Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Abstract

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.

Peritoneal dissemination of pancreatic cancer caused by endoscopic ultrasound-guided fine needle aspiration: A case report and literature review

“…In the current case, some small peritoneal disseminations were observed that were discontinuous from the main lesion. Similar pathological findings and dismal prognoses have been observed in cases of intra-pancreatic metastasis or multi-centric carcinogenesis[ 36 , 37 ]. Therefore, if a small cancerous lesion is observed within the pancreatic parenchyma, it needs to be differentiated from needle tract seeding.…”

Combination of KRAS and SMAD4 mutations in formalin‐fixed paraffin‐embedded tissues as a biomarker for pancreatic cancer

“…In PDAC, the decreased expression of SMAD4 identified by the immunolabeling of resected specimens has been reported to be associated with poor prognosis 14,38‐40 . In NGS, SMAD4 mutations are considered a poor prognostic factor in the analysis of DNA extracts from resected PDAC cells purified from cell lines or xenografts, 21 whereas they were not a prognostic factor in the analysis of DNA extracts from FFPE or fresh‐frozen specimens. To our knowledge, the current study is the first to report SMAD4 mutations as a prognostic factor for PDAC in NGS analysis using DNA extracts from FFPE.…”

“…By analyzing DNA extracts from fresh‐frozen samples, Hayashi et al 20 revealed that the number of driver gene mutations could be a prognostic factor; however, certain gene mutations associated with prognosis were not detected. Based on NGS analysis using FFPE samples, we previously reported that multiple PDAC involves multicentric carcinogenesis and intrapancreatic metastasis, which could be distinguished by comparing driver gene mutations; the latter has a dismal prognosis 21 . According to the NCCN Guidelines of 2019, somatic mutational profiling of tumor tissue is recommended for PDAC 22 .…”

“…Based on NGS analysis using FFPE samples, we previously reported that multiple PDAC involves multicentric carcinogenesis and intrapancreatic metastasis, which could be distinguished by comparing driver gene mutations; the latter has a dismal prognosis. 21 According to the NCCN Guidelines of 2019, somatic mutational profiling of tumor tissue is recommended for PDAC. 22 In the future, it is expected that genetic tests from resected specimens will be routine for almost all cases of PDAC.…”

Urgent distal pancreatectomy for intraperitoneal hemorrhage due to the spontaneous rupture of a pancreatic metastatic tumor from synovial sarcoma: a case report

“…Tumors that metastasize to the pancreas include pancreatic cancer and other organ malignancies [15,16]. Tumor metastasis from other organs to the pancreas is rare and occurs in approximately 2% of pancreatic tumors [7].…”