|
1
|
Brown JW, Lin X, Nicolazzi GA, Liu X, Nguyen T, Radyk MD, Burclaff J, Mills JC. Cathartocytosis: Jettisoning of Unwanted Material during Cellular Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.11.598489. [PMID: 38915707 PMCID: PMC11195262 DOI: 10.1101/2024.06.11.598489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins were not only digested during paligenosis but also excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was mechanistically independent of autophagy. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis". Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins would aid in downscaling and might also help bind and flush pathogens away from tissue.
Collapse
|
|
2
|
Pian LL, Song MH, Wang TF, Qi L, Peng TL, Xie KP. Identification and analysis of pancreatic intraepithelial neoplasia: opportunities and challenges. Front Endocrinol (Lausanne) 2025; 15:1401829. [PMID: 39839479 PMCID: PMC11746065 DOI: 10.3389/fendo.2024.1401829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 12/17/2024] [Indexed: 01/23/2025] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field.
Collapse
Affiliation(s)
- Ling-ling Pian
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Mei-hui Song
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Teng-fei Wang
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Ling Qi
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Tie-li Peng
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Ke-ping Xie
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
| |
Collapse
|
|
3
|
Moris D, Liapis I, Gupta P, Ziogas IA, Karachaliou GS, Dimitrokallis N, Nguyen B, Radkani P. An Overview for Clinicians on Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas. Cancers (Basel) 2024; 16:3825. [PMID: 39594780 PMCID: PMC11593033 DOI: 10.3390/cancers16223825] [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: 10/10/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Currently, there is no reliable method of discerning between low-risk and high-risk intraductal papillary mucinous neoplasms (IPMNs). Operative resection is utilized in an effort to resect those lesions with high-grade dysplasia (HGD) prior to the development of invasive disease. The current guidelines recommend resection for IPMN that involve the main pancreatic duct. Resecting lesions with HGD before their progression to invasive disease and the avoidance of resection in those patients with low-grade dysplasia is the optimal clinical scenario. Therefore, the importance of developing preoperative models able to discern HGD in IPMN patients cannot be overstated. Low-risk patients should be managed with nonsurgical treatment options (typically MRI surveillance), while high-risk patients would undergo resection, hopefully prior to the formation of invasive disease. Current research is evolving in multiple directions. First, there is an ongoing effort to identify reliable markers for predicting malignant transformation of IPMN, mainly focusing on genomic and transcriptomic data from blood, tissue, and cystic fluid. Also, multimodal models of combining biomarkers with clinical and radiographic data seem promising for providing robust and accurate answers of risk levels for IPMN patients.
Collapse
Affiliation(s)
- Dimitrios Moris
- MedStar Georgetown Transplant Institute, Washington, DC 20007, USA; (P.G.); (B.N.); (P.R.)
| | - Ioannis Liapis
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Piyush Gupta
- MedStar Georgetown Transplant Institute, Washington, DC 20007, USA; (P.G.); (B.N.); (P.R.)
| | - Ioannis A. Ziogas
- Department of Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA;
| | - Georgia-Sofia Karachaliou
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA;
| | - Nikolaos Dimitrokallis
- 1st Department of Surgery & Organ Transplant Unit, Evangelismos General Hospital, 10676 Athens, Greece;
| | - Brian Nguyen
- MedStar Georgetown Transplant Institute, Washington, DC 20007, USA; (P.G.); (B.N.); (P.R.)
| | - Pejman Radkani
- MedStar Georgetown Transplant Institute, Washington, DC 20007, USA; (P.G.); (B.N.); (P.R.)
| |
Collapse
|
|
4
|
Tobi M, Khoury N, Al-Subee O, Sethi S, Talwar H, Kam M, Hatfield J, Levi E, Hallman J, Moyer MP, Kresty L, Lawson MJ, McVicker B. Predicting Regression of Barrett's Esophagus-Can All the King's Men Put It Together Again? Biomolecules 2024; 14:1182. [PMID: 39334948 PMCID: PMC11430295 DOI: 10.3390/biom14091182] [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: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett's esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age (p < 0.007); lower platelet levels (p < 0.02); rectal p87 elevation in SR (p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) (p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR.
Collapse
Affiliation(s)
- Martin Tobi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Nabiha Khoury
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
- Department of Medicine, Wayne State University, 42 W. Warren Ave., Detroit, MI 48201, USA
| | - Omar Al-Subee
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Seema Sethi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Harvinder Talwar
- Department of Medicine, Wayne State University, 42 W. Warren Ave., Detroit, MI 48201, USA
| | - Michael Kam
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - James Hatfield
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Edi Levi
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Jason Hallman
- Departments of Medicine, Research and Development, John D. Dingell VAMC, 3636 John R. St., Detroit, MI 48201, USA
| | - Mary Pat Moyer
- INCELL Corporation LLC, 12734 Cimarron Path, San Antonio, TX 78249, USA
| | - Laura Kresty
- Department of Thoracic Surgery, University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA
| | - Michael J. Lawson
- Department of Internal Medicine, University of California at Sacramento, Davis, CA 95616, USA
| | - Benita McVicker
- VA Medical Center, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68005, USA
| |
Collapse
|
|
5
|
Paolino G, Basturk O, Esposito I, Hong SM, Brosens LA, Tarcan Z, Wood LD, Gkountakos A, Omori Y, Mattiolo P, Ciulla C, Marchegiani G, Pea A, Bevere M, De Robertis R, D'Onofrio M, Salvia R, Cheng L, Furukawa T, Scarpa A, Adsay V, Luchini C. Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the Pancreas: A Systematic and Critical Review. Mod Pathol 2024; 37:100554. [PMID: 38950698 DOI: 10.1016/j.modpat.2024.100554] [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: 02/08/2024] [Revised: 05/23/2024] [Accepted: 06/20/2024] [Indexed: 07/03/2024]
Abstract
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine its most essential features with the systematic review tool. PubMed, Scopus, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathologic, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131/237; 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1 out of 5 cases (49/237; 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1 or pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and molecular features were as follows. The most commonly expressed mucins were MUC5AC (110/112; 98.2%) and MUC6 (78/84; 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (P < .01). Moreover, fusions involving PRKACA or PRKACB gene were detected in all of the 68 cases examined, with PRKACB::ATP1B1 being the most common (27/68 cases; 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (P < .01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features. Considering the clinical or prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management.
Collapse
Affiliation(s)
- Gaetano Paolino
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy; Pathology Unit, Azienda Socio Sanitaria Territoriale Spedali Civili Di Brescia, Brescia, Italy
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Irene Esposito
- Institute of Pathology, University Hospital of Duesseldorf, Duesseldorf, Germany
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Lodewijk A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Zeynep Tarcan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anastasios Gkountakos
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Yuko Omori
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy; Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Paola Mattiolo
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Calogero Ciulla
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Giovanni Marchegiani
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Antonio Pea
- Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Michele Bevere
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Riccardo De Robertis
- Section of Radiology, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Mirko D'Onofrio
- Section of Radiology, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Roberto Salvia
- Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, Rhode Island
| | - Toru Furukawa
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Aldo Scarpa
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy; ARC-Net Research Center, University of Verona, Verona, Italy
| | - Volkan Adsay
- Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Claudio Luchini
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy; ARC-Net Research Center, University of Verona, Verona, Italy.
| |
Collapse
|
|
6
|
Gardner TB, Park WG, Allen PJ. Diagnosis and Management of Pancreatic Cysts. Gastroenterology 2024; 167:454-468. [PMID: 38442782 DOI: 10.1053/j.gastro.2024.02.041] [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: 10/09/2023] [Revised: 01/01/2024] [Accepted: 02/18/2024] [Indexed: 03/07/2024]
Abstract
As pancreatic cyst incidence rises, likely due to the ubiquitous increase in cross-sectional imaging, their management presents multiple challenges for both the practitioner and patient. It is critical that all pancreatic cysts are appropriately characterized, as treatment decisions depend on an accurate diagnosis. Diagnostic modalities such as cytology, biopsy, and cyst fluid biomarkers allow for definitive diagnosis of virtually all lesions. Some cysts, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and cystic pancreatic endocrine neoplasms, have malignant potential and must be surveyed. Other cysts, such as serous cystadenomas and pancreatic fluid collections, do not have malignant potential. Surveillance strategies vary widely depending on cyst type and size and while multiple medical societies advocate surveillance, their published surveillance guidelines are heterogenous. Cysts with high-risk stigmata or worrisome features are usually resected, depending on the patient's surgical fitness. In patients unfit for resection, newer endoscopic ablative techniques are advocated. Controversial aspects regarding cyst management include whether surveillance can be stopped, how surveillance should be performed, and the extensive financial burden cyst management places on the health care system. Further study into the natural history of cystic lesions, including definitive determination of the rate of malignant transformation for each cyst type, is essential.
Collapse
Affiliation(s)
- Timothy B Gardner
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
| | - Walter G Park
- Section of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Peter J Allen
- Division of Surgical Oncology, Duke University Medical Center, Durham, North Carolina
| |
Collapse
|
|
7
|
Sheik DA, Byers K, Thomas M, Rajesh UC, Ifuku K, Kirkwood K, Al-Haddad M, Craik CS, Davisson VJ. Addressing the unmet clinical need for low-volume assays in early diagnosis of pancreatic cancer. FRONTIERS IN GASTROENTEROLOGY (LAUSANNE, SWITZERLAND) 2023; 2:1258998. [PMID: 38846269 PMCID: PMC11156210 DOI: 10.3389/fgstr.2023.1258998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/09/2024]
Abstract
The incidental detection of pancreatic cysts, an opportunity for the early detection of pancreatic cancer, is increasing, owing to an aging population and improvements in imaging technology. The classification of pancreatic cystic precursors currently relies on imaging and cyst fluid evaluations, including cytology and protein and genomic analyses. However, there are persistent limitations that obstruct the accuracy and quality of information for clinicians, including the limited volume of the complex, often acellular, and proteinaceous milieu that comprises pancreatic cyst fluid. The constraints of currently available clinical assays lead clinicians to the subjective and inconsistent application of diagnostic tools, which can contribute to unnecessary surgery and missed pancreatic cancers. Herein, we describe the pathway toward pancreatic cyst classification and diagnosis, the volume requirements for several clinically available diagnostic tools, and some analytical and diagnostic limitations for each assay. We then discuss current and future work on novel markers and methods, and how to expand the utility of clinical pancreatic cyst fluid samples. Results of ongoing studies applying SERS as a detection mode suggest that 50 μL of pancreatic cyst fluid is more than sufficient to accurately rule out non-mucinous pancreatic cysts with no malignant potential from further evaluation. This process is expected to leave sufficient fluid to analyze a follow-up, rule-in panel of markers currently in development that can stratify grades of dysplasia in mucinous pancreatic cysts and improve clinical decision-making.
Collapse
Affiliation(s)
- Daniel A. Sheik
- Research and Technology Department, Amplified Sciences, Inc, West Lafayette, IN, United States
| | - Kaleb Byers
- Research and Technology Department, Amplified Sciences, Inc, West Lafayette, IN, United States
| | - Mini Thomas
- Research and Technology Department, Amplified Sciences, Inc, West Lafayette, IN, United States
| | | | - Kelli Ifuku
- Department of Surgery, University of California, San Francisco, CA, United States
| | - Kimberly Kirkwood
- Department of Surgery, University of California, San Francisco, CA, United States
| | - Mohammed Al-Haddad
- Division of Gastroenterology and Hepatology, Indiana University (IU) School of Medicine, Indianapolis, IN, United States
| | - Charles S. Craik
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States
| | - V. Jo Davisson
- Research and Technology Department, Amplified Sciences, Inc, West Lafayette, IN, United States
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, West Lafayette, IN, United States
| |
Collapse
|
|
8
|
Siddappa PK, Park WG. Pancreatic Cyst Fluid Analysis. Gastrointest Endosc Clin N Am 2023; 33:599-612. [PMID: 37245938 DOI: 10.1016/j.giec.2023.03.006] [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: 05/30/2023]
Abstract
Pancreatic cyst fluid analysis can help diagnose pancreatic cyst type and the risk of high-grade dysplasia and cancer. Recent evidence from molecular analysis of cyst fluid has revolutionized the field with multiple markers showing promise in accurate diagnosis and prognostication of pancreatic cysts. The availability of multi-analyte panels has great potential for more accurate prediction of cancer.
Collapse
Affiliation(s)
- Pradeep K Siddappa
- Division of Gastroenterology & Hepatology, Stanford University, Stanford, CA, USA
| | - Walter G Park
- Division of Gastroenterology & Hepatology, Stanford University, Stanford, CA, USA.
| |
Collapse
|
|
9
|
Peller MT, Das KK. Blood-Based Biomarkers in the Diagnosis and Risk Stratification of Pancreatic Cysts. Gastrointest Endosc Clin N Am 2023; 33:559-581. [PMID: 37245936 DOI: 10.1016/j.giec.2023.03.009] [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: 05/30/2023]
Abstract
The use of blood-based biomarkers for the assessment of pancreatic cystic lesions is a rapidly growing field with incredible potential. CA 19-9 remains the only blood-based marker in common use, while many novel biomarkers are in early stages of development and validation. We highlight current work in the fields of proteomics, metabolomics, cell-free DNA/circulating tumor DNA, extracellular vesicles, and microRNA among others, as well as barriers to development and future directions in the work of blood-based biomarkers for pancreatic cystic lesions.
Collapse
Affiliation(s)
- Matthew T Peller
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA
| | - Koushik K Das
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA.
| |
Collapse
|
|
10
|
Mormul A, Włoszek E, Nowoszewska J, Fudalej M, Budzik M, Badowska-Kozakiewicz A, Deptała A. Rare Non-Neuroendocrine Pancreatic Tumours. Cancers (Basel) 2023; 15:cancers15082216. [PMID: 37190144 DOI: 10.3390/cancers15082216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/30/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
The most common tumour of the pancreas is ductal adenocarcinoma (PDAC). It remains one of the most lethal non-neuroendocrine solid tumours despite the use of a multi-approach strategy. Other, less-common neoplasms, which are responsible for 15% of pancreatic lesions, differ in treatment and prognosis. Due to the low incidence rate, there is a lack of information about the rarest pancreatic tumours. In this review, we described six rare pancreatic tumours: intraductal papillary mucinous neoplasm (IPMN), mucinous cystadenoma (MCN), serous cystic neoplasm (SCN), acinar cell carcinoma (ACC), solid pseudopapillary neoplasm (SPN) and pancreatoblastoma (PB). We distinguished their epidemiology, clinical and gross features, covered the newest reports about courses of treatment and systematised differential diagnoses. Although the most common pancreatic tumour, PDAC, has the highest malignant potential, it is still essential to properly classify and differentiate less-common lesions. It is vital to continue the search for new biomarkers, genetic mutations and the development of more specific biochemical tests for determining malignancy in rare pancreatic neoplasms.
Collapse
Affiliation(s)
- Agata Mormul
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Emilia Włoszek
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Julia Nowoszewska
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Michał Budzik
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | | | - Andrzej Deptała
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| |
Collapse
|
|
11
|
Iyer MK, Shi C, Eckhoff AM, Fletcher A, Nussbaum DP, Allen PJ. Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification. SCIENCE ADVANCES 2023; 9:eade4582. [PMID: 36930707 PMCID: PMC10022906 DOI: 10.1126/sciadv.ade4582] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.
Collapse
Affiliation(s)
| | - Chanjuan Shi
- Department of Pathology, Duke University, Durham, NC, USA
| | | | | | | | | |
Collapse
|
|
12
|
Das KK, Brown JW. 3'-sulfated Lewis A/C: An oncofetal epitope associated with metaplastic and oncogenic plasticity of the gastrointestinal foregut. Front Cell Dev Biol 2023; 11:1089028. [PMID: 36866273 PMCID: PMC9971977 DOI: 10.3389/fcell.2023.1089028] [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: 11/03/2022] [Accepted: 01/10/2023] [Indexed: 02/16/2023] Open
Abstract
Metaplasia, dysplasia, and cancer arise from normal epithelia via a plastic cellular transformation, typically in the setting of chronic inflammation. Such transformations are the focus of numerous studies that strive to identify the changes in RNA/Protein expression that drive such plasticity along with the contributions from the mesenchyme and immune cells. However, despite being widely utilized clinically as biomarkers for such transitions, the role of glycosylation epitopes is understudied in this context. Here, we explore 3'-Sulfo-Lewis A/C, a clinically validated biomarker for high-risk metaplasia and cancer throughout the gastrointestinal foregut: esophagus, stomach, and pancreas. We discuss the clinical correlation of sulfomucin expression with metaplastic and oncogenic transformation, as well as its synthesis, intracellular and extracellular receptors and suggest potential roles for 3'-Sulfo-Lewis A/C in contributing to and maintaining these malignant cellular transformations.
Collapse
Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Jeffrey W Brown
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| |
Collapse
|
|
13
|
Das KK. The "Next Generation" of Pancreatic Cyst Fluid Biomarkers? Gastroenterology 2023; 164:21-23. [PMID: 36341737 DOI: 10.1053/j.gastro.2022.10.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 02/03/2023]
Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
| |
Collapse
|
|
14
|
Wietrzykowska-Grishanovich D, Pawlik E, Neubauer K. Biochemical Intracystic Biomarkers in the Differential Diagnosis of Pancreatic Cystic Lesions. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58080994. [PMID: 35893110 PMCID: PMC9331360 DOI: 10.3390/medicina58080994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/20/2022] [Accepted: 07/23/2022] [Indexed: 11/16/2022]
Abstract
Background and Objectives: Pancreatic cystic lesions (PCLs) are frequently incidental findings. The prevalence of PCLs is increasing, mainly due to advancements in imaging techniques, but also because of the aging of the population. PCLs comprise challenging clinical problems, as their manifestations vary from benign to malignant lesions. Therefore, the recognition of PCLs is achieved through a complex diagnostic and surveillance process, which in turn is usually long-term, invasive, and expensive. Despite the progress made in the identification of novel biomarkers in the cystic fluid that also support the differentiation of PCLs, their application in clinical practice is limited. Materials and Methods: We conducted a systematic review of the literature published in two databases, Pubmed and Embase, on biochemical biomarkers in PCLs that may be applied in the diagnostic algorithms of PCLs. Results: Eleven studies on intracystic glucose, twenty studies on intracystic carcinoembryonic antigen (CEA), and eighteen studies on other biomarkers were identified. Low levels of intracystic glucose had high sensitivity and specificity in the differentiation between mucinous and non-mucinous cystic neoplasms. Conclusions: CEA and glucose are the most widely studied fluid biochemical markers in pancreatic cystic lesions. Glucose has better diagnostic accuracy than CEA. Other biochemical biomarkers require further research.
Collapse
Affiliation(s)
- Dominika Wietrzykowska-Grishanovich
- Department of Gastroenterology and Hepatology, University Teaching Hospital, Borowska 213, 50-556 Wroclaw, Poland;
- Correspondence: (D.W.-G.); (K.N.)
| | - Ewa Pawlik
- Department of Gastroenterology and Hepatology, University Teaching Hospital, Borowska 213, 50-556 Wroclaw, Poland;
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
- Correspondence: (D.W.-G.); (K.N.)
| |
Collapse
|
|
15
|
Ferguson S, Yang KS, Zelga P, Liss AS, Carlson JCT, del Castillo CF, Weissleder R. Single-EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer. SCIENCE ADVANCES 2022; 8:eabm3453. [PMID: 35452280 PMCID: PMC9032977 DOI: 10.1126/sciadv.abm3453] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 03/07/2022] [Indexed: 05/02/2023]
Abstract
Tumor cell-derived extracellular vesicles (EVs) are being explored as circulating biomarkers, but it is unclear whether bulk measurements will allow early cancer detection. We hypothesized that a single-EV analysis (sEVA) technique could potentially improve diagnostic accuracy. Using pancreatic cancer (PDAC), we analyzed the composition of putative cancer markers in 11 model lines. In parental PDAC cells positive for KRASmut and/or P53mut proteins, only ~40% of EVs were also positive. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmut and P53mut protein was detectable at much lower levels, generally in <0.1% of vesicles. These vesicles were detectable by the new sEVA approach in 15 of the 16 patients. Using a modeling approach, we estimate that the current PDAC detection limit is at ~0.1-cm3 tumor volume, below clinical imaging capabilities. These findings establish the potential for sEVA for early cancer detection.
Collapse
Affiliation(s)
- Scott Ferguson
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
| | - Katherine S. Yang
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
| | - Piotr Zelga
- Department of Surgery, Massachusetts General Hospital, 32 Fruit St, Boston, MA 02114, USA
| | - Andrew S. Liss
- Department of Surgery, Massachusetts General Hospital, 32 Fruit St, Boston, MA 02114, USA
| | - Jonathan C. T. Carlson
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Carlos Fernandez del Castillo
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
- Department of Surgery, Massachusetts General Hospital, 32 Fruit St, Boston, MA 02114, USA
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
- Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA
| |
Collapse
|
|
16
|
Das KK, Mullady DK. Main Pancreatic Duct Dilation in IPMN: When (and Where) to Get "Worried"? Clin Gastroenterol Hepatol 2022; 20:272-275. [PMID: 33581356 DOI: 10.1016/j.cgh.2021.02.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Daniel K Mullady
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| |
Collapse
|
|
17
|
Brown JW, Das KK, Kalas V, Das KM, Mills JC. mAb Das-1 recognizes 3'-Sulfated Lewis A/C, which is aberrantly expressed during metaplastic and oncogenic transformation of several gastrointestinal Epithelia. PLoS One 2021; 16:e0261082. [PMID: 34910746 PMCID: PMC8673611 DOI: 10.1371/journal.pone.0261082] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/23/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett's esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. METHODS In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. RESULTS The epitope recognized by mAb Das-1 is 3'-Sulfo-Lewis A/C (3'-Sulfo-LeA/C). 3'-Sulfo-LeA/C is broadly reexpressed across numerous GI epithelia and elsewhere during metaplastic and carcinomatous transformation. DISCUSSION 3'-Sulfo-LeA/C is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.
Collapse
Affiliation(s)
- Jeffrey W. Brown
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
| | - Koushik K. Das
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
| | - Vasilios Kalas
- Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
- Physician Scientist Training Program, Department of Medicine, McGaw Medical Center of Northwestern University, Chicago, Illinois, United States of America
| | - Kiron M. Das
- Division of Gastroenterology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
| | - Jason C. Mills
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
- Department of Developmental Biology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America
| |
Collapse
|
|
18
|
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: 40] [Impact Index Per Article: 10.0] [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).
Collapse
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
| |
Collapse
|
|
19
|
Heidarian A, Das KK, Mino-Kenudson M, Fernandez-Del Castillo C, Pitman MB. Cytology adds value to monoclonal antibody Das-1 testing for detection of high-risk pancreatic cysts. J Am Soc Cytopathol 2021; 10:249-254. [PMID: 33541830 DOI: 10.1016/j.jasc.2021.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/08/2020] [Accepted: 01/04/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Determining the risk of malignancy in a pancreatic cyst (PC) is a clinical and diagnostic challenge. Monoclonal antibody (mAb) Das-1 test was shown to have high sensitivity, specificity, and accuracy in detecting high-risk (HR) cysts. Das-1 mAb test detects HR mucinous cysts with high-grade dysplasia (HGD), invasive carcinoma, and/or intestinal-type epithelium. Correlation of mAb Das-1 testing of PC fluids with cytomorphologic findings has not been evaluated. MATERIALS AND METHODS We correlated cytology with mAb Das-1 test results and resection histology in 26 PCs. There were 18 intraductal papillary mucinous neoplasms (IPMN), 1 intraductal oncocytic papillary neoplasm (IOPN), 4 mucinous cystic neoplasms (MCN), 2 serous cystadenomas, and 1 cystic pancreatic neuroendocrine tumor (PanNET). HR cysts included cysts with high-grade atypia on cytology or HGD on histology, invasive carcinoma, IOPNs, and cystic PanNETs. Intestinal type IPMNs were also HR cysts on histology. RESULTS In 17 cases (65.38%), cytology and mAb Das-1 test correlated with histology. There were 2 (7.69%) mAb Das-1 test negative HR PCs diagnosed by cytology. Five (19.23%) mAb Das-1 test positive HR PCs had mucin only or cells with low-grade dysplasia on cytology. Two mAb Das-1 test positive HR PCs had nondiagnostic cytology. HR IOPN and cystic PanNET were not detected by mAb Das-1 test. CONCLUSION The mAb Das-1 is a sensitive and specific biomarker for detecting HR mucinous PCs. Adding cytology to mAb Das-1 testing improves the sensitivity for the detection of nonmucinous HR PC. Together, cytology with mAb Das-1 testing is more accurate than either one alone.
Collapse
Affiliation(s)
- Amin Heidarian
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Koushik K Das
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
20
|
Yang KS, Ciprani D, O'Shea A, Liss AS, Yang R, Fletcher-Mercaldo S, Mino-Kenudson M, Fernández-Del Castillo C, Weissleder R. Extracellular Vesicle Analysis Allows for Identification of Invasive IPMN. Gastroenterology 2021; 160:1345-1358.e11. [PMID: 33301777 PMCID: PMC7956058 DOI: 10.1053/j.gastro.2020.11.046] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/21/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Advances in cross-sectional imaging have resulted in increased detection of intraductal papillary mucinous neoplasms (IPMNs), and their management remains controversial. At present, there is no reliable noninvasive method to distinguish between indolent and high risk IPMNs. We performed extracellular vesicle (EV) analysis to identify markers of malignancy in an attempt to better stratify these lesions. METHODS Using a novel ultrasensitive digital extracellular vesicle screening technique (DEST), we measured putative biomarkers of malignancy (MUC1, MUC2, MUC4, MUC5AC, MUC6, Das-1, STMN1, TSP1, TSP2, EGFR, EpCAM, GPC1, WNT-2, EphA2, S100A4, PSCA, MUC13, ZEB1, PLEC1, HOOK1, PTPN6, and FBN1) in EV from patient-derived cell lines and then on circulating EV obtained from peripheral blood drawn from patients with IPMNs. We enrolled a total of 133 patients in two separate cohorts: a clinical discovery cohort (n = 86) and a validation cohort (n = 47). RESULTS From 16 validated EV proteins in plasma samples collected from the discovery cohort, only MUC5AC showed significantly higher levels in high-grade lesions. Of the 11 patients with invasive IPMN (inv/HG), 9 had high MUC5AC expression in plasma EV of the 11 patients with high-grade dysplasia alone, only 1 had high MUC5AC expression (sensitivity of 82%, specificity of 100%). These findings were corroborated in a separate validation cohort. The addition of MUC5AC as a biomarker to imaging and high-riskstigmata allowed detection of all cases requiring surgery, whereas imaging and high-risk stigmata alone would have missed 5 of 14 cases (36%). CONCLUSIONS MUC5AC in circulating EV can predict the presence of invasive carcinoma within IPMN. This approach has the potential to improve the management and follow-up of patients with IPMN including avoiding unnecessary surgery.
Collapse
Affiliation(s)
- Katherine S Yang
- Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts
| | - Debora Ciprani
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Aileen O'Shea
- Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Andrew S Liss
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Robert Yang
- Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
21
|
Das KK, Brown JW, Fernandez Del-Castillo C, Huynh T, Mills JC, Matsuda Y, Das KM, Mino-Kenudson M. mAb Das-1 identifies pancreatic ductal adenocarcinoma and high-grade pancreatic intraepithelial neoplasia with high accuracy. Hum Pathol 2021; 111:36-44. [PMID: 33524436 DOI: 10.1016/j.humpath.2021.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is a microscopic precursor lesion to pancreatic ductal adenocarcinoma (PDAC); however, there are few biomarkers that segregate high-grade PanIN/PDAC from low-grade PanIN lesions. mAb Das-1 is a monoclonal antibody against a colonic epithelial antigen that is reactive to premalignant conditions of the upper gastrointestinal tract including Barrett's esophagus, incomplete-type gastric intestinal metaplasia, and intraductal papillary mucinous neoplasm of the pancreas at high risk of malignancy. We sought to examine a role for Das-1 expression in differentiating high-grade PanIN/PDAC from low-grade PanIN lesions. We examined surgical specimens from 86 patients and 2 autopsied pancreata (74 with and 14 without PDAC) with 107 distinct PanIN lesions, 74 PDAC cases, and 32 associated lymph node metastases, with internal controls of normal pancreatic ducts observed in 56 cases. All of the normal pancreatic duct controls (0/56) and low-grade PanIN (0/95) lesions were nonreactive to Das-1. Das-1 expression among high-grade PanIN (7/12, 58%), PDAC (55/74, 74%), and lymph node metastasis (21/32, 66%) cases was significantly higher (p < 0.0001). Clinicopathologically, Das-1 reactivity was significantly correlated with nodal metastasis (p = 0.021). Overall, the sensitivity, specificity, and accuracy of Das-1 in segregating high-grade PanIN/PDAC from low-grade PanIN lesions and normal ducts were 72%, 100%, and 90%, respectively. Thus, mAb Das-1 reacts with high specificity with high-grade PanIN and PDAC and may help in preoperative diagnosis and/or clinical risk stratification.
Collapse
Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Washington University, St. Louis, 63110, USA.
| | - Jeffrey W Brown
- Division of Gastroenterology, Washington University, St. Louis, 63110, USA
| | | | - Tiffany Huynh
- Department of Pathology, Massachusetts General Hospital, Boston, 02114, USA
| | - Jason C Mills
- Division of Gastroenterology, Washington University, St. Louis, 63110, USA
| | - Yoko Matsuda
- Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa, 761-0793, Japan
| | - Kiron M Das
- Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, 08901, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston, 02114, USA; Department of Pathology, Harvard Medical School, Boston, 02115, USA.
| |
Collapse
|
|
22
|
Liu Y, Kaur S, Huang Y, Fahrmann JF, Rinaudo JA, Hanash SM, Batra SK, Singhi AD, Brand RE, Maitra A, Haab BB. Biomarkers and Strategy to Detect Preinvasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN. Cancer Epidemiol Biomarkers Prev 2020; 29:2513-2523. [PMID: 32532830 PMCID: PMC7710622 DOI: 10.1158/1055-9965.epi-20-0161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/20/2020] [Accepted: 06/05/2020] [Indexed: 12/19/2022] Open
Abstract
Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools. This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance. We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field. The outlook for improving the early detection of PDAC looks promising, and the pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
Collapse
Affiliation(s)
- Ying Liu
- Van Andel Institute, Grand Rapids, Michigan
| | | | - Ying Huang
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Johannes F Fahrmann
- Sheikh Ahmed Center for Pancreatic Cancer Research, MD Anderson Cancer Center, Houston, Texas
| | - Jo Ann Rinaudo
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Samir M Hanash
- Sheikh Ahmed Center for Pancreatic Cancer Research, MD Anderson Cancer Center, Houston, Texas
| | | | - Aatur D Singhi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Randall E Brand
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, MD Anderson Cancer Center, Houston, Texas
| | | |
Collapse
|
|
23
|
Molecular Diagnosis of Cystic Neoplasms of the Pancreas: a Review. J Gastrointest Surg 2020; 24:1201-1214. [PMID: 32128679 DOI: 10.1007/s11605-020-04537-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 01/29/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND The prevalence of incidental pancreatic cystic neoplasms (PCNs) has increased dramatically with advancements in cross-sectional imaging. Diagnostic imaging is limited in differentiating between benign and malignant PCNs. The aim of this review is to provide an overview of biomarkers that can be used to distinguish PCNs. METHODS A review of the literature on molecular diagnosis of cystic neoplasms of the pancreas was performed. RESULTS Pancreatic cysts can be categorized into inflammatory and non-inflammatory lesions. Inflammatory cysts include pancreatic pseudocysts. Noninflammatory lesions include both mucinous and non-mucinous lesions. Mucinous lesions include intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm. Non-mucinous lesions include serous cystadenoma and solid-pseudopapillary tumor of the pancreas. Imaging, cyst aspiration, and histologic findings, as well as carcinoembryonic antigen and amylase are commonly used to distinguish between cyst types. However, molecular techniques to detect differences in genetic mutations, protein expression, glycoproteomics, and metabolomic profiling are important developments in distinguishing between cyst types. DISCUSSION Nomograms incorporating common clinical, laboratory, and imaging findings have been developed in a better effort to predict malignant IPMN. The incorporation of top molecular biomarker candidates to nomograms may improve the predictive ability of current models to more accurately diagnose malignant PCNs.
Collapse
|
|
24
|
Molecular markers contribute to the clinical diagnosis for pancreatic cystic neoplasms. Chin Med J (Engl) 2020; 133:847-852. [PMID: 32106125 PMCID: PMC7147649 DOI: 10.1097/cm9.0000000000000716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
A pancreatic cystic neoplasm (PCN) is a rare pancreatic disease. Malignant PCNs are usually identified incidentally while evaluating other lesions. However, PCNs are being identified more frequently owing to the increased use of abdominal imaging. Malignant PCNs have complicated and diverse biological behaviors, including various malignant risk factors, diverse molecular features, natural history, and complex pathological classifications. Although many diagnostic methods, such as cross-sectional imaging and endoscopic evaluation, have been developed, malignant PCNs are still difficult to differentiate from benign tumors. On searching for related articles in the recent decade, we found that some molecular biomarkers such as carcinoembryonic antigen could be useful for discriminating between malignant tumors and benign tumors. However, cytopathologic evaluation is the most useful method for differentiating between benign and malignant lesions. Although cytopathologic evaluation has a specificity of 100% for identifying malignancies, its accuracy is often hampered by the low cellularity of PCN cells in the cystic fluid. Herein, we review the progress in the use of cellular and molecular markers for the accurate identification of PCNs.
Collapse
|
|
25
|
Hao S, Takahashi C, Snyder RA, Parikh AA. Stratifying Intraductal Papillary Mucinous Neoplasms by Cyst Fluid Analysis: Present and Future. Int J Mol Sci 2020; 21:ijms21031147. [PMID: 32050465 PMCID: PMC7037360 DOI: 10.3390/ijms21031147] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 12/11/2022] Open
Abstract
A significant proportion of patients with intraductal papillary mucinous neoplasms (IPMNs) undergo surgical resection in order to prevent or treat pancreatic cancer at the risk of significant perioperative morbidity. Efforts have been made to stratify the potential risk of malignancy based on the clinical and radiographic features of IPMN to delineate which cysts warrant resection versus observation. An analysis of the cyst fluid obtained by preoperative endoscopic examination appears to be correlative of cyst type and risk, whereas serum markers and radiographic findings have not yet reached a level of sensitivity or specificity that proves they are clinically meaningful. In this review, we investigate the current cyst fluid analysis studies and present those that have shown promise in effectively stratifying high-risk versus low-risk lesions. While new cyst fluid markers continue to be identified, additional efforts in testing panels and marker composites in conjunction with clinical algorithms have also shown promise in distinguishing dysplasia and the risk of malignancy. These should be tested prospectively in order to determine their role in guiding the surveillance of low-risk lesions and to evaluate the new markers detected by proteomics and genetic sequencing.
Collapse
Affiliation(s)
- Scarlett Hao
- Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA; (S.H.); (C.T.)
| | - Caitlin Takahashi
- Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA; (S.H.); (C.T.)
| | - Rebecca A. Snyder
- Division of Surgical Oncology, Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA;
| | - Alexander A. Parikh
- Division of Surgical Oncology, Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA;
- Correspondence: ; Tel.: +1-252-744-4110
| |
Collapse
|
|
26
|
Carmicheal J, Patel A, Dalal V, Atri P, Dhaliwal AS, Wittel UA, Malafa MP, Talmon G, Swanson BJ, Singh S, Jain M, Kaur S, Batra SK. Elevating pancreatic cystic lesion stratification: Current and future pancreatic cancer biomarker(s). Biochim Biophys Acta Rev Cancer 2019; 1873:188318. [PMID: 31676330 DOI: 10.1016/j.bbcan.2019.188318] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/25/2019] [Accepted: 10/25/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incredibly deadly disease with a 5-year survival rate of 9%. The presence of pancreatic cystic lesions (PCLs) confers an increased likelihood of future pancreatic cancer in patients placing them in a high-risk category. Discerning concurrent malignancy and risk of future PCL progression to cancer must be carefully and accurately determined to improve survival outcomes and avoid unnecessary morbidity of pancreatic resection. Unfortunately, current image-based guidelines are inadequate to distinguish benign from malignant lesions. There continues to be a need for accurate molecular and imaging biomarker(s) capable of identifying malignant PCLs and predicting the malignant potential of PCLs to enable risk stratification and effective intervention management. This review provides an update on the current status of biomarkers from pancreatic cystic fluid, pancreatic juice, and seromic molecular analyses and discusses the potential of radiomics for differentiating PCLs harboring cancer from those that do not.
Collapse
Affiliation(s)
- Joseph Carmicheal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Asish Patel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vipin Dalal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Amaninder S Dhaliwal
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Uwe A Wittel
- Department of General- and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, Freiburg, Germany
| | - Mokenge P Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Geoffrey Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Benjamin J Swanson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shailender Singh
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
27
|
Das KK, Geng X, Brown JW, Morales-Oyarvide V, Huynh T, Pergolini I, Pitman MB, Ferrone C, Al Efishat M, Haviland D, Thompson E, Wolfgang C, Lennon AM, Allen P, Lillemoe KD, Fields RC, Hawkins WG, Liu J, Castillo CFD, Das KM, Mino-Kenudson M. Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions. Gastroenterology 2019; 157:720-730.e2. [PMID: 31175863 PMCID: PMC6707850 DOI: 10.1053/j.gastro.2019.05.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 04/29/2019] [Accepted: 05/13/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.
Collapse
MESH Headings
- Adult
- Aged
- Antibodies/analysis
- Antibodies/immunology
- Antibodies, Monoclonal/immunology
- Antibody Specificity
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/immunology
- Enzyme-Linked Immunosorbent Assay
- Female
- Humans
- Male
- Middle Aged
- Neoplasms, Cystic, Mucinous, and Serous/chemistry
- Neoplasms, Cystic, Mucinous, and Serous/immunology
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Neoplasms, Cystic, Mucinous, and Serous/surgery
- Pancreatic Cyst/chemistry
- Pancreatic Cyst/immunology
- Pancreatic Cyst/pathology
- Pancreatic Cyst/surgery
- Pancreatic Intraductal Neoplasms/chemistry
- Pancreatic Intraductal Neoplasms/immunology
- Pancreatic Intraductal Neoplasms/pathology
- Pancreatic Intraductal Neoplasms/surgery
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/surgery
- Predictive Value of Tests
- Reproducibility of Results
- Risk Assessment
- United States
Collapse
Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Washington University, St Louis, Missouri.
| | - Xin Geng
- Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Jeffrey W Brown
- Division of Gastroenterology, Washington University, St Louis, Missouri
| | | | - Tiffany Huynh
- Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Ilaria Pergolini
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Martha B Pitman
- Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Cristina Ferrone
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Mohammad Al Efishat
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dana Haviland
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elizabeth Thompson
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Anne Marie Lennon
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Peter Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Ryan C Fields
- Department of Surgery, Washington University, St Louis, Missouri
| | | | - Jingxia Liu
- Department of Surgery, Washington University, St Louis, Missouri
| | | | - Kiron M Das
- Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Mari Mino-Kenudson
- Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
| |
Collapse
|
|
28
|
Lim J, Allen PJ. The diagnosis and management of intraductal papillary mucinous neoplasms of the pancreas: has progress been made? Updates Surg 2019; 71:209-216. [PMID: 31175628 DOI: 10.1007/s13304-019-00661-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are premalignant mucin-producing epithelial tumors that arise from the pancreatic ductal system. These cystic tumors represent 15-30% of cystic lesions of the pancreas [Basturk et al. in Am J Surg Pathol 39(12):1730-1741, 1; Ferrone et al. in Arch Surg (Chicago, Ill: 1960) 144(5):448-454, 2, Kosmahl et al. in Virchows Arch Int J Pathol 445(2):168-178, 3; Spinelli et al. in Ann Surg. 239(5):651-657, 4]. It is believed that IPMN can progress from low-grade dysplasia to high-grade dysplasia to invasive cancer, and this pathway of progression accounts for 20-30% of pancreatic cancer [Adsay et al. in Am J Surg Pathol 28(7):839-848, 5; Tanaka et al. in J Gastroenterol 40(7):669-675, 6; Wu et al. in Sci Transl Med 3(92):92ra66, 7]. Furthermore, it is also widely believed that IPMN represent a field defect of the pancreas in which the entire ductal system is at risk of developing invasive carcinoma, not only in the area of radiographically detectable IPMN, and thus the remaining gland should undergo surveillance after partial pancreatectomy [Salvia et al. in Ann Surg 239(5):678-685, 8; Izawa et al. in Cancer 92(7):1807-1817, 9; Yamaguchi and Tanaka in Jpn J Clin Oncol 41(7):836-840, 10]. Increasingly, surgeons are faced with the dilemma between recommending highly complex resections-that have significant morbidity and mortality-in patients who may have low-risk IPMN (low-grade dysplasia), or alternatively, recommending observation for those who could possibly be harboring a radiographically occult malignancy. Given the complexity of the management decisions for patients with IPMN, the purpose of this paper is to review the current literature and to provide a summary of how accurate we are currently with the identification of high-grade dysplasia or progression to carcinoma in patients who present with IPMN.
Collapse
Affiliation(s)
- Jenny Lim
- Department of Surgical Oncology, Duke University, Durham, NC, 27710, USA.
| | - Peter J Allen
- Department of Surgical Oncology, Duke University, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke Health System, Durham, NC, 27710, USA
| |
Collapse
|
|
29
|
Singhi AD, Koay EJ, Chari ST, Maitra A. Early Detection of Pancreatic Cancer: Opportunities and Challenges. Gastroenterology 2019; 156:2024-2040. [PMID: 30721664 PMCID: PMC6486851 DOI: 10.1053/j.gastro.2019.01.259] [Citation(s) in RCA: 468] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/08/2019] [Accepted: 01/15/2019] [Indexed: 12/17/2022]
Abstract
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
Collapse
Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Eugene J Koay
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
30
|
Abstract
Pancreatic cysts are common and are incidentally detected in up to 13.5% of individuals. Intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) are precursors to pancreatic adenocarcinoma. Most will never develop into pancreatic cancer. Several types of pancreatic cysts have no malignant potential. Solid tumors can present as a pancreatic cysts. Guidelines recommend surveillance. Management includes differentiating IPMNs and MCNs from other types, identifying those at highest risk of harboring pancreatic cancer or high-grade dysplasia, and referral to a multidisciplinary group for evaluation and consideration of surgical resection.
Collapse
Affiliation(s)
- Olaya I Brewer Gutierrez
- Division of Gastroenterology and Hepatology, Johns Hopkins Medical Institution, The Johns Hopkins Hospital, Sheikh Zayed Building, 1800 Orleans Street, Suite M2058, Baltimore, MD 21287, USA
| | - Anne Marie Lennon
- Medicine, Multidisciplinary Pancreatic Cyst Clinic, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Room 7125J, Baltimore, MD 21231, USA; Surgery, Multidisciplinary Pancreatic Cyst Clinic, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Room 7125J, Baltimore, MD 21231, USA; Oncology, Multidisciplinary Pancreatic Cyst Clinic, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Room 7125J, Baltimore, MD 21231, USA; Radiology, Multidisciplinary Pancreatic Cyst Clinic, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Room 7125J, Baltimore, MD 21231, USA.
| |
Collapse
|
|
31
|
Kaplan JH, Gonda TA. The Use of Biomarkers in the Risk Stratification of Cystic Neoplasms. Gastrointest Endosc Clin N Am 2018; 28:549-568. [PMID: 30241643 DOI: 10.1016/j.giec.2018.05.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cyst fluid biomarkers may be used to identify pancreatic cyst subtypes. Biomarkers are selected based on their ability to accurately distinguish mucinous from nonmucinous cysts and to risk stratify cysts based on malignant potential. Biomarkers of interest include but are not limited to amylase, oncogenes, DNA analysis, and epigenetic markers. The introduction of next-generation sequencing and molecular panels has aided in improved diagnostic accuracy and risk stratification. This review presents the diagnostic performance of currently available biomarkers and proposes an algorithm to incorporate their use in the diagnosis of pancreatic cysts.
Collapse
Affiliation(s)
- Jeremy H Kaplan
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA
| | - Tamas A Gonda
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA.
| |
Collapse
|
|
32
|
Raman A, Lennon AM. Cyst Fluid Biomarkers - Diagnosis and Prediction of Malignancy for Cystic Lesions of the Pancreas. Visc Med 2018; 34:178-181. [PMID: 30140682 DOI: 10.1159/000490137] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cysts are common, and are identified in 2-13% of individuals undergoing cross-sectional imaging. Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are pancreatic cysts which are precursors to pancreatic adenocarcinoma. Currently available tools are imperfect at differentiating IPMNs and MCNs from other, benign types of pancreatic cysts. The role of molecular markers in the evaluation of pancreatic cysts and the identification of cysts with high-grade dysplasia or invasive adenocarcinoma is reviewed.
Collapse
Affiliation(s)
- Aadhithya Raman
- Department of Medicine, Surgery, Radiology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anne Marie Lennon
- Department of Medicine, Surgery, Radiology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
33
|
Quantitative proteomic analysis of pancreatic cyst fluid proteins associated with malignancy in intraductal papillary mucinous neoplasms. Clin Proteomics 2018; 15:17. [PMID: 29713252 PMCID: PMC5907296 DOI: 10.1186/s12014-018-9193-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 04/04/2018] [Indexed: 12/13/2022] Open
Abstract
Background
The application of advanced imaging technologies for identifying pancreatic cysts has become widespread. However, accurately differentiating between low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive intraductal papillary mucinous neoplasms (IPMNs) remains a diagnostic challenge with current biomarkers, necessitating the development of novel biomarkers that can distinguish IPMN malignancy.
Methods Cyst fluid samples were collected from nine IPMN patients (3 LGD, 3 HGD, and 3 invasive IPMN) during their pancreatectomies. An integrated proteomics approach that combines filter-aided sample preparation, stage tip-based high-pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data of pancreatic cyst fluid and discover marker candidates for IPMN malignancy. Biological processes of differentially expressed proteins that are related to pancreatic cysts and aggressive malignancy were analyzed using bioinformatics tools such as gene ontology analysis and Ingenuity pathway analysis. In order to confirm the validity of the marker candidates, 19 cyst fluid samples were analyzed by western blot.
Results A dataset of 2992 proteins was constructed from pancreatic cyst fluid samples. A subsequent analysis found 2963 identified proteins in individual samples, 2837 of which were quantifiable. Differentially expressed proteins between histological grades of IPMN were associated with pancreatic diseases and malignancy according to ingenuity pathway analysis. Eighteen biomarker candidates that were differentially expressed across IPMN histological grades were discovered—7 DEPs that were upregulated and 11 that were downregulated in more malignant grades. HOOK1 and PTPN6 were validated by western blot in an independent cohort, the results of which were consistent with our proteomic data. Conclusions This study demonstrates that novel biomarker candidates for IPMN malignancy can be discovered through proteomic analysis of pancreatic cyst fluid. Electronic supplementary material The online version of this article (10.1186/s12014-018-9193-1) contains supplementary material, which is available to authorized users.
Collapse
|
|
34
|
Abstract
Pancreatic cysts are extremely common, and are identified in between 2% to 13% on abdominal imaging studies. Most pancreatic cysts are pseudocysts, serous cystic neoplasms, mucinous cystic neoplasms, or intraductal papillary mucinous neoplasms. The management of pancreatic cysts depends on whether a cyst is benign, has malignant potential, or harbors high-grade dysplasia or invasive carcinoma. The diagnosis of pancreatic cysts, and assessment of risk of malignant transformation, incorporates clinical history, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound, and fine-needle aspiration of cyst fluid. This article reviews the cyst fluid markers that are currently used, as well as promising markers under development.
Collapse
Affiliation(s)
- Saowanee Ngamruengphong
- Division of Gastroenterology and Hepatology, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Sheikh Zayed Tower, Baltimore, MD 21287, USA
| | - Anne Marie Lennon
- Division of Gastroenterology and Hepatology, The Johns Hopkins Medical Institutions, 1800 Orleans Street, Sheikh Zayed Tower, Room 7125JB3, Baltimore, MD 21287, USA.
| |
Collapse
|
|
35
|
Morales-Oyarvide V, Fong ZV, Fernández-Del Castillo C, Warshaw AL. Intraductal Papillary Mucinous Neoplasms of the Pancreas: Strategic Considerations. Visc Med 2017; 33:466-476. [PMID: 29344522 DOI: 10.1159/000485014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Intraductal papillary mucinous neoplasms (IPMN) are cystic neoplasms with the potential for progression to pancreatic cancer. Recognized by the global medical community just over two decades ago, IPMN have gained great epidemiological and clinical relevance thanks to the widespread use of cross-sectional abdominal imaging, which has led to a surge in the number of incidental pancreatic cysts being diagnosed. As our understanding of this disease has improved, we now know that some IPMN have a very elevated risk of cancer and require surgical resection, while others are low-risk lesions and can be followed. The approach to IPMN must therefore strike a balance between preventing the over-utilization of surgery and the timely recognition and treatment of patients with high-risk lesions. Several clinical, radiographic, and laboratory parameters have been proposed to risk-stratify IPMN, leading to the publication of management guidelines that do not always converge in their recommendations. The goal of this clinical therapeutic review is to describe the strategic approach to IPMN at the Massachusetts General Hospital, and how our current understanding, management algorithm, and future directions have been informed by research efforts at our institution and other centers.
Collapse
Affiliation(s)
- Vicente Morales-Oyarvide
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhi Ven Fong
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
36
|
Ceyhan GO, Scheufele F, Friess H. [Resection of main duct and mixed type IPMN ≥5 mm]. Chirurg 2017; 88:913-917. [PMID: 28842734 DOI: 10.1007/s00104-017-0494-0] [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: 11/30/2022]
Abstract
The incidence of cystic pancreatic lesions is steadily increasing due to the technical advances in imaging. Within the group of cystic pancreatic lesions intraductal papillary mucinous neoplasms (IPMNs) depict an important entity. Due to a possible progression to malignancy the clinical strategy has to be well chosen. For primary diagnostic work-up imaging by magnetic resonance imaging (MRI) with MR cholangiopancreatography (MRCP) and computed tomography (CT) scanning is recommended. Additional information can be gained by endosonography and a biopsy of the cystic lesion, allowing analysis of biomarkers, such as GNAS and KRAS mutation as wells as NLR. These can help to differentiate between IPMN and other cystic lesions although the clinical importance for the diagnosis of main duct (MD) and mixed IPMN is limited. The current guidelines (Fukuoka and EU guidelines) recommend resection of MD and mixed IPMN following oncological standards. For the definition of MD-IPMN, a duct dilatation between 5-10 mm is needed when following the current guidelines; however, current publications claim an even lower cut-off of ≥5 mm due to the risk of malignant progression. Intraoperative frozen sections are recommended to evaluate the margins status and extended resection is recommended for residual high-grade dysplasia. Surveillance of potentially at risk patients is recommended at regular intervals of 6-12 months while patients with malignant IPMN should be followed according to pancreatic cancer protocols. A screening for extrapancreatic malignancy is not indicated.
Collapse
Affiliation(s)
- G O Ceyhan
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, 81675, München, Deutschland
| | - F Scheufele
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, 81675, München, Deutschland
| | - H Friess
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technischen Universität München, Ismaninger Str. 22, 81675, München, Deutschland.
| |
Collapse
|
|
37
|
Abstract
With increased utilization and ongoing advancements in cross-sectional abdominal imaging, the identification of a pancreatic cyst has become a frequent finding. While many pancreatic cysts are associated with a benign clinical course, others may transform into pancreatic ductal adenocarcinoma. However, distinguishing a benign from a malignant pancreatic cyst or pancreatic cyst with malignant potential on the basis of standard clinical findings, imaging parameters and ancillary studies can be challenging. Hence, a significant interest within the past decade has been the identification of novel biomarkers to accurately classify and prognosticate a pancreatic cyst. Within this review, we discuss novel DNA, miRNA, protein and metabolite biomarkers, and their relevance in clinical practice. In addition, we focus on future areas of research that have the potential to change pancreatic cyst management.
Collapse
|
|
38
|
Diversity of Precursor Lesions For Pancreatic Cancer: The Genetics and Biology of Intraductal Papillary Mucinous Neoplasm. Clin Transl Gastroenterol 2017; 8:e86. [PMID: 28383565 PMCID: PMC5415899 DOI: 10.1038/ctg.2017.3] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Accepted: 01/03/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA), one of the most lethal cancers worldwide, is associated with two main types of morphologically distinct precursors—pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Although the progression of PanIN into invasive cancer has been well characterized, there remains an urgent need to understand the biology of IPMNs, which are larger radiographically detectable cystic tumors. IPMNs comprise a number of subtypes with heterogeneous histopathologic and clinical features. Although frequently remaining benign, a significant proportion exhibits malignant progression. Unfortunately, there are presently no accurate prognosticators for assessing cancer risk in individuals with IPMN. Moreover, the fundamental mechanisms differentiating PanIN and IPMN remain largely obscure, as do those that distinguish IPMN subtypes. Recent studies, however, have identified distinct genetic profiles between PanIN and IPMN, providing a framework to better understand the diversity of the precursors for PDA. Here, we review the clinical, biological, and genetic properties of IPMN and discuss various models for progression of these tumors to invasive PDA.
Collapse
|
|
39
|
Greer JB, Ferrone CR. Spectrum and Classification of Cystic Neoplasms of the Pancreas. Surg Oncol Clin N Am 2016; 25:339-50. [PMID: 27013368 DOI: 10.1016/j.soc.2015.11.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
As patients are living longer and axial imaging is more widespread, increasing numbers of cystic neoplasms of the pancreas are found. Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are the most common. The revised Sendai guidelines provide a safe algorithm for expectant management of certain cystic neoplasms; however, studies are ongoing to identify further subgroups that can be treated nonoperatively. For those patients with high-risk clinical features or symptoms, surgical resection can be performed safely at high-volume pancreatic centers. Accurate diagnosis is critical for accurate decision making.
Collapse
Affiliation(s)
- Jonathan B Greer
- General Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB-425, Boston, MA 02114, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA.
| |
Collapse
|
|
40
|
Fong ZV, Fernández-del Castillo C. Intraductal Papillary Mucinous Neoplasm of the Pancreas. Surg Clin North Am 2016; 96:1431-1445. [DOI: 10.1016/j.suc.2016.07.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
41
|
Hata T, Dal Molin M, Suenaga M, Yu J, Pittman M, Weiss M, Canto MI, Wolfgang C, Lennon AM, Hruban RH, Goggins M. Cyst Fluid Telomerase Activity Predicts the Histologic Grade of Cystic Neoplasms of the Pancreas. Clin Cancer Res 2016; 22:5141-5151. [PMID: 27230749 DOI: 10.1158/1078-0432.ccr-16-0311] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 05/10/2016] [Indexed: 12/25/2022]
Abstract
PURPOSE Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Because telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. EXPERIMENTAL DESIGN Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184 discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine-needle aspiration. Methodologic and clinical factors associated with telomerase activity were examined. RESULTS Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia ± associated invasive cancer had higher telomerase activity [median (interquartile range), 1,158 (295.9-13,033)] copies/μL of cyst fluid than those without [19.74 (2.58-233.6) copies/μL; P < 0.001)]. Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having "worrisome features," cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. CONCLUSIONS Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts. Clin Cancer Res; 22(20); 5141-51. ©2016 AACRSee related commentary by Allen et al., p. 4966.
Collapse
Affiliation(s)
- Tatsuo Hata
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Marco Dal Molin
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Masaya Suenaga
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Jun Yu
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Meredith Pittman
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Matthew Weiss
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Marcia I Canto
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Christopher Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Anne Marie Lennon
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
| |
Collapse
|
|
42
|
Yoshida K, Nagasaka T, Umeda Y, Tanaka T, Kimura K, Taniguchi F, Fuji T, Shigeyasu K, Mori Y, Yanai H, Yagi T, Goel A, Fujiwara T. Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms. J Cancer Res Clin Oncol 2016; 142:1557-69. [PMID: 27095449 PMCID: PMC4899496 DOI: 10.1007/s00432-016-2164-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/11/2016] [Indexed: 12/19/2022]
Abstract
Purpose Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN. Methods A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC). Results KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001). Conclusions Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2164-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Kazuhiro Yoshida
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Takeshi Nagasaka
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan.
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama, 700-8558, Japan
| | - Keisuke Kimura
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Fumitaka Taniguchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Tomokazu Fuji
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Kunitoshi Shigeyasu
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Yoshiko Mori
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Hiroyuki Yanai
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama, 700-8558, Japan
| | - Takahito Yagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| | - Ajay Goel
- Center for Gastrointestinal Cancer Research, Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, 75246, USA
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan
| |
Collapse
|
|
43
|
Abstract
PURPOSE OF REVIEW Our understanding of intraductal papillary mucinous neoplasm (IPMN) of the pancreas has remarkably grown within the last decade; nonetheless there is still an ongoing controversy if the majority of these potentially malignant neoplasms need to be resected or if observation in a subset is well tolerated. RECENT FINDINGS Novel cyst fluid biomarkers, like Gnas mutations or mab DAS-1, could play a pivotal role in the distinction of IPMN vs. other cystic lesions, in the sub-classification of IPMN and in the detection of IPMN with high-grade dysplasia or invasive cancer. Other recent studies focused on natural history of minimal- and extensive-mixed IPMN and the safety of the 2012 AIP guidelines. Small series also described that observation can be an option in selected frail patients with MD-IPMN. Further, data from a large European multicenter study analysis indicated that patients with IPMN do not have an increased frequency of extrapancreatic malignancies. SUMMARY Increasing knowledge about the nature of IPMN and their subtypes has resulted in an individualized approach in diagnosis and treatment. Owing to the availability of accurate diagnostic instruments, timing and indication for pancreatic resection have become more selective, sparing patients with harmless IPMN from major surgery.
Collapse
|
|
44
|
Abstract
BACKGROUND Pancreatic cystic lesions (PCL) are common. They are increasingly detected as an incidental finding of transabdominal ultrasound or cross-sectional imaging. In contrast to other parenchymal organs, dysontogenetic pancreatic cysts are extremely rare. In symptomatic patients the most frequent PCL are acute and chronic pseudocysts. The majority of incidental cystic lesions, however, are neoplasias which have different risks of malignancy. METHODS PubMed was searched for studies, reviews, meta-analyses, and guidelines using the following key words: ('pancreatic cystic lesions' OR 'cystic pancreatic lesions' OR 'intraductal papillary mucinous neoplasia' OR 'mucinous cystic neoplasia' OR 'pancreatic cyst' OR 'pancreatic pseudocyst') AND (management OR treatment OR outcome OR prognosis OR diagnosis OR imaging OR 'endoscopic ultrasound' EUS-FNA OR EUS OR 'endoscopic ultrasonography' OR CT OR MRI). Retrieved papers were reviewed with regard to the diagnostic and therapeutic management of incidental PCL. RESULTS In addition to clinical criteria, transabdominal ultrasonography including contrast-enhanced ultrasonography, cross-sectional radiological imaging, and endoscopic ultrasound (EUS) are used for diagnostic characterization and risk assessment. EUS plays an outstanding role in differential diagnosis and prognostic characterization of incidental PCL. In a single examination it is possible to perform high-resolution morphological description, perfusion imaging, as well as fine-needle aspiration of cyst content, cyst wall, and solid components. An international consensus guideline has defined worrisome and high-risk criteria for the risk assessment of mucinous pancreatic cysts, which are mainly based on the results of EUS and cross-sectional imaging. Nevertheless, despite diagnostic progress and guideline recommendations, differential diagnosis and management decisions remain difficult. This review will discuss problems in and approaches to the diagnosis of incidental PCL. CONCLUSION An evidence-based algorithm for the diagnosis of incidental PCL is proposed.
Collapse
Affiliation(s)
- Christian Jenssen
- Department of Internal Medicine, Märkisch Oderland Hospital GmbH, Strausberg/Wriezen, Germany
| | - Stefan Kahl
- Department of Internal Medicine, DRK Kliniken Berlin - Köpenick, Berlin, Germany
| |
Collapse
|
|
45
|
Brosens LAA, Hackeng WM, Offerhaus GJ, Hruban RH, Wood LD. Pancreatic adenocarcinoma pathology: changing "landscape". J Gastrointest Oncol 2015; 6:358-74. [PMID: 26261723 DOI: 10.3978/j.issn.2078-6891.2015.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/22/2015] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.
Collapse
Affiliation(s)
- Lodewijk A A Brosens
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Wenzel M Hackeng
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - G Johan Offerhaus
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Ralph H Hruban
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Laura D Wood
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| |
Collapse
|
|
46
|
Systematic Review of Pancreatic Cyst Fluid Biomarkers: The Path Forward. Clin Transl Gastroenterol 2015; 6:e88. [PMID: 26065716 PMCID: PMC4816245 DOI: 10.1038/ctg.2015.17] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 05/04/2015] [Indexed: 12/11/2022] Open
Abstract
There is significant research interest in developing and validating novel pancreatic cyst-fluid biomarkers given the increasing recognition of the prevalence of pancreatic cysts and their associated malignant potential. Although current international consensus guidelines are helpful, they fail to diagnose with certainty the cyst type and the level of epithelial dysplasia. They also fall short in predicting the future likelihood of malignant transformation. A systematic review was performed with the objective of summarizing cyst-fluid-based biomarkers that have been published in the medical literature over the past 10 years and characterizing the current quality of evidence. Our review demonstrates that there is an increasing interest in this topic with several different and innovative approaches including DNA, RNA, proteomic, and metabolomics profiling. Further techniques to improve upon cytological yield have also been studied. Besides identifying potentially useful clinical biomarkers, these empiric approaches have provided further insight into their pathogenesis. The level of evidence for the vast majority of these studies, however, is limited to retrospective early validation studies. The path forward will be to select out the most promising biomarkers and develop multicenter consortiums capable of capturing adequate sample sizes with appropriate study designs.
Collapse
|
|
47
|
Sahora K, Fernández-del Castillo C, Dong F, Marchegiani G, Thayer SP, Ferrone CR, Sahani DV, Brugge WR, Warshaw AL, Lillemoe KD, Mino-Kenudson M. Not all mixed-type intraductal papillary mucinous neoplasms behave like main-duct lesions: implications of minimal involvement of the main pancreatic duct. Surgery 2014; 156:611-21. [PMID: 25081232 DOI: 10.1016/j.surg.2014.04.023] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 04/14/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND The malignant potential of intraductal mucinous neoplasm of the pancreas (IPMN) is associated closely with main pancreatic duct (MPD) involvement. Because mixed-type IPMN is thought to have the same malignant potential as that of main-duct (MD)-IPMN, resection is recommended; however, the biological nature of mixed-type IPMN with only minimal involvement of MPD (min-mix-IPMN) may be different. METHODS A prospective database of 404 resected IPMNs was re-reviewed to subclassify mixed-type IPMNs. We defined min-mix-IPMN as absence of gross abnormalities (except for dilatation) of MPD and noncircumferential microscopic involvement of MPD limited to few sections. RESULTS We identified 46 min-mix-IPMNs, 163 IPMNs with extensive involvement of MPD (ex-mix-IPMN), 175 branch-duct (BD)-IPMNs, and 20 MD-IPMNs. The majority of min-mix-IPMNs were found incidentally and increased cyst size on surveillance was the leading operative indication. The median diameter of MPD was 2 mm in min-mix-IPMN versus 9 mm in ex-mix-IPMN (P < .0001), and cysts ≥10 mm were present in 62% of ex-mix-IPMNs versus 93% of min-mix-IPMNs (P < .0001). Most importantly, the vast majority of min-mix-IPMNs exhibited gastric-type epithelium, similar to BD-IPMNs, whereas intestinal-type epithelium was present in half of ex-mix-IPMNs, similar to MD-IPMNs. The prevalence of high-grade lesions was less in min-mix-IPMN than ex-mix-IPMN (P < .0001). These differences were reflected in better disease-specific outcomes of min-mix-IPMN compared with ex-mix-IPMN (P = .046). CONCLUSION Min-mix-IPMN often presents with no MPD dilation and is an incidental finding by microscopic examination. min-mix-IPMN shares the pathologic features and less aggressive biology with BD-IPMN. We propose that min-mix-IPMN be categorized differently than ex-mix-IPMN.
Collapse
MESH Headings
- Adenocarcinoma, Mucinous/classification
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Mucinous/surgery
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Pancreatic Ductal/classification
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Carcinoma, Papillary/classification
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/surgery
- Female
- Humans
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Pancreatic Ducts/pathology
- Pancreatic Ducts/surgery
- Pancreatic Neoplasms/classification
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/surgery
Collapse
Affiliation(s)
- Klaus Sahora
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Carlos Fernández-del Castillo
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Fei Dong
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Giovanni Marchegiani
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Sarah P Thayer
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Dushyant V Sahani
- Department of Radiology, Massachusetts General Hospital, Boston, MA; Department of Radiology, Harvard Medical School, Boston, MA
| | - William R Brugge
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA; Department of Internal Medicine, Harvard Medical School, Boston, MA
| | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston, MA; Department of Pathology, Harvard Medical School, Boston, MA.
| |
Collapse
|
|
48
|
Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BIOMED RESEARCH INTERNATIONAL 2014; 2014:474905. [PMID: 24783207 PMCID: PMC3982269 DOI: 10.1155/2014/474905] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 02/08/2014] [Accepted: 02/10/2014] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
Collapse
|