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Pitman MB. The World Health Organization Reporting System for Pancreaticobiliary Cytopathology: Review and Comparison to the Papanicolaou Society of Cytopathology System. Arch Pathol Lab Med 2025; 149:e39-e46. [PMID: 38190275 DOI: 10.5858/arpa.2023-0411-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2023] [Indexed: 01/10/2024]
Abstract
CONTEXT.— The World Health Organization (WHO) Reporting System for Pancreaticobiliary Cytopathology (WHO System) is the product of a joint venture between the World Health Organization, the International Academy of Cytology, and the International Agency for Research on Cancer. The WHO System revises the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System) and replaces the 6-tiered system with a 7-tiered system. OBJECTIVE.— To explain the WHO System and the differences with the PSC System. DATA SOURCES.— The WHO System and the PSC System of Reporting Pancreaticobiliary Cytopathology. CONCLUSIONS.— The diagnostic categories of the WHO System are "Insufficient/Inadequate/Nondiagnostic"; "Benign (Negative for Malignancy)"; "Atypical"; "Pancreaticobiliary Neoplasm, Low Risk/Low Grade (PaN-Low)"; "Pancreatic Neoplasm, High Risk/High Grade (PaN-High)"; "Suspicious for Malignancy"; and "Malignant." In the WHO System, the "benign" category includes both nonneoplastic and neoplastic lesions, so the "Neoplastic: Benign" category of the PSC system has been eliminated. Low-grade malignancies, pancreatic neuroendocrine tumors (PanNETs), and solid-pseudopapillary neoplasm (SPN) classified as "Neoplastic: Other" in the PSC System are classified as "Malignant" in the WHO System, leaving in the "Neoplasm" category intraductal lesions, which are divided into 2 new diagnostic categories: "Pancreaticobiliary Neoplasm (PaN)-Low Risk/Grade" and "PaN-High Risk/Grade." As with the PSC System, the WHO System advocates close correlation with imaging and encourages incorporation of ancillary testing into the final diagnosis, such as biochemical (carcinoembryonic antigen [CEA] and amylase) and molecular testing. The WHO System includes risk of malignancy per category, and reporting and diagnostic management options that recognize the variations in resources of low- and middle-income countries.
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Affiliation(s)
- Martha B Pitman
- From the Department of Pathology, Harvard Medical School, Boston, Massachusetts; and the Department of Pathology, Massachusetts General Hospital, Boston
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Centeno BA, Saieg M, Siddiqui MT, Perez-Machado M, Layfield LJ, Weynand B, Reid MD, Stelow EB, Lozano MD, Fukushima N, Cree IA, Mehrotra R, Schmitt FC, Field AS, Pitman MB. The World Health Organization Reporting System for Pancreaticobiliary Cytopathology: Overview and Summary. Cancer Cytopathol 2024; 132:396-418. [PMID: 38709670 DOI: 10.1002/cncy.22806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/12/2024] [Accepted: 01/17/2024] [Indexed: 05/08/2024]
Abstract
The recently published WHO Reporting System for Pancreaticobiliary Cytopathology (World Health Organization [WHO] System) is an international approach to the standardized reporting of pancreaticobiliary cytopathology, updating the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System). Significant changes were made to the categorization of benign neoplasms, intraductal neoplasms, mucinous cystic neoplasms, and malignant neoplasms considered low grade. Benign neoplasms, such as serous cystadenoma, categorized as Neoplastic: benign in the PSC system, are categorized as Benign/negative for malignancy in the WHO system. Pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, and gastrointestinal stromal tumor, categorized as Neoplastic: other in the PSC system, are categorized as Malignant in the WHO System in accord with their classification in the 5th edition WHO Classification of Digestive System Tumours (2019). The two new categories of Pancreaticobiliary Neoplasm Low-risk/grade and Pancreaticobiliary Neoplasm High-risk/grade are mostly limited to intraductal neoplasms and mucinous cystic neoplasms. Low-risk/grade lesions are mucinous cysts, with or without low-grade epithelial atypia. High-risk/grade lesions contain neoplastic epithelium with high-grade epithelial atypia. Correlation with clinical, imaging, and ancillary studies remains a key tenet. The sections for each entity are written to highlight key cytopathological features and cytopathological differential diagnoses with the pathologist working in low resource setting in mind. Each section also includes the most pertinent ancillary studies useful for the differential diagnosis. Sample reports are provided for each category. Finally, the book provides a separate section with risk of malignancy and management recommendations for each category to facilitate decision-making for clinicians.
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Affiliation(s)
| | - Mauro Saieg
- Santa Casa Medical School, Sao Paulo, Brazil
| | - Momin T Siddiqui
- Department of Pathology, Weill Cornell Medicine, New York, New York, USA
| | - Miguel Perez-Machado
- Department of Cellular Pathology, Royal Free Hampstead NHS Trust, London, England
| | - Lester J Layfield
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA
| | - Birgit Weynand
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Michelle D Reid
- Department of Pathology, Emory University Hospital, Atlanta, Georgia, USA
| | - Edward B Stelow
- Department of Pathology, University of Virginia Hospital, Charlottesville, Virginia, USA
| | - Maria D Lozano
- Department of Pathology, Clinica University of Navarra, Pamplona, Spain
| | - Noriyoshi Fukushima
- Department of Diagnostic Pathology, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Ian A Cree
- International Agency for Research on Cancer [IARC], World Health Organization, Lyon, France
| | - Ravi Mehrotra
- Indian Cancer Genomic Atlas, Centre for Health, Innovation and Policy Foundation, Noida, Uttar Pradesh, India
| | - Fernando C Schmitt
- Faculty of Medicine, Department of Pathology, University of Porto, Porto, Portugal
- CINTESIS@RISE, Porto University, Porto, Portugal
| | - Andrew S Field
- Department of Anatomical Pathology, St Vincent's Hospital, Sydney, New South Wales, Australia
- University of New South Wales Sydney and University of Notre Dame, Sydney, New South Wales, Australia
| | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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3
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Pitman MB, Centeno BA, Reid MD, Saeig M, Siddiqui MT, Layfield LJ, Perez-Machado M, Weynand B, Stelow EB, Lozano MD, Fukushima N, Cree IA, Mehrotra R, Schmitt FC, Field AS. A brief review of the WHO reporting system for pancreaticobiliary cytopathology. J Am Soc Cytopathol 2023; 12:243-250. [PMID: 37003924 DOI: 10.1016/j.jasc.2023.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023]
Abstract
The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer have developed an approach to standardized reporting of pancreaticobiliary cytopathology. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO System) revises the Papanicolaou Society of Cytopathology (PSC) System for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the 6 PSC categories with 7 categories: "Insufficient/Inadequate/Nondiagnostic"; "Benign/Negative for malignancy"; "Atypical"; "Pancreaticobiliary neoplasm, low risk/grade (PaN-low)"; "Pancreatic neoplasm, high risk/grade (PaN-High)"; "Suspicious for malignancy"; and "Malignant". In the PSC system, there is a single category for "Neoplastic" lesions that includes 2 groups, 1 for benign neoplasms and 1 named "Neoplastic-other", dominated by premalignant intraductal neoplasms primarily intraductal papillary mucinous neoplasms and low-grade malignant neoplasms (pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). In the WHO System, benign neoplasms with virtually no risk of malignancy are included in the "Benign" category and low-grade malignancies (PanNET and SPN) are included in the "Malignant" category, as per the 5th edition of the WHO Classification of Digestive System Tumors, while the non-invasive pre-malignant lesions of the ducts are divided by the cytomorphological grade of the epithelium into PaN-low and PaN-high with distinctly different risks of malignancy. Within each category, key diagnostic cytopathologic features and the ancillary studies for diagnostic and prognostic evaluation, as well as the implications of diagnosis for patient care and management, are outlined. Reporting and diagnostic management options recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries.
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Affiliation(s)
- Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | | | - Michelle D Reid
- Department of Pathology, Emory University Hospital, Atlanta, Georgia
| | - Mauro Saeig
- Santa Casa Medical School, Sao Paulo, Brazil
| | - Momin T Siddiqui
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Lester J Layfield
- Pathology and Anatomic Science Department, University of Missouri, Columbia, Missouri
| | - Miguel Perez-Machado
- Department of Cellular Pathology, Royal Free Hampstead NHS Trust, London, England
| | - Birgit Weynand
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Edward B Stelow
- Department of Pathology, University of Virginia Hospital, Charlottesville, Virginia
| | - Maria D Lozano
- Department of Pathology, Clinical University of Navarra, Pamplona, Spain
| | - Noriyoshi Fukushima
- Department of Diagnostic Pathology, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Ian A Cree
- International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
| | - Ravi Mehrotra
- Indian Cancer Genomic Atlas, Centre for Health, Innovation and Policy Foundation, Noida, India
| | - Fernando C Schmitt
- Department of Pathology, Faculty of Medicine of University of Porto, Porto, Portugal
| | - Andrew S Field
- Department of Anatomical Pathology, St Vincent's Hospital, Sydney, and University of New South Wales Sydney and University of Notre Dame, Sydney, Australia
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Park MA, Zaw T, Yoder SJ, Gomez M, Genilo-Delgado M, Basinski T, Katende E, Dam A, Mok SRS, Monteiro A, Mohammadi A, Jeong DK, Jiang K, Centeno BA, Hodul P, Malafa M, Fleming J, Chen DT, Mo Q, Teer JK, Permuth JB. A pilot study to evaluate tissue- and plasma-based DNA driver mutations in a cohort of patients with pancreatic intraductal papillary mucinous neoplasms. G3 (BETHESDA, MD.) 2022; 13:6861874. [PMID: 36454217 PMCID: PMC9911050 DOI: 10.1093/g3journal/jkac314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 08/22/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic ductal adenocarcinoma that are challenging to manage due to limited imaging, cytologic, and molecular markers that accurately classify lesions, grade of dysplasia, or focus of invasion preoperatively. The objective of this pilot study was to determine the frequency and type of DNA mutations in a cohort of surgically resected, pathologically confirmed IPMN, and to determine if concordant mutations are detectable in paired pretreatment plasma samples. Formalin-fixed paraffin-embedded (FFPE) tissue from 46 surgically resected IPMNs (31 low-grade, 15 high-grade) and paired plasma from a subset of 15 IPMN cases (10 low-grade, 5 high-grade) were subjected to targeted mutation analysis using a QIAseq Targeted DNA Custom Panel. Common driver mutations were detected in FFPE from 44 of 46 (95.6%) IPMN cases spanning all grades; the most common DNA mutations included: KRAS (80%), RNF43 (24%), and GNAS (43%). Of note, we observed a significant increase in the frequency of RNF43 mutations from low-grade to high-grade IPMNs associated or concomitant with invasive carcinoma (trend test, P = 0.01). Among the subset of cases with paired plasma, driver mutations identified in the IPMNs were not detected in circulation. Overall, our results indicate that mutational burden for IPMNs is a common occurrence, even in low-grade IPMNs. Furthermore, although blood-based biopsies are an attractive, noninvasive method for detecting somatic DNA mutations, the QIAseq panel was not sensitive enough to detect driver mutations that existed in IPMN tissue using paired plasma in the volume we were able to retrieve for this retrospective study.
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Affiliation(s)
| | | | - Sean J Yoder
- Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Maria Gomez
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Maria Genilo-Delgado
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Toni Basinski
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Esther Katende
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Aamir Dam
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Shaffer R S Mok
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Alvaro Monteiro
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Amir Mohammadi
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Daniel K Jeong
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Kun Jiang
- Department of Anatomic Pathology, H. Lee Moffitt Cancer & Research Institute, Tampa, FL 33620, USA
| | - Barbara A Centeno
- Department of Anatomic Pathology, H. Lee Moffitt Cancer & Research Institute, Tampa, FL 33620, USA
| | - Pamela Hodul
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Mokenge Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Jason Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA
| | - Dung-Tsa Chen
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer & Research Institute, Tampa, FL 33620, USA
| | - Qianxing Mo
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer & Research Institute, Tampa, FL 33620, USA
| | | | - Jennifer B Permuth
- Corresponding author: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA.
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Taherian M, Wang H, Wang H. Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers. Cells 2022; 11:cells11193068. [PMID: 36231030 PMCID: PMC9563270 DOI: 10.3390/cells11193068] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/21/2022] [Accepted: 09/24/2022] [Indexed: 11/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients.
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Affiliation(s)
- Mehran Taherian
- Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hua Wang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huamin Wang
- Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-713-563-1846; Fax: +1-713-563-1848
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Pancreatic ductal adenocarcinoma: tumor microenvironment and problems in the development of novel therapeutic strategies. Clin Exp Med 2022:10.1007/s10238-022-00886-1. [DOI: 10.1007/s10238-022-00886-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/30/2022] [Indexed: 12/19/2022]
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Asano G, Miyabe K, Kato H, Yoshida M, Sawada T, Okamoto Y, Sahashi H, Atsuta N, Kachi K, Kato A, Jinno N, Natsume M, Hori Y, Naitoh I, Hayashi K, Matsuo Y, Takahashi S, Suzuki H, Kataoka H. Relevance of gene mutations and methylation to the growth of pancreatic intraductal papillary mucinous neoplasms based on pyrosequencing. Sci Rep 2022; 12:419. [PMID: 35013462 PMCID: PMC8748617 DOI: 10.1038/s41598-021-04335-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
Abstract
We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r = - 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis.
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Affiliation(s)
- Go Asano
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Katsuyuki Miyabe
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.
- Department of Gastroenterology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, 466-8650, Japan.
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Michihiro Yoshida
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Takeshi Sawada
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Yasuyuki Okamoto
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Hidenori Sahashi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Naoki Atsuta
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Kenta Kachi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Akihisa Kato
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Naruomi Jinno
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Makoto Natsume
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Yasuki Hori
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Kazuki Hayashi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
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Tanaka M, Heckler M, Liu B, Heger U, Hackert T, Michalski CW. Cytologic Analysis of Pancreatic Juice Increases Specificity of Detection of Malignant IPMN-A Systematic Review. Clin Gastroenterol Hepatol 2019; 17:2199-2211.e21. [PMID: 30630102 DOI: 10.1016/j.cgh.2018.12.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can progress to cancer. Biomarkers have been identified that were reported to increase the accuracy of identification of malignant lesions; we performed a systematic review of the accuracy of these markers. METHODS We performed a systematic review of published studies on biomarkers of malignant IPMNs by searching MEDLINE and Web of Science databases from January 2005 through December 2017. Our methods were developed based on the Meta-analysis Of Observational Studies in Epidemiology guidelines. Pooled sensitivity, specificity, receiver operating characteristic curves, and their respective areas under the curve (AUC) were calculated from groups of markers (cell-, protein-, or DNA-based) measured in samples collected before and after surgery. A hypothetical test model was developed to determine how to meaningfully amend the revised Fukuoka guidelines, focusing on increasing test specificity for patients with IPMNs that have worrisome features. RESULTS We collected data from 193 published studies, comprising 12,297 patients, that analyzed 7 preoperative and 21 postoperative markers of IPMNs. The 3 biomarkers that identified malignant IPMNs with the largest AUC values were pancreatic juice cytology (AUC, 0.84; sensitivity, 0.54; specificity, 0.91), serum protein carbohydrate antigen 19-9 (AUC, 0.81; sensitivity, 0.45; specificity, 0.90), and cyst fluid cytology (AUC, 0.82; sensitivity, 0.57; specificity, 0.84). A combination of cytologic and immunohistochemical analysis of MUC1 and MUC2 in pancreatic juice samples identified malignant IPMNs with the largest AUC and sensitivity values (AUC, 0.85; sensitivity, 0.85; specificity, 0.65). In a test model, inclusion of cytologic analysis of pancreatic juice in the guideline algorithm significantly increased the specificity of detection of malignant IPMNs. CONCLUSIONS In a systematic review, we found cytologic analysis of pancreatic juice to have the greatest effect in increasing the specificity of detection of malignant IPMNs. We propose addition of this test to the Fukuoka guidelines for assessment of patients with IPMNs with worrisome features.
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Affiliation(s)
- Masayuki Tanaka
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Max Heckler
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Bing Liu
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Ulrike Heger
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany.
| | - Christoph W Michalski
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Germany; Department of Surgery, Halle University Hospital, Martin Luther University Halle-Wittenberg, Halle, Germany
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Liu Q, Wu Q, Yu M, Shi H, Lu B. Emerging relationships between papillary proliferation of the endometrium and endometrial carcinoma: evidence from an immunohistochemical and molecular analysis. Virchows Arch 2019; 475:201-209. [PMID: 31079233 DOI: 10.1007/s00428-019-02589-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/18/2019] [Accepted: 05/07/2019] [Indexed: 01/04/2023]
Abstract
Papillary proliferation of the endometrium (PPE) is an uncommon lesion that frequently shows mucinous metaplasia. PPE occasionally has concurrent or preceding endometrial hyperplasia and carcinomas, but there is little molecular evidence to support the relationships between PPEs and endometrial neoplasia. In this study, we analyzed the clinicopathological and immunohistochemical features in 30 PPEs (22 simple PPEs and 8 complex papillary hyperplasia (CPH)). Hotspot mutations of KRAS, PI3KCA, AKT1, PTEN (exons 3, 5, and 7), and ARID1A (exons 1 and 14) were detected by pyrosequencing or bidirectional Sanger sequencing. We found that endometrial hyperplasia and carcinoma were more common in CPHs (4/6, 66.7%) than in simple PPEs (4/21, 19.0%) (p < 0.05). Compared with the adjacent normal endometrium, PPEs frequently showed loss of PAX2 (56.7%) and PTEN (10%) expression, diffuse p16 expression (36.7%), decreased PR expression (84.3%), and lower Ki67 labeling index (median 1%, range 1-15%). Simple PPEs and CPHs had similar immunohistochemical features (p > 0.05). KRAS mutations were identified in 14 PPEs and 1 concurrent endometrial carcinoma. The prevalence of KRAS mutations was not statistically different between simple PPEs (10/21, 45.5%) and CPHs (4/8, 50%) (p > 0.05), but was higher in PPEs displaying mucinous metaplasia (12/24, 50%) than in those without (2/6, 33.3%) (p < 0.05). One simple PPE with a KRAS mutation had an AKT1 mutation. No PPEs demonstrated mutations in PI3KCA, PTEN, and ARID1A. In conclusion, both simple PPE and CPH share some common molecular alterations with endometrial neoplasia, in which, KRAS mutations might be a driver.
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Affiliation(s)
- Qin Liu
- Department of Surgical Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiongyan Wu
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Minghua Yu
- Department of Surgical Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Haiyan Shi
- Department of Surgical Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bingjian Lu
- Department of Surgical Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. .,Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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10
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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.
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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.
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11
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Zińczuk J, Zaręba K, Guzińska-Ustymowicz K, Kędra B, Kemona A, Pryczynicz A. p16, p21, and p53 proteins play an important role in development of pancreatic intraepithelial neoplastic. Ir J Med Sci 2018; 187:629-637. [PMID: 29388054 DOI: 10.1007/s11845-018-1751-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 01/17/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Deregulation of cell cycle takes place during the development of many cancers as well as pancreatic ductal adenocarcinoma (PDA), which develops from precursor lesions, most frequently including pancreatic intraepithelial neoplasia (PanIN). AIMS The aim of this study was to evaluate and compare the expression of p16, p21, and p53 proteins taking part in the regulation of the cell cycle in normal pancreatic ducts and pancreatic intraepithelial neoplasia at its various advancing stages. METHODS The expressions of p16, p21, and p53 were assessed immunohistochemically in 70 patients with different pancreatic diseases (pancreatic ductal adenocarcinoma, pancreatitis, and pancreatic cysts), showing also pancreatic intraepithelial neoplasia. The results correlated with chosen clinicopathological parameters. RESULTS Our study revealed a difference in p16, p21, and p53 expressions between normal pancreatic ducts and various stages of PanIN. p16 expression progressively decreased, whereas p21 and p53 increased from normal pancreas to PanIN 1, 2, and 3. The expression of p21 was associated with age, p53 with PanIN location in the pancreas and p16 with the type of primary diseases. Simultaneously, we observed a directly proportional relationship between the expression of p21 and p53 proteins and inversely proportional between the p16 and the p21 and p53 proteins. CONCLUSIONS p16, p21, and p53 proteins play an important role in the deregulation of the cell cycle and participate in the development of pancreatic intraepithelial neoplasia. Immunohistochemical evaluation of their expressions may be helpful in the diagnosis of PanIN.
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Affiliation(s)
- Justyna Zińczuk
- Department of General Pathomorphology, Medical University of Białystok, Białystok, Poland.
| | - Konrad Zaręba
- 2nd Clinical Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | | | - Bogusław Kędra
- 2nd Clinical Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Andrzej Kemona
- Department of General Pathomorphology, Medical University of Białystok, Białystok, Poland
| | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Białystok, Białystok, Poland
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12
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Can we better predict the biologic behavior of incidental IPMN? A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas. Langenbecks Arch Surg 2017; 403:151-194. [DOI: 10.1007/s00423-017-1644-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/24/2017] [Indexed: 02/07/2023]
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13
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Shimura T, Kofunato Y, Okada R, Yashima R, Okada K, Araki K, Hosouchi Y, Kuwano H, Takenoshita S. MIB-1 labeling index, Ki-67, is an indicator of invasive intraductal papillary mucinous neoplasm. Mol Clin Oncol 2016; 5:317-322. [PMID: 27446570 DOI: 10.3892/mco.2016.908] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/09/2016] [Indexed: 01/25/2023] Open
Abstract
Despite strict criteria for the observation of intraductal papillary mucinous neoplasm (IPMN), it remains difficult to distinguish invasive IPMN from non-invasive IPMN. The aim of the present study was to identify an indicator of invasive IPMN. The present study retrospectively evaluated 53 patients (28 with non-invasive and 25 with invasive IPMN) who underwent resection of IPMN, and examined the usefulness of the MIB-1 labeling index as an indicator of invasive IPMN. The MIB-1 labeling indexes in patients with invasive IPMN were significantly higher compared with those with non-invasive IPMN (P<0.001). A receiver operating characteristic curve revealed that the area under the curve was 0.822. These results suggested that a cut-off level for the MIB-1 labeling index should be set to 15.5% to distinguish invasive from non-invasive IPMN. A multivariate analysis using a logistic regression model revealed the MIB-1 labeling index (hazard ratio, 18.692; 95% confidential interval, 4.171-83.760; P<0.001) and the existence of mural nodules (hazard ratio, 6.187, 95% confidential interval, 1.039-36.861; P=0.045) were predictive factors for invasive IPMN. However, no statistically significant differences were observed between patients with a lower MIB-1 labeling index and patients with a higher MIB-1 labeling index (P=0.798). The MIB-1 labeling index must be considered as a candidate for the classification of IPMN.
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Affiliation(s)
- Tatsuo Shimura
- Department of Cancer Biology and Electronics, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Yasuhide Kofunato
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Ryo Okada
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Rei Yashima
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Koji Okada
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Kenichiro Araki
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Yasuo Hosouchi
- Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Gunma 371-0821, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Seiichi Takenoshita
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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14
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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: 34] [Impact Index Per Article: 3.4] [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.
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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
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15
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Abstract
Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.
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16
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Locus/Chromosome Aberrations in Intraductal Papillary Mucinous Neoplasms Analyzed by Fluorescence In Situ Hybridization. Am J Surg Pathol 2015; 39:512-20. [DOI: 10.1097/pas.0000000000000360] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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17
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Paini M, Crippa S, Partelli S, Scopelliti F, Tamburrino D, Baldoni A, Falconi M. Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas. World J Gastroenterol 2014; 20:10008-10023. [PMID: 25110429 PMCID: PMC4123331 DOI: 10.3748/wjg.v20.i29.10008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Since the first description of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in the eighties, their identification has dramatically increased in the last decades, hand to hand with the improvements in diagnostic imaging and sampling techniques for the study of pancreatic diseases. However, the heterogeneity of IPMNs and their malignant potential make difficult the management of these lesions. The objective of this review is to identify the molecular characteristics of IPMNs in order to recognize potential markers for the discrimination of more aggressive IPMNs requiring surgical resection from benign IPMNs that could be observed. We briefly summarize recent research findings on the genetics and epigenetics of intraductal papillary mucinous neoplasms, identifying some genes, molecular mechanisms and cellular signaling pathways correlated to the pathogenesis of IPMNs and their progression to malignancy. The knowledge of molecular biology of IPMNs has impressively developed over the last few years. A great amount of genes functioning as oncogenes or tumor suppressor genes have been identified, in pancreatic juice or in blood or in the samples from the pancreatic resections, but further researches are required to use these informations for clinical intent, in order to better define the natural history of these diseases and to improve their management.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/classification
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Papillary/classification
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/pathology
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genetic Testing
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/classification
- Neoplasms, Cystic, Mucinous, and Serous/genetics
- Neoplasms, Cystic, Mucinous, and Serous/metabolism
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreatic Neoplasms/classification
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Phenotype
- Predictive Value of Tests
- Signal Transduction
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18
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Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, Fassan M, Antonello D, Sadakari Y, Castelli P, Zamboni G, Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT, Goggins M, Scarpa A. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol 2014; 233:217-227. [PMID: 24604757 PMCID: PMC4057302 DOI: 10.1002/path.4344] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 02/03/2014] [Accepted: 02/22/2014] [Indexed: 12/12/2022]
Abstract
Intraductal neoplasms are important precursors to invasive pancreatic cancer and provide an opportunity to detect and treat pancreatic neoplasia before an invasive carcinoma develops. The diagnostic evaluation of these lesions is challenging, as diagnostic imaging and cytological sampling do not provide accurate information on lesion classification, the grade of dysplasia or the presence of invasion. Moreover, the molecular driver gene mutations of these precursor lesions have yet to be fully characterized. Fifty-two intraductal papillary neoplasms, including 48 intraductal papillary mucinous neoplasms (IPMNs) and four intraductal tubulopapillary neoplasms (ITPNs), were subjected to the mutation assessment in 51 cancer-associated genes, using ion torrent semiconductor-based next-generation sequencing. P16 and Smad4 immunohistochemistry was performed on 34 IPMNs and 17 IPMN-associated carcinomas. At least one somatic mutation was observed in 46/48 (96%) IPMNs; 29 (60%) had multiple gene alterations. GNAS and/or KRAS mutations were found in 44/48 (92%) of IPMNs. GNAS was mutated in 38/48 (79%) IPMNs, KRAS in 24/48 (50%) and these mutations coexisted in 18/48 (37.5%) of IPMNs. RNF43 was the third most commonly mutated gene and was always associated with GNAS and/or KRAS mutations, as were virtually all the low-frequency mutations found in other genes. Mutations in TP53 and BRAF genes (10% and 6%) were only observed in high-grade IPMNs. P16 was lost in 7/34 IPMNs and 9/17 IPMN-associated carcinomas; Smad4 was lost in 1/34 IPMNs and 5/17 IPMN-associated carcinomas. In contrast to IPMNs, only one of four ITPNs had detectable driver gene (GNAS and NRAS) mutations. Deep sequencing DNA from seven cyst fluid aspirates identified 10 of the 13 mutations detected in their associated IPMN. Using next-generation sequencing to detect cyst fluid mutations has the potential to improve the diagnostic and prognostic stratification of pancreatic cystic neoplasms.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Carcinoma, Pancreatic Ductal/chemistry
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Papillary/chemistry
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/pathology
- DNA Mutational Analysis/methods
- Female
- Genetic Predisposition to Disease
- High-Throughput Nucleotide Sequencing
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Multiplex Polymerase Chain Reaction
- Mutation
- Neoplasm Grading
- Neoplasms, Cystic, Mucinous, and Serous/chemistry
- Neoplasms, Cystic, Mucinous, and Serous/genetics
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Phenotype
- Retrospective Studies
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Affiliation(s)
- Eliana Amato
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Marco dal Molin
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
- Department of Surgery, General Surgery B, University of VeronaItaly
| | - Andrea Mafficini
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Jun Yu
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
| | - Giuseppe Malleo
- Department of Surgery, General Surgery B, University of VeronaItaly
| | - Borislav Rusev
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Matteo Fassan
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Davide Antonello
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Yoshihiko Sadakari
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
| | - Paola Castelli
- Department of Pathology, Ospedale Sacro CuoreNegrar, Italy
| | - Giuseppe Zamboni
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
- Department of Pathology, Ospedale Sacro CuoreNegrar, Italy
| | - Anirban Maitra
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
| | - Roberto Salvia
- Department of Surgery, General Surgery B, University of VeronaItaly
| | - Ralph H Hruban
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
| | - Claudio Bassi
- Department of Surgery, General Surgery B, University of VeronaItaly
| | - Paola Capelli
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Rita T Lawlor
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
| | - Michael Goggins
- Department of Pathology, Sol Goldman Pancreatic Research Center, Johns Hopkins Medical InstitutionBaltimore, MD, USA
| | - Aldo Scarpa
- ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of VeronaItaly
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19
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Bergmann F, Aulmann S, Welsch T, Herpel E, Werner J, Schirmacher P, Bläker H. Molecular analysis of pancreatic acinar cell cystadenomas: Evidence of a non-neoplastic nature. Oncol Lett 2014; 8:852-858. [PMID: 25009661 PMCID: PMC4081433 DOI: 10.3892/ol.2014.2163] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 03/21/2014] [Indexed: 11/05/2022] Open
Abstract
The biology of pancreatic acinar cell cystadenomas has not been clearly defined. However, a non-neoplastic process, caused by a cell differentiation failure leading to a cystic transformation, has been discussed, as well as a benign neoplastic lesion. Pancreatic acinar cell cystadenomas usually consist of thin-walled unilocular or multilocular cysts, and mural nodules have been described in two cases of a recent series. In one of these nodules, chromosomal imbalances were detected, which provided preliminary evidence for a neoplastic process. The aim of the current study was to further characterize the lesions by molecular analyses. In four cases without mural nodules, the clonality was assessed by performing mutational analyses within the highly variable displacement-loop region of the mitochondrial DNA. As a result, no closer correlation was identified between different foci within the tumors than between the tumors and adjacent normal pancreatic acinar tissue, indicating polyclonality of these lesions. Further molecular analyses revealed no mutations of the β-catenin and K-ras genes. In addition, no immunohistochemical evidence was identified for mutations of Smad4 or p53. In conclusion, the results of the current study demonstrated that pancreatic acinar cell cystadenomas are non-neoplastic lesions, with the potential exception of those rare cases with mural nodules.
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Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Sebastian Aulmann
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Thilo Welsch
- Department of General Surgery, University of Heidelberg, Heidelberg D-69120, Germany ; Institute of Pathology, Charité Berlin, Campus Mitte, Berlin D-10117, Germany
| | - Esther Herpel
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Jens Werner
- Department of General Surgery, University of Heidelberg, Heidelberg D-69120, Germany
| | - Peter Schirmacher
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany ; Department of Surgery, University of Dresden, Dresden D-01307, Germany
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20
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Mochizuki K, Kondo T, Oishi N, Kawasaki T, Nakazawa T, Yamane T, Katoh R. Immature squamous metaplasia (focal atypical epithelial hyperplasia) of the pancreatic duct-immunohistochemical distinction from intraductal carcinoma. Histopathology 2013; 63:343-50. [PMID: 23829443 DOI: 10.1111/his.12180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/01/2013] [Indexed: 11/28/2022]
Abstract
AIMS Immature squamous metaplasia of the pancreatic duct (ISMPD) can be difficult to differentiate from an intraductal carcinoma of the pancreas (ICP), and little is known about the pathological nature of ISMPD. The aim of this study was to analyse 20 ISMPD and 10 ICP tissue samples. METHODS AND RESULTS ISMPD shares some characteristics with ICP. Seven of 20 ISMPD samples were covered by a layer of pancreatic duct epithelium, whereas this was not seen in the ICP samples. Immunohistochemistry of ISMPD revealed positivity for p63 (100%), cytokeratin 5/6 (95%), cytokeratin 7 (95%), cytokeratin 20 (10%), and MUC-1 (95%), and the samples were negative for p53, carcinoembryonic antigen (CEA), and bcl-2. In contrast, ICP was positive for p63 (40%), p53 (10%), cytokeratin 7 (90%), cytokeratin 20 (20%), CEA (30%), and MUC-1 (80%), and negative for cytokeratin 5/6. However, in 84% (16) of the ISMPD samples, cytokeratin 7 was expressed only by an epithelial layer at the apical surface; this expression pattern was not found in any of the 10 ICP samples. The mean Ki67 labelling index was 1.0% in ISMPD and 18.5% in ICP. CONCLUSIONS Our study suggests that immunohistochemical staining for cytokeratin 5/6 and Ki67 constitutes the best combination for differentiating ISMPD from ICP.
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Affiliation(s)
- Kunio Mochizuki
- Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
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21
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Lo B, Strasser G, Sagolla M, Austin CD, Junttila M, Mellman I. Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways. ACTA ACUST UNITED AC 2013; 199:1117-30. [PMID: 23266956 PMCID: PMC3529533 DOI: 10.1083/jcb.201208080] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
A combination of ex vivo embryonic tissue culture, genetic manipulation, and chemical genetics reveals novel details of Lkb1-mediated regulation of tissue morphogenesis. The tumor suppressor Lkb1/STK11/Par-4 is a key regulator of cellular energy, proliferation, and polarity, yet its mechanisms of action remain poorly defined. We generated mice harboring a mutant Lkb1 knockin allele that allows for rapid inhibition of Lkb1 kinase. Culturing embryonic tissues, we show that acute loss of kinase activity perturbs epithelial morphogenesis without affecting cell polarity. In pancreas, cystic structures developed rapidly after Lkb1 inhibition. In lung, inhibition resulted in cell-autonomous branching defects. Although the lung phenotype was rescued by an activator of the Lkb1 target adenosine monophosphate–activated kinase (AMPK), pancreatic cyst development was independent of AMPK signaling. Remarkably, the pancreatic phenotype evolved to resemble precancerous lesions, demonstrating that loss of Lkb1 was sufficient to drive the initial steps of carcinogenesis ex vivo. A similar phenotype was induced by expression of mutant K-Ras with p16/p19 deletion. Combining culture of embryonic tissues with genetic manipulation and chemical genetics thus provides a powerful approach to unraveling developmental programs and understanding cancer initiation.
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Affiliation(s)
- Bryan Lo
- Genentech, South San Francisco, CA 94080, USA
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Xiao SY. Intraductal papillary mucinous neoplasm of the pancreas: an update. SCIENTIFICA 2012; 2012:893632. [PMID: 24278753 PMCID: PMC3820567 DOI: 10.6064/2012/893632] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 10/18/2012] [Indexed: 06/02/2023]
Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a cystic tumor of the pancreas. The etiology is unknown, but increasing evidence suggests the involvement of several tumorigenesis pathways, including an association with hereditary syndromes. IPMN occurs more commonly in men, with the mean age at diagnosis between 64 and 67 years old. At the time of diagnosis, it may be benign, with or without dysplasia, or frankly malignant with an invasive carcinoma. Tumors arising from the main pancreatic duct are termed main-duct IPMNs, those involving the branch ducts, branch-duct IPMNs. In general, small branch-duct IPMNs are benign, particularly in asymptomatic patients, and can be safely followed. In contrast, main-duct tumors should be surgically resected and examined carefully for an invasive component. In the absence of invasion, patient's survival is excellent, from 94 to 100%. For patients with an IPMN-associated invasive carcinoma, the prognosis overall is better than those with a de novo pancreatic ductal adenocarcinoma, with a 5-year survival of 40% to 60% in some series. However, no survival advantage can be demonstrated if the invasive component in an IPMN patient is that of the conventional tubular type (versus mucinous carcinoma). Several histomorphologic variants are recognized, although the clinical significance of this "subtyping" is not well defined.
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Affiliation(s)
- Shu-Yuan Xiao
- Department of Pathology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC6101, Chicago, IL 60637, USA
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Genetic markers of malignant transformation in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. Pancreas 2012; 41:1195-205. [PMID: 22750975 PMCID: PMC4850028 DOI: 10.1097/mpa.0b013e3182580fb4] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES The objective of this study was to determine the relationship between specific genetic alterations and malignant transformation in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS Quantitative meta-analysis was conducted of studies through October 2010 that adhered to the 1996 World Health Organization guidelines for distinguishing adenoma and borderline IPMN versus carcinoma in surgically resected specimens using a random-effects model. We developed a 6-point scoring system to assess study quality. RESULTS Thirty-nine studies (1235 IPMN samples) satisfied the inclusion criteria, and we conducted pooled analysis of 8 genetic markers: MUC1, MUC2, MUC5AC, kRas, p53, hTERT (human telomerase reverse transcriptase), cyclooxygenase 2, and Shh (Sonic hedgehog). Markers having the strongest association with malignant IPMN were hTERT (odds ratio [OR], 11.4; 95% confidence interval [CI], 3.5-36.7) and Shh (OR, 6.9; 95% CI, 2.4-20.2), whereas MUC5AC (OR, 1.0; 95% CI, 0.1-13.9) and kRas (OR, 2.0; 95% CI, 1.0-4.3) showed weak association with IPMN histologic progression. CONCLUSIONS Expression of hTERT is strongly associated with malignant transformation in IPMN, consistent with up-regulation of hTERT as a key step in progression of IPMN to cancer. Expression of kRas and MUC5AC is common but not strongly associated with IPMN histologic progression. The quality criteria used here may guide future reporting of genetic markers related to malignant transformation of IPMN.
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Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma. Mod Pathol 2012; 25:1496-507. [PMID: 22766790 DOI: 10.1038/modpathol.2012.113] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, β-catenin, P16(INK4A), TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n=16) and PTEN (n=14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P=0.029) and PR (P<0.001), and overexpression of P16(INK4A) (P=0.014). There were no significant differences in the levels of expression of ER, PTEN, β-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P=0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas.
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Abstract
OBJECTIVES The diagnosis of high-grade intraductal papillary mucinous neoplasm (IPMN) is difficult to distinguish from low-grade IPMN. The aim of this study was to identify potential markers for the discrimination of high-grade and invasive (HgInv) IPMN from low- and moderate-grade dysplasia IPMN. METHODS Laser capture microdissection was used to isolate distinct foci of low-grade, moderate-grade, high-grade, and invasive IPMN from paraffin-embedded archival tissue from 14 patients who underwent resection for IPMN. Most samples included multiple grades in the same specimen. Affymetrix Human Exon microarrays were used to compare low- and moderate-grade dysplasia IPMN with HgInv IPMN. RESULTS Sixty-two genes were identified as showing significant changes in expression (P ≤ 0.05 and a 2-fold cutoff), including up-regulation of 41 in HgInv IPMN. Changes in gene expression are associated with biological processes related to malignant behavior including cell motion, cell proliferation, response to hypoxia, and epithelial-to-mesenchymal transition. In addition, altered signaling in several transforming growth factor β-related pathways was exhibited in the progression of IPMN to malignancy. CONCLUSIONS This study identifies a set of genes associated with the progression of IPMN to malignancy. These genes are potential markers that could be used to identify IPMN requiring surgical resection.
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Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M, Ohta M, Tada M, Tanaka Y, Ikenoue T, Tateishi K, Isayama H, Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K. Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. J Gastroenterol 2012; 47:203-213. [PMID: 22041919 DOI: 10.1007/s00535-011-0482-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 09/01/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes. METHODS Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined. RESULTS There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%). CONCLUSIONS There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.
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Affiliation(s)
- Dai Mohri
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma. Pancreas 2012; 41:114-20. [PMID: 22143341 DOI: 10.1097/mpa.0b013e318220c1fa] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. METHODS We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. RESULTS The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001).The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. CONCLUSIONS MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.
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Dal Molin M, Hong SM, Hebbar S, Sharma R, Scrimieri F, de Wilde RF, Mayo SC, Goggins M, Wolfgang CL, Schulick RD, Lin MT, Eshleman JR, Hruban RH, Maitra A, Matthaei H. Loss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas. Hum Pathol 2011; 43:585-91. [PMID: 21940037 DOI: 10.1016/j.humpath.2011.06.009] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 06/14/2011] [Accepted: 06/15/2011] [Indexed: 02/06/2023]
Abstract
A better molecular characterization of intraductal papillary mucinous neoplasm (IPMN), the most frequent cystic precursor lesion of pancreatic adenocarcinoma, may have a pivotal role in its early detection and in the development of effective therapeutic strategies. BRG1, a central component of the chromatin remodeling complex SWI/SNF regulating transcription, is inactive in several malignancies. In this study, we evaluate the Brg1 expression in intraductal papillary mucinous neoplasm to better understand its role in the pancreatic carcinogenesis. Tissue microarrays of 66 surgically resected IPMNs were immunolabeled for the Brg1 protein. Expression patterns were then correlated with clinicopathologic parameters. Normal pancreatic epithelium strongly immunolabeled for Brg1. Reduced Brg1 expression was observed in 32 (53.3%) of the 60 evaluable IPMN lesions and occurred more frequently in high-grade IPMNs (13 of 17 showed loss; 76%) compared to intermediate-grade (15 of 29 showed loss; 52%) and low-grade IPMNs (4 of 14 showed loss; 28%) (P = .03). A complete loss of Brg1 expression was observed in 5 (8.3%) of the 60 lesions. Finally, a decrease in Brg1 protein expression was furthermore found in a low-passage noninvasive IPMN cell line by Western blot analysis. We did not observe correlation between Brg1 expression and IPMN subtype or with location of the cyst. We provide first evidence that Brg1 expression is lost in noninvasive cystic precursor lesions of pancreatic adenocarcinoma.
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Affiliation(s)
- Marco Dal Molin
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD 21231, USA
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Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a grossly visible (≥1 cm), mucin-producing neoplasm that arises in the main pancreatic duct and/or its branches. Patients with intraductal papillary mucinous neoplasm can present with symptoms caused by obstruction of the pancreatic duct system, or they can be asymptomatic. There are 3 clinical subtypes of intraductal papillary mucinous neoplasm: main duct, branch duct, and mixed. Five histologic types of intraductal papillary mucinous neoplasm are recognized: gastric foveolar type, intestinal type, pancreatobiliary type, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Noninvasive intraductal papillary mucinous neoplasms are classified into 3 grades based on the degree of cytoarchitectural atypia: low-, intermediate-, and high-grade dysplasia. The most important prognosticator, however, is the presence or absence of an associated invasive carcinoma. Some main duct-intraductal papillary mucinous neoplasms progress into invasive carcinoma, mainly tubular adenocarcinoma (conventional pancreatic ductal adenocarcinoma) and colloid carcinoma. Branch duct-intraductal papillary mucinous neoplasms have a low risk for malignant transformation. Preoperative prediction of the malignant potential of an intraductal papillary mucinous neoplasm is of growing importance because pancreatic surgery has its complications, and many small intraductal papillary mucinous neoplasms, especially branch duct-intraductal papillary mucinous neoplasms, have an extremely low risk of progressing to an invasive cancer. Although most clinical decision making relies on imaging, a better understanding of the molecular genetics of intraductal papillary mucinous neoplasm could help identify molecular markers of high-risk lesions. When surgery is performed, intraoperative frozen section assessment of the pancreatic resection margin can guide the extent of resection. Intraductal papillary mucinous neoplasms are often multifocal, and surgically resected patients should be followed for metachronous disease.
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High-throughput mutation profiling in intraductal papillary mucinous neoplasm (IPMN). J Gastrointest Surg 2011; 15:503-11. [PMID: 21225475 DOI: 10.1007/s11605-010-1411-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Accepted: 12/08/2010] [Indexed: 01/31/2023]
Abstract
BACKGROUND Specific mutations leading to the development of various histological grades of intraductal papillary mucinous neoplasm (IPMN) have been partially characterized. METHODS Analysis of 323 oncogenic mutations in 22 tumor-related genes was conducted, using a chip-based matrix-assisted laser desorption time-of-flight mass spectrometer of DNA extracted from microdissected cells of low-grade (n = 14), borderline (n = 6), and invasive IPMN (n = 7). Additional assays were performed on the DNA extracted from dyplastic cells found in the background of the adenocarcinoma. RESULTS We identified 9 K-ras mutations (low grade, 2/14; borderline, 1/6; invasive, 6/7), 3 p53 mutations (low grade, 1/14; invasive 2/7), and 2 PIK3CA mutations (low grade, 1/14; invasive, 1/7). K-ras, p53, and PIK3CA mutations present in the invasive cancer were absent in the adjacent precursor cells in 50% of the cases. In one patient, K-ras mutation was present in the precursor lesion and absent in the adjacent invasive lesion. CONCLUSIONS Of the 22 screened tumor-related genes, only K-ras, p53, and PIK3CA mutations were found in IPMN. K-ras mutations are more prevalent in invasive than premalignant IPMN. The variable coexistence of mutations in the invasive cancer and in the adjacent precursor cells may point to the heterogeneous nature of this tumor.
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Histologic, immunohistochemical, and molecular classification of 52 IPMNs of the pancreas. Appl Immunohistochem Mol Morphol 2009; 17:31-9. [PMID: 18813127 DOI: 10.1097/pai.0b013e31817c02c6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas account for approximately 5% of pancreatic neoplasms. Prognosis is superior to that of pancreatic invasive ductal carcinoma. IPMNs reveal a variety of epithelial linings expressing different mucin staining patterns and may progress along different oncogenic pathways. MATERIALS AND METHODS Fifty-two IPMNs were studied for expression of MUC1, MUC2, p16, p21, HER2, cyclin D1, and p53 protein and for mutations in K-ras, HER2, p53, EGFR, and BRAF genes. The cases were evaluated for dysplasia, presence of invasion, and morphology of lining epithelium. RESULTS Twenty-six IPMNs appeared intestinal (IN). Five were low, 12 moderate, and 9 high grade. K-ras mutations were found in 15, EGFR mutations in 2, and BRAF mutation in 1. Seven cases were pancreaticobiliary (PB) and all showed moderate to high-grade dysplasia. Six K-ras mutations and 2 p53 mutations were found in PB tumors. p53 mutations were in cases with high-grade dysplasia. Nineteen IPMNs demonstrated a gastric foveolar (GF) pattern. The majority of GF cases had low or moderate dysplasia. Sixteen revealed K-ras mutations and 1 case each demonstrated a HER2 or p53 mutation. Five IPMNs revealed invasive adenocarcinoma, including a colloid carcinoma from an IN type epithelium. CONCLUSIONS IN pattern IPMNs were the most common. Mixed histology was common. K-ras mutations were most common, but did not correlate with dysplasia. p53 mutations were seen in 6% of cases (only in GF and PB subtypes). A HER2 mutation was found in a GF IPMN. EGFR and BRAF mutations were restricted to IN IPMNs. These findings suggest the possibility of alternate pathways for carcinogenesis between epithelial subtypes of IPMNs.
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Ohuchida K, Mizumoto K, Miyasaka Y, Yu J, Cui L, Yamaguchi H, Toma H, Takahata S, Sato N, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M. Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis. J Pathol 2007; 213:275-82. [PMID: 17940995 DOI: 10.1002/path.2250] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Controversy exists regarding the clinical significance of S100A2 in the progression of tumours. In pancreatic cancer, little is known about the role of S100A2. The aim of this study was to clarify the clinical significance of S100A2 expression in pancreatic carcinogenesis. We microdissected invasive ductal carcinoma (IDC) cells from 22 lesions, pancreatic intraepithelial neoplasia (PanIN) cells from five lesions, intraductal papillary mucinous neoplasm (IPMN) cells from 38 lesions, pancreatitis-affected epithelial (PAE) cells from 16 lesions, and normal ductal cells from 18 normal pancreatic tissues. S100A2 expression in 14 pancreatic cancer cell lines, microdissected cells and formalin-fixed paraffin-embedded (FFPE) samples was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Microdissection analyses revealed that IDC cells expressed higher levels of S100A2 than did IPMN, PAE or normal cells (all comparisons, p < 0.007). Cell lines from metastatic sites expressed higher levels of S100A2 than those from primary sites. PanIN cells expressed higher levels of S100A2 than normal cells (p = 0.018). IDC cells associated with poorly differentiated adenocarcinoma expressed higher levels of S100A2 than did IDC cells without poorly differentiated adenocarcinoma (p = 0.006). Analyses of FFPE samples revealed that levels of S100A2 were higher in samples from patients who survived < 1000 days after surgery than in those from patients who survived > 1000 days (p = 0.043). Immunohistochemical analysis was consistent with qRT-PCR. S100A2 may be a marker of tumour progression or prognosis in pancreatic carcinogenesis and pancreatic cancer.
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Affiliation(s)
- K Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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