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Facciorusso A, Arvanitakis M, Crinò SF, Fabbri C, Fornelli A, Leeds J, Archibugi L, Carrara S, Dhar J, Gkolfakis P, Haugk B, Iglesias Garcia J, Napoleon B, Papanikolaou IS, Seicean A, Stassen PMC, Vilmann P, Tham TC, Fuccio L. Endoscopic ultrasound-guided tissue sampling: European Society of Gastrointestinal Endoscopy (ESGE) Technical and Technology Review. Endoscopy 2025; 57:390-418. [PMID: 40015316 DOI: 10.1055/a-2524-2596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
This Technical and Technology Review from the European Society of Gastrointestinal Endoscopy (ESGE) represents an update of the previous document on the technical aspects of endoscopic ultrasound (EUS)-guided sampling in gastroenterology, including the available types of needle, technical aspects of tissue sampling, new devices, and specimen handling and processing. Among the most important new recommendations are:ESGE recommends end-cutting fine-needle biopsy (FNB) needles over reverse-bevel FNB or fine-needle aspiration (FNA) needles for tissue sampling of solid pancreatic lesions; FNA may still have a role when rapid on-site evaluation (ROSE) is available.ESGE recommends EUS-FNB or mucosal incision-assisted biopsy (MIAB) equally for tissue sampling of subepithelial lesions ≥20 mm in size. MIAB could represent the first choice for smaller lesions (<20 mm) if proper expertise is available.ESGE does not recommend the use of antibiotic prophylaxis before EUS-guided tissue sampling of solid masses and EUS-FNA of pancreatic cystic lesions.
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Affiliation(s)
- Antonio Facciorusso
- Department of Experimental Medicine, Section of Gastroenterology, University of Salento, Lecce, Italy
| | - Marianna Arvanitakis
- Department of Gastroenterology, Digestive Oncology and Hepatopancreatology, HUB Hôpital Erasme, Brussels, Belgium
| | - Stefano Francesco Crinò
- Department of Medicine, Gastroenterology and Digestive Endoscopy Unit, The Pancreas Institute, University Hospital of Verona, Verona, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, AUSL Romagna, Forlì-Cesena, Italy
| | - Adele Fornelli
- Pathology Unit, Ospedale Maggiore "C.A. Pizzardi", AUSL Bologna, Bologna, Italy
| | - John Leeds
- Department of Gastroenterology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Livia Archibugi
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Carrara
- Department of Biomedical Sciences, Humanitas Pieve Emanuele University, Milan, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jahnvi Dhar
- Department of Gastroenterology and Hepatology, Punjab Institute of Liver and Biliary Sciences, Mohali, India
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, "Konstantopoulio-Patision" General Hospital of Nea Ionia, Athens, Greece
| | - Beate Haugk
- Department of Cellular Pathology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Julio Iglesias Garcia
- Department of Gastroenterology and Hepatology, Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela, Santiago, Spain
| | - Bertrand Napoleon
- Department of Gastroenterology, Hôpital privé Jean Mermoz, Lyon, France
| | - Ioannis S Papanikolaou
- Hepatogastroenterology Unit, Second Department of Propaedeutic Internal Medicine, Medical School, National and Kapodastrian University of Athens, Attikon University General Hospital, Athens, Greece
| | - Andrada Seicean
- Department of Gastroenterology, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Pauline M C Stassen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Peter Vilmann
- Gastroenterology Unit, Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Tony C Tham
- Division of Gastroenterology, Ulster Hospital, Belfast, Northern Ireland
| | - Lorenzo Fuccio
- Department of Medical Sciences and Surgery, University of Bologna, Bologna, Italy
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Kwan MC, Pitman MB, Zhang ML. Cytologic, histologic, and clinical correlation of minor mutations in pancreatic cysts. Cancer Cytopathol 2025; 133:e22935. [PMID: 39865498 DOI: 10.1002/cncy.22935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/19/2024] [Accepted: 12/05/2024] [Indexed: 01/28/2025]
Abstract
BACKGROUND Major mutations (e.g., KRAS, GNAS, TP53, SMAD4) in pancreatic cyst fluid (PCF) are useful for classifying and risk stratifying certain cyst types, particularly in cases with nondiagnostic cytology. However, the significance of uncommon minor mutations in PCF has yet to be reported. METHODS In total, 127 PCF specimens (2014-2021) from 121 patients that underwent molecular analysis were identified, and detailed clinicopathologic data were recorded. Molecular testing was performed using a laboratory-developed next-generation sequencing panel. RESULTS Forty-five variants other than KRAS, GNAS, RNF43, TP53, CDKN2A, and SMAD4 were detected. Variants that were detected in five or more cases included ARID1A (n = 28), VHL (n = 17), BRAF (n = 12), ATM (n = 8), APC (n = 8), MEN1 (n = 5), serine threonine kinase 11 (STK11; n = 5), PIK3CA (n = 5), and CDH1 (n = 5). Thirty-eight of 121 patients (31%) had histologic confirmation on follow-up resection. Twenty-seven of 28 cysts (96%) with ARID1A mutations had concurrent KRAS/GNAS mutations; 17 (61%) were diagnosed as neoplastic mucinous cysts on cytology, and 10 (36%) were diagnosed as intraductal papillary mucinous neoplasm (IPMN) on histology (80% low grade). No patients developed disease recurrence or died of disease. Cysts with STK11 mutations had RAS co-mutations (KRAS, n = 5; NRAS, n = 1), and four of those five cysts (80%) were mucinous neoplasms with high-grade atypia on cytology. All three resection specimens were IPMNs with high-grade dysplasia or invasive carcinoma, and two of those patients died of disease. CONCLUSIONS In PCFs, ARID1A mutations were consistently associated with IPMNs (predominantly low grade) with no recurrences or deaths from disease. STK11 mutations appeared to be associated with high-risk mucinous cysts. The detection of minor variants may provide useful preoperative information and add value beyond single-gene genotyping of major mutations.
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Affiliation(s)
- Melanie C Kwan
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - M Lisa Zhang
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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Corradi C, Gentiluomo M, Adsay V, Sainz J, Camisa PR, Wlodarczyk B, Crippa S, Tavano F, Capurso G, Campa D. Multi-omic markers of intraductal papillary mucinous neoplasms progression into pancreatic cancer. Semin Cancer Biol 2025; 109:25-43. [PMID: 39733817 DOI: 10.1016/j.semcancer.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and common form of pancreatic cancer, it has no specific symptoms, and most of the patients are diagnosed when the disease is already at an advanced stage. Chemotherapy typically has only a modest effect, making surgery the most effective treatment option. However, only a small percentage of patients are amenable to surgery. One viable strategy to reduce PDAC death burden associated with the disease is to focus on precursor lesions and identify markers able to predict who will evolve into PDAC. While most PDACs are believed to be preceded by pancreatic intraepithelial neoplasms (PanINs), 5-10 % arise from Intraductal papillary mucinous neoplasms (IPMNs), which are mass-forming cystic lesions that are very common in the general population. IPMNs offer an invaluable model of pancreatic carcinogenesis for researchers to analyse, as well as a target population for PDAC early detection by clinicians. The evolution of IPMN into cancer is a complex and multistep process, therefore the identification of individual markers will not be the solution. In recent years, multiple omics technologies have been instrumental to identify possible biomarkers of IPMN progression and carcinogenesis. The only foreseeable strategy will be to integrate multi-omics data, alongside clinical and morphological features, into a progression score or signature using either standard epidemiologic tools or artificial intelligence. The aim of this manuscript is to review the current knowledge on genetic biomarkers and to briefly mention also additional omics, such as metabolomics, the exposome, the miRNome and epigenomics of IPMNs.
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Affiliation(s)
| | | | - Volkan Adsay
- Department of Pathology, Koç University School of Medicine and Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Juan Sainz
- Department of Biochemistry and Molecular Biology, University of Granada, Granada, Spain
| | - Paolo Riccardo Camisa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Barbara Wlodarczyk
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Stefano Crippa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy
| | - Gabriele Capurso
- Vita-Salute San Raffaele University, Milan, Italy; Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy.
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Biswas S, Afrose S, Mita MA, Hasan MR, Shimu MSS, Zaman S, Saleh MA. Next-Generation Sequencing: An Advanced Diagnostic Tool for Detection of Pancreatic Disease/Disorder. JGH Open 2024; 8:e70061. [PMID: 39605899 PMCID: PMC11599877 DOI: 10.1002/jgh3.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
The pancreas is involved in digestion and glucose regulation in the human body. Given the recognized link between chronic pancreatitis and pancreatic cancer, addressing pancreatic disorders and pancreatic cancer is particularly challenging. This review aims to highlight the limitations of traditional methods in diagnosing pancreatic disorders and cancer and explore several next-generation sequencing (NGS) approaches as a promising alternative. There are distinct clinical symptoms that are shared by a number of clinical phenotypes of pancreatic illness induced by particular genetic mutations. Traditional diagnostic methods encompass computed tomography, magnetic resonance imaging, contrast-enhanced Doppler ultrasound, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, transabdominal ultrasound, laparoscopy, and positron emission tomography have a prognostic ability of only 5% or less and a 5-year survival rate. Genetic sequencing can be employed as an alternative to conventional diagnostic techniques. Sanger sequencing and NGS are currently largely operated genome analysis, with no exception for pancreatic disease diagnosis. The NGS methods can sequence millions to billions of short DNA fragments, enabling enormous sample screening in a short amount of time with low-abundance detection, like in 0.1%-1% mutation prevalence declining approximate cost. Whole-genome sequencing, whole-exome sequencing, RNA sequencing, and single-cell NGS are a few NGS methods utilized to diagnose pancreatic disease. For both research and clinical applications, the NGS techniques can provide a precise diagnosis of pancreatic disorders in a short amount of time at a reasonable expenditure.
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Affiliation(s)
- Suvro Biswas
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
| | - Shamima Afrose
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | - Mohasana Akter Mita
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | - Md. Robiul Hasan
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | | | - Shahriar Zaman
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
| | - Md. Abu Saleh
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
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Gyimesi G, Keczer B, Rein P, Horváth M, Szűcs Á, Marjai T, Szijártó A, Hritz I. Diagnostic performance of intracystic carcinoembryonic antigen (CEA) versus glucose in differentiation of mucinous and non-mucinous pancreatic cysts. Pathol Oncol Res 2024; 30:1611881. [PMID: 39449683 PMCID: PMC11499142 DOI: 10.3389/pore.2024.1611881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/26/2024] [Indexed: 10/26/2024]
Abstract
Background and Objectives Pancreatic cysts have various potential for malignant transformation. Differentiating mucinous from non-mucinous cysts is crucial to make the right decision about further management, since mucinous cysts carry the risk of malignancy. Using endoscopic ultrasound (EUS) guided fine needle aspiration to determine intracystic carcinoembryonic antigen (CEA) levels is the recommended method for identifying mucinous cysts, although intracystic glucose assessment has also proved to be an effective tool. This study aims to compare the diagnostic performance of intracystic glucose and CEA in distinguishing between mucinous and non-mucinous pancreatic cystic lesions. Methods In this single center study, we prospectively collected and analyzed the data of 91 consecutive patients who underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) with cytological analysis and measurement of intracystic CEA and glucose levels. The cyst type was classified based on radiological and EUS morphology, string sign, CEA, cytological and histological findings in resected cases. The diagnosis was established retrospectively by three experienced gastroenterologists blinded for glucose level in cases without definitive cytology or histology. We calculated the sensitivity, specificity, the positive- and negative predictive value of glucose and CEA respectively, and compared the two methods. Results The sensitivity of intracystic glucose versus CEA proved to be 96.2% vs. 69.2% in identifying mucinous cysts, while the specificity of glucose was shown to be 79.5%, compared to 100% for CEA. Conclusion Intracystic glucose is a sensitive, easily accessible biomarker in identifying mucinous pancreatic cysts, however, the specificity is lower compared to CEA. The measurement of intracystic glucose level could help in decision-making in daily clinical practice, however the diagnostic performance of the method remains inferior to "through-the-needle" techniques, such as confocal laser endomicroscopy and Moray forceps biopsy.
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Affiliation(s)
- György Gyimesi
- School of Doctoral Studies, Semmelweis University, Budapest, Hungary
- Department of Gastroenterology, Spital Thurgau AG, Münsterlingen, Switzerland
| | - Bánk Keczer
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Péter Rein
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Miklós Horváth
- Department of Surgery, Transplantation and Gastroenterology, Division of Interventional Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Ákos Szűcs
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Tamás Marjai
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Attila Szijártó
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - István Hritz
- Department of Surgery, Transplantation and Gastroenterology, Division of Interventional Gastroenterology, Semmelweis University, Budapest, Hungary
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Piecoro DW, Allison DB. Precision Medicine in Cytopathology. Surg Pathol Clin 2024; 17:329-345. [PMID: 39129134 DOI: 10.1016/j.path.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Over the last decade, cancer diagnostics has undergone a notable transformation with increasing complexity. Minimally invasive diagnostic tests, driven by advanced imaging and early detection protocols, are redefining patient care and reducing the need for more invasive procedures. Modern cytopathologists now safeguard patient samples for vital biomarker and molecular testing. In this article, we explore ancillary testing modalities and the role of biomarkers in organ-specific contexts, underscoring the transformative impact of precision medicine. Finally, the advent of more than 80 Food and Drug Administration-approved predictive biomarkers signals a new era, guiding cancer care toward personalized and targeted strategies.
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Affiliation(s)
- Dava W Piecoro
- Department of Pathology and Laboratory Medicine, 800 Rose Street, MS117, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Derek B Allison
- Department of Pathology and Laboratory Medicine, 800 Rose Street, MS117, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Markey Cancer Center, Lexington, KY 40536, USA; Department of Urology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
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Iwashita T, Uemura S, Shimizu M. Endoscopic ultrasound-guided fine-needle aspiration for pancreatic cystic lesions: a comprehensive review. J Med Ultrason (2001) 2024; 51:219-226. [PMID: 38051460 DOI: 10.1007/s10396-023-01389-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/09/2023] [Indexed: 12/07/2023]
Abstract
Advancements in diagnostic radiology have amplified the incorporation of these techniques into routine clinical practice. Concurrently, the frequency of incidentally identifying pancreatic cystic lesions (PCLs) has surged. PCLs encompass diverse categories contingent upon their origin. Among them, branch duct-intraductal papillary mucinous neoplasms (BD-IPMN) and mucinous cystic neoplasms (MCN) are categorized as mucinous cystic lesions that have malignant potential. Even solid neoplasms occasionally show cystic degeneration. Therefore, precise differential PCL diagnosis is crucial to optimize clinical management strategies and detect malignant transformations. Endoscopic ultrasound (EUS) affords comprehensive visualization of the pancreas with high-resolution ultrasound, complemented by fine-needle aspiration (FNA) under real-time EUS guidance, which is a minimally invasive procedure for obtaining pathological samples. This synergy has established EUS and EUS-FNA as vital procedures in the management of PCLs, enabling differentiation of PCLs. Cyst fluid analysis has played a pivotal role in deciding the optimal management strategy. The efficacy of cytological analysis is limited by scant cytologic material. The "string sign" test evaluates fluid viscosity, and its simplicity warrants initial consideration. Amylase and tumor markers, such as CEA, have been studied, but they yield varied sensitivity and specificity. Glucose and genetic mutations (KRAS, GNAS) exhibit promise, while comprehensive genomic profiling underscores genetic insights. Through-the-needle biopsy and needle-based confocal laser endomicroscopy also show high diagnostic yield. EUS-FNA, however, entails risks like infection and needle tract seeding, emphasizing the need for proper utilization. Pancreatic cyst fluid analysis augments diagnostic accuracy and informs clinical decisions, making it a valuable adjunct to imaging.
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Affiliation(s)
- Takuji Iwashita
- First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu, 502-0061, Japan.
| | - Shinya Uemura
- First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu, 502-0061, Japan
| | - Masahito Shimizu
- First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu, 502-0061, Japan
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Pflüger MJ, Jamouss KT, Afghani E, Lim SJ, Rodriguez Franco S, Mayo H, Spann M, Wang H, Singhi A, Lennon AM, Wood LD. Predictive ability of pancreatic cyst fluid biomarkers: A systematic review and meta-analysis. Pancreatology 2023; 23:868-877. [PMID: 37230894 DOI: 10.1016/j.pan.2023.05.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/10/2023] [Accepted: 05/13/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Mucinous pancreatic cysts harbor the potential to progress to highly lethal pancreatic ductal adenocarcinoma (PDAC). Since these precursor cysts require cancer surveillance or surgical resection, they need to be reliably distinguished from harmless pancreatic cysts. Current clinical and radiographic assessment is imperfect and the value of cyst fluid analysis for differential diagnosis is unclear. Therefore, we set out to investigate the value of cyst fluid biomarkers in distinguishing pancreatic cysts. METHODS We performed a systematic review of the current literature to identify articles that evaluated the diagnostic performance of clinically relevant and promising candidate cyst fluid biomarkers, with a particular emphasis on DNA-based biomarkers. Meta-analysis was performed for biomarkers targeted at identifying cyst type and presence of high-grade dysplasia or PDAC. RESULTS Data from a total of 42 studies was analyzed. Mutations in KRAS and/or GNAS allowed identification of mucinous cysts with a sensitivity of 79% and specificity of 98%. This exceeded the performance of the traditional biomarker carcinoembryonic antigen (CEA; sensitivity 58%, specificity 87%). Mutations in VHL were specific for serous cystadenomas (SCAs; sensitivity 56%, specificity 99%) and help to exclude mucinous cysts. Mutations in CDKN2A, PIK3CA, SMAD4, and TP53 each had high specificities of 97%, 97%, 98%, and 95%, respectively, to identify high-grade dysplasia or PDAC in mucinous cysts. CONCLUSIONS Cyst fluid analysis can be a valuable tool in the characterization of pancreatic cysts, with relevant clinical implications. Our results support the use of DNA-based cyst fluid biomarkers in the multidisciplinary diagnostic work-up of pancreatic cysts.
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Affiliation(s)
- Michael Johannes Pflüger
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Surgery CCM|CVK, Charité, Universitätsmedizin Berlin, Germany; Graduate School of Life Sciences, Utrecht University, The Netherlands
| | - Kevin Tony Jamouss
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elham Afghani
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Su Jin Lim
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Harrison Mayo
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Marcus Spann
- Johns Hopkins University School of Medicine, Welch Medical Library, Baltimore, MD, USA
| | - Hao Wang
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aatur Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Anne Marie Lennon
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA.
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Nikiforova MN, Wald AI, Spagnolo DM, Melan MA, Grupillo M, Lai YT, Brand RE, O’Broin-Lennon AM, McGrath K, Park WG, Pfau PR, Polanco PM, Kubiliun N, DeWitt J, Easler JJ, Dam A, Mok SR, Wallace MB, Kumbhari V, Boone BA, Marsh W, Thakkar S, Fairley KJ, Afghani E, Bhat Y, Ramrakhiani S, Nasr J, Skef W, Thiruvengadam NR, Khalid A, Fasanella K, Chennat J, Das R, Singh H, Sarkaria S, Slivka A, Gabbert C, Sawas T, Tielleman T, Vanderveldt HD, Tavakkoli A, Smith LM, Smith K, Bell PD, Hruban RH, Paniccia A, Zureikat A, Lee KK, Ongchin M, Zeh H, Minter R, He J, Nikiforov YE, Singhi AD. A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts. Ann Surg 2023; 278:e789-e797. [PMID: 37212422 PMCID: PMC10481930 DOI: 10.1097/sla.0000000000005904] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
OBJECTIVE We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.
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Affiliation(s)
- Marina N. Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Abigail I. Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Daniel M. Spagnolo
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Melissa A. Melan
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Maria Grupillo
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Yi-Tak Lai
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Randall E. Brand
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Anne Marie O’Broin-Lennon
- The Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Kevin McGrath
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Walter G. Park
- Department of Medicine, Stanford University, Stanford, CA
| | - Patrick R. Pfau
- Department of Medicine, University of Wisconsin, Madison, WI
| | - Patricio M. Polanco
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Nisa Kubiliun
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - John DeWitt
- Department of Gastroenterology and Hepatology, Indiana University Health Medical Center, Indianapolis, IN
| | - Jeffrey J. Easler
- Department of Gastroenterology and Hepatology, Indiana University Health Medical Center, Indianapolis, IN
| | - Aamir Dam
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL
| | - Shaffer R. Mok
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL
| | - Michael B. Wallace
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Jacksonville, FL
- Sheikh Shakhbout Medical City, Abu Dhabi, UAE
| | - Vivek Kumbhari
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | - Brian A. Boone
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, WV
| | - Wallis Marsh
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, WV
| | - Shyam Thakkar
- Department of Medicine, Section of Gastroenterology & Hepatology, West Virginia University Health Sciences Center, Morgantown, WV
| | - Kimberly J. Fairley
- Department of Medicine, Section of Gastroenterology & Hepatology, West Virginia University Health Sciences Center, Morgantown, WV
| | - Elham Afghani
- The Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Yasser Bhat
- Department of Gastroenterology, Palo Alto Medical Foundation (PAMF), Mountain View, CA
| | - Sanjay Ramrakhiani
- Department of Gastroenterology, Palo Alto Medical Foundation (PAMF), Mountain View, CA
| | - John Nasr
- Department of Medicine, Wheeling Hospital, West Virginia University Health Sciences Center, Morgantown, WV
| | - Wasseem Skef
- Division of Gastroenterology and Hepatology, Department of Medicine, Loma Linda University Medical Center, Loma Linda, CA
| | - Nikhil R. Thiruvengadam
- Division of Gastroenterology and Hepatology, Department of Medicine, Loma Linda University Medical Center, Loma Linda, CA
| | - Asif Khalid
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Kenneth Fasanella
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Jennifer Chennat
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Rohit Das
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Harkirat Singh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Savreet Sarkaria
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Charles Gabbert
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Tarek Sawas
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Thomas Tielleman
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Anna Tavakkoli
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Lynette M. Smith
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE
| | - Katelyn Smith
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Phoenix D. Bell
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ralph H. Hruban
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Alessandro Paniccia
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Amer Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Kenneth K. Lee
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Melanie Ongchin
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Herbert Zeh
- Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, TX
| | - Rebecca Minter
- Department of Surgery, University of Wisconsin, Madison, WI
| | - Jin He
- The Sol Goldman Pancreatic Cancer Research Center, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Yuri E. Nikiforov
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Aatur D. Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
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10
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Papadopoulos N, Hruban RH. Molecular Mechanisms of Cystic Neoplasia‐. THE PANCREAS 2023:630-637. [DOI: 10.1002/9781119876007.ch82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Chaudhary D, Banga P, Sakhuja P, Goyal S, Saran RK, Batra VV, Srivastava S, Agarwal AK. Classification of endoscopic ultrasound guided fine needle aspiration cytology of pancreatic space occupying lesions by Papanicolaou Society of Cytopathology System: A five year study. Diagn Cytopathol 2023; 51:105-116. [PMID: 36165589 DOI: 10.1002/dc.25058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Majority of the pancreatic cancer patients present at an advanced stage and have poor 5 year survival rate. Thus, there is a need for early detection of pancreatic cancer with the initiation of the therapy. MATERIALS & METHODS This is a retrospective study including all the endoscopic ultrasound guided (EUS) guided pancreatic FNAs from 2016 to 2020. The aspirate smears were analyzed and classified according to The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSCPC). RESULTS A total of 245 EUS guided FNAs from pancreatic lesions were included. Cyto-histological correlation was done wherever available. Category I (non diagnostic) accounted for 40 cases (16%) cases, Category II (negative) comprised of 44 cases (18%); and Category III (Atypical) had 5 cases (2%). Category IV neoplastic-benign category included 3 cases of serous cystadenoma, while neoplastic-others category included pancreatic neuroendocrine tumors (n = 21), solid pseudo-papillary neoplasms (SPEN) (n = 12) and mucinous cystic neoplasms (n = 4). A total of 7 cases (2.8%) were reported in Category V (Suspicious). A diagnosis of adenocarcinoma (Category VI) was rendered in 105 cases (42.8%) cases. Rarer types included non Hodgkins lymphoma (n = 3) and one case of primary undifferentiated carcinoma with osteoclastic giant cells. Cyto-histological correlation in all categories was available in 58 cases with 8 false negative cases. Thus overall sensitivity of EUS guided FNAC was found to be 87.8% with a diagnostic yield of 83.6% while sensitivity in diagnosing adenocarcinoma was 96.9%. CONCLUSION The present study highlights the spectrum of EUS guided FNA of pancreatic lesions in a subset of North Indian population and classified them according to PSCPC. EUS guided FNAC is a sensitive investigation which plays a crucial role in confirming the diagnosis of pancreatic space occupying lesions (SOLs) in advanced stage.
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Affiliation(s)
| | | | - Puja Sakhuja
- Department of Pathology, GIPMER, New Delhi, India
| | - Surbhi Goyal
- Department of Pathology, GIPMER, New Delhi, India
| | | | | | | | - Anil K Agarwal
- Surgical Gastroenterology Department, GIPMER, New Delhi, India
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12
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Schubach A, Kothari S, Kothari T. Pancreatic Cystic Neoplasms: Diagnosis and Management. Diagnostics (Basel) 2023; 13:207. [PMID: 36673017 PMCID: PMC9857870 DOI: 10.3390/diagnostics13020207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 12/31/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Pancreatic cancer is one of the most lethal cancers, largely related to the difficulties with early detection, as it typically presents in later stages. Pancreatic cystic neoplasms (PCN) are commonly diagnosed as incidental findings on routine imaging. PCN is becoming more frequently detected with the increasing ease and frequency of obtaining cross-sectional images. Certain subtypes of pancreatic cysts have the potential to progress to malignancy, and therefore, clinicians are tasked with creating a patient-centered management plan. The decision of whether to undergo surgical resection or interval surveillance can be challenging given the criteria, including PCN size, pancreatic duct dilation, presence of a mural nodule, and clinical symptoms that play a potential role in risk stratification. Furthermore, the guidelines available from the major gastrointestinal societies all differ in their management recommendations. In this review, we detail an overview of the different types of PCNs and compare major guidelines for both diagnosis and management. We include emerging evidence for next-generation sequencing as well as confocal needle endomicroscopy to aid in the diagnosis and determination of malignancy potential and diagnosis.
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Affiliation(s)
- Abigail Schubach
- Department of Internal Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Shivangi Kothari
- Department of Gastroenterology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Truptesh Kothari
- Department of Gastroenterology, University of Rochester Medical Center, Rochester, NY 14642, USA
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13
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Raut P, Nimmakayala RK, Batra SK, Ponnusamy MP. Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm. Biochim Biophys Acta Rev Cancer 2023; 1878:188851. [PMID: 36535512 PMCID: PMC9898173 DOI: 10.1016/j.bbcan.2022.188851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/08/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are all considered "Pancreatic cystic neoplasms (PCNs)" and show a varying risk of developing into pancreatic ductal adenocarcinoma (PDAC). These lesions display different molecular characteristics, mutations, and clinical manifestations. A lack of detailed understanding of PCN subtype characteristics and their molecular mechanisms limits the development of efficient diagnostic tools and therapeutic strategies for these lesions. Proper in vivo mouse models that mimic human PCNs are also needed to study the molecular mechanisms and for therapeutic testing. A comprehensive understanding of the current status of PCN biology, mechanisms, current diagnostic methods, and therapies will help in the early detection and proper management of patients with these lesions and PDAC. This review aims to describe all these aspects of PCNs, specifically IPMNs, by describing the future perspectives.
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Affiliation(s)
- Pratima Raut
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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14
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Paniccia A, Polanco PM, Boone BA, Wald AI, McGrath K, Brand RE, Khalid A, Kubiliun N, O'Broin-Lennon AM, Park WG, Klapman J, Tharian B, Inamdar S, Fasanella K, Nasr J, Chennat J, Das R, DeWitt J, Easler JJ, Bick B, Singh H, Fairley KJ, Sarkaria S, Sawas T, Skef W, Slivka A, Tavakkoli A, Thakkar S, Kim V, Vanderveldt HD, Richardson A, Wallace MB, Brahmbhatt B, Engels M, Gabbert C, Dugum M, El-Dika S, Bhat Y, Ramrakhiani S, Bakis G, Rolshud D, Millspaugh G, Tielleman T, Schmidt C, Mansour J, Marsh W, Ongchin M, Centeno B, Monaco SE, Ohori NP, Lajara S, Thompson ED, Hruban RH, Bell PD, Smith K, Permuth JB, Vandenbussche C, Ernst W, Grupillo M, Kaya C, Hogg M, He J, Wolfgang CL, Lee KK, Zeh H, Zureikat A, Nikiforova MN, Singhi AD. Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts. Gastroenterology 2023; 164:117-133.e7. [PMID: 36209796 PMCID: PMC9844531 DOI: 10.1053/j.gastro.2022.09.028] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 08/22/2022] [Accepted: 09/16/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
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Affiliation(s)
- Alessandro Paniccia
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Patricio M Polanco
- Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, Texas
| | - Brian A Boone
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kevin McGrath
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Randall E Brand
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Asif Khalid
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Nisa Kubiliun
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Anne Marie O'Broin-Lennon
- The Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Walter G Park
- Department of Medicine, Stanford University, Stanford, California
| | - Jason Klapman
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Benjamin Tharian
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Sumant Inamdar
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Kenneth Fasanella
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - John Nasr
- Department of Medicine, Wheeling Hospital, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Jennifer Chennat
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Rohit Das
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - John DeWitt
- Department of Gastroenterology and Hepatology, Indiana University Health Medical Center, Indianapolis, Indiana
| | - Jeffrey J Easler
- Department of Gastroenterology and Hepatology, Indiana University Health Medical Center, Indianapolis, Indiana
| | - Benjamin Bick
- Department of Gastroenterology and Hepatology, Indiana University Health Medical Center, Indianapolis, Indiana
| | - Harkirat Singh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kimberly J Fairley
- Department of Medicine, Section of Gastroenterology & Hepatology, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Savreet Sarkaria
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Tarek Sawas
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Wasseem Skef
- Department of Medicine, Division of Gastroenterology and Hepatology, Loma Linda University Medical Center, Loma Linda, California
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anna Tavakkoli
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Shyam Thakkar
- Department of Medicine, Section of Gastroenterology & Hepatology, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Victoria Kim
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | | | | | - Michael B Wallace
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Bhaumik Brahmbhatt
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Megan Engels
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Charles Gabbert
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Mohannad Dugum
- Digestive Health Center, Essentia Health-Duluth Clinic, Duluth, Minnesota
| | - Samer El-Dika
- Department of Medicine, Stanford University, Stanford, California
| | - Yasser Bhat
- Department of Gastroenterology, Palo Alto Medical Foundation (PAMF), Mountain View, California
| | - Sanjay Ramrakhiani
- Department of Gastroenterology, Palo Alto Medical Foundation (PAMF), Mountain View, California
| | | | | | | | - Thomas Tielleman
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Carl Schmidt
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - John Mansour
- Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, Texas
| | - Wallis Marsh
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Melanie Ongchin
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Barbara Centeno
- Department of Pathology, Moffitt Cancer Center, Tampa, Florida
| | - Sara E Monaco
- Department of Pathology, Geisinger Medical Center, Danville, Pennsylvania
| | - N Paul Ohori
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Sigfred Lajara
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Elizabeth D Thompson
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Ralph H Hruban
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Katelyn Smith
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jennifer B Permuth
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Christopher Vandenbussche
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Wayne Ernst
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Maria Grupillo
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Cihan Kaya
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Melissa Hogg
- Department of Surgery, NorthShore University Health System, Chicago, Illinois
| | - Jin He
- The Sol Goldman Pancreatic Cancer Research Center, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Christopher L Wolfgang
- The Sol Goldman Pancreatic Cancer Research Center, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Surgery, NYU Langone Health, New York, New York
| | - Kenneth K Lee
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Herbert Zeh
- Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, Texas
| | - Amer Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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15
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Serial EUS-Guided FNA for the Surveillance of Pancreatic Cysts: A Study of Long-Term Performance of Tumor Markers. Dig Dis Sci 2022; 67:5248-5255. [PMID: 35229208 PMCID: PMC10153767 DOI: 10.1007/s10620-022-07427-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 02/01/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM The natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time. METHODS Patients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available. RESULTS A total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1-115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023). CONCLUSION KRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.
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16
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Bell PD, Singhi AD. Integrating Molecular Analysis into the Pathologic Evaluation of Pancreatic Cysts. Surg Pathol Clin 2022; 15:455-468. [PMID: 36049828 DOI: 10.1016/j.path.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
The development of cross-sectional imaging techniques has enhanced the detection of pancreatic cystic lesions (PCLs). PCLs are found in approximately 2% of the general population, often as incidentally detected lesions on computed tomography or MRI during the evaluation of other medical conditions. Broadly, PCLs are classified as mucinous or nonmucinous. Mucinous PCLs include mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. Nonmucinous PCLs include pseudocysts, serous cystadenomas, solid pseudopapillary neoplasms, and cystic pancreatic neuroendocrine tumors, as well as cystic acinar cell carcinoma, cystic degeneration of pancreatic ductal adenocarcinoma, lymphoepithelial cyst, and others.
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Affiliation(s)
- Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop St. Pittbsurgh, PA 15213, USA.
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop St. Pittbsurgh, PA 15213, USA
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17
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Abstract
Early detection of high-risk pancreatic cystic lesions enables potentially curative surgical resection, and early detection of lesions without worrisome features may lead to appropriate surveillance. Regrettably, differentiating premalignant and malignant cysts from nonmalignant ones remains challenging. However, emerging additional diagnostic tools, including the needle biopsy with microforceps and needle-based confocal laser endomicroscopy, are of exciting potential along with cyst fluid analysis".
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Affiliation(s)
- Sahin Coban
- Department of Gastroenterology, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA 02138, USA.
| | - Omer Basar
- Department of Gastroenterology, The University of Missouri, Columbia, MO 65211, USA
| | - William R Brugge
- Department of Gastroenterology, Harvard Medical School, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA 02138, USA
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18
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Sharma RK, Bush N, Rana SS, Srinivasan R, Nada R, Gupta R, Rana S, Singh T. Lower cyst fluid carcinoembryonic antigen cutoff is helpful in the differential diagnosis of mucinous versus non-mucinous pancreatic cysts. Indian J Gastroenterol 2022; 41:397-404. [PMID: 36057043 DOI: 10.1007/s12664-022-01269-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 06/02/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Pancreatic cystic lesions (PCLs) are being diagnosed with increased frequency and have varying neoplastic potential. We conducted this multimodal, prospective study to evaluate the role of tumor cytology and molecular markers to differentiate PCL subtypes. METHODS Consecutive undiagnosed patients with PCLs (n = 100, mean age: 50.37 years; 41% males) were prospectively studied. Cyst fluid carcinoembryonic antigen (CEA), CA19.9, CA125, CA72.4, and vascular endothelial growth factor-alpha (VEGF-α) levels were measured by quantitative enzyme-linked immunosorbent assay (ELISA) method. Mutational analysis of the KRAS gene (exon 2, Codon 12 and 13) and GNAS gene (Exon 8, Codon 201) were performed by Sanger's sequencing. RESULTS The mean cyst size was 4.32 ± 2.4 cm. Fluid cytology revealed definitive diagnosis in 21 (22.3%) patients. All malignant PCLs could be identified on cytology whereas 10/14 (71%) non-malignant mucinous PCLs could also be identified on cytology based on mucin staining. Among the tested tumor markers, cyst fluid CEA had the best diagnostic performance for differentiation between mucinous and non-mucinous PCLs (AUC 0.933 [95% CI 0.86-0.91]). At a cyst fluid CEA cutoff level of 45.0 ng/mL, the sensitivity, specificity, positive predictive value, and negative predictive value for differentiation between mucinous and non-mucinous cysts were 88.5%, 96.8%, 92.0%, and 95.3%, respectively (p < 0.05). KRAS and GNAS mutation had no significant diagnostic benefit in comparison to fluid cytology and CEA levels. CONCLUSIONS Fluid CEA at a lower cutoff of 45 ng/mL is the most accurate marker to differentiate between mucinous and non-mucinous PCL. The KRAS and GNAS mutational analysis does not improve upon the diagnostic performance of fluid cytology and tumor markers.
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Affiliation(s)
- Ravi Kumar Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Nikhil Bush
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Surinder Singh Rana
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
| | - Radhika Srinivasan
- Department of Cytology and Gynecology Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Ritambhra Nada
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Rajesh Gupta
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Satyavati Rana
- Department of Community Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Tarundeep Singh
- Department of Community Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
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19
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Abstract
Andrew Canakis.
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Affiliation(s)
- Andrew Canakis
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Linda S Lee
- Division of Gastroenterology Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
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20
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Hirabayashi K, Saika T, Nakamura N. Background features in the cytology of pancreatic neoplasms. DEN OPEN 2022; 2:e105. [PMID: 35873514 PMCID: PMC9302047 DOI: 10.1002/deo2.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/09/2022] [Accepted: 02/13/2022] [Indexed: 11/05/2022]
Abstract
Cytology is a useful method for diagnosing pancreatic neoplasms. Although endoscopic ultrasound‐guided fine‐needle aspiration has recently become the mainstream method for the diagnosis of pancreatic neoplasms, pancreatic juice and pancreatic duct brushing cytology continue to be useful diagnostic methods for the investigation of pancreatic neoplasms. Diagnoses using pancreatic cytology are primarily based on the features related to tumor cells; however, evaluation of the background features provides important information that could further aid the diagnosis. Pancreatic neoplasms show various histological types, each of which is associated with its own characteristic background features. The necrotic background, desmoplastic stroma, and presence of cancer‐associated fibroblasts are background features of pancreatic ductal adenocarcinoma, a mucinous background is associated with intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, and hyaline globules are observed in solid pseudopapillary neoplasms. However, some background features are associated with more than one histological type of pancreatic neoplasm, highlighting the importance to base a diagnosis on the results of a comprehensive analysis of not only the background features but also the tumor cells. Here, we provide a review of the key background cytological features of pancreatic neoplasms, which can serve as a guide to improve diagnosis and research.
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Affiliation(s)
| | - Tsubasa Saika
- Diagnostic Pathology Center Tokai University Hospital Kanagawa Japan
| | - Naoya Nakamura
- Department of Pathology Tokai University School of Medicine Kanagawa Japan
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21
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Assarzadegan N, Babaniamansour S, Shi J. Updates in the Diagnosis of Intraductal Neoplasms of the Pancreas. Front Physiol 2022; 13:856803. [PMID: 35309060 PMCID: PMC8931033 DOI: 10.3389/fphys.2022.856803] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer worldwide. There are many reasons for this dismal prognosis, including the advanced stage at the time of diagnosis and the lack of effective therapeutic approaches. Intraductal papillary mucinous neoplasms (IPMNs) represent detectable and treatable precursor lesions of PDAC. Our understanding of the pathology of IPMNs has evolved over the past few decades, and new advances in diagnostic tools have emerged. The new World Health Organization (WHO) classification scheme now recognizes the previously considered variants of IPMNs, such as intraductal oncocytic papillary neoplasms (IOPNs) and intraductal tubulopapillary neoplasms (ITPNs), as distinct neoplasms. New imaging and molecular diagnostic tests are being developed to recognize these PDAC precursor lesions better. Here, we review the advances in diagnostic tools for IPMNs, IOPNs, and ITPNs, emphasizing the new (5th edition, 2019) WHO classification for pathological diagnosis, molecular markers, new laboratory tests, and imaging tools.
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Affiliation(s)
| | | | - Jiaqi Shi
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
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22
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Sakihama K, Koga Y, Yamamoto T, Shimada Y, Yamada Y, Kawata J, Shindo K, Nakamura M, Oda Y. RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm. Virchows Arch 2022; 480:1189-1199. [PMID: 35066614 DOI: 10.1007/s00428-022-03277-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/23/2021] [Accepted: 01/12/2022] [Indexed: 11/26/2022]
Abstract
Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.
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Affiliation(s)
- Kukiko Sakihama
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Koga
- Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Takeo Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Shimada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Kawata
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan.
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23
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Nikas IP, Mountzios G, Sydney GI, Ioakim KJ, Won JK, Papageorgis P. Evaluating Pancreatic and Biliary Neoplasms with Small Biopsy-Based Next Generation Sequencing (NGS): Doing More with Less. Cancers (Basel) 2022; 14:cancers14020397. [PMID: 35053560 PMCID: PMC8773813 DOI: 10.3390/cancers14020397] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/05/2022] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Pancreatic cancer and cholangiocarcinoma are aggressive diseases mostly diagnosed at an advanced and inoperable stage. This review presents the value of next-generation sequencing (NGS) when performed on small biopsies—including fine-needle aspiration/biopsy samples, brushings, pancreatic juice and bile, and also blood—in the field of pancreatobiliary neoplasia. NGS could guide physicians while evaluating pancreatic solid and cystic lesions or suspicious biliary strictures, performing surveillance in high-risk individuals, or monitoring the disease and assessing prognosis in already diagnosed cancer patients. Evidence suggests that NGS performed on small biopsies is a robust tool for the diagnosis and pre-operative risk stratification of pancreatic and biliary lesions, whereas it also carries significant prognostic and therapeutic value. However, effective standardization of the pre-analytical and analytical assay parameters used for each clinical scenario is needed to fully implement NGS into routine practice and provide more personalized management in patients with suspected or established pancreatobiliary neoplasia. Abstract Pancreatic cancer and cholangiocarcinoma are lethal diseases mainly diagnosed at an inoperable stage. As pancreatobiliary surgical specimens are often unavailable for further molecular testing, this review aimed to highlight the diagnostic, prognostic, and therapeutic impact of next-generation sequencing (NGS) performed on distinct small biopsies, including endoscopic ultrasound fine-needle aspirations and biopsies of pancreatic solid and cystic lesions, biliary duct brushings, and also “liquid biopsies” such as the pancreatic juice, bile, and blood. NGS could clarify indeterminate pancreatic lesions or biliary strictures, for instance by identifying TP53 or SMAD4 mutations indicating high-grade dysplasia or cancer. It could also stratify pancreatic cystic lesions, by distinguishing mucinous from non-mucinous cysts and identifying high-risk cysts that should be excised in surgically fit patients, whereas the combination of cytology, elevated cystic CEA levels and NGS could improve the overall diagnostic accuracy. When NGS is performed on the pancreatic juice, it could stratify high-risk patients under surveillance. On the plasma, it could dynamically monitor the disease course and response to therapy. Notably, the circulating tumor DNA (ctDNA) levels have been associated with staging, grading, and survival. Lastly, NGS has shown potential in identifying potentially actionable molecular alterations. In conclusion, NGS applied on small biopsies could carry significant diagnostic, prognostic, and therapeutic value.
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Affiliation(s)
- Ilias P. Nikas
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus; (G.I.S.); (K.J.I.)
- Correspondence:
| | - Giannis Mountzios
- Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, 11526 Athens, Greece;
| | - Guy I. Sydney
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus; (G.I.S.); (K.J.I.)
- Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Kalliopi J. Ioakim
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus; (G.I.S.); (K.J.I.)
- Department of Internal Medicine, Limassol General Hospital, Limassol 4131, Cyprus
| | - Jae-Kyung Won
- Department of Pathology, Seoul National University Hospital and College of Medicine, Seoul 03080, Korea;
| | - Panagiotis Papageorgis
- Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus;
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24
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Luthra A, Hart PA, Papachristou GI, Porter K, Dillhoff ME, Manilchuk A, Cloyd JM, Pawlik TM, Tsung A, Conwell DL, Krishna SG. Cost-Benefit Analysis and Resource Implications of Endoscopic Ultrasound-Guided Confocal Endomicroscopy in Pancreatic Cysts. TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY 2022; 24:35-44. [DOI: 10.1016/j.tige.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2023]
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Gao J, Han F, Wang X, Duan S, Zhang J. Multi-Phase CT-Based Radiomics Nomogram for Discrimination Between Pancreatic Serous Cystic Neoplasm From Mucinous Cystic Neoplasm. Front Oncol 2021; 11:699812. [PMID: 34926238 PMCID: PMC8672034 DOI: 10.3389/fonc.2021.699812] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 11/15/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose This study aimed to develop and verify a multi-phase (MP) computed tomography (CT)-based radiomics nomogram to differentiate pancreatic serous cystic neoplasms (SCNs) from mucinous cystic neoplasms (MCNs), and to compare the diagnostic efficacy of radiomics models for different phases of CT scans. Materials and Methods A total of 170 patients who underwent surgical resection between January 2011 and December 2018, with pathologically confirmed pancreatic cystic neoplasms (SCN=115, MCN=55) were included in this single-center retrospective study. Radiomics features were extracted from plain scan (PS), arterial phase (AP), and venous phase (VP) CT scans. Algorithms were performed to identify the optimal features to build a radiomics signature (Radscore) for each phase. All features from these three phases were analyzed to develop the MP-Radscore. A combined model comprised the MP-Radscore and imaging features from which a nomogram was developed. The accuracy of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration tests, and decision curve analysis. Results For each scan phase, 1218 features were extracted, and the optimal ones were selected to construct the PS-Radscore (11 features), AP-Radscore (11 features), and VP-Radscore (12 features). The MP-Radscore (14 features) achieved better performance based on ROC curve analysis than any single phase did [area under the curve (AUC), training cohort: MP-Radscore 0.89, PS-Radscore 0.78, AP-Radscore 0.83, VP-Radscore 0.85; validation cohort: MP-Radscore 0.88, PS-Radscore 0.77, AP-Radscore 0.83, VP-Radscore 0.84]. The combination nomogram performance was excellent, surpassing those of all other nomograms in both the training cohort (AUC, 0.91) and validation cohort (AUC, 0.90). The nomogram also performed well in the calibration and decision curve analyses. Conclusions Radiomics for arterial and venous single-phase models outperformed the plain scan model. The combination nomogram that incorporated the MP-Radscore, tumor location, and cystic number had the best discriminatory performance and showed excellent accuracy for differentiating SCN from MCN.
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Affiliation(s)
- Jiahao Gao
- Department of Radiology, Huashan Hospital North, Fudan University, Shanghai, China.,Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Fang Han
- Department of Radiology, Huashan Hospital North, Fudan University, Shanghai, China.,Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaoshuang Wang
- Department of Radiology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Shaofeng Duan
- Department of Life Sciences, GE Healthcare, Shanghai, China
| | - Jiawen Zhang
- Department of Radiology, Huashan Hospital North, Fudan University, Shanghai, China.,Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
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26
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Gonzalez-Mancera MS, Ahmadian SS, Gomez-Fernandez C, Velez-Torres J, Jorda M, García-Buitrago MT. Risk of malignancy associated with the diagnostic categories proposed by the Papanicolaou Society of Cytopathology for pancreaticobiliary specimens: An institutional experience. Diagn Cytopathol 2021; 50:49-56. [PMID: 34856075 DOI: 10.1002/dc.24910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/13/2021] [Accepted: 11/22/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND The guidelines published by the Papanicolaou Society of Cytopathology (PSC) intend to unify the reporting language in pancreaticobiliary specimens and improve communication between cytopathologists and clinicians. The six categories in the system will determine the best management for patients. However, there is limited evidence regarding the risk of malignancy (ROM) associated with each category. METHODS A retrospective search was performed for pancreaticobiliary fine-needle aspiration (FNA) reports with corresponding surgical follow-up. Cases were reclassified according to the PSC. The ROM, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each category. RESULTS A total of 297 cases were identified and reclassified as: 30 nondiagnostic (category I), 45 negative for malignancy (II), 20 atypical (III), 42 neoplastic: other (IVB), 19 suspicious for malignancy (V), and 141 malignant (VI). The absolute ROM was 10% for category I, 8.9% for category II, 60% for category III, 4.8% for category IV when the neoplasms were not characterized as malignant, and 100% when categorized as malignant; 100% for category V, and 95.7% for category VI. Sensitivity, specificity, positive predictive value, and negative predictive value for neoplasia and malignancy, including categories IV to VI, were 96.6%, 88.4%, 97.5%, and 84.4%, respectively. CONCLUSIONS The categories developed by the PSC stratify the ROM. Aspirates designated as categories V and VI had the highest ROM. Our rate of atypical category complies with the recommended rate of <10%. This scheme provides valuable information to clinicians treating patients with pancreatic lesions.
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Affiliation(s)
- Miguel S Gonzalez-Mancera
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Saman S Ahmadian
- Department of Pathology and Laboratory Medicine, Jackson Health System, Miami, Florida, USA
| | - Carmen Gomez-Fernandez
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jaylou Velez-Torres
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Merce Jorda
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Monica T García-Buitrago
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
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27
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O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol 2021; 27:4045-4087. [PMID: 34326612 PMCID: PMC8311531 DOI: 10.3748/wjg.v27.i26.4045] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).
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Affiliation(s)
- Robert S O'Neill
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
| | - Alina Stoita
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
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28
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Early detection of pancreatic cancer using DNA-based molecular approaches. Nat Rev Gastroenterol Hepatol 2021; 18:457-468. [PMID: 34099908 DOI: 10.1038/s41575-021-00470-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2021] [Indexed: 02/08/2023]
Abstract
Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.
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Navarro SM, Corwin MT, Katz DS, Lamba R. Incidental Pancreatic Cysts on Cross-Sectional Imaging. Radiol Clin North Am 2021; 59:617-629. [PMID: 34053609 DOI: 10.1016/j.rcl.2021.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Incidental pancreatic cysts are commonly encountered in radiology practice. Although some of these are benign, mucinous varieties have a potential to undergo malignant transformation. Characterization of some incidental pancreatic cysts based on imaging alone is limited, and given that some pancreatic cysts have a malignant potential, various societies have created guidelines for the management and follow-up of incidental pancreatic cysts. This article reviews the imaging findings and work-up of pancreatic cysts and gives an overview of the societal guidelines for the management and follow-up of incidental pancreatic cysts.
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Affiliation(s)
- Shannon M Navarro
- Department of Radiology, UC Davis, 4860 Y Street, Suite 3100, Sacramento, CA 95817, USA.
| | - Michael T Corwin
- Department of Radiology, UC Davis, 4860 Y Street, Suite 3100, Sacramento, CA 95817, USA
| | - Douglas S Katz
- Department of Radiology, NYU Winthrop, 259 First Street, Mineola, NY 11501, USA
| | - Ramit Lamba
- Department of Radiology, UC Davis, 4860 Y Street, Suite 3100, Sacramento, CA 95817, USA
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30
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Visani M, Acquaviva G, De Leo A, Sanza V, Merlo L, Maloberti T, Brandes AA, Franceschi E, Di Battista M, Masetti M, Jovine E, Fiorino S, Pession A, Tallini G, de Biase D. Molecular alterations in pancreatic tumors. World J Gastroenterol 2021; 27:2710-2726. [PMID: 34135550 PMCID: PMC8173386 DOI: 10.3748/wjg.v27.i21.2710] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/25/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these "inconclusive" specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.
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Affiliation(s)
- Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Viviana Sanza
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Lidia Merlo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Alba A Brandes
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Enrico Franceschi
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Monica Di Battista
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Michele Masetti
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Elio Jovine
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna 40133, Italy
| | - Annalisa Pession
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
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Simpson RE, Flick KF, Gromski MA, Al-Haddad MA, Easler JJ, Sherman S, Fogel EL, Schmidt CM, DeWitt JM. Utility of DNA Profiling From Main Pancreatic Duct Fluid by Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography to Screen for Malignant Potential. Pancreas 2021; 49:714-722. [PMID: 32433411 DOI: 10.1097/mpa.0000000000001549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The yield of genetic testing of main pancreatic duct (MPD) fluid collected during endoscopic retrograde cholangiopancreatography (ERCP) versus endoscopic ultrasound-guided fine-needle aspiration is unclear. METHODS Consecutive MPD fluid samples obtained by endoscopic ultrasound/ERCP with DNA profiling were reviewed, excluding specimens designated "no amplification." Invasive disease included invasive cancer or malignant cytology. RESULTS One hundred ten samples from 109 patients who underwent ERCP (n = 32) or endoscopic ultrasound-guided fine-needle aspiration (n = 78) were analyzed (2007-2018). Leading indications were dilated MPD and suspected intraductal papillary mucinous neoplasm. Elevated DNA quantity, KRAS, loss of heterozygosity (LOH), and GNAS mutations occurred in 61.5%, 25.5%, 16.4%, and 8.7% of samples, respectively. Elevated DNA quantity occurred more frequently in ERCP samples (84.4% vs 51.9%, P = 0.002); other mutation yields were similar (P > 0.05). Invasive pathology (P = 0.032) was associated with LOH in the subset of patients who underwent surgery (n = 44). Adverse events occurred more frequently after ERCP (28.1% vs 9.0%, P = 0.016). CONCLUSIONS Endoscopic MPD fluid sampling may yield genetic data to improve diagnosis and risk stratification. In our surgical cohort, LOH was the sole predictor of invasive pathology. Endoscopic ultrasound-guided fine-needle aspiration of MPD fluid, when possible, is preferred because of superior safety profile.
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Affiliation(s)
| | | | - Mark A Gromski
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
| | - Mohammad A Al-Haddad
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
- Indiana University Health Pancreatic Cyst and Cancer Early Detection Center
| | - Jeffrey J Easler
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
| | - Stuart Sherman
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
| | - Evan L Fogel
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
| | - C Max Schmidt
- From the Departments of Surgery
- Indiana University Health Pancreatic Cyst and Cancer Early Detection Center
- Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - John M DeWitt
- Medicine, Division of Gastroenterology, Indiana University School of Medicine
- Indiana University Health Pancreatic Cyst and Cancer Early Detection Center
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McCarty TR, Paleti S, Rustagi T. Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations for diagnosis of intraductal papillary mucinous neoplasia and mucinous cystic lesions: a systematic review and meta-analysis. Gastrointest Endosc 2021; 93:1019-1033.e5. [PMID: 33359054 DOI: 10.1016/j.gie.2020.12.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 12/09/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Although molecular analysis of pancreatic cyst fluid may aid pancreatic cyst classification, clinical practice remains highly variable. Therefore, we performed a systematic review and meta-analysis to evaluate the diagnostic performance of KRAS and GNAS mutations in EUS-acquired pancreatic cyst fluid for diagnosis of intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic lesions (MCLs). METHODS Individualized searches were developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and meta-analysis analyzed according to the Cochrane Diagnostic Test Accuracy working group methodology. A bivariate model was used to compute the pooled sensitivity and specificity and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence interval (95% CI). RESULTS Six studies (785 lesions) were included. For IPMNs and MCLs, KRAS + GNAS (combination) had significantly higher diagnostic accuracy than KRAS alone and GNAS alone (all P < .001). The pooled sensitivity, specificity, and diagnostic accuracy of KRAS + GNAS mutations for diagnosis of IPMNs were 94% (95% CI, 72-99; I2 = 86.74%), 91% (95% CI, 72-98; I2 = 89.83), and 97% (95% CI, 95-98), respectively, with each significantly higher compared with carcinoembryonic antigen (CEA) alone (all P < .001). For diagnosis of MCLs, KRAS + GNAS had a similar sensitivity and specificity compared with CEA alone; however, diagnostic accuracy was significantly improved (97% [95% CI, 95-98] vs 89% [95% CI, 86-91]; P < .001). CONCLUSIONS Molecular analysis for KRAS + GNAS mutations in EUS-acquired pancreatic cyst fluid has high sensitivity and specificity with significantly improved diagnostic accuracy for diagnosis of IPMNs and MCLs when compared with CEA alone.
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Affiliation(s)
- Thomas R McCarty
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Swathi Paleti
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
| | - Tarun Rustagi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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Reid MD. Cytologic Assessment of Cystic/Intraductal Lesions of the Pancreatobiliary Tract. Arch Pathol Lab Med 2021; 146:280-297. [PMID: 33836534 DOI: 10.5858/arpa.2020-0553-ra] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2021] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Because of new and improved imaging techniques, cystic/intraductal pancreatobiliary tract lesions are increasingly being discovered, and brushings or endoscopic ultrasound/computed tomography/magnetic resonance imaging-guided fine-needle aspiration biopsies from these lesions have become an integral part of pathologists' daily practice. Because patient management has become increasingly conservative, accurate preoperative diagnosis is critical. Cytologic distinction of low-risk (pseudocysts, serous cystadenoma, lymphoepithelial cysts, and squamoid cysts of the pancreatic duct) from high-risk pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) requires incorporation of clinical, radiologic, and cytologic findings, in conjunction with chemical and molecular analysis of cyst fluid. Cytopathologists must ensure appropriate specimen triage, along with cytologic interpretation, cyst classification, and even grading of some (mucinous) cysts. Epithelial atypia in mucinous cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) has transitioned from a 3-tiered to a 2-tiered classification system, and intraductal oncocytic papillary neoplasms and intraductal tubulopapillary neoplasms have been separately reclassified because of their distinctive clinicopathologic characteristics. Because these lesions may be sampled on brushing or fine-needle aspiration biopsy, knowledge of their cytomorphology is critical. OBJECTIVE.— To use an integrated, multidisciplinary approach for the evaluation of cystic/intraductal pancreatobiliary tract lesions (incorporating clinical, radiologic, and cytologic findings with [chemical/molecular] cyst fluid analysis and ancillary stains) for definitive diagnosis and classification. DATA SOURCES.— Review of current literature on the cytopathology of cystic/intraductal pancreatobiliary tract lesions. CONCLUSIONS.— Our knowledge/understanding of recent updates in cystic/intraductal pancreatobiliary lesions can ensure that cytopathologists appropriately triage specimens, judiciously use and interpret ancillary studies, and incorporate the studies into reporting.
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Affiliation(s)
- Michelle D Reid
- From the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
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The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology: A Retrospective Review. JOURNAL OF MOLECULAR PATHOLOGY 2021. [DOI: 10.3390/jmp2020010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Since the introduction of the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology, much experience has been gained and published concerning the utility of the diagnostic categories, malignancy risk of the categories and reproducibility of the system. This new information has resulted in modifications to the system which will become part of the World Health Organization (WHO) System for Reporting Pancreatic Cytology. Herein we report our experience with the system and information from the published literature.
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Schmitz D, Kazdal D, Allgäuer M, Trunk M, Vornhusen S, Nahm AM, Doll M, Weingärtner S, Endris V, Penzel R, Kirchner M, Brandt R, Neumann O, Sültmann H, Budczies J, Kienle P, Magdeburg R, Hetjens S, Schirmacher P, Bergmann F, Rudi J, Stenzinger A, Volckmar AL. KRAS/GNAS-testing by highly sensitive deep targeted next generation sequencing improves the endoscopic ultrasound-guided workup of suspected mucinous neoplasms of the pancreas. Genes Chromosomes Cancer 2021; 60:489-497. [PMID: 33686791 DOI: 10.1002/gcc.22946] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 12/28/2022] Open
Abstract
Pancreatic cysts or dilated pancreatic ducts are often found by cross-sectional imaging, but only mucinous lesions can become malignant. Therefore, distinction between mucinous and non-mucinous lesions is crucial for adequate patient management. We performed a prospective study including targeted next generation sequencing (NGS) of cell-free DNA in the diagnostic endoscopic ultrasound (EUS)-guided workup. Pancreatic cyst(s) or main duct fluid obtained by EUS-guided FNA was analysed by carcinoembryonic antigen (CEA), cytology and deep targeted NGS of 14 known gastrointestinal cancer genes (AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, TP53, APC) with a limit of detection down to variant allele frequency of 0.01%. Results were correlated to histopathology and clinical follow-up. One hundred and thirteen patients with pancreatic cyst(s) and/or a dilated pancreatic main duct (≥5 mm) were screened. Sixty-six patients had to be excluded, mainly due to inoperability or small cyst size (≤10 mm). Forty-seven patients were enrolled for further analysis. A final diagnosis was available in 27 cases including 8 negative controls. In 43/47 (91.5%) of patients a KRAS- and/or GNAS-mutation was diagnosed by NGS. 27.0% of the KRAS-mutated and 10.0% of the GNAS-mutated lesions harbored multiple mutations. KRAS/GNAS-testing by NGS, cytology, and CEA had a sensitivity and specificity of 94.7/100%, 38.1/100%, and 42.1/75.0%, respectively. KRAS/GNAS-testing was significantly superior to CEA (P = .0209) and cytology (P = .0016). In conclusion, KRAS/GNAS-testing by deep targeted NGS is a suitable method to distinguish mucinous from non-mucinous pancreatic lesions, suggesting its usage as a single diagnostic test. Results must be confirmed in a larger cohort.
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MESH Headings
- Aged
- Aged, 80 and over
- Chromogranins/genetics
- Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods
- Endoscopic Ultrasound-Guided Fine Needle Aspiration/standards
- Female
- GTP-Binding Protein alpha Subunits, Gs/genetics
- Genetic Testing/methods
- Genetic Testing/standards
- High-Throughput Nucleotide Sequencing/methods
- High-Throughput Nucleotide Sequencing/standards
- Humans
- Male
- Middle Aged
- Neoplasms, Cystic, Mucinous, and Serous/diagnostic imaging
- Neoplasms, Cystic, Mucinous, and Serous/genetics
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreatic Cyst/diagnostic imaging
- Pancreatic Cyst/genetics
- Pancreatic Cyst/pathology
- Pancreatic Neoplasms/diagnostic imaging
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- Sensitivity and Specificity
- Sequence Analysis, DNA/methods
- Sequence Analysis, DNA/standards
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Affiliation(s)
- Daniel Schmitz
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Michael Allgäuer
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Marcus Trunk
- Institute of Pathology, SYNLAB GmbH Mannheim, Mannheim, Germany
| | - Sylke Vornhusen
- Institute of Pathology, SYNLAB GmbH Mannheim, Mannheim, Germany
| | - Anna-Maria Nahm
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Heidelberg, Germany
| | - Matthias Doll
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Heidelberg, Germany
| | - Simon Weingärtner
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Roland Penzel
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Regine Brandt
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Olaf Neumann
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Holger Sültmann
- German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Budczies
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Peter Kienle
- Department of General and Visceral Surgery, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Mannheim, Germany
| | - Richard Magdeburg
- Department of General and Visceral Surgery, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Mannheim, Germany
| | - Svetlana Hetjens
- Medical Statistics, Biomathematics and Information Processing of Mannheim University Hospital, University Hospital of Heidelberg, Mannheim, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Bergmann
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Jochen Rudi
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus and St. Hedwigsklinik, University of Heidelberg, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
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Herranz Pérez R, de la Morena López F, Majano Rodríguez PL, Molina Jiménez F, Vega Piris L, Santander Vaquero C. Molecular analysis of pancreatic cystic neoplasm in routine clinical practice. World J Gastrointest Endosc 2021; 13:56-71. [PMID: 33623640 PMCID: PMC7890406 DOI: 10.4253/wjge.v13.i2.56] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cystic pancreatic lesions consist of a wide variety of lesions that are becoming increasingly diagnosed with the growing use of imaging techniques. Of these, mucinous cysts are especially relevant due to their risk of malignancy. However, morphological findings are often suboptimal for their differentiation. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) with molecular analysis has been suggested to improve the diagnosis of pancreatic cysts.
AIM To determine the impact of molecular analysis on the detection of mucinous cysts and malignancy.
METHODS An 18-month prospective observational study of consecutive patients with pancreatic cystic lesions and an indication for EUS-FNA following European clinical practice guidelines was conducted. These cysts included those > 15 mm with unclear diagnosis, and a change in follow-up or with concerning features in which results might change clinical management. EUS-FNA with cytological, biochemical and glucose and molecular analyses with next-generation sequencing were performed in 36 pancreatic cysts. The cysts were classified as mucinous and non-mucinous by the combination of morphological, cytological and biochemical analyses when surgery was not performed. Malignancy was defined as cytology positive for malignancy, high-grade dysplasia or invasive carcinoma on surgical specimen, clinical or morphological progression, metastasis or death related to neoplastic complications during the 6-mo follow-up period. Next-generation sequencing results were compared for cyst type and malignancy.
RESULTS Of the 36 lesions included, 28 (82.4%) were classified as mucinous and 6 (17.6%) as non-mucinous. Furthermore, 5 (13.9%) lesions were classified as malignant. The amount of deoxyribonucleic acid obtained was sufficient for molecular analysis in 25 (69.4%) pancreatic cysts. The amount of intracystic deoxyribonucleic acid was not statistically related to the cyst fluid volume obtained from the lesions. Analysis of KRAS and/or GNAS showed 83.33% [95% confidence interval (CI): 63.34-100] sensitivity, 60% (95%CI: 7.06-100) specificity, 88.24% (95%CI: 69.98-100) positive predictive value and 50% (95%CI: 1.66-98.34) negative predictive value (P = 0.086) for the diagnosis of mucinous cystic lesions. Mutations in KRAS and GNAS were found in 2/5 (40%) of the lesions classified as non-mucinous, thus recategorizing those lesions as mucinous neoplasms, which would have led to a modification of the follow-up plan in 8% of the cysts in which molecular analysis was successfully performed. All 4 (100%) malignant cysts in which molecular analysis could be performed had mutations in KRAS and/or GNAS, although they were not related to malignancy (P > 0.05). None of the other mutations analyzed could detect mucinous or malignant cysts with statistical significance (P > 0.05).
CONCLUSION Molecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous. Mutations were not able to detect malignant lesions.
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Affiliation(s)
- Raquel Herranz Pérez
- Department of Gastroenterology and Hepatology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid 28006, Spain
| | - Felipe de la Morena López
- Department of Gastroenterology and Hepatology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid 28006, Spain
| | - Pedro L Majano Rodríguez
- Molecular Biology Laboratory, Department of Gastroenterology and Hepatology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid 28006, Spain
| | - Francisca Molina Jiménez
- Molecular Biology Laboratory, Department of Gastroenterology and Hepatology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid 28006, Spain
| | - Lorena Vega Piris
- Methodological Support Unit, Department of Statistical Analysis, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, CP Madrid, Madrid 28006, Spain
| | - Cecilio Santander Vaquero
- Department of Gastroenterology and Hepatology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid 28006, Spain
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Ren R, Krishna SG, Chen W, Frankel WL, Shen R, Zhao W, Avenarius MR, Garee J, Caruthers S, Jones D. Activation of the RAS pathway through uncommon BRAF mutations in mucinous pancreatic cysts without KRAS mutation. Mod Pathol 2021; 34:438-444. [PMID: 32792597 DOI: 10.1038/s41379-020-00647-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
Diagnostic testing of pancreatic cyst fluid obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has traditionally utilized elevated carcinoembryonic antigen (CEA) (≥192 ng/ml) and cytomorphologic examination to differentiate premalignant mucinous from benign pancreatic cystic lesions (PCLs). Molecular testing for KRAS/GNAS mutations has been shown to improve accuracy of detecting mucinous PCLs. Using a targeted next-generation sequencing (NGS) panel, we assess the status of PCL-associated mutations to improve understanding of the key diagnostic variables. Molecular analysis of cyst fluid was performed on 108 PCLs that had concurrent CEA and/or cytological analysis. A 48-gene NGS assay was utilized, which included genes commonly mutated in mucinous PCLs such as GNAS, KRAS, CDKN2A, and TP53. KRAS and/or GNAS mutations were seen in 59 of 68 (86.8%) cases with multimodality diagnosis of a mucinous PCL. Among 31 patients where surgical histopathology was available, the sensitivity, specificity, and diagnostic accuracy of NGS for the diagnosis of mucinous PCL was 88.5%, 100%, and 90.3%, respectively. Cytology with mucinous/atypical findings were found in only 29 of 62 cases (46.8%), with fluid CEA elevated in 33 of 58 cases (56.9%). Multiple KRAS mutations at different variant allele frequencies were seen in seven cases favoring multiclonal patterns, with six of them showing at least two separate PCLs by imaging. Among the 6 of 10 cases with GNAS + /KRAS- results, uncommon, non-V600E exon 11/15 hotspot BRAF mutations were identified. The expected high degree of accuracy of NGS detection of KRAS and/or GNAS mutations for mucinous-PCLs, as compared with CEA and cytological examination, was demonstrated. Multiple KRAS mutations correlated with multifocal cysts demonstrated by radiology. In IPMNs that lacked KRAS mutations, the concurring BRAF mutations with GNAS mutations supports an alternate mechanism of activation in the Ras pathway.
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Affiliation(s)
- Rongqin Ren
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA.
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Somashekar G Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University, Columbus, OH, USA
| | - Wei Chen
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Wendy L Frankel
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Rulong Shen
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Weiqiang Zhao
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Matthew R Avenarius
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jason Garee
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA
| | - Sean Caruthers
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA
| | - Dan Jones
- James Molecular Laboratory at Polaris, The Ohio State University James Cancer Center, Columbus, OH, USA
- Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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38
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Luthra AK, Pusateri AJ, Pfeil SA, Groce JR, Hussan H, Stanich PP, Strobel S, Patel A, Behzadi J, Chan MQ, Ramsey ML, Ugbarugba E, Allen KD, Patel S, Farah F, Patel A, Vedachalam S, Blaszczak AM, Lee D, Porter K, Krishna SG. Confocal Laser Endomicroscopy Interpretation and Differentiation of Pancreatic Cysts: A Randomized Trial of Teaching Modalities. TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY 2021; 23:8-17. [DOI: 10.1016/j.tige.2020.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2023]
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Fulmer CG, Park K, Dilcher T, Ho M, Mirabelli S, Alperstein S, Hissong EM, Pittman M, Siddiqui M, Heymann JJ, Yantiss RK, Borczuk AC, Fernandes H, Sigel C, Song W, Mosquera JM, Rao R. Next-generation sequencing of residual cytologic fixative preserved DNA from pancreatic lesions: A pilot study. Cancer Cytopathol 2020; 128:840-851. [PMID: 32598087 PMCID: PMC9285651 DOI: 10.1002/cncy.22315] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/01/2020] [Accepted: 05/21/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a sensitive and specific tool in the risk stratification of pancreatic lesions, including cysts. The sensitivity and specificity of EUS-FNA has been shown to improve when cytology is combined with next-generation sequencing (NGS). Ideally, fresh cyst fluid is used for NGS. In this pilot study, we explore the possibility of sequencing DNA derived from residual alcohol-fixed pancreatic aspirates. METHODS Residual cytologic fixatives (n = 42) from 39 patients who underwent EUS-FNA for pancreatic lesions were collected along with demographics, imaging, and laboratory studies. Samples were designated as nonneoplastic/nonmucinous benign (NB), mucinous cyst (MC), pancreatic ductal adenocarcinoma (PDAC), or well-differentiated neuroendocrine tumor (NET) on the basis of cytopathologic evaluation and sequenced on the Oncomine platform (ThermoFisher Scientific, Waltham, Massachusetts). RESULTS Ten of 14 (71.4%) MCs exhibited clinically significant variants, including KRAS, GNAS, and TP53. Ten of 15 (66.7%) PDACs had KRAS alterations, and 9 of 15 (60%) showed variants in TP53. No variants were detected in any NETs. Only 1 of 9 (11.1%) NB aspirates showed variants in KRAS and MAP2K. Sequencing of formalin-fixed, paraffin-embedded tissue revealed variants identical to those detected in fixative-derived DNA in 4 of 5 cases (80%). CONCLUSION Residual DNA from alcohol-fixed aspirates are an underutilized source for NGS. Sequencing residual fixative-derived DNA has the potential to be integrated into the workup of pancreatic aspirates, possibly impacting management.
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Affiliation(s)
- Clifton G Fulmer
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, The Cleveland Clinic, Cleveland, OH
| | - Kyung Park
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Thomas Dilcher
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Mai Ho
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Susanna Mirabelli
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Susan Alperstein
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Erika M. Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Meredith Pittman
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Momin Siddiqui
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jonas J. Heymann
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Rhonda K. Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Alain C. Borczuk
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Helen Fernandes
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Carlie Sigel
- Department of Pathology, The Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wei Song
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Rema Rao
- The Leopold G. Koss Division of Cytology, The Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
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Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
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Advances in the management of pancreatic cystic neoplasms. Curr Probl Surg 2020; 58:100879. [PMID: 34144739 DOI: 10.1016/j.cpsurg.2020.100879] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/09/2020] [Indexed: 12/11/2022]
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The Diagnostic Accuracy of Mutant KRAS Detection from Pancreatic Secretions for the Diagnosis of Pancreatic Cancer: A Meta-Analysis. Cancers (Basel) 2020; 12:cancers12092353. [PMID: 32825312 PMCID: PMC7564395 DOI: 10.3390/cancers12092353] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/14/2020] [Accepted: 08/18/2020] [Indexed: 12/18/2022] Open
Abstract
This meta-analysis aims to identify the diagnostic accuracy of mutations in the Kirsten Rat Sarcoma (KRAS) oncogene in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). The survival of PDAC remains poor often due to the fact that disease is advanced at diagnosis. We analysed 22 studies, with a total of 2156 patients, to identify if the detection of KRAS mutations from pancreatic exocrine secretions yields sufficient specificity and sensitivity to detect patients with PDAC amongst healthy individuals. The majority of the studies were retrospective, samples were obtained endoscopically or surgically, and included comparator populations of patients with chronic pancreatitis and pre-malignant pancreatic lesions (PanIN) as well as healthy controls. We performed several analyses to identify the diagnostic accuracy for PDAC among these patient populations. Our results highlighted that the diagnostic accuracy of KRAS mutation for PDAC was of variable sensitivity and specificity when compared with PanINs and chronic pancreatitis, but had a higher specificity among healthy individuals. The sensitivity of this test must be improved to prevent missing early PDAC or PanINs. This could be achieved with rigorous prospective cohort studies, in which high-risk patients with normal cross-sectional imaging undergo surveillance following KRAS mutation testing.
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Management of Incidental Pancreatic Cystic Lesions: Integrating Novel Diagnostic and Prognostic Factors With Current Clinical Guidelines. J Clin Gastroenterol 2020; 54:415-427. [PMID: 32011401 DOI: 10.1097/mcg.0000000000001310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Owing to increased detection rates, the diagnosis and management of incidental pancreatic cysts has become a common predicament. Up to 13% of patients undergoing cross-sectional imaging studies for other indications are found to have pancreatic cystic lesions. Although most cystic lesions are benign, the malignant potential of several types of pancreatic cysts makes accurate classification vital to directing therapy. To this end, advances in the last decade led to better characterization of pancreatic cyst morphology and hence enhanced the ability to predict underlying histopathology, and biological behavior. Although accurate classification remains a challenge, the utilization of complementary diagnostic tools is the optimal approach to dictate management. The following review includes a description of pancreatic cysts, a critical review of current and emerging diagnostic techniques and a review of recent guidelines in the management of incidental pancreatic cysts.
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Sakhdari A, Moghaddam PA, Pejchal M, Cosar EF, Hutchinson L. Sequential molecular and cytologic analyses provides a complementary approach to the diagnosis of pancreatic cystic lesions: a decade of clinical practice. J Am Soc Cytopathol 2020; 9:38-44. [PMID: 31711852 DOI: 10.1016/j.jasc.2019.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/10/2019] [Accepted: 09/13/2019] [Indexed: 06/10/2023]
Abstract
INTRODUCTION Many pancreatic cystic lesions (PCL) are of neoplastic nature with potential to progress to pancreatic adenocarcinoma. Early stratification of patients to either clinical observation or surgical intervention can considerably increase the survival rate. Recent studies have shown the value of molecular analysis to current diagnostic modalities.The aim of this study is to evaluate the diagnostic improvement by utilizing multiple sequential cytologic and molecular cyst fluid analyses. MATERIALS AND METHODS We prospectively evaluated 58 patients for whom multiple endoscopic ultrasound-guided fine-needle aspiration of cyst fluid specimens were available. Specimens were subjected to next generation sequencing to identify any recurrent gene mutations commonly found in PCL. The molecular findings were compared with cytologic and final diagnoses. RESULTS Cytologic diagnoses were classified into 3 groups: non-diagnostic (first visit: 33.9%, cumulative: 15.8%, P = 0.03), negative (1st visit: 53.6%, cumulative: 56.1%, P = 0.85) and atypical/suspicious/positive (first visit: 12.5%, cumulative: 28.1%, P = 0.06). The mutational analyses were clustered into indeterminate/failure (first visit: 1.7%, cumulative: 0%), KRAS/GNAS/VHL group (first visit: 50.0%, cumulative: 53.4%) and any mutation (first visit: 50.0%, cumulative: 53.4%). Mutational analysis identifies up to 72% and 71% whereas cytologic analysis classified up to 46% and 63% of lesions correctly in first and multiple visits, respectively. CONCLUSIONS The cytology and molecular analyses provide a complementary approach to patients with PCL. Power of molecular analysis in detection of a neoplastic lesion is significantly higher in one visit (P = 0.01) with comparable detection rates (P = 0.43) for both cytologic and molecular analyses after multiple visits.
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Affiliation(s)
- Ali Sakhdari
- Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, Canada.
| | | | - Martina Pejchal
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Ediz F Cosar
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Lloyd Hutchinson
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts
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Iwashita T, Uemura S, Mita N, Iwasa Y, Ichikawa H, Senju A, Yasuda I, Shimizu M. Utility of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration for the diagnosis and management of pancreatic cystic lesions: Differences between the guidelines. Dig Endosc 2020; 32:251-262. [PMID: 31709639 DOI: 10.1111/den.13579] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/29/2019] [Accepted: 11/07/2019] [Indexed: 12/18/2022]
Abstract
Recent advances and frequent use of cross-sectional imaging studies have increased opportunities for incidental diagnoses of pancreatic cystic lesions (PCL). In the management of PCL, distinguishing between mucinous versus non-mucinous and malignant versus benign cysts is important to diagnose pancreatic cancer in its early stage. For this reason, there have been several guidelines to manage PCL. Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) play important roles in the guidelines, although there are some differences in their roles. In this review, we aimed to evaluate the current status of EUS and EUS-FNA in the management of PCL and the status of these procedures in the guidelines.
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Affiliation(s)
- Takuji Iwashita
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Shinya Uemura
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Naoki Mita
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Yuhei Iwasa
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Hironao Ichikawa
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Akihiko Senju
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
| | - Ichiro Yasuda
- Third Department of Internal Medicine, University of Toyama Hospital, Toyama, Japan
| | - Masahito Shimizu
- First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan
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van Huijgevoort NCM, Del Chiaro M, Wolfgang CL, van Hooft JE, Besselink MG. Diagnosis and management of pancreatic cystic neoplasms: current evidence and guidelines. Nat Rev Gastroenterol Hepatol 2019; 16:676-689. [PMID: 31527862 DOI: 10.1038/s41575-019-0195-x] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/31/2019] [Indexed: 12/11/2022]
Abstract
Pancreatic cystic neoplasms (PCN) are a heterogeneous group of pancreatic cysts that include intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystic neoplasms and other rare cystic lesions, all with different biological behaviours and variable risk of progression to malignancy. As more pancreatic cysts are incidentally discovered on routine cross-sectional imaging, optimal surveillance for patients with PCN is becoming an increasingly common clinical problem, highlighting the need to balance cancer prevention with the risk of (surgical) overtreatment. This Review summarizes the latest developments in the diagnosis and management of PCN, including the quality of available evidence. Also discussed are the most important differences between the PCN guidelines from the American Gastroenterological Association, the International Association of Pancreatology and the European Study Group on Cystic Tumours of the Pancreas, including diagnostic and follow-up strategies and indications for surgery. Finally, new developments in the management of patients with PCN are addressed.
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Affiliation(s)
- Nadine C M van Huijgevoort
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christopher L Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
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Tanaka M, Heckler M, Liu B, Heger U, Hackert T, Michalski CW. Cytologic Analysis of Pancreatic Juice Increases Specificity of Detection of Malignant IPMN-A Systematic Review. Clin Gastroenterol Hepatol 2019; 17:2199-2211.e21. [PMID: 30630102 DOI: 10.1016/j.cgh.2018.12.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can progress to cancer. Biomarkers have been identified that were reported to increase the accuracy of identification of malignant lesions; we performed a systematic review of the accuracy of these markers. METHODS We performed a systematic review of published studies on biomarkers of malignant IPMNs by searching MEDLINE and Web of Science databases from January 2005 through December 2017. Our methods were developed based on the Meta-analysis Of Observational Studies in Epidemiology guidelines. Pooled sensitivity, specificity, receiver operating characteristic curves, and their respective areas under the curve (AUC) were calculated from groups of markers (cell-, protein-, or DNA-based) measured in samples collected before and after surgery. A hypothetical test model was developed to determine how to meaningfully amend the revised Fukuoka guidelines, focusing on increasing test specificity for patients with IPMNs that have worrisome features. RESULTS We collected data from 193 published studies, comprising 12,297 patients, that analyzed 7 preoperative and 21 postoperative markers of IPMNs. The 3 biomarkers that identified malignant IPMNs with the largest AUC values were pancreatic juice cytology (AUC, 0.84; sensitivity, 0.54; specificity, 0.91), serum protein carbohydrate antigen 19-9 (AUC, 0.81; sensitivity, 0.45; specificity, 0.90), and cyst fluid cytology (AUC, 0.82; sensitivity, 0.57; specificity, 0.84). A combination of cytologic and immunohistochemical analysis of MUC1 and MUC2 in pancreatic juice samples identified malignant IPMNs with the largest AUC and sensitivity values (AUC, 0.85; sensitivity, 0.85; specificity, 0.65). In a test model, inclusion of cytologic analysis of pancreatic juice in the guideline algorithm significantly increased the specificity of detection of malignant IPMNs. CONCLUSIONS In a systematic review, we found cytologic analysis of pancreatic juice to have the greatest effect in increasing the specificity of detection of malignant IPMNs. We propose addition of this test to the Fukuoka guidelines for assessment of patients with IPMNs with worrisome features.
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Affiliation(s)
- Masayuki Tanaka
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Max Heckler
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Bing Liu
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Ulrike Heger
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany.
| | - Christoph W Michalski
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany; Department of Surgery, Halle University Hospital, Martin Luther University Halle-Wittenberg, Halle, Germany
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Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing. Am J Gastroenterol 2019; 114:1539-1549. [PMID: 31306149 PMCID: PMC7294458 DOI: 10.14309/ajg.0000000000000284] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
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New Era of Endoscopic Ultrasound-Guided Tissue Acquisition: Next-Generation Sequencing by Endoscopic Ultrasound-Guided Sampling for Pancreatic Cancer. J Clin Med 2019; 8:jcm8081173. [PMID: 31387310 PMCID: PMC6723875 DOI: 10.3390/jcm8081173] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/20/2019] [Accepted: 08/02/2019] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is a lethal cancer with an increasing incidence. Despite improvements in chemotherapy, patients with pancreatic cancer continue to face poor prognoses. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the primary method for obtaining tissue samples of pancreatic cancer. Due to advancements in next-generation sequencing (NGS) technologies, multiple parallel sequencing can be applied to EUS-TA samples. Genomic biomarkers for therapeutic stratification in pancreatic cancer are still lacking, however, NGS can unveil potential predictive genomic biomarkers of treatment response. Thus, the importance of NGS using EUS-TA samples is becoming recognized. In this review, we discuss the recent advances in EUS-TA application for NGS of pancreatic cancer.
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50
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Faias S, Pereira L, Luís Â, Chaves P, Cravo M. Genetic testing vs microforceps biopsy in pancreatic cysts: Systematic review and meta-analysis. World J Gastroenterol 2019; 25:3450-3467. [PMID: 31341368 PMCID: PMC6639554 DOI: 10.3748/wjg.v25.i26.3450] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/17/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Carcinoembryonic antigen (CEA) and cytology in pancreatic cystic fluid are suboptimal for evaluation of pancreatic cystic neoplasms. Genetic testing and microforceps biopsy are promising tools for pre-operative diagnostic improvement but comparative performance of both methods is unknown.
AIM To compare the accuracy of genetic testing and microforceps biopsy in pancreatic cysts referred for surgery.
METHODS We performed a literature search in Medline, Scopus, and Web of Science for studies evaluating genetic testing of cystic fluid and microforceps biopsy of pancreatic cysts, with endoscopic ultrasound with fine-needle aspiration (EUS-FNA) prior to surgery and surgical pathology as reference standard for diagnosis. We evaluated the diagnostic accuracy for: 1- benign cysts; 2- mucinous low-risk cysts; 3- high-risk cysts, and the diagnostic yield and rate of correctly identified cysts with microforceps biopsy and molecular analysis. We also assessed publication bias, heterogeneity, and study quality.
RESULTS Eight studies, including 1206 patients, of which 203 (17%) referred for surgery who met the inclusion criteria were analyzed in the systematic review, and seven studies were included in the meta-analysis. Genetic testing and microforceps biopsies were identical for diagnosis of benign cysts. Molecular analysis was superior for diagnosis of both low and high-risk mucinous cysts, with sensitivities of 0.89 (95%CI: 0.79-0.95) and 0.57 (95%CI: 0.42-0.71), specificities of 0.88 (95%CI: 0.75-0.95) and 0.88 (95%CI: 0.80-0.93) and AUC of 0.9555 and 0.92, respectively. The diagnostic yield was higher in microforceps biopsies than in genetic analysis (0.73 vs 0.54, respectively) but the rates of correctly identified cysts were identical (0.73 with 95%CI: 0.62-0.82 vs 0.71 with 95%CI: 0.49-0.86, respectively).
CONCLUSION Genetic testing and microforceps biopsies are useful second tests, with identical results in benign pancreatic cysts. Genetic analysis performs better for low- and high-risk cysts but has lower diagnostic yield.
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Affiliation(s)
- Sandra Faias
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa de Francisco Gentil, EPE, Lisboa 1099-023, Portugal
- Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã 6200-506, Portugal
- GRUBI-Grupo de Revisões Sistemáticas, Universidade da Beira Interior, Covilhã 6200-506, Portugal
| | - Luisa Pereira
- GRUBI-Grupo de Revisões Sistemáticas, Universidade da Beira Interior, Covilhã 6200-506, Portugal
- Centro de Matemática e Aplicações (CMA-UBI), Universidade da Beira Interior, Covilhã 6200-506, Portugal
| | - Ângelo Luís
- GRUBI-Grupo de Revisões Sistemáticas, Universidade da Beira Interior, Covilhã 6200-506, Portugal
- Centro de Investigação em Ciências da Saúde (CICS-UBI), Universidade da Beira Interior, Covilhã 6200-506, Portugal
| | - Paula Chaves
- Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã 6200-506, Portugal
- Department of Pathology, Instituto Português de Oncologia de Lisboa de Francisco Gentil, EPE, Lisboa 1099-023, Portugal
| | - Marília Cravo
- Department of Gastroenterology, Hospital Beatriz Ângelo, Loures 2674-514, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisboa 1099-023, Portugal
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