Masahiro Yamamoto, Noboru Ideno, Tomoki Nakafusa, Tomoyuki Araki, Shun Miura, Takashi Utsunomiya, Keiichi Shigematsu, Yuki Shimada, Takeo Yamamoto, Takaaki Fujimoto, Toshiya Abe, Yusuke Watanabe, Koji Tamura, Naoki Ikenaga, Kohei Nakata, Nao Fujimori, Nobuhiro Fujita, Kenoki Ohuchida, Hideya Onishi, Yoshihiro Ogawa, Kousei Ishigami, Shinichi Aishima, Yoshinao Oda
A subset of intraductal papillary mucinous neoplasms is characterized by a pancreatitis-associated biologic background defined by the PRSS1A16V germline variant and imaging features of early chronic pancreatitis. These findings suggest that microinflammatory processes may contribute to intraductal papillary mucinous neoplasm heterogeneity and highlight a potential link between pancreatitis-related genetic susceptibility and pancreatic neoplasia.
BACKGROUND: Intraductal papillary mucinous neoplasms of the pancreas are heterogenous lesions with variable malignant potential, suggesting underlying biologic diversity. Although inflammation has been implicated in pancreatic carcinogenesis, its contribution to intraductal papillary mucinous neoplasm biology remains poorly understood. We hypothesized that a subset of intraductal papillary mucinous neoplasms may arise in a pancreatitis-associated biologic background.
METHODS: Whole-exome sequencing was performed in 11 intestinal-type intraductal papillary mucinous neoplasms to explore unrecognized genetic alterations. The PRSS1 germline variant was subsequently validated by Sanger sequencing in 131 patients with intraductal papillary mucinous neoplasm and 50 control patients with pancreatic neuroendocrine neoplasms. Clinical features and imaging findings suggestive of early chronic pancreatitis were compared between variant carriers and noncarriers.
RESULTS: Whole-exome sequencing identified a pancreatitis-related germline mutation of PRSS1A16V as a candidate variant in intraductal papillary mucinous neoplasm. In the validation cohort, 12 of 131 patients with intraductal papillary mucinous neoplasm (9.2%) harbored the PRSS1A16V variant, whereas none of the controls did (P = .018). Clinicopathologic analysis revealed significantly higher frequencies of preoperative clinical symptoms (6/12, 50%; P = .041) and body weight loss (2/12, 16.7%; P = .0078) in the mutation-positive cohort. Imaging features suggestive of early chronic pancreatitis were observed more frequently in the mutation-positive cohort than in the mutation-negative cohort (6/12 [50%] vs 14/119 [11.8%]; P = .0031).
CONCLUSION: A subset of intraductal papillary mucinous neoplasms is characterized by a pancreatitis-associated biologic background defined by the PRSS1A16V germline variant and imaging features of early chronic pancreatitis. These findings suggest that microinflammatory processes may contribute to intraductal papillary mucinous neoplasm heterogeneity and highlight a potential link between pancreatitis-related genetic susceptibility and pancreatic neoplasia.