Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in the enteric nervous system.

Inositol pyrophosphates regulate diverse physiological processes; to better understand their functional roles, assessing their tissue-specific distribution is important. Here, we profiled inositol pyrophosphate levels in mammalian organs using an originally designed liquid chromatography-mass spectrometry (LC-MS) protocol and discovered that the gastrointestinal tract (GIT) contained the highest levels of diphosphoinositol pentakisphosphate (IP7) and its precursor inositol hexakisphosphate (IP6). Although their absolute levels in the GIT are diet dependent, elevated IP7 metabolism still exists under dietary regimens devoid of exogenous IP7. Of the major GIT cells, enteric neurons selectively express the IP7-synthesizing enzyme IP6K2. We found that IP6K2-knockout mice exhibited significantly impaired IP7 metabolism in the various organs including the proximal GIT. In addition, our LC-MS analysis displayed that genetic ablation of IP6K2 significantly impaired IP7 metabolism in the gut and duodenal muscularis externa containing myenteric plexus. Whole transcriptome analysis of duodenal muscularis externa further suggested that IP6K2 inhibition significantly altered expression levels of the gene sets associated with mature neurons, neural progenitor/stem cells, and glial cells, as well as of certain genes modulating neuronal differentiation and functioning, implying critical roles of the IP6K2-IP7 axis in developmental and functional regulation of the enteric nervous system. These results collectively reveal an unexpected role of mammalian IP7-a highly active IP6K2-IP7 pathway is conducive to the enteric nervous system.

Prognostic Impact of Margin Status in Distal Cholangiocarcinoma.

BACKGROUND: A positive ductal margin is strongly associated with poor survival in patients with distal cholangiocarcinoma. However, the significance of the radial margin status and its effect on survival are not fully clarified. METHODS: All patients with distal cholangiocarcinoma who underwent pancreatoduodenectomy between January 2000 and December 2018 at Tokai University Hospital were retrospectively analyzed. Positive margins were divided into positive ductal margin and positive radial margin. RESULTS: One hundred and eight consecutive patients with distal cholangiocarcinoma underwent pancreatoduodenectomy. Margin-negative R0 resection was performed in 85 patients (79%). Twenty-three patients (21%) had a positive resection margin (R1 resection). The 5-year survival rate and median overall survival for patients with R0 resection and those with R1 resection was 64%, 98 months and 25%, 26 months, respectively. There was a significant difference in survival between patients with R0 resection and those with R1 resection (p < 0.001). Patients with positive radial margin (n = 10) had a significantly worse outcome than those with positive ductal margin (n = 13) (p = 0.016). Univariate analysis showed that R1 resection, lymph node metastasis, tumor depth, portal vein invasion, pancreatic invasion, lymphatic invasion, and venous invasion were significant prognostic factors. Multivariate analysis confirmed that R1 resection and nodal involvement were significant independent prognostic indicators after surgical resection for distal cholangiocarcinoma. CONCLUSIONS: Positive surgical margin and nodal involvement were the strongest predictors of poor survival in patients with distal cholangiocarcinoma. Patients with a positive radial margin had a significantly worse outcome than those with a positive ductal margin.

Prognostic Impact of Positive Peritoneal Lavage Cytology on Resectable Pancreatic Body and Tail Cancer: A Retrospective Study.

BACKGROUND: The prognostic impact of positive peritoneal lavage cytology on pancreatic cancer is unclear. Therefore, this study aimed to evaluate its impact in resectable pancreatic body and tail cancer. METHODS: Between January 2006 and December 2019, 97 patients with pancreatic body and tail cancer underwent peritoneal lavage cytology and curative resection at our institution. We analyzed the impact of positive peritoneal lavage cytology on clinicopathological factors and on the prognosis of pancreatic body and tail cancer. RESULTS: Malignant cells were detected in 14 patients (14.4%) using peritoneal lavage cytology. In these patients, the tumor diameter was significantly larger (p < 0.001) and anterior serosal invasion (p = 0.034), splenic artery invasion (p = 0.013), lympho-vessel invasion (p = 0.025), and perineural invasion (p = 0.008) were significantly more frequent. The R1 resection rate was also significantly higher in patients with positive peritoneal lavage cytology than in negative patients (p = 0.015). Positive peritoneal lavage cytology had a significantly poor impact on overall survival (p = 0.001) and recurrence-free survival (p < 0.001). This cytology was also an independent poor prognostic factor for recurrence (p = 0.022) and was associated with peritoneal dissemination and liver metastasis. CONCLUSIONS: Positive peritoneal lavage cytology is considered to be indicative of more systemic disease in patients with resectable pancreatic body and tail cancer than in patients with negative peritoneal lavage cytology. Early detection of pancreatic cancer before it develops micrometastases is important to improve prognosis, and CY+ patients require more intensive multimodality treatment than standard treatment for resectable pancreatic cancer.

Prediction of visceral pleural invasion of clinical stage I lung adenocarcinoma using thoracoscopic images and deep learning.

PURPOSE: To develop deep learning models using thoracoscopic images to identify visceral pleural invasion (VPI) in patients with clinical stage I lung adenocarcinoma, and to verify if these models can be applied clinically. METHODS: Two deep learning models, one based on a convolutional neural network (CNN) and the other based on a vision transformer (ViT), were applied and trained via 463 images (VPI negative: 269 images, VPI positive: 194 images) captured from surgical videos of 81 patients. Model performances were validated via an independent test dataset containing 46 images (VPI negative: 28 images, VPI positive: 18 images) from 46 test patients. RESULTS: The areas under the receiver operating characteristic curves of the CNN-based and ViT-based models were 0.77 and 0.84 (p = 0.304), respectively. The accuracy, sensitivity, specificity, and positive and negative predictive values were 73.91, 83.33, 67.86, 62.50, and 86.36% for the CNN-based model and 78.26, 77.78, 78.57, 70.00, and 84.62% for the ViT-based model, respectively. These models' diagnostic abilities were comparable to those of board-certified thoracic surgeons and tended to be superior to those of non-board-certified thoracic surgeons. CONCLUSION: The deep learning model systems can be utilized in clinical applications via data expansion.

Whole-genome copy number and immunohistochemical analyses on surgically resected intracholecystic papillary neoplasms.

Intracholecystic papillary neoplasms are newly defined precancerous lesions. According to Classification of the World Health Organization, they have four histological morphologies, which are biliary, gastric, intestinal, and oncocytic. This study evaluated 17 patients with resected intracholecystic papillary neoplasms in terms of histological, immunohistochemical, and copy number variation (CNV). The histological subtypes included 5 cases of low-grade (5 gastric) and 12 cases of high-grade (6 gastric and 6 biliary) neoplasms. Most cases showed high expression of MUC1, MUC5AC, and CK7, moderate expression of MUC6 and Ki-67, and low expression of CK20, MUC2, and CDX2. The CNV profile identified gain of 7q in 12%, and loss of 1p (18%), 5q (29%), 9p (35%), 12p (17%), 17p (24%), and 19p (18%). No CNVs were observed in low-grade neoplasms, whereas high-grade ones had increasing abnormalities. ß-catenin was often expressed in the nucleus of neoplasms with gastric morphology, suggesting the involvement of the Wnt/ß-catenin pathway. However, it was not expressed among those with biliary morphology, which instead exhibited high p53 expression. Neoplasms with biliary morphology showed more CNV changes (9p, 17p, 19p losses). Distinct immunological and CNV patterns were seen in both morphologies, suggesting differences in their pathogenesis. More CNVs accumulated with tumor progression.

Combined primary hepatic neuroendocrine carcinoma and hepatocellular carcinoma: case report and literature review.

BACKGROUND: Hepatocellular carcinoma (HCC) can grow in a mosaic pattern, often combined with various non-hepatocellular cells. However, HCC combined with a neuroendocrine carcinoma (NEC) component is rarely reported, and its clinical features, origin, diagnosis, and behavior have not been established. In the literature, mixed HCC-NEC tumors are categorized as either collision type or combined type, depending on their microscopic features. Here, we report a patient with a combined-type HCC-NEC tumor. CASE PRESENTATION: An asymptomatic 84-year-old woman was found to have a solid mass in the right lobe of the liver. Laboratory and radiologic examinations showed typical findings of HCC, including arterial-phase enhancement, and portal- and delay-phase washout. She was treated by partial laparoscopic hepatectomy of segment 5. Pathological examination showed that the tumor was predominantly HCC, partly admixed with an NEC component. A transitional zone between the HCC and NEC tissues was also observed. The tumor was finally diagnosed as a combined-type primary mixed NEC-HCC tumor. After the preoperative diagnosis, the patient underwent somatostatin receptor scintigraphy to detect the primary NEC lesion, but no accumulation was found in any other part of her body. She has been free of recurrence for 9 months since the surgery. CONCLUSION: Mixed HCC-NEC tumors are extremely rare, and correct diagnosis requires multidisciplinary collaboration. The accumulation of further cases is needed to help understand the exact pathology, diagnosis, and treatment of this disease.

The significance of tyrosine kinase receptor B and brain-derived neurotrophic factor expression in salivary duct carcinoma.

Salivary duct carcinoma (SDC) is a high-grade salivary gland neoplasm. It may occur de novo or secondarily from pleomorphic adenoma (ex-PA), with secondary development accounting for more than 50% of the cases. In recent years, the expression of tyrosine kinase receptor B (TrkB), which is in the same family as HER2, has been confirmed in various types of carcinomas. However, there are a few studies on SDC. In order to examine the expression and role of TrkB in SDC, we investigated it. Immunohistochemistry was used to detect the expression of TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in 20 patients with SDC. The mRNA levels of TrkB, BDNF, and NT-4 were analyzed using quantitative polymerase chain reaction. TrkB was negative in 10 cases and positive in 10 cases, BDNF was negative in 11 cases and positive in 9 cases, and NT-4 was positive in all cases. There was a high number of TrkB-positive cases in the pT4 group and The H-score of TrkB was also significantly higher in the stage III and IV groups. There was a high number of BDNF-positive cases in the ex-PA group and Histo-score of BDNF had a trend of high expression in ex-PA. There were no significant differences or correlations in mRNA expression. Our results suggest that TrkB may be involved in SDC tumor growth.

[A case of simultaneous multicentric cancer in the gallbladder duct and the common bile duct without pancreaticobiliary maljunction].

A 68-year-old man who underwent cholecystectomy for acute cholecystitis and was diagnosed with gallbladder duct carcinoma was referred to our hospital. Postoperative computed tomography showed thickening of the middle to lower bile duct without any tumorous lesions. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography revealed irregular wall thickening of the lower bile duct and apparent infiltration of gallbladder duct tumor to the common bile duct without pancreaticobiliary maljunction. Subtotal stomach-preserving pancreaticoduodenectomy was performed. Pathological examination showed papillary adenocarcinoma and tubular adenocarcinoma in the gallbladder duct and BilIN-3 lesion in the distal bile duct. The final diagnosis was biliary simultaneous multicentric cancer without pancreaticobiliary maljunction.

Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas.

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Loss of nectin-3 expression as a marker of tumor aggressiveness in pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (PanNETs) are rare, and prediction of aggressive characteristics, such as recurrence and metastasis and prognosis of PanNETs remain difficult. Nectins are cell adhesion molecules that regulate the formation of adherens and tight junctions. In this study, we investigated the clinicopathological significance of nectin-3 expression in patients with PanNETs. Immunohistochemical analysis of nectin-3 expression was performed on 78 cases of PanNET. Low nectin-3 expression in the membrane (positive ratio ≤25%) was observed in 62 cases (79.5%) and was significantly correlated with larger tumor size (>20 mm; P = 0.003), G2/G3 tumors (P = 0.025), higher Ki67 labeling index (≥3%; P = 0.009), lymphatic involvement (P = 0.047), advanced pT-factor (T2-T4; P = 0.003), lymph node metastasis (P = 0.006), advanced Union for International Cancer Control/American Joint Committee on Cancer-stage (Stage II-IV; P = 0.001), advanced ENETS stage (Stage IIa-IV; P = 0.001), nonfunctioning tumors (P = 0.002), and a shorter disease-free survival (P = 0.019). However, there was no significant correlation between nectin-3 expression in the membrane and/or cytoplasm and the clinicopathological parameters. The present results suggest that decreased nectin-3 expression in the membrane is associated with increased tumor aggressiveness of PanNETs. Clinically, immunohistochemical analysis of nectin-3 may help predict tumor aggressiveness for PanNETs.

Guidance for diagnosing autoimmune pancreatitis with biopsy tissues.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

Lung metastases from intraductal papillary neoplasm of the bile duct: a case report.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is considered a pre-cancerous biliary lesion and/or an early cancer lesion, although its classification remains unclear. The 2019 revised edition of the World Health Organization Classification of Tumors of the Digestive System proposed type 1 and type 2 as new classification categories, and meta-analyses and/or multi-center cohort studies are beginning to be reported. However, treatment for IPNB recurrence and metastasis remains unclear. CASE PRESENTATION: A 60-year-old man who was referred to our hospital after a suspected liver tumor was diagnosed using abdominal ultrasonography. Imaging findings revealed an irregularly shaped tumor in segment 5 (S5) of the liver (size 20 mm). The S5 lesion was suspected as IPNB, and segmentectomy was performed. The pathological findings revealed invasive carcinoma derived from IPNB, and immunohistochemistry revealed positive expression of MUC1, MUC5AC, and MUC6, but negative expression of CDX2 and MUC2. At 9 months after the surgery, computed tomography revealed a tumor in the right bile duct, which was diagnosed as liver recurrence of IPNB, and right hepatectomy was performed. The histopathological findings were the same as for the first resected specimen (i.e., IPNB). At 45 months after the second surgery, computed tomography revealed nodules in both lungs, which were diagnosed as lung metastases from IPNB and resected in two separate procedures. The pathological findings were metastatic carcinoma from IPNB for both lung lesions. The patient is currently alive and undergoing adjuvant chemotherapy (S-1), which was initiated 64 months after the first resection and 12 months after resection of the lung metastases. CONCLUSION: We encountered a rare case of lung metastases from IPNB, which were diagnosed immunohistologically. Because IPNB is generally a slow-growing tumor, resection may be feasible for IPNB recurrence and/or metastasis, which may be detected during long-term follow-up. Thus, even if resection is performed for primary IPNB, additional surgical treatment may be feasible in this setting.

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.

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.

Histological and immunohistochemical analyses of splenic epidermoid cysts.

Splenic epidermoid cyst (SEC) is a rare condition. We aimed to evaluate the immunohistochemical profiles of the epithelial lining of SECs. A total of 7 SEC cases were analyzed: 2 cases involved a monolayered epithelial lining and 5 cases involved a multilayered epithelial lining. Among the multilayered SECs, the superficial/luminal layer showed mucin 4 (MUC4), cytokeratin 5/6 (CK5/6), and CK7 expression in 5 cases (100%); MUC1, carcinoembryonic antigen (CEA), CA19-9, and thrombomodulin expression in 4 cases (80%); Wilms' tumor-1 (WT-1) and Hector Battifora mesothelial-1 (HBME-1) expression in 2 cases (40%), but it did not express p63 or D2-40. The basal layer expressed MUC1, CK5/6, p63, and thrombomodulin in 5 cases (100%); CK7 and WT-1 in 4 cases (80%); D2-40 in 3 cases (60%); CA19-9 and HBME-1 in 2 cases (40%) and MUC4 in 1 case (20%) but it did not express CEA. The analysis showed that all cases of multilayered SECs were negative for MUC2, MUC5AC, MUC6, CK20, calretinin, uroplakin-II, and uroplakin-III. Both cases of monolayered SECs expressed CK5/6, CK7, HBME-1, WT-1, and thrombomodulin but not MUC2, MUC4, MUC5AC, MUC6, p63, CEA, CK20, CA19-9, D2-40, uroplakin-II, or uroplakin-III. One case of monolayered SEC expressed MUC1 and calretinin. Our findings indicate that monolayered SECs have mesothelial-like characteristics, whereas multilayered SECs have glandular and squamous-like characteristics besides mesothelial-like characteristics. Furthermore, monolayered SECs may develop from mesothelial inclusion and monolayered SECs develop squamous and glandular metaplasia, which results in multilayered SECs.

Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma.

PURPOSE: Nectin-1 is a cell adhesion molecule that regulates the formation of adherens junctions and tight junctions. We measured the expression of nectin-1 in cancer-associated fibroblasts (CAFs) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Nectin-1 expression was measured via immunohistochemistry using tissue microarray blocks constructed from resected PDAC tissue from 258 patients. We screened for associations between nectin-1 expression and clinicopathological parameters. According to the percentage of CAFs stained, expression was classified as negative at ≤ 30% and positive at > 30%. RESULTS: Nectin-1 expression was confirmed in CAFs from 64 patients (24.8%), and was associated with lymph node metastasis (p = 0.016), advanced Union for International Cancer Control stage (p = 0.016), perineural invasion (p = 0.022), pancreatic head tumors (p = 0.023), and shorter overall survival (p = 0.003). Multivariate analysis revealed that nectin-1 expression in CAFs was an independent prognostic factor (p = 0.038). CONCLUSIONS: Diffuse nectin-1 expression in the CAFs of PDAC patients is associated with invasion, metastasis, and shorter survival.

Molecular alterations in sporadic pancreatic neuroendocrine microadenomas.

BACKGROUND: Pancreatic neuroendocrine microadenomas (pNEMAs) are neuroendocrine tumors measuring <5 mm in diameter. They are considered the precursor of pancreatic neuroendocrine tumors (pNETs). The aim of this study was to investigate the immunohistochemical differences between pNEMA, pNET, and hyperplasia of pancreatic islet cells (HPIL) in patients with non-familial syndromes. METHODS: We evaluated 21 pNEMAs, 19 HPILs, and 21 non-functional pNETs (10 G1 and 11 G2 cases) in patients with non-familial syndromes. Immunohistochemistry for tumor-associated markers death domain-associated protein (DAXX), alpha thalassemia/mental retardation X-linked (ATRX), cytokeratin 19 (CK19), bcl-2, and CD99 was performed. RESULTS: DAXX was expressed in 95%, 71%, and 71% of HPIL, pNEMA, and pNET samples, respectively; the differences were not significant. ATRX expression in pNEMA and pNET was significantly lower than that in HPIL, whereas there was no significant difference between pNEMA and pNET (HPIL: 95%, pNEMA: 43%, and pNET: 52%). All HPIL and pNEMA cases were negative for bcl-2 and positive for CD99, whereas 29% of pNETs were positive for bcl-2 and 24% were negative for CD99. CK19 expression in HPIL was significantly lower than in pNEMA and pNET, although no significant difference was observed between pNEMA and pNET (HPIL: 5%, pNEMA: 57%, and pNET: 43%). Among G1 and G2 pNETs, CD99 was expressed in 50% of G1 pNETs but not in any G2 pNET cases. CONCLUSION: Non-familial HPIL, pNEMA, and pNET patients exhibit distinct ATRX, CD99, CK19, and bcl-2 molecular profiles.

Bone morphogenetic protein-2 expression in an intraductal papillary mucinous neoplasm with marked ossification: A case report.

Intratumoral ossification has been reported in a number of epithelial tumors, but its presence in intraductal papillary mucinous neoplasms (IPMNs) is very rare. Herein, we present a rare case of IPMN with marked ossification. A 56-year-old Japanese man was under follow-up for a previously diagnosed IPMN. Seven years later, he was found to have dilatation of the main pancreatic duct and an enlarged solid mass, for which pancreaticoduodenectomy was performed. Macroscopically, multiple and cystically dilated pancreatic branch ducts, as well as a dilated main pancreatic duct, were identified. There was a solid, polypoid hard mass measuring 15 × 12 mm in the cystically dilated branch of the duct in the pancreatic head. Histological examination revealed papillary proliferation of atypical cuboidal or columnar epithelial cells in the dilated main and branch pancreatic ducts. The solid mass included an invasive adenocarcinoma component with a tubular or trabecular structure that showed pronounced ossification. We diagnosed the patient with invasive IPMN accompanied by marked ossification. Immunohistochemically, tumor cells in both the non-invasive and invasive lesions expressed bone morphogenetic protein-2 (BMP-2). While the mechanism of intratumoral ossification is unclear, it may have involved BMP-2 in the present case.

Nectin expression in pancreatic adenocarcinoma: nectin-3 is associated with a poor prognosis.

PURPOSE: Nectins are cell adhesion molecules that regulate the formation of adherens junctions and are linked with E-cadherin-based cell-cell adherens junctions. In pancreatic cancer, the expression of E-cadherin and nectins is considered to be related to metastasis, invasion and prognosis. METHODS: We evaluated the distribution of cells that were positive for nectin subtypes and E-cadherin using immunohistochemistry in specimens of human pancreatic adenocarcinoma, and correlated these results with the clinicopathological features and patient outcomes. RESULTS: The immunohistochemical distribution of nectin-1 and E-cadherin showed a good correlation (r = 0.523, p < 0.01). Tumors over 4 cm in diameter had more intense staining for nectin-4 than smaller tumors (p = 0.035). Nectin-2 expression correlated with a poorer histological grade (p = 0.04). The cases that showed diffuse nectin-3 expression had a better prognosis than those with negative expression (p = 0.018). CONCLUSION: Our results showed that the expression of nectin-3 in pancreatic cancer can be a prognostic factor.