Surgical and molecular pathology of pancreatic neoplasms

Hackeng et al. Diagnostic Pathology (2016) 11:47 DOI 10.1186/s13000-016-0497-z REVIEW Open Access Surgical and molecular pathology of pancreatic neoplasms Wenzel M. Hackeng1, Ralph H. Hruban2, G. Johan A. Offerhaus1 and Lodewijk A. A. Brosens1* Abstract Background: Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. Main body: Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. Conclusion: This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma. Keywords: Pancreas, Pancreatic cancer, Acinar cell carcinoma, Pancreatic neuroendocrine tumor, Solid-pseudopapillary neoplasm, Genetics, Histology, Methylation, microRNA, Sequencing Background Malignant neoplasms of the pancreas are currently classified based on the cellular direction of differentiation (ductal, acinar or neuroendocrine) of the neoplastic cells, combined with the macroscopic appearance (solid or cystic) of the tumors. Pancreatic ductal adenocarcinoma comprises about 90 % of all malignant pancreatic neoplasms. Of all other malignant pancreatic neoplasms (pancreatic neuroendocrine tumors, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma), neuroendocrine tumors are the most common, comprising approximately 5 % of malignant pancreatic tumors (Table 1). Recent genetic and epigenetic characterization of these histologically distinct pancreatic tumors has increased our understanding of common genetic signatures, and has also identified tumor specific genetic alterations (Table 2). In addition to serving as diagnostic tools, some genetic alterations can be exploited as targets for therapy, opening avenues for new treatments. In this review, histology, genetics and epigenetics of malignant * Correspondence: 1 Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Full list of author information is available at the end of the article pancreatic tumors and potential targets for treatment are discussed. Pancreatic ductal adenocarcinoma Infiltrating ductal adenocarcinoma, also known as pancreatic ductal adenocarcinoma (PDAC), accounts for 90 % of all malignant pancreatic neoplasms and occurs at a mean age of 66 years [1]. PDAC has a very poor prognosis with an overall 5-year survival of only 7 % [2]. At diagnosis, the majority of patients are inoperable due to locally advanced or metastatic disease. The median survival for patients with metastatic disease is less than a year [3]. Moreover, by the year 2030 pancreatic cancer is predicted to become the second leading cause of cancer-related death in the U.S. [4]. In view of the increasing incidence and the virtually unchanged poor prognosis of PDAC both new therapies for established pancreatic cancer as well as methods for prevention and early detection are desperately needed. Gross and microscopic findings PDACs are characteristically firm, ill-defined white-yellow masses (Fig. 1a). The pancreatic parenchyma upstream from PDACs is usually atrophic and the main pancreatic duct can be dilated. Microscopically, PDAC is composed © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Prevalence (% of all malignant pancreatic tumors) Mean Age Sex Direction of (SD) in predominance differentiation years Ductal/acinar/ endocrine Gross: Solid/ solid and cystic/cystic Microscopic Pancreatic ductal adenocarcinoma 90 % 66 (11) Male (3:2) Ductal Solid • Glandular and ductal structures Aberrant TP53 expression, SMAD4 loss, • Abundant desmoplastic stroma expression of MUC1, MUC3, MUC4, MUC5AC, CA19-9 • Eosinophilic to clear cytoplasm and enlarged pleomorphic nuclei • Perineural, lymphatic and blood vessel invasion Pancreatic neuroendocrine tumor/carcinoma 5% 58 (15) Male (3:2) Endocrine • Nested or trabecular growth Solid, sometimes pattern cystic • Granular amphophilic to degeneration eosinophilic cytoplasm • “Salt and pepper” chromatin Solidpseudopapillary neoplasm 1–2 % 29 (14) Female (9:1) Uncertain Solid and cystic Acinar cell Carcinoma 1–2 % 56 (15) Male (2:1) 6% between 8 and 15 Acinar Solid, • Enlarged uniform nuclei with sometimes prominent nucleoli cystic • Finely granular eosinophilic degeneration cytoplasm. • Small acinar units or sheets Acinar Solid, cystic in BWS a Pancreatoblastoma <1 % 5 (2), second peak around 40 Slightly male Immunohistochemical Hackeng et al. Diagnostic Pathology (2016) 11:47 Table 1 Differential diagnosis of malignant pancreatic neoplasms. Overview of pancreatic neoplasms with their relative prevalence, direction of differentiation, macroscopic and microscopic appearance, and immunohistochemical markers Expression of synaptophysin and chromogranin, peptide hormones (e.g. insulin and glucagon), aberrant nuclear TP53 expression in PanNECs • Poorly cohesive uniform cells Abnormal nuclear labeling for β-catenin, expression of CD10, • Extensive degenerative paranuclear dot-like CD99 labeling or lymphoid enhancerchanges. binding factor 1 (LEF1). Loss of membranous E-cadherin • Eosinophilic or clear vacuolated cytoplasm Round to oval nuclei, often grooved or indented. • Eosinophilic globules and foamy macrophages • Similar to ACC • Squamoid nests required for diagnosis • Neuroendocrine or ductal component. BCL10, expression of pancreatic exocrine enzymes: trypsin, chymotrypsin, lipase Expression of pancreatic exocrine enzymes, BCL10, SMAD4 loss, Abnormal nuclear labeling for β-catenin BWS Beckwith-Wiedemann syndrome a Page 2 of 17 Hackeng et al. Diagnostic Pathology (2016) 11:47 Page 3 of 17 Table 2 Overview of pancreatic neoplasms with their key genetic alterations and several epigenetic alterations discussed in this review Pancreatic ductal adenocarcinoma Average n (...truncated)