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Pancreatic Neoplasms: HELP
Articles by Volkan N. Adsay
Based on 42 articles published since 2010
(Why 42 articles?)
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Between 2010 and 2020, Volkan Adsay wrote the following 42 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Pathologic Evaluation and Reporting of Intraductal Papillary Mucinous Neoplasms of the Pancreas and Other Tumoral Intraepithelial Neoplasms of Pancreatobiliary Tract: Recommendations of Verona Consensus Meeting. 2016

Adsay, Volkan / Mino-Kenudson, Mari / Furukawa, Toru / Basturk, Olca / Zamboni, Giuseppe / Marchegiani, Giovanni / Bassi, Claudio / Salvia, Roberto / Malleo, Giuseppe / Paiella, Salvatore / Wolfgang, Christopher L / Matthaei, Hanno / Offerhaus, G Johan / Adham, Mustapha / Bruno, Marco J / Reid, Michelle D / Krasinskas, Alyssa / Klöppel, Günter / Ohike, Nobuyuki / Tajiri, Takuma / Jang, Kee-Taek / Roa, Juan Carlos / Allen, Peter / Fernández-del Castillo, Carlos / Jang, Jin-Young / Klimstra, David S / Hruban, Ralph H / Anonymous6190823. ·*Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA †Department of Pathology, Massachusetts General Hospital, Boston, MA ‡Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Pathology, University of Verona, Verona, Italy ||Department of Surgery, Massachusetts General Hospital, Boston, MA **Department of Surgery, University of Verona, Verona, Italy ††Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD ‡‡Departments of Surgery, University of Bonn, Bonn, Germany §§Departments of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ¶¶Department of Surgery, Edouard Herriot Hospital, HCL, Lyon, France ||||Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands ***Departments of Pathology, Technical University, Munich, Germany †††Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan ‡‡‡Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan §§§Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea ¶¶¶Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile ||||||Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY ****Department of Surgery, Massachusetts General Hospital, Boston, MA ††††Department of Surgery, Seoul National University Hospital, Seoul, Korea ‡‡‡‡Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #25775066.

ABSTRACT: BACKGROUND: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). DESIGN: An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. RESULTS: (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤ 0.5, > 0.5-≤ 1, > 1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic). CONCLUSIONS: These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

2 Guideline International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. 2012

Tanaka, Masao / Fernández-del Castillo, Carlos / Adsay, Volkan / Chari, Suresh / Falconi, Massimo / Jang, Jin-Young / Kimura, Wataru / Levy, Philippe / Pitman, Martha Bishop / Schmidt, C Max / Shimizu, Michio / Wolfgang, Christopher L / Yamaguchi, Koji / Yamao, Kenji / Anonymous6680728. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. masaotan@med.kyushu-u.ac.jp ·Pancreatology · Pubmed #22687371.

ABSTRACT: The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated new guidelines. Since the levels of evidence for all items addressed in these guidelines are low, being 4 or 5, we still have to designate them "consensus", rather than "evidence-based", guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required.

3 Editorial Ki67 labeling index in neuroendocrine tumors of the gastrointestinal and pancreatobiliary tract: to count or not to count is not the question, but rather how to count. 2012

Adsay, Volkan. · ·Am J Surg Pathol · Pubmed #23154766.

ABSTRACT: -- No abstract --

4 Review Pathologic classification of "pancreatic cancers": current concepts and challenges. 2017

Mostafa, Mohamed E / Erbarut-Seven, Ipek / Pehlivanoglu, Burcin / Adsay, Volkan. ·Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA. · Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey. · Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA. nadsay@mcw.edu. ·Chin Clin Oncol · Pubmed #29307199.

ABSTRACT: As the most common and most important cancer of the pancreas, with rapid mortality and now also as the third leading cause of cancer-related deaths in the United States, pancreatic ductal adenocarcinoma (PDAC) has become synonymous with "pancreas cancer". PDAC is also the prototype of the "pancreatobiliary-type" adenocarcinomas, along the biliary tract, ampullary and gallbladder cancers with the similar morphology and behavior. Recent molecular profiling studies have identified distinct subsets of PDAC, potentially with different behaviors and targetability. Moreover, while PDAC is by far the most common cancer of the pancreas, there are various other types that occur in this organ and are erroneously classified together with PDAC. Many of these have different molecular and biologic characteristics that warrant their management separately although they are also technically "pancreatic cancers". While some are closely related to PDAC and have as aggressive behavior (such as adenosquamous carcinomas which are recently recognized under "basal" like category in profiling studies, which are actually even worse prognostically than PDACs), in the meantime, others such as colloid carcinoma has a much better behavior than PDAC, and as a carcinoma with intestinal lineage (MUC2/CDX2) colloid carcinoma may require an entirely different treatment approach as well. Similarly, medullary carcinomas also appear to have different biology. Additionally, non-ductal cancers such as acinar, neuroendocrine, solid-pseudopapillary neoplasms and pancreatoblastoma have their respective clinicopathologic and molecular associations and warrant careful elimination in the management and study protocols. Another very problematic aspect in the classification of "pancreas cancer" is its delineation from the cancers of neighboring organs, in particular, ampullary/duodenal and common bile duct (CBD) cancers, for which recently more refined criteria have been provided. Additionally, the possibility of metastasis from another site and lymphomas also need to be considered. In summary, there is a whole host of cancers that occur in the pancreas that ought to be considered carefully before a case is classified as an ordinary "pancreas cancer" (PDAC).

5 Review Paraduodenal pancreatitis: benign and malignant mimics at MRI. 2017

Mittal, Pardeep K / Harri, Peter / Nandwana, Sadhna / Moreno, Courtney C / Muraki, Takashi / Adsay, Volkan / Cox, Kelly / Pehlivanoglu, Burcin / Alexander, Lauren F / Chatterjee, Argha / Miller, Frank H. ·Department of Radiology and Imaging Sciences, Emory University School of Medicine, 1365 Clifton Road NE, Building A, Suite AT-627, Atlanta, GA, 30322, USA. pmittal@emory.edu. · Department of Radiology and Imaging Sciences, Emory University School of Medicine, 1365 Clifton Road NE, Building A, Suite AT-627, Atlanta, GA, 30322, USA. · Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Radiology Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ·Abdom Radiol (NY) · Pubmed #28660333.

ABSTRACT: Paraduodenal pancreatitis, also known as groove pancreatitis, is a rare form of chronic pancreatitis that masquerades as pancreatic adenocarcinoma affecting the pancreaticoduodenal groove, a potential space between the head of the pancreas, duodenum, and common bile duct. Two forms of groove pancreatitis have been described. The segmental form involves the pancreatic head with development of scar tissue within the groove, whereas the pure form affects the groove only, sparing the pancreatic head. Imaging findings of groove pancreatitis often overlap with primary duodenal, ampullary, or pancreatic neoplasms, which often results in a diagnostic challenge. In addition, paraduodenal pancreatitis can be mistaken for cystic pancreatic lesions, especially when there is involvement of the duodenal wall. Preoperative recognition of this entity is very important in order to avoid unnecessary procedures, although surgery, such as pancreaticoduodenectomy, may still be required to relieve obstructive symptoms. In this article, the pathophysiology and magnetic resonance imaging characteristics of paraduodenal pancreatitis and important benign and malignant mimics are discussed.

6 Review Acinar neoplasms of the pancreas-A summary of 25 years of research. 2016

Klimstra, David S / Adsay, Volkan. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065. Electronic address: klimstrd@mskcc.org. · Department of Anatomic Pathology, Emory University, Atlanta, GA. ·Semin Diagn Pathol · Pubmed #27320062.

ABSTRACT: Our understanding about the family of acinar neoplasms of the pancreas has grown substantially over the past 25 years. The prototype is acinar cell carcinoma, an uncommon variant of pancreatic carcinoma that demonstrates production of pancreatic exocrine enzymes, verifiable using immunohistochemistry, and exhibits characteristic histologic features. Related neoplasms include mixed acinar carcinomas such as mixed acinar neuroendocrine carcinoma and mixed acinar ductal carcinoma. In the pediatric age group, pancreatoblastoma is also closely related. Cystic and extrapancreatic forms have been described. These neoplasms share molecular alterations that are distinct from the more common ductal and neuroendocrine neoplasms of the pancreas. Although there is a broad range of genetic findings, a number of potential therapeutic targets have emerged. This review explores the clinical and pathologic features of pancreatic acinar neoplasms along with their more common molecular phenotypes. The differential diagnosis with other pancreatic neoplasms is explored as well.

7 Review Serous Neoplasms of the Pancreas: A Clinicopathologic Analysis of 193 Cases and Literature Review With New Insights on Macrocystic and Solid Variants and Critical Reappraisal of So-called "Serous Cystadenocarcinoma". 2015

Reid, Michelle D / Choi, Hye-Jeong / Memis, Bahar / Krasinskas, Alyssa M / Jang, Kee-Taek / Akkas, Gizem / Maithel, Shishir K / Sarmiento, Juan M / Kooby, David A / Basturk, Olca / Adsay, Volkan. ·Departments of *Pathology §Surgery, Emory University Hospital, Atlanta, GA ∥Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY †Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan ‡Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. ·Am J Surg Pathol · Pubmed #26559376.

ABSTRACT: The literature on "variants" and "malignant" counterparts of pancreatic serous cystic neoplasms (SCNs) is highly conflicted. Clinicopathologic characteristics of 193 SCNs were investigated, along with a critical literature review. For the macrocystic (oligocystic) variant, in this largest series, a demographic profile in contrast to current literature was elucidated, with 21% frequency, predominance in female individuals (4:1), body/tail location (1.7×), younger age of patients (mean age, 50 y), and frequent radiologic misdiagnosis as other megacystic neoplasms. Solid SCNs were rare (n=4, 2%) and often misinterpreted radiologically as neuroendocrine tumors. Available fine-needle aspiration in 11 cases was diagnostic in only 1. Radiologic impression was "malignancy" in 5%. Associated secondary tumors were detected in 13% of resections, mostly neuroendocrine. Secondary "infiltration" (direct adhesion/penetration) of spleen, stomach, colon, and/or adjacent nodes was seen in 6 (3%) fairly large SCNs (mean, 11 cm) with no distant metastasis. Three SCNs recurred locally, but completeness of original resection could not be verified. Our only hepatic SCN lacked a concurrent pancreatic tumor. Literature appraisal revealed that there are virtually no deaths that are directly attributable to dissemination/malignant behavior of SCNs, and most cases reported as "malignant" in fact would no longer fulfill the more recent World Health Organization criteria but instead would represent either (1) local adhesion/persistence of tumor, (2) cases with no histologic verification of malignancy, or (3) liver SCNs with benevolent behavior (likely representing multifocality, rather than true metastasis, especially considering there was no fatality related to this and no reported metastases to other remote sites). In conclusion, in contrast to the literature, the clinicopathologic characteristics of solid and macrocystic SCN variants are similar to their microcystic counterpart, although their radiologic diagnosis is challenging. Recurrence/secondary invasion of neighboring organs occurs rarely in larger SCNs but seems innocuous. An SCN should not be classified as "malignant" unless there is clear-cut evidence of histologic malignancy or documented distant metastasis.

8 Review Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics. 2014

Reid, Michelle D / Choi, Hyejeong / Balci, Serdar / Akkas, Gizem / Adsay, Volkan. ·Department of Pathology, Emory University School of Medicine, Atlanta, GA. · Department of Pathology, Emory University School of Medicine, Atlanta, GA. Electronic address: nadsay@emory.edu. ·Semin Diagn Pathol · Pubmed #25441309.

ABSTRACT: We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as "serous." Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to "clear cell neoplasms" seen in various other organs that are associated with the von Hippel-Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets.

9 Clinical Trial Combination gemcitabine/cisplatin therapy and ERCC1 expression for resected pancreatic adenocarcinoma: Results of a Phase II prospective trial. 2016

Postlewait, Lauren M / Ethun, Cecilia G / Kooby, David A / Sarmiento, Juan M / Chen, Zhengjia / Staley, Charles A / Brutcher, Edith / Adsay, Volkan / El-Rayes, Bassel / Maithel, Shishir K. ·Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia. · Division of General Surgery, Department of Surgery, Emory University, Atlanta, Georgia. · Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia. · Department of Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia. · Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, Georgia. ·J Surg Oncol · Pubmed #27501338.

ABSTRACT: BACKGROUND: Standard adjuvant treatment for pancreatic adenocarcinoma (PDAC) is gemcitabine [Gem(CONKO-001: Gem vs. placebo DFS:13.4 vs. 6.7 mo; P < 0.001; OS:22.8 vs. 20.2 mo; P = 0.01)]. Addition of cisplatin (Cis) to Gem has resulted in increased PFS for advanced and metastatic disease, which may be predicted by low expression of excision repair cross-complementing group-1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis, stratifying results by tumor ERCC1 expression. METHODS: Patients with resected PDAC were enrolled (2010-2013) and received Gem(1,000 mg/m(2) )/Cis(50 mg/m(2) ). Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low or high expression. Primary outcomes were recurrence-free and overall survival (RFS/OS). RESULTS: Of 22 pts, 16(73%) were Stage IIB, 5(23%) Stage IIA, and 1(4%) Stage IA. Grade 3/4 toxicity occurred in 13 pts (59%); neutropenia was most common (n = 9;41%). Median follow-up was 37.5 months. Median RFS was 16.7 mo; OS was 35.5 mo. Low ERCC1 (n = 15;75%) compared to high ERCC1 (n = 5;25%) was not associated with improved RFS (12.4 vs. 16.7 mo; P = 0.68) or OS (Median not reached vs. 21.6 mo; P = 0.22). CONCLUSIONS: Adjuvant Gem/Cis is feasible in patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in most patients. J. Surg. Oncol. 2016;114:336-341. © 2016 Wiley Periodicals, Inc.

10 Article Hepatobiliary Mucinous Cystic Neoplasms With Ovarian Type Stroma (So-Called "Hepatobiliary Cystadenoma/Cystadenocarcinoma"): Clinicopathologic Analysis of 36 Cases Illustrates Rarity of Carcinomatous Change. 2018

Quigley, Brian / Reid, Michelle D / Pehlivanoglu, Burcin / Squires, Malcolm H / Maithel, Shishir / Xue, Yue / Hyejeong, Choi / Akkas, Gizem / Muraki, Takashi / Kooby, David A / Sarmiento, Juan M / Cardona, Ken / Sekhar, Aarti / Krasinskas, Alyssa / Adsay, Volkan. ·Departments of Pathology. · Surgery. · Department of Pathology, Ulsan University College of Medicine, Ulsan, Korea. · Radiology, School of Medicine, Emory University, Atlanta, GA. · Department of Pathology, Medical College of Wisconsin Milwaukee, WI, USA. ·Am J Surg Pathol · Pubmed #29016404.

ABSTRACT: The literature is highly conflicting on hepatobiliary mucinous cystic neoplasms (MCNs), aka "hepatobiliary cystadenoma/cystadenocarcinoma," largely because ovarian stroma (OS) was not a requirement until WHO-2010 and is not widely applied even today. In this study, MCNs (with OS) accounted for 24 of 229 (11%) resected hepatic cysts in one institution. Eight of the 32 (25%) cysts that had been originally designated as hepatobiliary cystadenoma/cystadenocarcinoma at the time of diagnosis proved not to have an OS during this review and were thus re-classified as non-MCN. In total, 36 MCNs (with OS) were analyzed-24 from the institutional files and 12 consultation cases. All were women. Mean age was 51 (28 to 76 y). Mean size was 11 cm (5 to 23 cm). Most (91%) were intrahepatic and in the left lobe (72%). Preoperative imaging mentioned "neoplasm" in 14 (47%) and carcinoma was a differential in 6 (19%) but only 2 proved to have carcinoma. Microscopically, only 47% demonstrated diffuse OS (>75% of the cyst wall/lining); OS was often focal. The cyst lining was often composed of non-mucinous biliary epithelium, and this was predominant in 50% of the cases. Degenerative changes of variable amount were seen in most cases. In situ and invasive carcinoma was seen in only 2 cases (6%), both with small invasion (7 and 8 mm). Five cases had persistence/recurrence, 2 confirmed operatively (at 7 mo and 15 y). Of the 2 cases with carcinoma, one had "residual cyst or hematoma" by radiology at 4 months, and the other was without disease at 3 years. In conclusion, many cysts (25%) previously reported as hepatobiliary cystadenoma/cystadenocarcinoma are not MCNs. True MCNs are uncommon among resected hepatic cysts (11%), occur exclusively in females, are large, mostly intrahepatic and in the left lobe (72%). Invasive carcinomas are small and uncommon (6%) compared with their pancreatic counterpart (16%). Recurrences are not uncommon following incomplete excision.

11 Article A FISH assay efficiently screens for BRAF gene rearrangements in pancreatic acinar-type neoplasms. 2018

Wang, Lu / Basturk, Olca / Wang, Jiajing / Benayed, Ryma / Middha, Sumit / Zehir, Ahmet / Linkov, Irina / Rao, Mamta / Aryeequaye, Ruth / Cao, Long / Chmielecki, Juliann / Ross, Jeffrey / Stephens, Philip J / Adsay, Volkan / Askan, Gokce / Balci, Serdar / Klimstra, David S. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Foundation Medicine, Cambridge, MA, USA. · Department of Pathology, Albany Medical College, Albany, NY, USA. · Department of Pathology, Emory University, Atlanta, GA, USA. ·Mod Pathol · Pubmed #28884748.

ABSTRACT: Approximately 1-2% of pancreatic neoplasms are acinar cell carcinomas. Recently, BRAF gene rearrangements were identified in over 20% of acinar-type neoplasms, which included both pure acinar cell carcinomas and mixed carcinomas with acinar differentiation, using next-generation sequencing-based platforms, providing a potential therapeutic target for patients with these neoplasms. Thus, it is clinically important to develop a rapid, cost- and material-efficient assay to screen for BRAF gene fusions in pancreatic acinar-type neoplasms. We developed a dual color, break-apart FISH assay to detect BRAF gene rearrangements in these neoplasms and evaluated its performance in comparison to next-generation sequencing-based studies. A blinded BRAF rearrangement FISH investigation was performed on 31 acinar-type neoplasms that had been studied previously by next-generation sequencing-based analysis as well as on 18 additional acinar-type neoplasms that were accrued over the past 2 years. In total, BRAF fusions were identified in 12/49 (24%) acinar-type neoplasms by FISH. BRAF fusion partners were uncovered by using targeted next-generation sequencing studies in 11 FISH-positive cases that had sufficient material for next-generation sequencing studies. SND1 was the most frequent fusion partner involved in BRAF-fusion acinar-type neoplasms (50%), followed by HERPUD1 (18%). No BRAF fusions were identified by next-generation sequencing in any of the FISH-negative cases investigated. FISH analysis showed that BRAF rearrangements were diffusely present across tumor-rich areas in BRAF-fusion acinar-type neoplasms, which is consistent with an oncogenic driver alteration pattern. Thus, we demonstrated that, in comparison to targeted next-generation sequencing-based technologies, the FISH assay is highly sensitive and specific as well as time- and cost-efficient in the detection of BRAF fusions in acinar-type neoplasms. The FISH assay can be easily implemented in diagnostic settings to identify acinar-type neoplasms patients potentially suitable for targeted therapy to inhibit MAPK pathway activity.

12 Article Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. 2017

Basturk, Olca / Berger, Michael F / Yamaguchi, Hiroshi / Adsay, Volkan / Askan, Gokce / Bhanot, Umesh K / Zehir, Ahmet / Carneiro, Fatima / Hong, Seung-Mo / Zamboni, Giuseppe / Dikoglu, Esra / Jobanputra, Vaidehi / Wrzeszczynski, Kazimierz O / Balci, Serdar / Allen, Peter / Ikari, Naoki / Takeuchi, Shoko / Akagawa, Hiroyuki / Kanno, Atsushi / Shimosegawa, Tooru / Morikawa, Takanori / Motoi, Fuyuhiko / Unno, Michiaki / Higuchi, Ryota / Yamamoto, Masakazu / Shimizu, Kyoko / Furukawa, Toru / Klimstra, David S. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Tokyo Medical University, Tokyo, Japan. · Department of Pathology, Emory University, Atlanta, GA, USA. · Department of Pathology, Centro Hospitalar São João/Faculty of Medicine of Porto University and Institute for Research and Innovation in Health/Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. · Department of Pathology, University of Verona, Ospedale S.C.-Don Calabria-Negrar, Verona, Italy. · New York Genome Center, Molecular Diagnostics, New York, NY, USA. · Department of Pathology, Colombia University Medical Center, New York, NY, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. ·Mod Pathol · Pubmed #28776573.

ABSTRACT: Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

13 Article Cytologic features and clinical implications of undifferentiated carcinoma with osteoclastic giant cells of the pancreas: An analysis of 15 cases. 2017

Reid, Michelle D / Muraki, Takashi / HooKim, Kim / Memis, Bahar / Graham, Rondell P / Allende, Daniela / Shi, Jiaqi / Schaeffer, David F / Singh, Remmi / Basturk, Olca / Adsay, Volkan. ·Department of Pathology, Emory University Hospital, Atlanta, Georgia. · Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Pathology, Cleveland Clinic, Cleveland, Ohio. · Department of Pathology, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Pathology, Northside Hospital, Atlanta, Georgia. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. ·Cancer Cytopathol · Pubmed #28371566.

ABSTRACT: BACKGROUND: The cytologic features of undifferentiated pancreatic carcinoma with osteoclastic giant cells (UOC) are rarely described. METHODS: Cytologic and clinicopathologic characteristics in 15 UOC fine-needle aspiration (FNA) specimens were analyzed. RESULTS: FNA specimens were obtained from 6 men and 8 women with a mean age of 65 years who had UOCs (head, n = 7; body, n = 3; and tail, n = 4) with a mean radiologic size 7.3 cm, and some had a cystic component (n = 9). Three cell types (osteoclastic giant cells, pleomorphic tumor giant cells, and spindled/histiocytoid cells) were observed in 12 of 15 specimens (80%); and pancreatic ductal adenocarcinoma (PDAC) was present in 11 specimens. FNA diagnoses were UOC (n = 6), PDAC (n = 5), poorly differentiated carcinoma (n = 2), "suspicious for neoplasm" (n = 1), and "negative" (n = 1). Five of 5 specimens with osteoclastic giant cells were positive for cluster of differentiation 68 (CD68) (a glycoprotein that binds to low-density lipoprotein). Pleomorphic tumor giant cells and spindled/histiocytoid cells were positive for pancytokeratin (6 of 7 specimens), CAM5.2 (2 of 3 specimens), and epithelial membrane antigen (2 of 2 specimens). INI-1 protein expression was retained in 3 of 3 specimens. The Ki-67 labeling index was assessed in 3 specimens and was 12%, 18%, and 40%; 4 of 12 resected UOCs were pure, and 8 were mixed with PDAC. One resection specimen had intraductal papillary mucinous neoplasm, and 2 had mucinous cystic neoplasms. The median overall survival (OS) of patients who had UOCs identified on FNA was 8 months (6 died [OS, 8 months; range, 2-22 months], and 8 remained alive [OS, 3 months; range, 1-27 months]), which was similar to the survival of 74 patients who had PDACs identified on FNA (OS, 15 months; P = .279) but worse than that of the 27 patients with UOCs who did not undergo FNA (OS, 92 months; P = .0135). CONCLUSIONS: The 3 classical UOC cell types are identifiable on FNA, making cytologic diagnosis possible if considered in the differential. A PDAC component is often also observed. The survival advantage of UOC over pure PDAC appears to be negated by FNA and requires further investigation. Cancer Cytopathol 2017;125:563-75. © 2017 American Cancer Society.

14 Article Rosai-Dorfman Disease Manifesting as a Pancreatic Head Mass Diagnosed Nonoperatively. 2017

Smith, Demetria J / Sekhar, Aarti / Memis, Bahar / Adsay, Volkan N / Alese, Olatunji B. ·Emory University, Atlanta, GA. ·J Oncol Pract · Pubmed #27997302.

ABSTRACT: -- No abstract --

15 Article Intraductal Tubulopapillary Neoplasm of the Pancreas: A Clinicopathologic and Immunohistochemical Analysis of 33 Cases. 2017

Basturk, Olca / Adsay, Volkan / Askan, Gokce / Dhall, Deepti / Zamboni, Giuseppe / Shimizu, Michio / Cymes, Karina / Carneiro, Fatima / Balci, Serdar / Sigel, Carlie / Reid, Michelle D / Esposito, Irene / Baldaia, Helena / Allen, Peter / Klöppel, Günter / Klimstra, David S. ·Departments of *Pathology #Surgery, Memorial Sloan Kettering Cancer Center, New York, NY †Departments of Pathology, Emory University School of Medicine, Atlanta, GA ‡Departments of Pathology, University of Verona and Negrar Hospital, Verona, Italy §Departments of Pathology, Hakujikai Memorial Hospital, Tokyo, Japan ∥Departments of Pathology, Centro Hospitalar São João/University of Porto and Institute for Research and Innovation in Health/Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal. ¶Departments of Pathology, Heinrich-Heine-University of Düsseldorf, Düsseldorf **Departments of Pathology, Technical University, Munich, Germany. ·Am J Surg Pathol · Pubmed #27984235.

ABSTRACT: Intraductal tubulopapillary neoplasm (ITPN) is a relatively recently described member of the pancreatic intraductal neoplasm family. Thus, the literature on its histologic and immunohistochemical features, clinical behavior, and its similarities and differences from other pancreatic neoplasms is limited. Thirty-three cases of ITPN, the largest series to date, were identified. Immunohistochemical labeling for cytokeratins, glycoproteins, pancreatic enzymes, markers for intestinal and neuroendocrine differentiation, and antibodies associated with genetic alterations previously described in pancreatic neoplasms was performed. Clinicopathologic features and survival was assessed. Seventeen patients were female and 14 were male. Mean age was 55 years (range, 25 to 79 y). Median overall tumor size was 4.5 cm (range, 0.5 to 15 cm). Forty-five percent of the tumors occurred in the head, 32% in the body/tail, and 23% showed diffuse involvement. Microscopically, the tumors were characterized by intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. Although it was often challenging to determine its extent, invasion was present in 71%. Almost all tumors labeled for CAM5.2, CK7, and CK19; most expressed CA19.9, MUC1, and MUC6. CDX2, MUC2, trypsin, chymotrypsin, chromogranin, and synaptophysin were not expressed. SMAD4 expression was retained in 100%; p16 expression and p53 overexpression was seen in 33% and 27%, respectively. Follow-up information was available for 22 patients (median follow-up, 45 mo; range, 11 to 173 mo). Two patients with invasive carcinoma died of disease at 23 and 41 months, respectively. One patient died of unrelated causes at 49 months. Twelve patients were alive with disease. Seven patients were alive with no evidence of disease. The overall 1-, 3-, and 5-year survival rates were 100% in patients without an invasive component and 100%, 91%, and 71%, respectively, in patients with an invasive component (P=0.7). ITPN is a distinct clinicopathologic entity in the pancreas. Despite the difficulties of determining the extent of invasive carcinoma in many cases, the overall outcome seems to be relatively favorable and substantially better than that of conventional pancreatic ductal adenocarcinoma, even when only the cases with invasive carcinoma are considered.

16 Article "Simple Mucinous Cyst" of the Pancreas: A Clinicopathologic Analysis of 39 Examples of a Diagnostically Challenging Entity Distinct From Intraductal Papillary Mucinous Neoplasms and Mucinous Cystic Neoplasms. 2017

Krasinskas, Alyssa M / Oakley, Gerard J / Bagci, Pelin / Jang, Kee-Taek / Kuan, Shih-Fan / Reid, Michelle D / Erbarut, Ipek / Adsay, Volkan. ·*Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA †Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA ‡Department of Pathology, Marmara University, Istanbul, Turkey §Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. ·Am J Surg Pathol · Pubmed #27740966.

ABSTRACT: Pancreatic cysts >1 cm lined by nonpapillary mucinous epithelium without ovarian-type stroma pose diagnostic challenges. The term "simple mucinous cyst" was recently proposed for this entity. Our goal was to determine the clinicopathologic characteristics of these cysts, as they have not been previously described. Of the 39 patients with pancreatic resections included in this study, the mean age was 65 years and the female-to-male ratio was 4:1. The characteristics of the cysts are as follows: 82% had elevated cyst fluid carcinoembryonic antigen levels, 67% were unilocular, 69% occurred in the body/tail, 92% did not communicate with pancreatic ducts, the mean size was 2.4 cm (range, 1.0 to 5.5 cm), the cyst contents tended to be serous (48%) or viscous (28%), all had a smooth lining (only 1 had focal excrescences) composed of bland columnar mucinous epithelium (low-grade dysplasia) in 92% with focal high-grade dysplasia in 8%, and 65% had degenerative changes (granulation-like tissue, hemorrhage, and myxoid stroma). The cyst lining was CK7+ and 97% had a MUC5AC+ and/or MUC6+ gastric phenotype; overt intestinal features were absent. In total, 55% of cysts tested (fluid and/or resections) harbored KRAS mutations. The term "simple mucinous cyst" is useful to apply to >1 cm mucinous cysts that do not have characteristic features of intraductal papillary mucinous neoplasms or mucinous cystic neoplasms. KRAS mutations can be detected in these typically bland cysts, and in rare instances, focal high-grade dysplasia may be present. Hence, these cysts should be viewed as neoplastic and treated similarly to other mucinous pancreatic cysts.

17 Article Non-ampullary-duodenal carcinomas: clinicopathologic analysis of 47 cases and comparison with ampullary and pancreatic adenocarcinomas. 2017

Xue, Yue / Vanoli, Alessandro / Balci, Serdar / Reid, Michelle M / Saka, Burcu / Bagci, Pelin / Memis, Bahar / Choi, Hyejeong / Ohike, Nobuyike / Tajiri, Takuma / Muraki, Takashi / Quigley, Brian / El-Rayes, Bassel F / Shaib, Walid / Kooby, David / Sarmiento, Juan / Maithel, Shishir K / Knight, Jessica H / Goodman, Michael / Krasinskas, Alyssa M / Adsay, Volkan. ·Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. · Department of Molecular Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy. · Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea. · Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan. · Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan. · Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. · Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA. ·Mod Pathol · Pubmed #27739441.

ABSTRACT: Literature on non-ampullary-duodenal carcinomas is limited. We analyzed 47 resected non-ampullary-duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry (n=38) revealed commonness of 'gastro-pancreatobiliary markers' (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas 'intestinal markers' were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary-duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary (n=355) and pancreatic ductal (n=227) carcinomas, non-ampullary-duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs 1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary-duodenal carcinomas (59 and 52%; P=0.78), but was significantly better than the ampullary ductal (41 and 29%, P<0.001) and pancreatic (28 and 18%, P<0.001) carcinomas. In conclusion, non-ampullary-duodenal carcinomas are more histologically heterogeneous than previously appreciated. Their morphologic versatility (commonly showing gastro-pancreatobiliary lineage and hitherto unrecognized patterns), frequent plaque-like growth minus an adenoma component, and frequent expression of gastro-pancreatobiliary markers suggest that many non-ampullary-duodenal carcinomas may arise from Brunner glands or gastric metaplasia or heterotopic pancreatobiliary epithelium. The clinical behavior of non-ampullary-duodenal carcinoma is closer to that of ampullary-duodenal subset of ampullary carcinomas, but is significantly better than that of ampullary ductal and pancreatic cancers. The frequency of mismatch repair protein alterations suggest that routine testing should be considered, especially in the non-ampullary-duodenal carcinomas with plaque-like growth and pushing-border infiltration.

18 Article Nonmucinous Biliary Epithelium Is a Frequent Finding and Is Often the Predominant Epithelial Type in Mucinous Cystic Neoplasms of the Pancreas and Liver. 2017

Zhelnin, Kristen / Xue, Yue / Quigley, Brian / Reid, Michelle D / Choi, Hyejeong / Memis, Bahar / Adsay, Volkan / Krasinskas, Alyssa M. ·*Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA †Department of Pathology, College of Medicine, Ulsan University, Ulsan, Republic of Korea. ·Am J Surg Pathol · Pubmed #27673548.

ABSTRACT: Mucinous cystic neoplasms (MCNs) can occur in the pancreas and liver. Classically, these cystic lesions are lined by columnar mucinous epithelium with underlying ovarian-type stroma. It has been proposed that cysts with ovarian-type stroma and nonmucinous epithelium be considered separate entities in both the pancreas and liver. Using a series of 104 pancreatic and 32 hepatic cases, we aimed to further characterize the epithelium present in MCNs. Mucinous epithelium was defined as pancreatic intraepithelial neoplasia-like columnar cells with pale pink/clear apical mucin. Epithelial cells ranging from flat to cuboidal to short columnar without obvious mucin or goblet cells were classified as nonmucinous/biliary epithelium. A mixture (at least 5%) of mucinous and nonmucinous/biliary epithelium was noted in 81%. Almost half (47%) of the cases had abundant (>50%) nonmucinous/biliary epithelium. Of the 71 cases with ≤50% nonmucinous/biliary epithelium, 8 cases demonstrated high-grade dysplasia (7 pancreas, 1 liver) and 14 demonstrated invasive adenocarcinoma (11 pancreas, 3 liver). Conversely, of the 58 cases with >50% nonmucinous/biliary epithelium, not a single case of high-grade dysplasia (P=0.007) or invasive carcinoma (P<0.001) was identified. In summary, nonmucinous/biliary epithelium frequently occurs in MCNs of the pancreas and liver. As mucinous and nonmucinous/biliary epithelia often occur together, there does not appear to be enough evidence to regard cases with predominantly nonmucinous/biliary epithelium as separate entities. Our findings suggest that mucinous change is a "progression" phenomenon in MCNs of the pancreas and liver, and only when abundant mucinous epithelium is present is there a risk of progression to malignancy.

19 Article Ampullary carcinoma is often of mixed or hybrid histologic type: an analysis of reproducibility and clinical relevance of classification as pancreatobiliary versus intestinal in 232 cases. 2016

Reid, Michelle D / Balci, Serdar / Ohike, Nobuyuki / Xue, Yue / Kim, Grace E / Tajiri, Takuma / Memis, Bahar / Coban, Ipek / Dolgun, Anil / Krasinskas, Alyssa M / Basturk, Olca / Kooby, David A / Sarmiento, Juan M / Maithel, Shishir K / El-Rayes, Bassel F / Adsay, Volkan. ·Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan. · Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. · Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan. · Department of Pathology, Istanbul Bilim University, Florence Nightingale Hospital, Istanbul, Turkey. · Department of Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey. · Department of Pathology, Wayne State University, Detroit, MI, USA. · Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. · Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. ·Mod Pathol · Pubmed #27586202.

ABSTRACT: Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was 'fair' (κ 0.39; P<0.001) with complete agreement in 23%. Using agreement by 3/5 observers as 'consensus' 40% of cases were classified as 'mixed' pancreatobiliary and intestinal. When observers were asked to provide a final diagnosis based on the predominant pattern in cases initially classified as mixed, there was 'moderate' agreement (κ 0.44; P<0.0001) with 5/5 agreeing in 35%. Cases classified as pancreatobiliary by consensus (including those with pure-pancreatobiliary or mixed-predominantly pancreatobiliary features) had shorter overall (median 41 months) and 5-year survival (38%) than those classified as pure-intestinal/mixed-predominantly intestinal (80 months and 57%, respectively; P=0.026); however, on multivariate analysis this was not independent of established prognostic parameters. Interestingly, when compared with 476 cases of pancreatic ductal adenocarcinomas, the pancreatobiliary-type ampullary carcinomas had better survival (16 versus 41 months, P<0.001), even when matched by size and node status. In conclusion, presumably because of the various cell types comprising the region, ampullary carcinomas frequently show mixed phenotypes and intratumoral heterogeneity, which should be considered when devising management protocols. Caution is especially warranted when applying this histologic classification to biopsies and tissue microarrays. While ampullary carcinomas with more pancreatobiliary morphology have a worse prognosis than intestinal ones this does not appear to be an independent prognostic factor. However, pancreatobiliary-type ampullary carcinomas have a much better prognosis than their pancreatic counterparts.

20 Article Undifferentiated Carcinoma With Osteoclastic Giant Cells of the Pancreas: Clinicopathologic Analysis of 38 Cases Highlights a More Protracted Clinical Course Than Currently Appreciated. 2016

Muraki, Takashi / Reid, Michelle D / Basturk, Olca / Jang, Kee-Taek / Bedolla, Gabriela / Bagci, Pelin / Mittal, Pardeep / Memis, Bahar / Katabi, Nora / Bandyopadhyay, Sudeshna / Sarmiento, Juan M / Krasinskas, Alyssa / Klimstra, David S / Adsay, Volkan. ·Departments of *Pathology and Laboratory Medicine ∥Radiology #Surgery, Emory University School of Medicine, Atlanta, GA †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Pathology, Detroit Medical Center, Detroit, MI ‡Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea §Department of Pathology, Marmara University, Istanbul, Turkey. ·Am J Surg Pathol · Pubmed #27508975.

ABSTRACT: Undifferentiated carcinomas with osteoclastic giant cells of the pancreas (OGC) are rare tumors. The current impression in the literature is that they are highly aggressive tumors similar in prognosis to ductal adenocarcinomas. In this study, the clinicopathologic characteristics of 38 resected OGCs were investigated and contrasted with 725 resected pancreatic ductal adenocarcinomas without osteoclastic cells (PDCs). The frequency among systematically reviewed pancreatic cancers was 1.4%. OGCs showed a slight female predominance (62.9%, vs. 51.4% in PDCs). The mean age was 57.9 years (vs. 65.0). The mean size of invasive cancer was 5.3 cm (vs. 3.2). They were characterized by nodular, pushing-border growth, and 8 arose in tumoral intraepithelial neoplasms (4 in mucinous cystic neoplasms, 4 in intraductal papillary mucinous neoplasms type lesions), and 23 (61%) also showed prominent intraductal/intracystic growth. Twenty-nine (76%) had an invasive ductal/tubular adenocarcinoma component. Osteoid was seen in 12. Despite their larger size, perineural invasion and nodal metastasis were uncommon (31.6% and 22.6%, vs. 85.5% and 64.0%, respectively). Immunohistochemistry performed on 24 cases revealed that osteoclastic cells expressed the histiocytic marker CD68, and background spindle cells and pleomorphic/giant carcinoma cells often showed p53 and often lacked cytokeratin. Survival of OGCs was significantly better than that of PDCs (5 yr, 59.1% vs. 15.7%, respectively, P=0.0009). In conclusion, pancreatic OGCs present with larger tumor size and in slightly younger patients than PDC, 21% arise in mucinous cystic neoplasms/intraductal papillary mucinous neoplasms, and 61% show intraductal/intracystic polypoid growth. OGCs have a significantly better prognosis than is currently believed in the literature.

21 Article Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model. 2016

Díaz, Begoña / Ostapoff, Katherine T / Toombs, Jason E / Lo, Jason / Bonner, Michael Y / Curatolo, Adam / Adsay, Volkan / Brekken, Rolf A / Arbiser, Jack L. ·Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. · Division of Medical Oncology and Hematology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. · Department of Surgery, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA. · Department of Pharmacology, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA. · Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA. · Atlanta Veterans Administration Medical Center, Atlanta, GA, USA. · Winship Cancer Institute, Atlanta, GA, USA. · Vascular Biology Program, Department of Surgery Children's Hospital Boston, Boston, MA, USA. · Karp Family Research Laboratories, Harvard Medical School, Boston, MA, USA. · Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. ·Oncotarget · Pubmed #27438140.

ABSTRACT: Pancreatic carcinoma ranks among the most lethal of human cancers. Besides late detection, other factors contribute to its lethality, including a high degree of chemoresistance, invasion, and distant metastases. Currently, the mainstay of therapy involves resection of local disease in a minority of patients (Whipple procedure) and systemic gemcitabine. While systemic chemotherapy has some benefit, even with optimal treatment, the five year survival after diagnosis is dismal. Thus, treatment of pancreatic carcinoma remains a tremendous unmet need.The organometallic compound tris DBA palladium is a potent inhibitor of N-myristoyltransferase 1 (NMT1), an enzyme that catalyzes the transfer of myristate to protein substrates. This compound is highly effective in vivo against murine models of melanoma with both mutant and wild type b-RAF genotypes. Based upon the signaling similarities between melanoma and pancreatic carcinoma, we evaluated the efficacy of tris DBA palladium in vitro and in vivo against pancreatic carcinoma. We found that tris DBA palladium decreased proliferation and colony formation of pancreatic cancer cells in vitro. In an orthotopic mouse model, tris DBA palladium was highly active in inhibiting growth, ascites production, and distant metastases in vivo. Furthermore, tris DBA palladium impaired chemotaxis and inhibited cilia formation in Pan02 cells in a NMT1-dependent manner. We propose that NMT1 is a novel regulator of cilia formation and tris DBA palladium a novel inhibitor of cilia formation and metastasis in pancreatic cancer. Thus, further evaluation of tris DBA palladium for the treatment of pancreatic cancer is warranted.

22 Article Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms:  A Potential Diagnostic Pitfall. 2016

Askan, Gokce / Deshpande, Vikram / Klimstra, David S / Adsay, Volkan / Sigel, Carlie / Shia, Jinru / Basturk, Olca. ·From the Memorial Sloan Kettering Cancer Center, New York, NY. · Massachusetts General Hospital, Boston. · Emory University, Atlanta, GA. · From the Memorial Sloan Kettering Cancer Center, New York, NY basturko@mskcc.org. ·Am J Clin Pathol · Pubmed #27425386.

ABSTRACT: OBJECTIVES: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that frequently metastasizes to the liver and may present a diagnostic challenge due to its morphologic similarity to hepatocellular carcinoma. We investigated α-fetoprotein (AFP), hepatocyte paraffin antigen 1 (HepPar 1), glypican 3, arginase 1, and albumin messenger RNA (mRNA) in situ hybridization (ISH) in pancreatic neoplasms with ACC differentiation to assess their diagnostic value. METHODS: AFP, HepPar 1, glypican 3, and arginase 1 immunohistochemical staining was performed on 28 ACCs using a tissue microarray. Albumin mRNA ISH was performed on full-faced sections. RESULTS: Fifteen tumors were positive for at least one marker. Glypican 3 was positive in seven of 28, AFP in five 28, and albumin mRNA ISH in five of 20. None expressed arginase 1. CONCLUSIONS: Hepatocellular differentiation markers, including albumin mRNA ISH, may be positive in ACC, but arginase 1 appears to be uniformly negative. Thus, its use may improve the accuracy in distinguishing these neoplasms from hepatocellular carcinoma. If ACC diagnosis is considered, acinar differentiation can be reliably demonstrated by trypsin/chymotrypsin.

23 Article The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes. 2016

Basturk, Olca / Tan, Marcus / Bhanot, Umesh / Allen, Peter / Adsay, Volkan / Scott, Sasinya N / Shah, Ronak / Berger, Michael F / Askan, Gokce / Dikoglu, Esra / Jobanputra, Vaidehi / Wrzeszczynski, Kazimierz O / Sigel, Carlie / Iacobuzio-Donahue, Christine / Klimstra, David S. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Surgery, University of South Alabama, Mobile, AL, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Pathology, Emory University, Atlanta, GA, USA. · Department of Molecular Diagnostics, New York Genome Center, New York, USA. · Department of Pathology, Columbia University Medical Center, New York, USA. ·Mod Pathol · Pubmed #27282351.

ABSTRACT: In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the 'oncocytic subtype' of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms. Nine pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median=4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical 'oncocytic subtype' of intraductal papillary mucinous neoplasms but not in the other two atypical ones. In the neoplasm with flat oncocytic epithelium, the only mutated gene was KRAS. All components of the intestinal subtype intraductal papillary mucinous neoplasms with focal oncocytic epithelium manifested TP53, GNAS, and RNF43 mutations. In conclusion, this study elucidates that 'oncocytic subtype' of intraductal papillary mucinous neoplasm is not only morphologically distinct but also genetically distinct from other intraductal papillary mucinous neoplasm subtypes. Considering that now its biologic behavior is also being found to be different than other intraductal papillary mucinous neoplasm subtypes, 'oncocytic subtype' of intraductal papillary mucinous neoplasm warrants being recognized separately.

24 Article Pancreatic Ductal Adenocarcinoma is Spread to the Peripancreatic Soft Tissue in the Majority of Resected Cases, Rendering the AJCC T-Stage Protocol (7th Edition) Inapplicable and Insignificant: A Size-Based Staging System (pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is More Valid and Clinically Relevant. 2016

Saka, Burcu / Balci, Serdar / Basturk, Olca / Bagci, Pelin / Postlewait, Lauren M / Maithel, Shishir / Knight, Jessica / El-Rayes, Bassel / Kooby, David / Sarmiento, Juan / Muraki, Takashi / Oliva, Irma / Bandyopadhyay, Sudeshna / Akkas, Gizem / Goodman, Michael / Reid, Michelle D / Krasinskas, Alyssa / Everett, Rhonda / Adsay, Volkan. ·Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Istanbul Medipol University, Istanbul, Turkey. · Yildirim Beyazit University, Ankara, Turkey. · Department of Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Marmara University, Istanbul, Turkey. · Department of Surgical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Epidemiology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of General Surgery, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. volkan.adsay@emory.edu. ·Ann Surg Oncol · Pubmed #26832882.

ABSTRACT: BACKGROUND: Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. METHODS: To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. RESULTS: Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2-4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001). CONCLUSIONS: This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

25 Article TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer. 2016

La Rosa, Stefano / Bernasconi, Barbara / Frattini, Milo / Tibiletti, Maria Grazia / Molinari, Francesca / Furlan, Daniela / Sahnane, Nora / Vanoli, Alessandro / Albarello, Luca / Zhang, Lizhi / Notohara, Kenji / Casnedi, Selenia / Chenard, Marie-Pierre / Adsay, Volkan / Asioli, Sofia / Capella, Carlo / Sessa, Fausto. ·Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy. stefano.larosa@ospedale.varese.it. · Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. · Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland. · Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Department of Pathology, Kurashiki Central Hospital, Kurashiki, Japan. · Centre de Pathologie, Strasbourg, France. · Department of Pathology, Hospital De Hautepierre, Strasbourg, France. · Department of Pathology, Emory University, Atlanta, GA, USA. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. ·Virchows Arch · Pubmed #26586531.

ABSTRACT: The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

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