miR-4653-3p overexpression is associated with a poor prognosis of pancreatic ductal adenocarcinoma via HIPK2 downregulation.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant tumor. Several upregulated and downregulated microRNAs (miRNAs) are associated with invasiveness, tumorigenesis, and prognosis of PDAC. Herein, using in situ hybridization, we evaluated miR-4653-3p expression and pancreatic intraepithelial neoplasia (PanIN) and the association between miR-4653-3p expression and clinicopathological factors in PDAC patients. The miR-4653-3p target was also identified. Ninety PDAC cases, including 30 each with normal pancreatic ducts, low-grade PanINs, and high-grade PanINs, were evaluated. miR-4653-3p expression increased in the order-normal pancreatic duct, low-grade PanIN, high-grade PanIN, and PDAC-with no expression detected in normal pancreatic duct. High expression significantly correlated with advanced pathological T stage, lymph node metastasis, advanced Union for International Cancer Control stage, perineural invasion, venous involvement, and shorter overall and disease-specific survival. Homeodomain Interacting Protein Kinase 2 (HIPK2) was identified as a miR-4653-3p target based on mRNA microarray analysis and database screening. In MIA PaCa-2 cells, miR-4653-3p significantly downregulated HIPK2 expression. HIPK2 expression, unlike that of miR-4653-3p, decreased in the order-normal pancreatic duct, low-grade PanIN, high-grade PanIN, and PDAC. Low HIPK2 expression was associated with shorter overall and disease-specific survival in PDAC patients. Thus, miR-4653-3p associates with tumorigenesis and worse prognosis, partly by reducing HIPK2 expression.

Background features in the cytology of pancreatic neoplasms.

Cytology is a useful method for diagnosing pancreatic neoplasms. Although endoscopic ultrasound-guided fine-needle aspiration has recently become the mainstream method for the diagnosis of pancreatic neoplasms, pancreatic juice and pancreatic duct brushing cytology continue to be useful diagnostic methods for the investigation of pancreatic neoplasms. Diagnoses using pancreatic cytology are primarily based on the features related to tumor cells; however, evaluation of the background features provides important information that could further aid the diagnosis. Pancreatic neoplasms show various histological types, each of which is associated with its own characteristic background features. The necrotic background, desmoplastic stroma, and presence of cancer-associated fibroblasts are background features of pancreatic ductal adenocarcinoma, a mucinous background is associated with intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, and hyaline globules are observed in solid pseudopapillary neoplasms. However, some background features are associated with more than one histological type of pancreatic neoplasm, highlighting the importance to base a diagnosis on the results of a comprehensive analysis of not only the background features but also the tumor cells. Here, we provide a review of the key background cytological features of pancreatic neoplasms, which can serve as a guide to improve diagnosis and research.

Low expression of DDX5 is associated with poor prognosis in patients with pancreatic ductal adenocarcinoma.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC. METHODS: DDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival. RESULTS: The nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2-pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC. CONCLUSION: These results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis.

Hyalinized stroma is a characteristic feature of pancreatic intraductal oncocytic papillary neoplasm: An immunohistochemical study.

Hyalinized stroma (HS) is a dense, eosinophilic, and amorphous extracellular material in the stroma. HS is observed in several tumors; however, it has not been comprehensively studied in pancreatic intraductal papillary mucinous neoplasm (IPMN) or intraductal oncocytic papillary neoplasm (IOPN). Here, we aimed to evaluate the immunohistochemical and microscopic characteristics of HS in IPMN and IOPN. The prevalence of HS was determined in 168 cases of IPMN, including intestinal type (IPMN-I), gastric type (IPMN-G), and pancreatobiliary type (IPMN-PB), as well as in 11 cases of IOPN. Immunohistochemical staining for laminin and collagen (types I, II, III, IV, and V), as well as Congo red staining were performed in IPMN and IOPN cases containing HS. The prevalence of HS among the IPMN and IOPN specimens was 1.2% (2/168 cases) and 45.5% (5/11 cases), respectively. The prevalence rates of HS in each IPMN subtype were as follows: 2.2% (2/91 cases) in IPMN-G, and 0% in IPMN-PB and IPMN-I. All seven HS cases were positive for collagen I, III, IV, and V but were negative for Congo red staining. Most cases showed negative, focal, or weak expression of laminin and type II collagen. These findings indicate that HS is associated with IOPN and is primarily composed of collagen fibers.

Cancer-associated fibroblasts are a useful cytological finding for diagnosing pancreatic ductal adenocarcinoma.

INTRODUCTION: Cancer-associated fibroblasts (CAFs) are activated fibroblasts or myofibroblasts that play a crucial role in the invasiveness of pancreatic ductal adenocarcinoma (PDAC). In this study, the cytological features and diagnostic significance of CAFs based on pancreatic duct brushing cytology (PDBC) were evaluated. METHODS: The prevalence of fibrous stroma (FS) including CAFs on PDBC in 42 PDAC cases and 33 benign cases was retrospectively investigated. The average nuclear size of fibroblasts was compared between PDAC and benign cases to distinguish CAFs from normal FS. RESULTS: Overall, FS was observed in 25 PDAC cases (60%) and eight benign cases (24%). The average nuclear size of FS in PDAC cases was significantly larger than that in benign cases. From the receiver operating characteristics analysis, the cut-off value of the nuclear size of FS for the diagnosis of PDAC was defined as 10.22 µm. FS with nuclei over 10.22 µm in size in PDAC cases had clear prominent nucleoli. In contrast, FS in benign cases had no clear nucleoli. Thus, CAFs on PDBC were considered to be FS with nuclei over 10.22 µm in size and prominent nucleoli. The presence of CAFs on PDBC had 100% positive predictive value and specificity for the diagnosis of PDAC. CONCLUSIONS: This study suggested that CAFs on PDBC could be distinguished from normal FS by large nuclear size (over 10.22 µm) and prominent nucleoli and that CAFs on PDBC may be used for the diagnosis of PDAC.