• Cytology
• KRAS
• Pancreatic ductal adenocarcinoma
• Peritoneal washing fluid

• Humans
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/pathology
• Proto-Oncogene Proteins p21(ras)/genetics
• Male
• Female
• Aged
• Mutation
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/pathology
• Middle Aged
• Peritoneal Lavage
• Aged, 80 and over
• Ascitic Fluid/pathology
• ROC Curve
• Sensitivity and Specificity
• Adult

• cohort studies
• oncogenes
• outcome
• pancreatectomy
• pancreatic ductal adenocarcinoma

• Humans
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Mutation
• Carcinoma
• Smad4 Protein/genetics
• Smad4 Protein/metabolism
• Cyclin-Dependent Kinase Inhibitor p16/metabolism

• Daiwa Securities Health Foundation
• Japan Society for the Promotion of Science
• Pancreas Research Foundation of Japan
• Takeda Science Foundation

• Warburg effect
• glucose metabolism
• pancreatic ductal adenocarcinoma
• tumor microenvironment

Synchronous primary pancreatic ductal adenocarcinoma (PDAC) is very rare and can be formed either through multicentric carcinogenesis or intrapancreatic metastasis. We report the case of an 80-year-old man with a history of type 2 diabetes mellitus who presented with abdominal pain and weight loss. Laboratory tests showed elevated levels of blood glucose and CA 19-9, and Computed Tomography revealed two hypoenhancing lesions in the head and tail of the pancreas. Endoscopic ultrasound, which is the imaging method of choice for pancreatic cancer, was performed with a fine needle biopsy, and the cytological analysis diagnosed PDAC in both lesions. The patient underwent total pancreatectomy, and pathologic evaluation revealed synchronous primary PDAC with moderate to poor differentiation in the head and tail in the setting of IPMN (intraductal papillary mucinous neoplasia) and chronic pancreatitis. After his recovery from postoperative pulmonary embolism, the patient was discharged home with sufficient glycemic control. Multifocal PDAC occurs more often when precursor lesions, such as IPMN, pre-exist. The optimal treatment for multiple lesions spread all over the pancreas is total pancreatectomy. Diabetes mellitus is a serious complication of total pancreatectomy (new-onset or type 3c), but overall, long-term survival has been significantly improved.

• Humans
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/pathology
• Pancreas/diagnostic imaging
• Pancreas/pathology
• Endosonography
• Ultrasonography, Interventional
• Biopsy
• Endoscopic Ultrasound-Guided Fine Needle Aspiration

Pancreatic cancer is a highly malignant disease with treatment resistance to standardized chemotherapies. In addition, only a small fraction of patients with pancreatic cancer has, to date, actionable genetic aberrations, leading to a narrow therapeutic window for molecularly targeted therapies or immunotherapies. A lot of preclinical and translational studies are ongoing to discover potential vulnerabilities to treat pancreatic cancer. Histologically, human pancreatic cancer is characterized by abundant cancer-associated fibrotic stroma, called “desmoplastic stroma”. Recent technological advances have revealed that desmoplastic stroma in pancreatic cancer is much more complicated than previously thought, playing pleiotropic roles in manipulating tumor cell fate and anti-tumor immunity. Moreover, real-world specimen-based analyses of pancreatic cancer stroma have also uncovered spatial heterogeneity and an intertumoral variety associated with molecular alterations, clinicopathological factors, and patient outcomes. This review describes an overview of the current efforts in the field of pancreatic cancer stromal biology and discusses treatment opportunities of stroma-modifying therapies against this hard-to-treat cancer.

Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.

• Adenocarcinoma, Mucinous/pathology
• Carbohydrates
• Carcinoma, Pancreatic Ductal/pathology
• Humans
• Pancreatic Intraductal Neoplasms
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/pathology
• Retrospective Studies

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a biopsy technique widely used to diagnose pancreatic tumors because of its high sensitivity and specificity. Although needle-tract seeding caused by EUS-FNA has been recently reported, dissemination of pancreatic cancer cells is generally considered to be a rare complication that does not affect patient prognosis. However, the frequency of dissemination and needle-tract seeding appears to have been underestimated. We present a case of peritoneal dissemination of pancreatic cancer due to preoperative EUS-FNA.

An 81-year-old man was referred to the Department of Surgery of our hospital in Japan owing to the detection of a pancreatic mass on computed tomography during medical screening. Trans-gastric EUS-FNA revealed that the mass was an adenocarcinoma; hence laparoscopic distal pancreatectomy with lympha-denectomy was performed. No intraoperative peritoneal dissemination and liver metastasis were visually detected, and pelvic lavage cytology was negative for carcinoma cells. The postoperative surgical specimen was negative for carcinoma cells at the dissected margin and the cut end margin; however, pathological findings revealed adenocarcinoma cells on the peritoneal surface proximal to the needle puncture site, and the cells were suspected to be disseminated via EUS- FNA. Hence, the patient received adjuvant therapy with S-1 (tegafur, gimeracil, and oteracil potassium); however, computed tomography performed 5 mo after surgery revealed liver metastasis and cancerous peritonitis. The patient received palliative therapy and died 8 mo after the operation.

The indications of EUS-FNA should be carefully considered to avoid iatrogenic dissemination, especially for cancers in the pancreatic body or tail.

• Case report
• Pancreatic carcinoma
• Endoscopic ultrasound-guided fine needle aspiration
• Peritoneal dissemination
• Cancerous peritonitis
• Biopsy

• Adenocarcinoma/surgery
• Aged, 80 and over
• Endoscopic Ultrasound-Guided Fine Needle Aspiration/adverse effects
• Humans
• Japan
• Male
• Pancreatectomy/adverse effects
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/surgery

Synovial sarcoma is a soft tissue malignancy that frequently affects the extremities, adjacent to the large joints. Synovial sarcoma has a high rate of distant metastasis; however, pancreatic metastasis is extremely rare, and to our knowledge, there has been no report of bleeding due to spontaneous tumor rupture. This study reports the case of a patient with synovial sarcoma pancreatic metastasis causing tumor rupture and bleeding, which was successfully managed with emergent distal pancreatectomy.

A 27-year-old woman underwent extensive resection of the primary tumor and partial lung resection after chemotherapy for left femoral synovial sarcoma and multiple lung metastases 4 years prior. During the follow-up, a 35-mm tumor was noted in the pancreatic tail on abdominal computed tomography (CT), and no other distant metastases were detected via positron emission tomography CT. Laparoscopic distal pancreatectomy was scheduled for pancreatic metastasis of synovial sarcoma. However, before the scheduled pancreatectomy could be conducted, the patient visited the emergency department because of abdominal pain that occurred after consuming a small amount of alcohol, and CT showed ascites with high CT values and leakage of contrast media. She was diagnosed with intra-abdominal hemorrhage due to a ruptured metastatic pancreatic tumor, and an emergency operation was performed. In total, 1500 mL of blood was evacuated from the abdomen, and the bleeding pancreatic tail tumor was resected. Histopathological findings revealed synovial sarcoma metastasis and a ruptured tumor capsule, and tumor cells were observed in the hematoma. After discharge on postoperative day 18, the patient was carefully monitored and confirmed to be in relapse-free survival, without chemotherapy, at 6 months post-surgery.

While the rate of tumor growth varies depending on the grade of the tumor, the possibility of rupture should be considered even in metastatic pancreatic tumors. In the case of pancreatic tumor rupture with stable circulation, radiological evaluation for oncology is necessary, and primary resection may be compatible with resectable cases.

• Case report
• Distal pancreatectomy
• Intraperitoneal hemorrhage
• Metastatic pancreatic tumor
• Spontaneous rupture
• Synovial sarcoma

Formalin‐fixed paraffin‐embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We analyzed 50 cancer‐related gene mutations including driver genes in PDAC, using next‐generation sequencing (NGS) to clarify the association between gene mutations and prognosis. DNA was extracted from FFPE tissues obtained from 74 patients with untreated resectable PDAC who underwent surgery at our institution between 2013 and 2018. Fifty of the 74 patients with DNA extracts from FFPE samples suitable for NGS were analyzed. The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A. There were no cases of single SMAD4 mutations; its rate of coincidence with KRAS or TP53 mutations was 30% and 2%, respectively. The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse‐free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P = .014) and overall survival (OS; MST, 22.3 months vs. not reached, P = .048). On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77‐10.08; P = .001) and OS (HR 6.730; 95% CI, 1.93‐23.43; P = .003). The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.

• KRAS
• SMAD4
• next-generation sequencing
• pancreatic ductal adenocarcinoma
• prognosis

• multicentric occurrence
• multiple pancreatic cancers
• next-generation sequence
• pancreatic carcinogenesis
• pancreatic intraepithelial neoplasia