS突变并诱导内在CDX2表达的胃型上皮细胞可能会随着克隆选择和包括RNF43和ß-catenin在内的其他分子畸变而演变成肠型IPMN，这可能由于复杂的绒毛状生长而进一步发展。失去方向的细胞周期调节，非典型等级的加速，并提前显示出侵袭性表型。