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Pancreatic Neoplasms: HELP
Articles by Olca Baştürk
Based on 58 articles published since 2010
(Why 58 articles?)
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Between 2010 and 2020, Olca Basturk wrote the following 58 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
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 Review Intraductal Neoplasms of the Pancreas: An Update. 2017

Aşkan, Gökçe / Bağci, Pelin / Memiş, Bahar / Baştürk, Olca. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, NEW YORK, NY, USA. ·Turk Patoloji Derg · Pubmed #28272684.

ABSTRACT: With improvements in imaging to detect silent pancreatic lesions and increases in the number of centers now performing pancreatic surgery, more surgeries have been performed for indications other than invasive carcinoma. This has enormously added to our knowledge of the intraductal neoplasms of the pancreas. In addition, our understanding of the genetics of these lesions has expanded with the introduction of routine molecular genetic analyses. In this review, we provide an update into the most common intraductal neoplasms, namely intraductal papillary mucinous neoplasm and intraductal tubulopapillary neoplasm. We first focus on their clinicopathologic and molecular features of relevance to the practicing pathologist and then discuss their differential diagnoses.

3 Review Benign Tumors and Tumorlike Lesions of the Pancreas. 2016

Basturk, Olca / Askan, Gokce. ·Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: basturko@mskcc.org. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Surg Pathol Clin · Pubmed #27926363.

ABSTRACT: The pancreas is a complex organ that may give rise to large number of neoplasms and non-neoplastic lesions. This article focuses on benign neoplasms, such as serous neoplasms, and tumorlike (pseudotumoral) lesions that may be mistaken for neoplasm not only by clinicians and radiologists, but also by pathologists. The family of pancreatic pseudotumors, by a loosely defined conception of that term, includes a variety of lesions including heterotopia, hamartoma, and lipomatous pseudohypertrophy. Autoimmune pancreatitis and paraduodenal ("groove") pancreatitis may also lead to pseudotumor formation. Knowledge of these entities will help in making an accurate diagnosis.

4 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.

5 Review ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. 2015

Maragliano, Roberta / Vanoli, Alessandro / Albarello, Luca / Milione, Massimo / Basturk, Olca / Klimstra, David S / Wachtel, Antonio / Uccella, Silvia / Vicari, Emanuela / Milesi, Marina / Davì, Maria Vittoria / Scarpa, Aldo / Sessa, Fausto / Capella, Carlo / La Rosa, Stefano. ·*Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy ‡‡Department of Pathology, Ospedale di Circolo, Varese, Italy †Department of Molecular Medicine, University of Pavia, Pavia, Italy ‡Department of Pathology, San Raffaele Hospital, Milan, Italy §Department of Pathology, National Institute of Cancer, Milan, Italy #Department of Pathology, Multimedica, Milan, Italy **Department of Medicine, "G.B. Rossi" University Hospital, Verona, Italy ††ARC-NET Research Center and Department of Pathology and Diagnostics, University of Verona, Verona, Italy ∥Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY ¶Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru. ·Am J Surg Pathol · Pubmed #25353285.

ABSTRACT: Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.

6 Review Intraductal neoplasms of the pancreas. 2014

Klöppel, Günter / Basturk, Olca / Schlitter, Anna Melissa / Konukiewitz, Björn / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. Electronic address: guenter.kloeppel@lrz.tum.de. · Memorial Sloan-Kettering Cancer Center, New York, New York. · Institute of Pathology, Technische Universität München, Munich, Germany. ·Semin Diagn Pathol · Pubmed #25282472.

ABSTRACT: There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions.

7 Review Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement. 2012

Adsay, N Volkan / Bagci, Pelin / Tajiri, Takuma / Oliva, Irma / Ohike, Nobuyuki / Balci, Serdar / Gonzalez, Raul S / Basturk, Olca / Jang, Kee-Taek / Roa, Juan Carlos. ·Department of Pathology, Emory University, School of Medicine, Atlanta, Georgia, USA. volkan.adsay@emory.edu ·Semin Diagn Pathol · Pubmed #23062420.

ABSTRACT: Tumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the gallbladder does not have the distinct layering of the other gastrointestinal organs, the definitions of Tis/T1a/T1b lack practicality, and therefore, "early gallbladder carcinoma" category proposed in high-risk regions may have to be recognized instead. Involvement of the Rokitansky-Aschoff sinuses should be a part of the evaluation and management of these early gallbladder cancers; for advanced cancers, documentation of hepatic versus serosal involvement is necessary. In summary, T-staging of ampulla-pancreatobiliary tract tumors has many challenges. Proper grossing and appreciation of histo-anatomic subtleties of this region are crucial in addressing these issues and achieving more applicable and clinically relevant staging systems in the future.

8 Article Whipple Grossing in the Era of New Staging: Should We Standardize? 2019

Shi, Jiaqi / Basturk, Olca. ·Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. jiaqis@umich.edu. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. BasturkO@mskcc.org. ·Diagnostics (Basel) · Pubmed #31569496.

ABSTRACT: Whipple procedure, also known as pancreatoduodenectomy, is the most common surgery for the removal of tumors of the head of the pancreas, ampulla, distal common bile duct, or periampullary duodenum. It is also one of the most challenging resection specimens grossed by surgical pathologists. A thorough and consistent evaluation of the gross surgical specimen is the most critical first step for accurate diagnosis, determination of tumor origin, staging, and evaluation of margin status. However, there has been no standard grossing protocol for Whipple specimens, which has led to inaccurate diagnoses, staging, and inconsistent reporting. This issue has become even more challenging in the era of the size-based tumor staging systems recommended by the new 8th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Moreover, new concerns have been raised regarding how to best evaluate margin status and lymph nodes. Studies have shown that different Whipple grossing methods can significantly impact margin assessment and lymph node yield and thus affect R0/R1 status and clinical stage. Other important issues under debate include nomenclature, definitions of margin (versus surface), and R1 status. Consistent Whipple grossing and standardization of reporting will provide better communication and more accurate diagnosis and staging, as well as prognostic prediction.

9 Article CT radiomics associations with genotype and stromal content in pancreatic ductal adenocarcinoma. 2019

Attiyeh, Marc A / Chakraborty, Jayasree / McIntyre, Caitlin A / Kappagantula, Rajya / Chou, Yuting / Askan, Gokce / Seier, Kenneth / Gonen, Mithat / Basturk, Olca / Balachandran, Vinod P / Kingham, T Peter / D'Angelica, Michael I / Drebin, Jeffrey A / Jarnagin, William R / Allen, Peter J / Iacobuzio-Donahue, Christine A / Simpson, Amber L / Do, Richard K. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, C-276F, New York, NY, 10065, USA. dok@mskcc.org. ·Abdom Radiol (NY) · Pubmed #31243486.

ABSTRACT: PURPOSE: The aim of this study was to investigate the relationship between CT imaging phenotypes and genetic and biological characteristics in pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective study, consecutive patients between April 2015 and June 2016 who underwent PDAC resection were included if previously consented to a targeted sequencing protocol. Mutation status of known PDAC driver genes (KRAS, TP53, CDKN2A, and SMAD4) in the primary tumor was determined by targeted DNA sequencing and results were validated by immunohistochemistry (IHC). Radiomic features of the tumor were extracted from the preoperative CT scan and used to predict genotype and stromal content. RESULTS: The cohort for analysis consisted of 35 patients. Genomic and IHC analysis revealed alterations in KRAS in 34 (97%) patients, and changes in expression of CDKN2A in 29 (83%), SMAD4 in 16 (46%), and in TP53 in 29 (83%) patients. Models created from radiomic features demonstrated associations with SMAD4 status and the number of genes altered. The number of genes altered was the only significant predictor of overall survival (p = 0.016). By linear regression analysis, a prediction model for stromal content achieved an R CONCLUSIONS: In this study, we demonstrate that in PDAC SMAD4 status and tumor stromal content can be predicted using radiomic analysis of preoperative CT imaging. These data show an association between resectable PDAC imaging features and underlying tumor biology and their potential for future precision medicine.

10 Article Progression Patterns in the Remnant Pancreas after Resection of Non-Invasive or Micro-Invasive Intraductal Papillary Mucinous Neoplasms (IPMN). 2018

Al Efishat, Mohammad / Attiyeh, Marc A / Eaton, Anne A / Gönen, Mithat / Basturk, Olca / Klimstra, David / D'Angelica, Michael I / DeMatteo, Ronald P / Kingham, T Peter / Balachandran, Vinod / Jarnagin, William R / Allen, Peter J. ·Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. allenp@mskcc.org. ·Ann Surg Oncol · Pubmed #29589164.

ABSTRACT: BACKGROUND: Although IPMN are thought to represent a whole-gland disease, segmental resection remains the most frequently performed treatment. We sought to determine the rates, patterns, and predictors of IPMN progression in the pancreatic remnant following segmental resection of noninvasive or microinvasive IPMN. METHODS: A prospectively maintained database was queried to identify all patients who underwent resection of noninvasive or microinvasive IPMN (≤ 10 mm of invasive component) between 1989 and 2015. Progression (recurrence) was defined as either the development of cancer, a new IPMN cystic lesion > 1 cm or ≥ 50% increase in the diameter of residual IPMN lesions in the remnant. Univariate and multivariate cox regression models were created to determine predictors of progression. RESULTS: A total of 319 patients underwent resection for noninvasive and microinvasive IPMN. The median age was 68, 53% had branch-duct (BD) IPMN, and 6% had microinvasive disease. After a median follow-up of 42 months, 71 patients (22%) experienced IPMN progression. Within this group of 71 patients, 11 (16% of recurrence) developed invasive cancer in the pancreatic remnant after a median of 28 months. Twelve patients (17%) experienced progression > 5 years following initial resection. On multivariate analysis, a distal location of the initial lesion was associated with an increased risk of progression (multivariate hazards ratio = 2.43, confidence interval 1.47-4.0, p < 0.001). CONCLUSIONS: In this study, 22% of patients had disease progression following resection of noninvasive or microinvasive IPMN; 16% of these progressions represented invasive disease. These patients represent a high-risk group and should undergo long-term radiographic surveillance.

11 Article Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence? 2018

Jordan, Emmet J / Lowery, Maeve A / Basturk, Olca / Allen, Peter J / Yu, Kenneth H / Tabar, Viviane / Beal, Kathryn / Reidy, Diane L / Yamada, Yoshiya / Janjigian, Yelena / Abou-Alfa, Ghassan K / O'Reilly, Eileen M. ·Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. · Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. · Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY. · Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. · Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY. Electronic address: oreillye@mskcc.org. ·Clin Colorectal Cancer · Pubmed #29496399.

ABSTRACT: PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach.

12 Article Well differentiated grade 3 pancreatic neuroendocrine tumors compared with related neoplasms: A morphologic study. 2018

Sigel, Carlie S / Krauss Silva, Vitor Werneck / Reid, Michelle D / Chhieng, David / Basturk, Olca / Sigel, Keith M / Daniel, Tanisha D / Klimstra, David S / Tang, Laura H. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Emory University Hospital, Atlanta, Georgia. · Department of Pathology, University of Washington, Seattle, Washington. · Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. ·Cancer Cytopathol · Pubmed #29451738.

ABSTRACT: BACKGROUND: Pancreatic neuroendocrine neoplasms with a Ki-67 labeling index greater than 20% were reclassified in 2017 by the World Health Organization into well differentiated (WD) and poorly differentiated grade 3 neuroendocrine carcinoma (NEC). The authors describe the cytologic features of grade 3 WD pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NEC. METHODS: Fine-needle aspirates from 65 pancreatic neuroendocrine neoplasms were reviewed, and their cytomorphologic features were compared across grade 2, WD grade 3, and PD small cell type (PD-S), large cell type (PD-L), and type not otherwise specified (PD-NOS) neoplasms. RESULTS: The 65 aspirates consisted of 19 grade 2 neoplasms, 32 WD grade 3 neoplasms, and 14 NECs (6 PD-S, 5 PD-L, and 3 PD-NOS). The medians Ki-67 proliferation index was 11% (range, 3.2%-17%) in grade 2 neoplasms, 40% (range, 21%-89%) in WD grade 3 neoplasms, 80% (range, 63%-95%) in PD-S neoplasms, 39% (range, 25%-61%) in PD-L neoplasms, and 70% (range, 30%-80%) in PD-NOS neoplasms. Both grade 2 and WD grade 3 neoplasms were associated with plasmacytoid morphology and smooth nuclear contours, but WD grade 3 neoplasms had significant increases in abundant cytoplasm (72% vs 17%; P = .007), nuclear tangles (75% vs 42%; P = .006), and apoptosis (86% vs 58%; P = .005). Compared with NECs, WD grade 3 neoplasms had increased plasmacytoid morphology (75% vs 7%; P < .001), smooth nuclear contours (94% vs 64%; P = .02), round nuclei (59% vs 21%; P = .01), and less pleomorphism (13% vs 50%; P = .004), molding (9% vs 79%; P < .001), and necrosis (13% vs 43%; P = .003). WD grade 3 neoplasms had less pleomorphism (13% vs 50%; P = .04), less necrosis (13% vs 60%; P = .04), and more plasmacytoid morphology (75% vs 20%; P = .03) than PD-L. CONCLUSIONS: The prevalence of cytologic features differs in WD grade 3 pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NECs, and these differences assist in the recognition of this newly classified entity. Cancer Cytopathol 2018;126:326-35. © 2018 American Cancer Society.

13 Article Imaging features of malignant abdominal neuroendocrine tumors with rare presentation. 2018

Corrias, Giuseppe / Monti, Serena / Horvat, Natally / Tang, Laura / Basturk, Olca / Saba, Luca / Mannelli, Lorenzo. ·Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Radiology, University of Cagliari, Via Università, 40, 09124 Cagliari, CA, Italy. · IRCCS SDN, Naples, Italy. · Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Radiology, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Department of Radiology, Universidade de São Paulo, São Paulo, SP, Brazil. · Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: tangl@mskcc.org. · Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: basturko@mskcc.org. · Department of Radiology, University of Cagliari, Via Università, 40, 09124 Cagliari, CA, Italy. · Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: mannellilorenzo@yahoo.it. ·Clin Imaging · Pubmed #29448120.

ABSTRACT: BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (NETs) are rare entities arising from neuroendocrine cells in the gastroenteric tract and pancreas. The purpose of this article is to present four cases of gastroenteropancreatic NETs that featured a challenging diagnosis. CASE PRESENTATION: We report a case series of four NETs, each with different features. All NETs were suspected based on clinical and biochemical data. The workup of the abnormalities was performed with CT, PET or MRI. CONCLUSION: The diagnosis of NETs is challenging and generally based on clinical manifestations, blood biochemical tests, imaging techniques, and pathology.

14 Article Extracellular matrix proteins and carcinoembryonic antigen-related cell adhesion molecules characterize pancreatic duct fluid exosomes in patients with pancreatic cancer. 2018

Zheng, Jian / Hernandez, Jonathan M / Doussot, Alexandre / Bojmar, Linda / Zambirinis, Constantinos P / Costa-Silva, Bruno / van Beek, Elke J A H / Mark, Milica T / Molina, Henrik / Askan, Gokce / Basturk, Olca / Gonen, Mithat / Kingham, T Peter / Allen, Peter J / D'Angelica, Michael I / DeMatteo, Ronald P / Lyden, David / Jarnagin, William R. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Children's Cancer and Blood Foundation Laboratories, Department of Pediatrics, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA; Department of Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Proteomics Resource Center, The Rockefeller University, New York, NY, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: jarnagiw@mskcc.org. ·HPB (Oxford) · Pubmed #29339034.

ABSTRACT: BACKGROUND: Exosomes are nanovesicles that have been shown to mediate carcinogenesis in pancreatic ductal adenocarcinoma (PDAC). Given the direct communication of pancreatic duct fluid with the tumor and its relative accessibility, we aimed to determine the feasibility of isolating and characterizing exosomes from pancreatic duct fluid. METHODS: Pancreatic duct fluid was collected from 26 patients with PDAC (n = 13), intraductal papillary mucinous neoplasm (IPMN) (n = 8) and other benign pancreatic diseases (n = 5) at resection. Exosomes were isolated by serial ultracentrifugation, proteins were identified by mass spectrometry, and their expression was evaluated by immunohistochemistry. RESULTS: Exosomes were isolated from all specimens with a mean concentration of 5.9 ± 1 × 10 CONCLUSION: This is the first study showing that exosome isolation is feasible from pancreatic duct fluid, and that exosomal proteins may be utilized to diagnose patients with PDAC.

15 Article Assessment of cytologic differentiation in high-grade pancreatic neuroendocrine neoplasms: A multi-institutional study. 2018

Sigel, Carlie S / Krauss Silva, Vitor Werneck / Reid, Michelle D / Chhieng, David / Basturk, Olca / Sigel, Keith M / Daniel, Tanisha D / Klimstra, David S / Tang, Laura H. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Emory University Hospital, Atlanta, Georgia. · Department of Pathology, University of Washington, Seattle, Washington. · Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. ·Cancer Cytopathol · Pubmed #29044913.

ABSTRACT: BACKGROUND: Well-differentiated (WD) and poorly differentiated (PD) pancreatic neuroendocrine neoplasms are biologically distinct entities with different therapies and prognoses. WD neoplasms with elevated proliferation (Ki-67 > 20%) have been shown to have an overlapping histology with PD neuroendocrine carcinomas. This study compared expert cytomorphologic assessments of differentiation in pancreatic neuroendocrine neoplasms in a multi-institutional study. METHODS: Fine-needle aspiration specimens from pancreatic neuroendocrine neoplasms (grade 2 [G2] and grade 3 [G3] according to the 2017 World Health Organization classification; n = 72) were diagnosed independently by 3 cytopathologists as WD or PD (poorly differentiated large cell type [PD-L] or poorly differentiated small cell type [PD-S]) purely on the basis of cytomorphology. Their diagnoses were compared with a final classification supported by immunohistochemistry (retinoblastoma (RB), death domain- associated protein (DAXX), and α thalassemia/mental retardation syndrome X-linked (ATRX) protein expression), targeted mutation analysis (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), prior history of G1/G2 histology, and consensus. RESULTS: The rate of agreement on differentiation was 38% (15 WD cases and 12 PD cases) for the 70 cases included (55 WD cases [n = 19 G2, n = 31 G3, and n = 5 could not be graded] and 15 PD cases [n = 6 PD-S, n = 6 PD-L, and n = 3 PD, not otherwise specified). Two cases could not be classified by the employed methods. PD carcinomas had a higher rate of agreement (10 of 15 [67%]) than WD neoplasms (15 of 55 [27%]). Round nuclei and plasmacytoid cells were associated with agreement for WD cases, whereas apoptosis and angulated nuclei were associated with disagreement. Necrosis was associated with agreement for PD cases. CONCLUSIONS: A purely morphologic approach to the distinction between G2 and G3 pancreatic neuroendocrine neoplasms based on cytology can be challenging, with disagreement found among experienced cytopathologists. Cancer Cytopathol 2018;126:44-53. © 2017 American Cancer Society.

16 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.

17 Article Malignant transformation of glucagonoma with SPECT/CT In-111 OctreoScan features: A case report. 2017

Corrias, Giuseppe / Horvat, Natally / Monti, Serena / Basturk, Olca / Lin, Oscar / Saba, Luca / Bodei, Lisa / Reidy, Diane L / Mannelli, Lorenzo. ·Department of Radiology, Memorial Sloan Kettering Cancer Center, NY. · Department of Radiology, University of Cagliari, Cagliari, Italy. · Department of Radiology, Hospital Sírio-Libanês, São Paulo. · Department of Radiology, Universidade de São Paulo, São Paulo, SP, Brazil. · IRCCS SDN, Naples, Italy. · Department of Pathology. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. ·Medicine (Baltimore) · Pubmed #29390362.

ABSTRACT: RATIONALE: Glucagonoma is an uncommon disease but it has been associated with a pattern of symptoms defined as glucagonoma syndrome. These symptoms, if promptly recognized, could help to speed up the diagnosing process. PATIENT CONCERNS: We report a case of a 68-year-old woman with a pancreatic glucagonoma. Her symptoms at the onset were typical of the glucagonoma syndrome. DIAGNOSES: After a significant weight loss, she underwent a computer tomography scan of the abdomen, which showed a hypervascular lesion of the tail of the pancreas and hypervascular lesions of the liver. An ultrasound guided biopsy was performed and pathology was consistent with glucagonoma. Her blood glucagon levels were elevated. OUTCOMES: She was treated with chemotherapy and somatostatin analogs. After 4 years, the disease had a malignant transformation, and metastases suddenly started to grow up. She stopped being responsive to treatment and eventually passed away. LESSONS: Due to its rarity, clinical diagnosis is challenging and generally it comes after a long interval since the onset of symptoms. Awareness of physicians and dermatologists of the characteristic necrolytic migratory erythema, and of the other symptoms, often leads to early diagnosis.

18 Article Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. 2017

Balachandran, Vinod P / Łuksza, Marta / Zhao, Julia N / Makarov, Vladimir / Moral, John Alec / Remark, Romain / Herbst, Brian / Askan, Gokce / Bhanot, Umesh / Senbabaoglu, Yasin / Wells, Daniel K / Cary, Charles Ian Ormsby / Grbovic-Huezo, Olivera / Attiyeh, Marc / Medina, Benjamin / Zhang, Jennifer / Loo, Jennifer / Saglimbeni, Joseph / Abu-Akeel, Mohsen / Zappasodi, Roberta / Riaz, Nadeem / Smoragiewicz, Martin / Kelley, Z Larkin / Basturk, Olca / Anonymous6670926 / Anonymous6680926 / Anonymous6690926 / Anonymous6700926 / Anonymous6710926 / Anonymous6720926 / Anonymous6730926 / Anonymous6740926 / Anonymous6750926 / Anonymous6760926 / Anonymous6770926 / Anonymous6780926 / Anonymous6790926 / Anonymous6800926 / Anonymous6810926 / Anonymous6820926 / Anonymous6830926 / Anonymous6840926 / Anonymous6850926 / Anonymous6860926 / Anonymous6870926 / Anonymous6880926 / Gönen, Mithat / Levine, Arnold J / Allen, Peter J / Fearon, Douglas T / Merad, Miriam / Gnjatic, Sacha / Iacobuzio-Donahue, Christine A / Wolchok, Jedd D / DeMatteo, Ronald P / Chan, Timothy A / Greenbaum, Benjamin D / Merghoub, Taha / Leach, Steven D. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK. · Cold Spring Harbor Laboratory, New York, New York, USA. · Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA. · Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Weill Cornell Medical College, Cornell University, New York, New York, USA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Tisch Cancer Institute, Departments of Medicine, Hematology and Medical Oncology, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire, USA. ·Nature · Pubmed #29132146.

ABSTRACT: Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8

19 Article Pancreatoblastoma With Metastatic Retroperitoneal Lymph Node and PET/CT. 2017

Corrias, Giuseppe / Ragucci, Monica / Basturk, Olca / Saba, Luca / Mannelli, Lorenzo. ·From the *Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY; †Department of Radiology, University of Cagliari, Via Università, Cagliari; ‡IRCCS SDN, Naples, Italy; and §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. ·Clin Nucl Med · Pubmed #28872552.

ABSTRACT: A previously healthy 4-year-old girl presented with petechial rash and low platelet count. There were no other symptoms. On abdominal ultrasound, a 4.7-cm heterogeneous mass was demonstrated anterior to the left kidney. An abdominal MRI subsequently performed demonstrated a heterogeneously enhancing mass at the same location extending to the pancreas and spleen. A surgical biopsy of the mass was obtained. Pathology reported a malignant epithelioid neoplasm consistent with pancreatoblastoma. The mass demonstrated intense FDG uptake on PET and an FDG avid retrocaval lymph node.

20 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.

21 Article Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype. 2017

Lowery, Maeve A / Jordan, Emmet J / Basturk, Olca / Ptashkin, Ryan N / Zehir, Ahmet / Berger, Michael F / Leach, Tanisha / Herbst, Brian / Askan, Gokce / Maynard, Hannah / Glassman, Danielle / Covington, Christina / Schultz, Nikolaus / Abou-Alfa, Ghassan K / Harding, James J / Klimstra, David S / Hechtman, Jaclyn F / Hyman, David M / Allen, Peter J / Jarnagin, William R / Balachandran, Vinod P / Varghese, Anna M / Schattner, Mark A / Yu, Kenneth H / Saltz, Leonard B / Solit, David B / Iacobuzio-Donahue, Christine A / Leach, Steven D / O'Reilly, Eileen M. ·Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. maevelowery@gmail.com oreillye@mskcc.org. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medicine, Weill Cornell Medical College, New York, New York. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. ·Clin Cancer Res · Pubmed #28754816.

ABSTRACT:

22 Article O6-Methylguanine DNA Methyltransferase Status Does Not Predict Response or Resistance to Alkylating Agents in Well-Differentiated Pancreatic Neuroendocrine Tumors. 2017

Raj, Nitya / Klimstra, David S / Horvat, Natally / Zhang, Liying / Chou, Joanne F / Capanu, Marinela / Basturk, Olca / Do, Richard Kinh Gian / Allen, Peter J / Reidy-Lagunes, Diane. ·From the Departments of *Medicine, †Pathology, ‡Radiology, §Biostatistics, and ∥Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. ·Pancreas · Pubmed #28609363.

ABSTRACT: OBJECTIVES: Alkylating agents have activity in well-differentiated pancreatic neuroendocrine tumors (WD panNETs). In glioblastoma multiforme, decreased activity of O-methylguanine DNA methyltransferase (MGMT) predicts response; in panNETs, MGMT relevance is unknown. METHODS: We identified patients with WD panNETs treated with alkylating agents, determined best overall response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and performed MGMT activity testing. RESULTS: Fifty-six patients were identified; 26 (46%) of the 56 patients experienced partial response, 24 (43%) of 56 experienced stable disease, and 6 (11%) of 56 experienced progression of disease. O-methylguanine DNA methyltransferase status was available for 36 tumors. For tumors with partial response, 10 (67%) of 15 were MGMT deficient, and 5 (33%) of 15 were MGMT intact. For tumors with stable disease, 7 (47%) of 15 were MGMT deficient, and 8 (53%) of 15 were MGMT intact. For tumors with progression of disease, 3 (50%) of 6 were MGMT deficient, and 3 (50%) of 6 were MGMT intact. CONCLUSIONS: We observed response and resistance to alkylating agents in MGMT-deficient and MGMT-intact tumors. O-methylguanine DNA methyltransferase status should not guide alkylating agent therapy in WD panNETs.

23 Article PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk. 2017

Sinha, Smrita / Fu, Ya-Yuan / Grimont, Adrien / Ketcham, Maren / Lafaro, Kelly / Saglimbeni, Joseph A / Askan, Gokce / Bailey, Jennifer M / Melchor, Jerry P / Zhong, Yi / Joo, Min Geol / Grbovic-Huezo, Olivera / Yang, In-Hong / Basturk, Olca / Baker, Lindsey / Park, Young / Kurtz, Robert C / Tuveson, David / Leach, Steven D / Pasricha, Pankaj J. ·David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Gastroenterology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland. · Weill Cornell Medical College, New York, New York. · Gastrointestinal Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. leachs@mskcc.org ppasric1@jhmi.edu. · Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, Maryland. leachs@mskcc.org ppasric1@jhmi.edu. ·Cancer Res · Pubmed #28386018.

ABSTRACT: Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of STAT3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial cross-talk as a potential novel target in PDAC treatment.

24 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.

25 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.

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