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Pancreatic Neoplasms: HELP
Articles by Michaël Noë
Based on 11 articles published since 2010
(Why 11 articles?)
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Between 2010 and 2020, Michaël Noë wrote the following 11 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review A "Clearer" View of Pancreatic Pathology: A Review of Tissue Clearing and Advanced Microscopy Techniques. 2019

Hong, Seung-Mo / Noë, Michaël / Hruban, Carolyn A / Thompson, Elizabeth D / Wood, Laura D / Hruban, Ralph H. ·Departments of Pathology. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD. ·Adv Anat Pathol · Pubmed #30256228.

ABSTRACT: Although pathologic lesions in the pancreas are 3-dimensional (3D) complex structures, we currently use thin 2D hematoxylin and eosin stained slides to study and diagnose pancreatic pathology. Two technologies, tissue clearing and advanced microscopy, have recently converged, and when used together they open the remarkable world of 3D anatomy and pathology to pathologists. Advances in tissue clearing and antibody penetration now make even dense fibrotic tissues amenable to clearing, and light sheet and confocal microscopies allow labeled cells deep within these cleared tissues to be visualized. Clearing techniques can be categorized as solvent-based or aqueous-based techniques, but both clearing methods consist of 4 fundamental steps, including pretreatment of specimens, permeabilization and/or removal of lipid, immunolabeling with antibody penetration, and clearing by refractive index matching. Specialized microscopes, including the light sheet microscope, the 2-photon microscope, and the confocal microscope, can then be used to visualize and evaluate the 3D histology. Both endocrine and exocrine pancreas pathology can then be visualized. The application of labeling and clearing to surgically resected human pancreatic parenchyma can provide detailed visualization of the complexities of normal pancreatic anatomy. It also can be used to characterize the 3D architecture of disease processes ranging from precursor lesions, such as pancreatic intraepithelial neoplasia lesions and intraductal papillary mucinous neoplasms, to infiltrating pancreatic ductal adenocarcinomas. The evaluation of 3D histopathology, including pathology of the pancreatic lesions, will provide new insights into lesions that previously were seen, and thought of, only in 2 dimensions.

2 Review Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature. 2018

Groot, Vincent P / Thakker, Sameer S / Gemenetzis, Georgios / Noë, Michaël / Javed, Ammar A / Burkhart, Richard A / Noveiry, Behnoud B / Cameron, John L / Weiss, Matthew J / VandenBussche, Christopher J / Fishman, Elliot K / Hruban, Ralph H / Wolfgang, Christopher L / Lennon, Anne Marie / He, Jin. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Surgery, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jhe11@jhmi.edu. ·HPB (Oxford) · Pubmed #29530477.

ABSTRACT: BACKGROUND: Lymphoepithelial cysts (LECs) are rare pancreatic cystic lesions. Since LECs are benign, preoperative diagnosis is important to differentiate from a cystic neoplasm and avoid unnecessary surgery. The aim of this study was to identify clinical, radiographic and cytopathologic features associated with LECs. METHODS: A retrospective review was performed of patients diagnosed with LEC between 1995 and 2017 at our hospital. Clinicopathologic and radiographic imaging features were documented. RESULTS: Of 29 patients with pancreatic LEC, 22 underwent surgical resection. The majority were male (n = 24) with a median age of 55 years (range, 21-74). During the evaluation, all patients underwent a CT, with endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) biopsy (n = 22) and/or MRI/MRCP (n = 11) performed in a smaller number of patients. A combination of exophytic tumor growth on imaging and the presence of specific cytomorphologic features on the EUS-FNA cytology biopsy led to the correct diagnosis of LEC and prevention of unnecessary surgery in 7 patients. DISCUSSION: Differentiating LECs from premalignant pancreatic cystic neoplasms remains difficult. Findings of an exophytic growth pattern of the lesion on abdominal imaging and the presence of specific cytomorphologic features in the EUS-FNA biopsy could help clinicians diagnose LEC preoperatively.

3 Review Pathology of Pancreatic Cancer Precursor Lesions. 2016

Noë, Michaël / Brosens, Lodewijk A A. ·Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: m.p.m.noe@umcutrecht.nl. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Surg Pathol Clin · Pubmed #27926360.

ABSTRACT: To better understand pancreatic ductal adenocarcinoma (PDAC) and improve its prognosis, it is essential to understand its origins. This article describes the pathology of the 3 well-established pancreatic cancer precursor lesions: pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. Each of these precursor lesions has unique clinical findings, gross and microscopic features, and molecular aberrations. This article focuses on histopathologic diagnostic criteria and reporting guidelines. The genetics of these lesions are briefly discussed. Early detection and adequate treatment of pancreatic cancer precursor lesions has the potential to prevent pancreatic cancer and improve the prognosis of PDAC.

4 Article Why is pancreatic cancer so deadly? The pathologist's view. 2019

Hruban, Ralph H / Gaida, Matthias M / Thompson, Elizabeth / Hong, Seung-Mo / Noë, Michaël / Brosens, Lodewijk Aa / Jongepier, Martine / Offerhaus, G Johan A / Wood, Laura D. ·Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of General Pathology, The University Hospital of Heidelberg, Heidelberg, Germany. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, The University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. ·J Pathol · Pubmed #30838636.

ABSTRACT: The remarkable aggressiveness of pancreatic cancer has never been fully explained. Although clearly multifactorial, we postulate that venous invasion, a finding seen in most pancreatic cancers but not in most cancers of other organs, may be a significant, underappreciated contributor to the aggressiveness of this disease. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5 Article Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome. 2018

Robinson, Cemre / Estrada, Andrea / Zaheer, Atif / Singh, Vikesh K / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Wood, Laura D / Noë, Michaël / Montgomery, Elizabeth A / Guthrie, Lori C / Lennon, Anne Marie / Boyce, Alison M / Collins, Michael T. ·Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland. · Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. · Department of Pediatrics, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut. · Division of Endocrinology and Diabetes, Children's National Health System, Washington, DC. · Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Departments of Surgery, Radiology, and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. ·J Clin Endocrinol Metab · Pubmed #30124968.

ABSTRACT: Context: McCune-Albright syndrome (MAS) is a rare disorder characterized by fibrous dysplasia of bone, café-au-lait macules, and hyperfunctioning endocrinopathies. It arises from somatic gain-of-function mutations in GNAS, which encodes the cAMP-regulating protein Gαs. Somatic GNAS mutations have been reported in intraductal papillary mucinous neoplasms (IPMNs) and various gastrointestinal (GI) tumors. The clinical spectrum and prevalence of MAS-associated GI disease is not well established. Objective: Define the spectrum and prevalence of MAS-associated GI pathology in a large cohort of patients with MAS. Design: Cross-sectional study. Setting: National Institutes of Health Clinical Center and The Johns Hopkins Hospital. Methods: Fifty-four consecutive subjects with MAS (28 males; age range, 7 to 67 years) were screened with magnetic resonance cholangiopancreatography (MRCP). Results: Thirty of 54 subjects (56%) had radiographic GI abnormalities. Twenty-five (46%) of the screened subjects had IPMNs (mean age of 35.1 years). Fourteen of the 25 had IPMNs alone, and 11 had IPMNs and abnormal hepatobiliary imaging. The 30 patients with MAS-associated GI pathology had a higher prevalence of acute pancreatitis, diabetes mellitus, and skeletal disease burden of fibrous dysplasia than patients without GI disease. Conclusions: A broad spectrum of GI pathology is associated with MAS. IPMNs are common and occur at a younger age than in the general population. Patients with MAS should be considered for screening with a focused GI history and baseline MRCP. Further determination of the natural history and malignant potential of IPMNs in MAS is needed.

6 Article PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications. 2018

Luchini, Claudio / Cros, Jerome / Pea, Antonio / Pilati, Camilla / Veronese, Nicola / Rusev, Borislav / Capelli, Paola / Mafficini, Andrea / Nottegar, Alessia / Brosens, Lodewijk A A / Noë, Michaël / Offerhaus, G Johan A / Chianchiano, Peter / Riva, Giulio / Piccoli, Paola / Parolini, Claudia / Malleo, Giuseppe / Lawlor, Rita T / Corbo, Vincenzo / Sperandio, Nicola / Barbareschi, Mattia / Fassan, Matteo / Cheng, Liang / Wood, Laura D / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · Department of Pathology, Beaujon Hospital, 92110 Clichy, France; Paris-Diderot School of Medicine, Inflammation Research Center, 75013 Paris, France. · Department of Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, 75006 Paris, France. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," 70013, Castellana Grotte, Bari, Italy. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands; Department of Pathology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands. · Surgical Pathology Unit, Santa Chiara Hospital, 38122 Trento, Italy. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. Electronic address: ldwood@jhmi.edu. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; ARC-Net Research Center, University of Verona, 37134 Verona, Italy. Electronic address: aldo.scarpa@univr.it. ·Hum Pathol · Pubmed #30031096.

ABSTRACT: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

7 Article Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology. 2018

Noë, Michaël / Rezaee, Neda / Asrani, Kaushal / Skaro, Michael / Groot, Vincent P / Wu, Pei-Hsun / Olson, Matthew T / Hong, Seung-Mo / Kim, Sung Joo / Weiss, Matthew J / Wolfgang, Christopher L / Makary, Martin A / He, Jin / Cameron, John L / Wirtz, Denis / Roberts, Nicholas J / Offerhaus, G Johan A / Brosens, Lodewijk A A / Wood, Laura D / Hruban, Ralph H. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: rhruban@jhmi.edu. ·Am J Pathol · Pubmed #29684363.

ABSTRACT: Visualizing pathologies in three dimensions can provide unique insights into the biology of human diseases. A rapid and easy-to-implement dibenzyl ether-based technique was used to clear thick sections of surgically resected human pancreatic parenchyma. Protocols were applicable to both fresh and formalin-fixed, paraffin-embedded tissue. The penetration of antibodies into dense pancreatic parenchyma was optimized using both gradually increasing antibody concentrations and centrifugal flow. Immunolabeling with antibodies against cytokeratin 19 was visualized using both light sheet and confocal laser scanning microscopy. The technique was applied successfully to 26 sections of pancreas, providing three-dimensional (3D) images of normal pancreatic tissue, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, and infiltrating pancreatic ductal adenocarcinomas. 3D visualization highlighted processes that are hard to conceptualize in two dimensions, such as invasive carcinoma growing into what appeared to be pre-existing pancreatic ducts and within venules, and the tracking of long cords of neoplastic cells parallel to blood vessels. Expanding this technique to formalin-fixed, paraffin-embedded tissue opens pathology archives to 3D visualization of unique biosamples and rare diseases. The application of immunolabeling and clearing to human pancreatic parenchyma provides detailed visualization of normal pancreatic anatomy, and can be used to characterize the 3D architecture of diseases including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and pancreatic ductal adenocarcinomas.

8 Article IPMNs with co-occurring invasive cancers: neighbours but not always relatives. 2018

Felsenstein, Matthäus / Noë, Michaël / Masica, David L / Hosoda, Waki / Chianchiano, Peter / Fischer, Catherine G / Lionheart, Gemma / Brosens, Lodewijk A A / Pea, Antonio / Yu, Jun / Gemenetzis, Georgios / Groot, Vincent P / Makary, Martin A / He, Jin / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Goggins, Michael G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #29500184.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

9 Article Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. 2017

Luchini, Claudio / Pea, Antonio / Lionheart, Gemma / Mafficini, Andrea / Nottegar, Alessia / Veronese, Nicola / Chianchiano, Peter / Brosens, Lodewijk Aa / Noë, Michaël / Offerhaus, G Johan A / Yonescu, Raluca / Ning, Yi / Malleo, Giuseppe / Riva, Giulio / Piccoli, Paola / Cataldo, Ivana / Capelli, Paola / Zamboni, Giuseppe / Scarpa, Aldo / Wood, Laura D. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · ARC-Net Research Center, University of Verona, Verona, Italy. · National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. · Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #28722124.

ABSTRACT: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

10 Article Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. 2017

Hosoda, Waki / Chianchiano, Peter / Griffin, James F / Pittman, Meredith E / Brosens, Lodewijk Aa / Noë, Michaël / Yu, Jun / Shindo, Koji / Suenaga, Masaya / Rezaee, Neda / Yonescu, Raluca / Ning, Yi / Albores-Saavedra, Jorge / Yoshizawa, Naohiko / Harada, Kenichi / Yoshizawa, Akihiko / Hanada, Keiji / Yonehara, Shuji / Shimizu, Michio / Uehara, Takeshi / Samra, Jaswinder S / Gill, Anthony J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico. · The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. · Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. · Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. · Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan. · Department of Pathology, Onomichi General Hospital, Onomich, Japan. · Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan. · Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·J Pathol · Pubmed #28188630.

ABSTRACT: High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

11 Article Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis. 2016

Hackeng, Wenzel M / Brosens, Lodewijk A A / Poruk, Katherine E / Noë, Michaël / Hosoda, Waki / Poling, Justin S / Rizzo, Anthony / Campbell-Thompson, Martha / Atkinson, Mark A / Konukiewitz, Björn / Klöppel, Günter / Heaphy, Christopher M / Meeker, Alan K / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, Technical University Munich, 81675 Munich, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Hum Pathol · Pubmed #27342911.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.