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Mattiolo P, Bevere M, Mafficini A, Verschuur AVD, Calicchia M, Hackeng WM, Simbolo M, Paiella S, Dreijerink KMA, Landoni L, Pedron S, Cingarlini S, Salvia R, Milella M, Lawlor RT, Valk GD, Vriens MR, Scarpa A, Brosens LA, Luchini C. Glucagon-Producing Pancreatic Neuroendocrine Tumors (Glucagonomas) are Enriched in Aggressive Neoplasms with ARX and PDX1 Co-expression, DAXX/ATRX Mutations, and ALT (Alternative Lengthening of Telomeres). Endocr Pathol 2024; 35:354-361. [PMID: 39331358 PMCID: PMC11659356 DOI: 10.1007/s12022-024-09826-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 09/28/2024]
Abstract
Glucagonomas are functioning pancreatic neuroendocrine tumors (PanNETs) responsible for glucagonoma syndrome. This study aims to shed light on the clinicopathological and molecular features of these neoplasms. Six patients with glucagonomas were identified. All neoplasms were investigated with immunohistochemistry for neuroendocrine markers (Synaptophysin, Chromogranin-A), ATRX, DAXX, ARX, and PDX1 transcription factors. Fluorescent in situ hybridization (FISH) for assessing alternative lengthening of telomeres (ALT), and next-generation sequencing (NGS) for molecular profiling were performed. All cases were large single masses (mean size of 8.2 cm), with necrolytic migratory erythema as the most common symptom (6/6 cases, 100%). All neoplasms were well-differentiated G1 tumors, except one case that was G2. The tumors consistently showed classic/conventional histomorphology, with solid-trabecular and nested architecture. Lymphatic and vascular invasion (6/6, 100%), perineural infiltration (4/6, 66.6%), and nodal metastasis (4/6, 66.6%) were frequently observed. Transcription factors expression showed strong ARX expression in all tumors, and PDX1 expression in 5/6 cases (83.3%), indicating co-occurring alpha- and beta-cell differentiation. NGS showed recurrent somatic MEN1 and ATRX/DAXX biallelic inactivation. Cases with ATRX or DAXX mutations also showed matched loss of ATRX or DAXX protein expression and ALT. One case harbored somatic MUTYH inactivation and showed a high tumor mutational burden (TMB, 41.0 mut/Mb). During follow-up, one patient died of the disease, and four patients developed distant metastasis. Pancreatic glucagonomas are distinct PanNETs with specific clinicopathological and molecular features, including histological aspects of biological aggressiveness, co-occurring alpha- and beta-cell differentiation, MEN1 and DAXX/ATRX mutations enrichment, and the possible presence of high-TMB as an actionable marker.
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Affiliation(s)
- Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Michele Bevere
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy
| | - Andrea Mafficini
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | | | - Martina Calicchia
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy
| | | | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Salvatore Paiella
- Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Koen M A Dreijerink
- Department of Endocrinology, Amsterdam UMC, Amsterdam, the Netherlands
- Department of Pathology, UMC Utrecht, Utrecht, the Netherlands
| | - Luca Landoni
- Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Serena Pedron
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Sara Cingarlini
- Unit of Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Roberto Salvia
- Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Michele Milella
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
- Unit of Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Rita T Lawlor
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Gerlof D Valk
- Department of Endocrine Oncology, UMC Utrecht, Utrecht, the Netherlands
| | - Menno R Vriens
- Department of Endocrine Surgery, UMC Utrecht, Utrecht, the Netherlands
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy.
| | - Lodewijk A Brosens
- Department of Pathology, UMC Utrecht, Utrecht, the Netherlands.
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
- ARC-NET Applied Research On Cancer Center, University of Verona, Verona, Italy.
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Moser E, Ura A, Vogel L, Steiger K, Mogler C, Evert M, Märkl B, Scheidhauer K, Martignoni M, Friess H, von Werder A, Marinoni I, Perren A, Klöppel G, Kasajima A. ARX, PDX1, ISL1, and CDX2 Expression Distinguishes 5 Subgroups of Pancreatic Neuroendocrine Tumors With Correlations to Histology, Hormone Expression, and Outcome. Mod Pathol 2024; 37:100595. [PMID: 39147030 DOI: 10.1016/j.modpat.2024.100595] [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: 05/30/2024] [Revised: 07/22/2024] [Accepted: 08/09/2024] [Indexed: 08/17/2024]
Abstract
Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and investigating their correlation with histologic, hormonal, molecular, and prognostic findings. One hundred eighty-five PanNETs (nonfunctioning 165 and functioning 20), resected between 1996 and 2023, were classified into 5 subgroups (A1, A2, B, C, and D) by cluster analysis based on ARX, PDX1, islet-1 (ISL1), and CDX2 expressions and correlated with trabecular vs solid histology, expression of insulin, glucagon, polypeptide (PP), somatostatin, serotonin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), DAXX/ATRX, MEN1, and alternative lengthening of telomerase status by fluorescence in situ hybridization, and disease-free survival. A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin, and somatostatin expression (P < .001). It included all insulinomas and had the best outcome (P < .01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin, and ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin, and was an independent poor prognosticator (P < .01). Differential expressions of ARX, PDX1, ISL1, and CDX2 stratified PanNETs into 5 subgroups with different histologies, hormone expressions, and outcomes. Subgroups A1 and A2 resembled the alpha-cell-like type, and subgroup B, the beta-cell-like type. Subgroup C with almost no transcription factor signature was unclear in cell lineage, whereas the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help establish the diagnosis, predict the outcome, and guide the treatment.
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Affiliation(s)
- Elisa Moser
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Ayako Ura
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Loreen Vogel
- Department of Nuclear Medicine, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Katja Steiger
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Carolin Mogler
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Bavaria, Germany
| | - Bruno Märkl
- Department of Pathology, Medical Faculty Augsburg, University of Augsburg, Augsburg, Bavaria, Germany
| | - Klemens Scheidhauer
- Department of Nuclear Medicine, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Marc Martignoni
- Department of Surgery, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Alexander von Werder
- Department of Internal Medicine II, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Ilaria Marinoni
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Günter Klöppel
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Atsuko Kasajima
- Department of Pathology, TUM School of Medicine and Health, Technical University Munich, Munich, Germany.
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Kellers F, Schulte DM, Jesinghaus M, Konukiewitz B. [Histo- and molecular pathology in gastroenteropancreatic neuroendocrine neoplasms]. Dtsch Med Wochenschr 2024; 149:887-893. [PMID: 39013409 DOI: 10.1055/a-2157-5460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
Neuroendocrine neoplasms are classified according to the WHO classification based on morphological criteria into neuroendocrine tumors, neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms. Neuroendocrine tumors are well differentiated neoplasms and show characteristic site-specific histological and molecular features, which is important for their clinical management. In cases dealing with metastasis, pathology often can help to identify the primary tumors using a small immunohistochemical marker panel. Neuroendocrine carcinomas are poorly differentiated neoplasms. They are subdivided into neuroendocrine carcinomas of small cell and large cell type. The molecular profile of neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasms shows a close relationship to conventional adenocarcinomas with site-specific features. Molecular analysis of neuroendocrine carcinomas and neuroendocrine-non-neuroendocrine neoplasms are not yet fully integrated in daily diagnostics and are mainly performed in the context of precision oncology.
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Konukiewitz B, Jesinghaus M, Kasajima A, Klöppel G. Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls. Virchows Arch 2021; 480:247-257. [PMID: 34647171 PMCID: PMC8986719 DOI: 10.1007/s00428-021-03211-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/06/2021] [Accepted: 09/21/2021] [Indexed: 12/29/2022]
Abstract
Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
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Affiliation(s)
- Björn Konukiewitz
- Institute of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität zu Kiel, Arnold-Heller-Straße 3/14, 24105, Kiel, Germany.
| | - Moritz Jesinghaus
- Institute of Pathology, Universitätsklinikum Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Atsuko Kasajima
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
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Gao H, Wang W, Zhang W, Xu H, Wu C, Li H, Ni Q, Yu X, Liu L. The distinctive characteristics of the micro-vasculature and immune cell infiltration in cystic pancreatic neuroendocrine tumors. J Endocrinol Invest 2021; 44:1011-1019. [PMID: 32856225 DOI: 10.1007/s40618-020-01396-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 08/15/2020] [Indexed: 01/13/2023]
Abstract
PURPOSE Hypervascularity is a main characteristic of pancreatic neuroendocrine tumors (PanNETs), and cystic PanNETs (CPanNETs) are unique type of PanNETs in which the microenvironment remains unknown. We aim to compare the micro-vasculature features and immune cell infiltration between CPanNETs and solid PanNETs (SPanNETs). METHODS Data of 301 SPanNET and 36 CPanNET patients from a high-volume institution were evaluated. CD4, CD8, CD11c, CD15, CD20, CD68, CD34 and α-SMA expression levels were assessed by immunohistochemistry and immunofluorescent double staining. The microvessel density (MVD) and microvessel integrity (MVI) were examined. RESULTS MVD and MVI expression levels in CPanNETs were significantly higher than those in SPanNETs (p = 0.025 and 0.0092, respectively). CPanNETs had higher proportions of T1 (p = 0.023) and G1 (p = 0.052) than SPanNETs. In SPanNETs, higher MVD occurred in stages T1, N0 and G1 than in the T2/T3, N1 and G2 subgroups. In CPanNETs, CD34-MVD was uncorrelated with the T stage or grade. Higher CD34-MVD, but not MVI, was associated with better DFS (HR 0.3209, 95% CI 0.1259-0.8176, p = 0.004). There were significantly more peritumoral infiltrating immune cells than their intratumoral counterparts (p < 0.001 for each) in CPanNETs and SPanNETs. The mean number of peritumoral CD68 + TAM in CPanNETs was significantly lower than that in SPanNETs (p = 0.008). The counts of other peritumoral immune cells did not significantly differ between CPanNETs and SPanNETs. CONCLUSIONS CPanNETs had a microenvironment distinct from that of SPanNETs, including higher CD34-MVD, higher MVI and lower TAM. This specific microenvironment structure may partially help predicting the prognosis of patients with PanNET.
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Affiliation(s)
- H Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - W Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - W Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - H Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - C Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - H Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - Q Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China
| | - X Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
| | - L Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Department of Pancreatic Surgery, Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
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Esposito I, Haeberle L. Nonmucinous Cystic Lesions of the Pancreas. Arch Pathol Lab Med 2021; 146:312-321. [PMID: 33503226 DOI: 10.5858/arpa.2020-0446-ra] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Pancreatic cystic lesions are increasingly diagnosed. Among other criteria, they are often distinguished in mucinous versus nonmucinous cysts. Mucinous pancreatic cystic lesions have received increasing attention, especially those known as precursors of pancreatic ductal adenocarcinoma. However, the group of nonmucinous cystic lesions of the pancreas includes numerous entities that may pose a diagnostic challenge. Their accurate diagnosis and classification are crucial for adequate patient management. OBJECTIVE.— To review the spectrum of nonmucinous cystic lesions of the pancreas, taking into consideration their epidemiology and typical clinical context, their characteristic gross morphology and histomorphology, as well as their immunohistochemical and molecular profile. DATA SOURCES.— Literature was searched and reviewed with MEDLINE via PubMed. Macroscopic and microscopic images were obtained from the archives of the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Germany. CONCLUSIONS.— Nonmucinous cysts of the pancreas comprise numerous, mostly rare entities displaying different biological behaviors. The most frequent are serous cystic neoplasms, solid-pseudopapillary neoplasms, cystic neuroendocrine tumors, and pancreatitis-associated pseudocysts. Accurate diagnosis can be achieved if characteristic clinical context, histomorphology, and immunoprofile are taken into account.
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Affiliation(s)
- Irene Esposito
- From the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany
| | - Lena Haeberle
- From the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany
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7
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Luchini C, Grillo F, Fassan M, Vanoli A, Capelli P, Paolino G, Ingravallo G, Renzulli G, Doglioni C, D’Amuri A, Mattiolo P, Pecori S, Parente P, Florena AM, Zamboni G, Scarpa A. Malignant epithelial/exocrine tumors of the pancreas. Pathologica 2020; 112:210-226. [PMID: 33179623 PMCID: PMC7931574 DOI: 10.32074/1591-951x-167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Federica Grillo
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppina Renzulli
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Claudio Doglioni
- Vita e Salute University, Milan, Italy
- Pathology Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Sara Pecori
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Ada M. Florena
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Italy
| | - Giuseppe Zamboni
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- IRCSS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
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8
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Konukiewitz B, von Hornstein M, Jesinghaus M, Steiger K, Weichert W, Detlefsen S, Kasajima A, Klöppel G. Pancreatic neuroendocrine tumors with somatostatin expression and paraganglioma-like features. Hum Pathol 2020; 102:79-87. [PMID: 32668277 DOI: 10.1016/j.humpath.2020.07.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
Abstract
A small fraction of pancreatic neuroendocrine tumors (PanNETs) shows a solid, paraganglioma-like (PG-like) histology. We wanted to know whether these PanNETs have a special hormone expression and are related to paragangliomas (PGs)/pheochromocytomas (PCs). We screened a series of 48 surgically resected PanNETs for their histological growth patterns and their association with expression of islet hormones. The PanNETs were divided into PG-like and non-PG-like tumors and immunohistochemically monitored for the expression of islet hormones, cytokeratins, and S100. The results were correlated to histological pattern, lymph node status, and data in 28 PGs/PCs, including 2 PGs attached to the pancreas. All PanNETs, in contrast to PGs/PCs, were cytokeratin positive. A PG-like growth pattern was identified in 9 of 48 PanNETs and correlated with somatostatin expression. Only half of the non-PG-like PanNETs also contained somatostatin-positive cells. Eight of 28 PGs/PCs expressed somatostatin, mostly in individual cells. PG-like PanNETs and non-PG-like PanNETs infiltrated the adjacent pancreatic tissue, whereas 2 to the pancreas-associated PGs were well demarcated. Lymph node metastases were detected in 58%, 39%, 57%, and 53% of the somatostatin-producing, somatostatin-negative, PG-like, and non-PG-like PanNETs, respectively. PG-like PanNETs, in contrast to PG/PCs, are characterized by the expression of cytokeratin and somatostatin, the development of lymph node metastasis, and the infiltration into pancreatic parenchyma. Non-PG-like PanNETs may also express somatostatin and show lymph node metastases to the same extent. A literature review of cases reported as PG of the pancreas reveals that only a small fraction of these tumors probably represents true pancreatic PGs.
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Affiliation(s)
- Björn Konukiewitz
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
| | | | - Moritz Jesinghaus
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
| | - Katja Steiger
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
| | - Wilko Weichert
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, 5000, Odense, Denmark.
| | - Atsuko Kasajima
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
| | - Günter Klöppel
- Department of Pathology, Technical University of Munich, 81675, Munich, Germany.
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9
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Abstract
Neuroendocrine neoplasms (NENs) of the gastrointestinal (GI) tract and pancreas are a rare and heterogeneous group of neoplasms characterized by common cellular features as well as unique site-specific traits. GI and pancreatic NENs are much rarer than the more common adenocarcinomas arising at these sites. However, the incidences of GI and pancreatic NENs have increased significantly, particularly in the stomach and common site, followed by rectum, appendix, colon, and stomach. Pancreatic NENs are also uncommon, with fewer than 1 per 100,000, accounting for 1% to 2% of all pancreatic neoplasms.
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Couvelard A, Scoazec JY. [Inherited tumor syndromes of gastroenteropancreatic and thoracic neuroendocrine neoplasms]. Ann Pathol 2020; 40:120-133. [PMID: 32035641 DOI: 10.1016/j.annpat.2020.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/12/2020] [Indexed: 12/31/2022]
Abstract
About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.
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Affiliation(s)
- Anne Couvelard
- Département de pathologie, hôpital Bichat, 75018 Paris, France
| | - Jean-Yves Scoazec
- Département de biologie et pathologie médicales, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France.
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11
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Kou HW, Yu MC, Chong SW, Hsu HY, Chou HH, Lee CW, Chen TC, Huang SF. Successful Localization and Resection of Small Pancreatic Cystic Insulinoma Using Intraoperative Near-Infrared Fluorescence Imaging: A Case Report and Literature Review. Pancreas 2020; 49:1388-1392. [PMID: 33122530 DOI: 10.1097/mpa.0000000000001678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Pancreatic cystic insulinoma is an uncommon tumor. Perioperative localization remained challenging if the tumor is atypical with cystic feature or in small size. Near-infrared (NIR) imaging is a technique by injecting fluorescent dye intravenously, which accumulates to the target lesion and creating signal by laser sources. The signal helps surgeons to identify the lesion during operation, but little experience has been reported regarding the use of imaging NIR technique for localizing cystic insulinoma. We present a 29-year-old female patient with a symptomatic pancreatic cystic insulinoma (1.2 cm) as assessed by clinical symptom, laboratory evidence, and magnetic resonance cholangiopancreatography. With an aid of NIR imaging technique, this cystic tumor was localized easily at operation. Also, the fluorescence imaging visualized the tumor part, guided us to identify the safe margin, and preserved the normal pancreatic structure. Pathologic report confirmed that the tumor was a well-differentiated cystic insulinoma. This case demonstrates that pancreatic cystic insulinoma in small size can be intraoperatively localized by NIR imaging, a relatively safe and easy technique.
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MESH Headings
- Administration, Intravenous
- Adult
- Female
- Fluorescent Dyes/administration & dosage
- Humans
- Indocyanine Green/administration & dosage
- Insulinoma/diagnostic imaging
- Insulinoma/pathology
- Insulinoma/surgery
- Intraoperative Care
- Neoplasms, Cystic, Mucinous, and Serous/diagnostic imaging
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Neoplasms, Cystic, Mucinous, and Serous/surgery
- Optical Imaging
- Pancreatectomy
- Pancreatic Neoplasms/diagnostic imaging
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/surgery
- Predictive Value of Tests
- Treatment Outcome
- Tumor Burden
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Affiliation(s)
- Hao-Wei Kou
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
| | - Ming-Chin Yu
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
- Department of Surgery, New Taipei Municipal TuCheng Hospital, TuCheng, New Taipei
| | - Sio-Wai Chong
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
| | - Heng-Yuan Hsu
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
- Department of Surgery, New Taipei Municipal TuCheng Hospital, TuCheng, New Taipei
| | - Hsu-Huan Chou
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
| | - Chao-Wei Lee
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
| | - Tse-Ching Chen
- Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Song-Fong Huang
- From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan
- Department of Surgery, New Taipei Municipal TuCheng Hospital, TuCheng, New Taipei
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12
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Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances. Adv Anat Pathol 2019; 26:13-30. [PMID: 29912000 DOI: 10.1097/pap.0000000000000201] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.
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13
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Hurtado-Pardo L, A Cienfuegos J, Ruiz-Canela M, Panadero P, Benito A, Hernández Lizoain JL. Cystic pancreatic neuroendocrine tumors (cPNETs): a systematic review and meta-analysis of case series. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 109:778-787. [PMID: 29072081 DOI: 10.17235/reed.2017.5044/2017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Cystic pancreatic neuroendocrine tumors represent 13% of all neuroendocrine tumors. The aim of this study is to analyze the phenotype and biologic behavior of resected cystic neuroendocrine tumors. A systematic review and meta-analysis were conducted until September 2016 using a search in Medline, Scopus, and EMBASE with the terms "cystic pancreatic endocrine neoplasm", "cystic islets tumors" and "cystic islets neoplasms". From the 795 citations recovered 80 studies reporting on 431 patients were selected. 87.1% (n = 387) were sporadic tumors and 10.3% (n = 40) corresponded to multiple endocrine neoplasia endocrine type 1. Were diagnosed incidentally 44.6% (n = 135). Cytology was found to have a sensitivity of 78.5%. Were non-functional tumors 85% (n = 338), and among the functional tumors, insulinoma was the most frequent. According to the European Neuroendocrine Tumor Society staging, 87.8% were limited to the pancreas (I-IIb), and 12.2% were advanced (III-IV). Disease-free survival at 5 years in stages (I-IIIa) and (IIIb-IV) was 91.5% and 54.2%, respectively; and was significantly lower (p = 0.0001) in functional tumors. In patients with multiple endocrine neoplasia there was a higher incidence of functional (62.5%) and multifocal (28.1%) tumors. Disease-free survival at 5 and 10 years was 60%. Cystic pancreatic neuroendocrine tumors exhibit phenotypical characteristics which are different to those of solid neuroendocrine tumors.
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Affiliation(s)
| | | | - Miguel Ruiz-Canela
- Department of Preventive Medicine and Public Healt, Medical School. University of Navarra, España
| | - Pablo Panadero
- Anatomía Patológica, Clínica Universidad de Navarra, España
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14
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Klassifikation und malignes Potenzial der zystischen Pankreastumoren. DER PATHOLOGE 2014; 36:99-112; quiz 113-4. [DOI: 10.1007/s00292-014-1971-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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15
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Abstract
Pancreatic neuroendocrine neoplasms include mainly well-differentiated neuroendocrine tumors but also rare poorly differentiated neuroendocrine carcinomas. Molecular mechanisms underlying pancreatic neuroendocrine tumorigenesis have recently been elucidated. While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly differentiated neuroendocrine carcinomas. With these discoveries, new molecular targeted therapies have become available and show promise in some patients with pancreatic well-differentiated neuroendocrine tumor.
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Affiliation(s)
- Chanjuan Shi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David S Klimstra
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, New York 10065.
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16
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Koh YX, Chok AY, Zheng HL, Tan CS, Goh BKP. A systematic review and meta-analysis of the clinicopathologic characteristics of cystic versus solid pancreatic neuroendocrine neoplasms. Surgery 2014; 156:83-96.e2. [PMID: 24878455 DOI: 10.1016/j.surg.2014.03.026] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 03/11/2014] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Cystic pancreatic neuroendocrine neoplasms (PNENs) are rare neoplasms, and presently, it is uncertain whether their behavior is similar or distinct from their solid counterparts. This study aimed to review systematically the present literature to compare the clinicopathologic characteristics of cystic PNENs versus their solid counterparts to determine whether cystic PNENs are likely to be a distinct entity from solid PNENs. METHODS Comparative studies of solid versus cystic PNENs studies were reviewed. Cystic and solid PNENs were compared on the basis of several clinicopathologic characteristics. RESULTS Seven nonrandomized case control studies compared 152 cystic versus 915 solid PNENs. Pooled analysis demonstrated that the likelihood of PNENs to be located in the head/uncinate of the pancreas was lower for cystic than solid neoplasms (27.7% vs 45.5%, odds ratio [OR] 0.452, 95% confidence interval [95% CI] 0.304-0.673, P < .001). Cystic PNENs were less likely to be functional (14% vs 24.4%, OR 0.405, 95% CI 0.221-0.742, P = .003) and were more likely to be benign/uncertain rather than malignant compared with solid PNENs (90.3% vs 65.9%, OR 3.151, 95% CI 1.297-7.652, P = .011). Cystic PNENs were more likely to have a mitotic count <2 per 10 hpf and a Ki67 index <2% (93.3% vs 72.7%, OR 4.897, 95% CI 2.139-11.209, P < .001 and 82.4% vs 54.1%, OR 4.079, 95% CI 2.177-7.641, P < .001), respectively. Cystic neoplasms were also less likely to have regional lymph node metastases than solid neoplasms (11.2% vs 28.9%, OR 0.387, 95% CI 0.219-0.685, P = .001).In this meta-analysis, there was no difference in the 5-year overall survival and 5-year disease-free survival between cystic vs solid PNENs (92.0% vs 86.8%, P .214) and (98.1% vs 83.9%, P = .185). CONCLUSION These findings suggest that cystic PNENs tend to be biologically less aggressive compared with their solid counterparts; more data, however, with respect to molecular analysis are required to establish whether cystic and solid PNENs were distinct pathologic entities.
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Affiliation(s)
- Ye-Xin Koh
- Division of Surgery, Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore
| | - Aik-Yong Chok
- Division of Surgery, Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore
| | - Hui-Li Zheng
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Chuen-Seng Tan
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Brian K P Goh
- Division of Surgery, Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.
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17
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Abstract
Incidentally discovered cystic tumors of the pancreas (CTP) are an increasingly frequent entity. It is essential to differentiate lesions whose malignant potential is either nil or negligible (pseudocyst, serous cystadenoma, simple cysts) from lesions with intermediate malignant potential (intraductal papillary mucinous tumor of the pancreas [IPMN] involving the secondary ducts, cystic endocrine tumor) or those with high malignant potential (mucinous cystadenoma, solid pseudopapillary tumors and IPMN involving the main pancreatic duct). The approach to defining malignant potential is based on diagnostic CT scan, magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), often complemented by EUS-guided cyst puncture for biochemical and cytological analysis of cyst fluid. Surgery for diagnostic purposes should be avoided because of its significant morbidity. For pseudocysts, simple cysts and serous cystadenomas, abstention is the general rule. Resection, preserving as much pancreatic parenchyma as possible, is the rule for IPMN involving the main pancreatic duct, mucinous cystadenomas, solid and pseudopapillary tumors, and cystic endocrine tumors. Resection is rarely indicated at the outset for IPMN involving secondary pancreatic ducts; morphologic observation is the general rule and preventive excision may be indicated secondarily. Good collaboration between surgeons, radiologists and endosonographists is necessary for optimal management of CTP.
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18
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Ghetie C, Cornfeld D, Ramfidis VS, Syrigos KN, Saif MW. Bone lesions in recurrent glucagonoma: A case report and review of literature. World J Gastrointest Oncol 2012; 4:152-5. [PMID: 22737277 PMCID: PMC3382662 DOI: 10.4251/wjgo.v4.i6.152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 02/22/2012] [Accepted: 03/02/2012] [Indexed: 02/05/2023] Open
Abstract
Glucagonomas are rare neuroendocrine tumors that arise from α cells of the pancreatic islets. Most of them are malignant and usually present as metastatic disease. Sites most commonly involved in metastases are the liver and regional lymph nodes. Bone metastases are rare events and only a few cases have been reported in the literature. We present the case of a 53-year-old male with a medical history of recurrent non-functioning glucagonoma. He presented 17 years after the initial diagnosis with new blastic bone lesions involving the T1 vertebra and the sacrum. Diagnostic steps and medical management in metastatic glucagonoma are also reviewed.
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Affiliation(s)
- Cristian Ghetie
- Cristian Ghetie, Danbury Hospital, Danbury, CT 06810, United States
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19
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Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 <2%) or G2 (Ki67 2-20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 >20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.
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Affiliation(s)
- Günter Klöppel
- Department of Pathology, Technical University of München, Ismaninger Strasse 22, 81675 München, Germany.
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20
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Castro PG, de León AM, Trancón JG, Martínez PA, Alvarez Pérez JA, Fernández Fernández JC, García Bernardo CM, Serra LB, González González JJ. Glucagonoma syndrome: a case report. J Med Case Rep 2011; 5:402. [PMID: 21859461 PMCID: PMC3171381 DOI: 10.1186/1752-1947-5-402] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Accepted: 08/22/2011] [Indexed: 01/23/2023] Open
Abstract
Introduction Glucagonoma syndrome is a rare paraneoplastic phenomenon, with an estimated incidence of one in 20 million, characterized by necrolytic migratory erythema, hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, cheilitis, steatorrhea, diarrhea, venous thrombosis and neuropsychiatric disturbances in the setting of a glucagon-producing alpha-cell tumor of the pancreas. Necrolytic migratory erythema is the presenting manifestation in the majority of cases, so its early suspicion and correct diagnosis is a key factor in the management of the patient. Case presentation We present the case of a 70-year-old Caucasian woman with glucagonoma syndrome due to an alpha-cell tumor located in the tail of the pancreas, successfully treated with surgical resection. Conclusion Clinicians should be aware of the unusual initial manifestations of glucagonoma. Early diagnosis allows complete surgical resection of the neoplasm and provides the only chance of a cure.
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Affiliation(s)
- Pablo Granero Castro
- Department of General Surgery and Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain.
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21
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Hermann G, Konukiewitz B, Schmitt A, Perren A, Klöppel G. Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2. Virchows Arch 2011; 459:147-54. [PMID: 21739268 DOI: 10.1007/s00428-011-1118-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 04/15/2011] [Accepted: 04/20/2011] [Indexed: 12/26/2022]
Abstract
We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.
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Affiliation(s)
- Gratiana Hermann
- Department of Pathology, Assaf Harofeh Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Schlitter AM, Esposito I, Klöppel G. Klassifikation und Diagnose zystischer Pankreastumoren. VISZERALMEDIZIN 2011. [DOI: 10.1159/000329194] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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