TY - JOUR
T1 - Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis
AU - Fujita, Yusuke
AU - Matsuda, Sachiko
AU - Sasaki, Yasushi
AU - Masugi, Yohei
AU - Kitago, Minoru
AU - Yagi, Hiroshi
AU - Abe, Yuta
AU - Shinoda, Masahiro
AU - Tokino, Takashi
AU - Sakamoto, Michiie
AU - Kitagawa, Yuko
N1 - Funding Information:
This work was supported by an endowed chair from Chugai Pharmaceutical Co., Ltd to the Department of Surgery, Keio University School of Medicine, and by KAKENHI from the Japan Society for the Promotion of Science (Grant number 18K15094 to YM and 16H06279 to TT). We are grateful to the Fourth Laboratory of the Department of Pathology in Keio University School of Medicine for assistance with tissue processing and staining.
Publisher Copyright:
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.
AB - There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.
KW - multicentric occurrence
KW - multiple pancreatic cancers
KW - next-generation sequence
KW - pancreatic carcinogenesis
KW - pancreatic intraepithelial neoplasia
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U2 - 10.1111/cas.14268
DO - 10.1111/cas.14268
M3 - Article
C2 - 31799787
AN - SCOPUS:85078041760
SN - 1347-9032
VL - 111
SP - 739
EP - 748
JO - Cancer Science
JF - Cancer Science
IS - 2
ER -
