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The patient was an elderly man in his early 80s who was admitted to our hospital due to anemia and tarry stools. An upper gastrointestinal endoscopy revealed a type 2 tumor in the second portion of the duodenum. An endoscopic biopsy revealed poorly differentiated adenocarcinoma. We performed a pancreaticoduodenectomy because neither lymphadenopathy nor distant metastases were found. Macroscopic findings revealed that the lesion was mainly in the second portion of the duodenum, and there was no evidence of invasion of the main pancreatic duct, the bile duct, or the ampulla of Vater. Histologically, the tumor was composed of atypical cells with polymorphic or spindle-shaped nuclei proliferating in a scattered fashion, and immunohistological examinations showed weakly positive results for cytokeratin(CK)AE1/AE3 and CK20 and positive results for vimentin but negative results for CK7. The tumor was diagnosed as undifferentiated carcinoma of the duodenum(pT4N0M0, pStage ⅡB). The patient recovered enough to be discharged and was followed up without postoperative adjuvant chemotherapy. He maintained recurrence-free survival for 27 months, after which lymph node and lung metastases reoccurred. This is a rare case of undifferentiated carcinoma of the duodenum treated by curative resection with a relatively favorable prognosis.

Background/aim: Sulphite oxidase (SUOX) is a metalloenzyme that catalyses ATP synthesis via oxidative phosphorylation in the mitochondria. Although SUOX has been reported to affect the invasiveness and differentiation of cancer cells, its clinicopathological significance in pancreatic adenocarcinoma (PDAC) remains unclear. In this study, we investigated the utility of SUOX expression as a prognostic factor in PDAC., Patients and Methods: This study included 56 patients with PDAC who underwent pancreatic resection at the Kurume University Hospital between 2014 and 2018. SUOX immunohistochemistry was evaluated using tissue microarray specimens from patients. Patients were classified into a high SUOX expression group (≥10% of cells stained) or a low SUOX expression group (<10% of cells stained), and the associations of SUOX with clinicopathological characteristics and survival were analysed. Statistical analysis was performed using Cox regression analysis, the Kaplan-Meier method, and log-rank test., Results: SUOX was expressed in the cytoplasm of normal pancreatic ductal epithelium, pancreatic acinar cells, and islets of Langerhans. Although we did not find any significant correlation between SUOX expression and clinicopathological factors, SUOX was identified as an independent prognostic factor based on univariate and multivariate analyses. Pathological stage was also an independent prognostic factor. The high SUOX expression group showed a significantly poorer prognosis than the low SUOX expression group (p=0.018)., Conclusion: SUOX-mediated mitochondrial metabolism in PDAC may be a factor influencing prognosis and SUOX may be a potential novel prognostic biomarker., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.

A 43-year-old woman who underwent surgical resection of invasive ductal carcinoma in the left breast at the age of 37 years old presented at our hospital for evaluation of pancreatic tumor. The original tumor was estrogen receptor(ER)progesterone receptor(PgR)and HER2 positive. At that time, she underwent radical mastectomy with no evident nodal disease. Postoperatively, the patient was placed on adjuvant tamoxifen therapy for several years. Six years following the original diagnosis of breast cancer, she was referred to the hospital for routine check-up while asymptomatic. Follow-up examination showed a solitary hypodense mass approximately 0.9 cm in size in the pancreas body on dynamic CT scan. The patient underwent a standard distal pancreatectomy with standard regional lymphadenectomy. Histopathological examination and immunohistochemical features revealed that the tumor was compatible with metastatic pancreatic adenocarcinoma from breast cancer.

Copy number gain (CNG), which includes both numerical and structural chromosomal abnormalities, has been investigated in many human cancers. We report a case of recurrence of anaplastic lymphoma kinase (ALK) rearrangement-positive lung adenocarcinoma with increased cellular pleomorphism and ALK copy number in pleural effusion cytology, and retrospectively compared the recurrent tumor with the primary tumor in terms of cytological features, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The patient was a woman in her 50s who was found to have a 20 × 20 mm sized mass in the lung by chest computed tomography (CT), and was diagnosed with ALK rearrangement-positive lung adenocarcinoma. The patient was administered ALK inhibitors, such as alectinib, however 4 years later dissemination to the pleural effusion was detected. The smear was of high cellularity, and a predominant population of large-sized pleomorphic adenocarcinoma cells with prominent nucleoli was observed. On FISH and IHC using cell block material, ALK rearrangement and ALK protein expression were identified again, along with recurrent ALK adenocarcinoma cells, which were observed to have an increased ALK copy number compared with the primary ALK adenocarcinoma cells. On the other hand, there was no discrepancy in the expression of various biomarkers between the primary and corresponding recurrent tumor. The present case showed a marked difference in cytological findings and CNG between the primary and recurrent tumor, indicating that DNA aneuploidy may be related to morphological change such as transformation to bizarre pleomorphic cells in patients receiving alectinib treatment., (© 2018 Wiley Periodicals, Inc.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis. However, the molecular mechanisms underlying the development of PDAC remain elusive. The aim of this study was to identify genes whose expressions are correlated with a poor prognosis in PDAC patients, and to unravel the mechanisms underlying the involvement of these genes in the development of the cancer., Methods: Global gene expression profiling was conducted in 39 specimens obtained from Japanese patients with PDAC to identify genes whose expressions were correlated with a shorter overall survival. The effect of gene silencing or overexpression of ARHGEF15 in pancreatic cancer cell lines was examined by introducing siRNAs of ARHGEF15 or the ARHGEF15 expression vector. After assessing the effect of ARHGEF15 deregulation on the Rho-family proteins by pull-down assay, wound healing, transwell and cell viability assays were carried out to investigate the cellular phenotypes caused by the perturbation., Results: The global mRNA expression profiling revealed that overexpression of ARHGEF15, a Rho-specific GEF, was significantly associated with a poor prognosis in patients with PDAC. We also found that the depletion of ARHGEF15 by RNA interference in pancreatic cancer cell lines downregulated the activities of molecules of the Rho signaling pathway, including RhoA, Cdc42 and Rac1. Then, we also showed that ARHGEF15 silencing significantly reduced the motility and viability of the cells, while its overexpression resulted in the development of the opposite phenotype in multiple pancreatic cancer cell lines., Conclusion: These data suggest that upregulation of ARHGEF15 contributes to the development of aggressive PDAC by increasing the growth and motility of the pancreatic cancer cells, thereby worsening the prognosis of these patients. Therefore, ARHGEF15 could serve as a novel therapeutic target in patients with PDAC.

Background and Aim: Diagnosis of the bile duct cancer still needs more accuracy. Studies on endoscopic retrograde cholangiopancreatography (ERCP)-guided brushing cytology were carried to evaluate the role of the endoscopic transpapillary brushing cytology for the diagnosis of bile duct cancer., Patients and Method: The study involved 76 consecutive patients who underwent ERCP-guided bile duct cytology for the diagnosis of bile duct cancer from 2008 to August 2012. Three types of cytological specimens were obtained using different sampling methods, i.e., bile aspiration cytology (BAC), brush tip cytology (BTC), and post brushing bile cytology (PBC), to investigate their diagnostic abilities, and comparatively studied with each macroscopic type of the surgically resected specimens., Results: The cancer-positive rate was 67.1 % (BAC alone: 41.9 %), and the use of BTC and PBC in addition to BAC yielded a statistically significant increase of the cancer-positive rate (p = 0.0031). In 34 resected cases, the cancer-positive rate in relation to the macroscopic type was improved by the addition of BTC and PBC to BAC alone for the papillary (87.5 vs. 40.0 %, p = 0.071) and nodular (100 vs. 70.0 %, p = 0.0603) types, but not for the flat type (62.5 vs. 57.1 %; p = 0.7651)., Conclusion: The diagnostic ability of ERCP-guided brushing cytology could be improved by the addition of PBC. However, the cancer-positive rate was the lowest for the flat type of bile duct cancer.

Background/purpose: By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD)., Methods: Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients., Results: All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward., Conclusions: Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.

Background: Insulinoma‐associated protein 1 (INSM1) has been reported to be a useful marker for diagnosing pancreatic neuroendocrine tumours (PNETs). However, INSM1 expression in endoscopic ultrasound‐guided fine needle aspiration cytology has not been examined. We evaluated INSM1 expression in the cytology of cases diagnosed with PNETs. Methods: We immunocytochemically stained INSM1 and Ki‐67 in 14 PNET cases, and according to the 2017 World Health Organisation criteria, seven PNET Grade 1 cases, four Grade 2 cases and three Grade 3/neuroendocrine carcinoma cases were identified. As a control for INSM1 and Ki‐67 expression, we used cytological specimens from 15 cases of pancreatic ductal adenocarcinoma. Results: In PNET cases, INSM1‐expressing tumour cells were identified in all cytological specimens of PNET. The median INSM1 expression rate in Grade 1 cases was 49.8% (mean ± standard deviation: 55.1 ± 12.5%, min: 39.3%, max: 74.1%), and in Grade 2 and Grade 3/neuroendocrine carcinoma cases was 81.1% (mean ± standard deviation: 77.6 ± 18.6%, min: 50.3%, max: 100%). However, there was no correlation between INSM1 and Ki‐67 expression (r = −0.15). The median expression rate in PNET cases was 64.3%, which was significantly higher than that in pancreatic ductal adenocarcinoma cases (P < 0.0001). Conclusion: INSM1 immunocytochemistry of cytological specimens obtained from endoscopic ultrasound‐guided fine needle aspiration cytology can accurately diagnose PNETs; therefore, INSM1 could be an important diagnostic tool in assessing therapeutic strategies, including molecular‐targeted therapy. Recently, neuroendocrine markers such as SYP, CGA, and NCAM have been used with high specificity and sensitivity for PNETs. However, there are similarities in cell structure and immunocytochemistry between pancreatic solid tumors. We reported INSM1 positivity in all histological specimens of PNETs examined including high grade PNETs. This can be considered a useful biomarker. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. [ABSTRACT FROM AUTHOR]