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Andersen KØ, Detlefsen S, Brusgaard K, Christesen HT. Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data. Front Endocrinol (Lausanne) 2024; 15:1351624. [PMID: 38868744 PMCID: PMC11167081 DOI: 10.3389/fendo.2024.1351624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/02/2024] [Indexed: 06/14/2024] Open
Abstract
Introduction Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. Methods A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Results Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. Discussion The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).
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Affiliation(s)
- Kirstine Øster Andersen
- Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Sönke Detlefsen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense, Denmark
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Klaus Brusgaard
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense, Denmark
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Henrik Thybo Christesen
- Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense, Denmark
- Steno Diabetes Center Odense, Odense, Denmark
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Tamang OY, Dahal P, Paudel S, Upadhyaya RP, Dawadi K, Shrestha A, Parajuli S. Von Hippel Lindau Disease with central nervous system and multiple visceral manifestations: A case report. Radiol Case Rep 2023; 18:4357-4362. [PMID: 37823048 PMCID: PMC10562168 DOI: 10.1016/j.radcr.2023.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 10/13/2023] Open
Abstract
Von Hippel-Lindau (VHL) disease is an autosomal-dominant syndrome caused by mutations in the VHL gene, located on the short arm of chromosome 3. Patients with VHL are likely to manifest with a spectrum of multiple benign and malignant tumors involving various organ systems. We present a case of a 28-year-old female without a remarkable family history who presented with complaints of hematuria and abdominal discomfort. Initial laboratory investigations confirmed hematuria. Subsequent abdominal computed tomography scan revealed heterogeneous enhancing solid mass in bilateral kidneys, avidly enhancing mass in the right adrenal gland, bilateral simple renal cortical cysts, and a pancreatic cyst. With a provisional diagnosis of VHL disease, an MRI of the brain and spine was performed, which showed the presence of a cerebellar hemangioblastoma. Her catecholamine and vanillylmandelic acid levels were in the normal range not in line with pheochromocytoma. The patient then underwent bilateral partial renal nephrectomy and right adrenalectomy. Histopathologic examination reported clear renal cell carcinoma and pheochromocytoma of the right adrenal gland mass. Molecular genetic testing confirmed the presence of VHL disease.
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Affiliation(s)
- Ongden Yonjen Tamang
- Department of Radiology and Imaging, Grande International Hospital, Kathmandu, Nepal
| | - Prajwal Dahal
- Department of Radiology and Imaging, Grande International Hospital, Kathmandu, Nepal
| | - Sharma Paudel
- Department of Radiology and Imaging, Tribhuvan University Teaching Hospital and Grande International Hospital, Kathmandu, Nepal
| | | | - Kapil Dawadi
- Department of Radiology and Imaging, Grande International Hospital, Kathmandu, Nepal
| | - Ashish Shrestha
- Department of Radiology and Imaging, Grande International Hospital, Kathmandu, Nepal
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Fields BKK, Demirjian NL, Ahmadzadehfar H, Yordanova A, Nabipour I, Jokar N, Assadi M, Joyce P, Gholamrezanezhad A. Imaging Approach to Pediatric and Adolescent Familial Cancer Syndromes. FAMILIAL ENDOCRINE CANCER SYNDROMES 2023:127-148. [DOI: 10.1007/978-3-031-37275-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Larcher A, Belladelli F, Fallara G, Rowe I, Capitanio U, Marandino L, Raggi D, Capitanio JF, Bailo M, Lattanzio R, Barresi C, Calloni SF, Barbera M, Andreasi V, Guazzarotti G, Pipitone G, Carrera P, Necchi A, Mortini P, Bandello F, Falini A, Partelli S, Falconi M, De Cobelli F, Salonia A. Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: A practical review of the literature for clinicians. Asian J Urol 2022; 9:430-442. [DOI: 10.1016/j.ajur.2022.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/27/2022] [Accepted: 08/17/2022] [Indexed: 10/14/2022] Open
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Hackeng WM, Assi HA, Westerbeke FHM, Brosens LAA, Heaphy CM. Prognostic and Predictive Biomarkers for Pancreatic Neuroendocrine Tumors. Surg Pathol Clin 2022; 15:541-554. [PMID: 36049835 DOI: 10.1016/j.path.2022.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) represent a clinically challenging disease because these tumors vary in clinical presentation, natural history, and prognosis. Novel prognostic biomarkers are needed to improve patient stratification and treatment options. Several putative prognostic and/or predictive biomarkers (eg, alternative lengthening of telomeres, alpha-thalassemia/mental retardation, X-linked (ATRX)/Death Domain Associated Protein (DAXX) loss) have been independently validated. Additionally, recent transcriptomic and epigenetic studies focusing on endocrine differentiation have identified PanNET subtypes that display similarities to either α-cells or β-cells and differ in clinical outcomes. Thus, future prospective studies that incorporate genomic and epigenetic biomarkers are warranted and have translational potential for individualized therapeutic and surveillance strategies.
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Affiliation(s)
- Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Hussein A Assi
- Department of Medicine, Boston University School of Medicine, 820 Harrison Avenue, FGH 2011, Boston, MA 02118, USA
| | - Florine H M Westerbeke
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Christopher M Heaphy
- Department of Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA; Department of Pathology & Laboratory Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA.
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Marchese U, Gaillard M, Pellat A, Tzedakis S, Abou Ali E, Dohan A, Barat M, Soyer P, Fuks D, Coriat R. Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors. Cancers (Basel) 2022; 14:433. [PMID: 35053593 PMCID: PMC8773540 DOI: 10.3390/cancers14020433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.
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Affiliation(s)
- Ugo Marchese
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Martin Gaillard
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Anna Pellat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Stylianos Tzedakis
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Einas Abou Ali
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Anthony Dohan
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Maxime Barat
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Philippe Soyer
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - David Fuks
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
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Von Hippel-Lindau Syndrome: Medical Syndrome or Surgical Syndrome? A Surgical Perspective. J Kidney Cancer VHL 2021; 9:27-32. [PMID: 34963877 PMCID: PMC8652351 DOI: 10.15586/jkcvhl.v9i1.206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 10/24/2021] [Indexed: 01/29/2023] Open
Abstract
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view.
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Lara DO, Atucha AF, López ML, Luis Cabriada Nuño J. Polycystic pancreas, gastrointestinal manifestation of von hippel-lindau disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45 Suppl 1:73-74. [PMID: 34896227 DOI: 10.1016/j.gastrohep.2021.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/14/2021] [Accepted: 11/29/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Daniel Oyón Lara
- Servicio de Aparato Digestivo, Hospital de Galdakao-Usansolo, Galdakao, Vizcaya, España; Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Vizcaya, España.
| | | | - María López López
- Servicio de Aparato Digestivo, Hospital de Galdakao-Usansolo, Galdakao, Vizcaya, España
| | - José Luis Cabriada Nuño
- Servicio de Aparato Digestivo, Hospital de Galdakao-Usansolo, Galdakao, Vizcaya, España; Instituto de Investigación Sanitaria Biocruces Bizkaia, Barakaldo, Vizcaya, España
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Laks S, van Leeuwaarde R, Patel D, Keutgen XM, Hammel P, Nilubol N, Links TP, Halfdanarson TR, Daniels AB, Tirosh A. Management recommendations for pancreatic manifestations of von Hippel-Lindau disease. Cancer 2021; 128:435-446. [PMID: 34735022 DOI: 10.1002/cncr.33978] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/26/2022]
Abstract
Von Hippel-Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.
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Affiliation(s)
- Shachar Laks
- Surgery C, Chaim Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rachel van Leeuwaarde
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Dhaval Patel
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Xavier M Keutgen
- Division of Endocrine Surgery, Department of Surgery, University of Chicago Medical Center, Chicago, Illinois
| | - Pascal Hammel
- Department of Digestive and Medical Oncology, Paul Brousse Hospital, Villejuif, France
| | - Naris Nilubol
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Thera P Links
- Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | | | - Anthony B Daniels
- Division of Ocular Oncology and Pathology, Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Amit Tirosh
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Neuroendocrine Tumors Service, VHL Clinical Care Center, Endocrine Oncology Genomics Laboratory, Chaim Sheba Medical Center, Tel Hashomer, Israel
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Diaconescu S, Gîlcă-Blanariu GE, Poamaneagra S, Marginean O, Paduraru G, Stefanescu G. Could the burden of pancreatic cancer originate in childhood? World J Gastroenterol 2021; 27:5322-5340. [PMID: 34539135 PMCID: PMC8409163 DOI: 10.3748/wjg.v27.i32.5322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/08/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
The presence of pancreatic cancer during childhood is extremely rare, and physicians may be tempted to overlook this diagnosis based on age criteria. However, there are primary malignant pancreatic tumors encountered in pediatric patients, such as pancreatoblastoma, and tumors considered benign in general but may present a malignant potential, such as the solid pseudo-papillary tumor, insulinoma, gastrinoma, and vasoactive intestinal peptide secreting tumor. Their early diagnosis and management are of paramount importance since the survival rates tend to differ for various types of these conditions. Many pediatric cancers may present pancreatic metastases, such as renal cell carcinoma, which may evolve with pancreatic metastatic disease even after two or more decades. Several childhood diseases may create a predisposition for the development of pancreatic cancer during adulthood; hence, there is a need for extensive screening strategies and complex programs to facilitate the transition from pediatric to adult healthcare. Nevertheless, genetic studies highlight the fact the specific gene mutations and family aggregations may be correlated with a special predisposition towards pancreatic cancer. This review aims to report the main pancreatic cancers diagnosed during childhood, the most important childhood diseases predisposing to the development of pancreatic malignancies, and the gene mutations associates with pancreatic malignant tumors.
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Affiliation(s)
- Smaranda Diaconescu
- Department of Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Department of Pediatric Gastroenterology, St Mary Emergency Children's Hospital, Iasi 700309, Romania
| | - Georgiana Emmanuela Gîlcă-Blanariu
- Department of Gastroenterology and Hepatology, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi 700115, Romania
- Department of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, Iasi 700111, Romania
| | - Silvia Poamaneagra
- Department of Pediatric Gastroenterology, St Mary Emergency Children's Hospital, Iasi 700309, Romania
- Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures 540142, Romania
| | - Otilia Marginean
- Department of Pediatrics, Research Center of Disturbance of Growth and Development on Children-Belive, University of Medicine and Pharmacy “Victor Babes” Timisoara, Timisoara 300041, Romania
- First Clinic of Pediatrics, "Louis Turcanu" Emergency Childen's Hospital, Timisoara 300011, Romania
| | - Gabriela Paduraru
- Department of Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Department of Pediatric Gastroenterology, St Mary Emergency Children's Hospital, Iasi 700309, Romania
| | - Gabriela Stefanescu
- Department of Gastroenterology and Hepatology, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi 700115, Romania
- Department of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, Iasi 700111, Romania
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Chagpar R, Naples R, Siperstein AE. Pancreatic Neuroendocrine Tumors. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:938-948.e4. [DOI: 10.1016/b978-0-323-67293-1.00084-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Szalat A, Oleinikov K, Nahmias A, Meiner V, Ben-Haim S, Atlan K, Lev-Cohain N, Appelbaum L, Gomori M, Mazeh H, Khalaileh A, Pe'er J, Lossos A, Shoshan Y, Grozinsky-Glasberg S, Gross DJ. VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report. Endocr Pract 2020; 26:1131-1142. [PMID: 33471715 DOI: 10.4158/ep-2020-0220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/18/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.
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Affiliation(s)
- Auryan Szalat
- From the Neuroendocrine Tumor Unit, Department of Endocrinology, ENETS Centre of Excellence.
| | - Kira Oleinikov
- From the Neuroendocrine Tumor Unit, Department of Endocrinology, ENETS Centre of Excellence
| | - Avital Nahmias
- From the Neuroendocrine Tumor Unit, Department of Endocrinology, ENETS Centre of Excellence
| | | | | | | | | | | | | | | | | | | | - Alexander Lossos
- the Leslie and Michael Gaffin Center for Neuro-Oncology, Departments of Oncology and Neurology
| | - Yigal Shoshan
- the Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | | | - David J Gross
- From the Neuroendocrine Tumor Unit, Department of Endocrinology, ENETS Centre of Excellence
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Johnston ME, Carter MM, Wilson GC, Ahmad SA, Patel SH. Surgical management of primary pancreatic neuroendocrine tumors. J Gastrointest Oncol 2020; 11:578-589. [PMID: 32655937 PMCID: PMC7340810 DOI: 10.21037/jgo.2019.12.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 12/24/2019] [Indexed: 12/18/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas, and their incidence is increasing. PanNETs are a diverse group of diseases which range from benign to malignant, can be sporadic or associated with genetic mutations, and be functional or nonfunctional. In as much, the treatment and management of PanNETs can vary from a "Wait and See" approach to orthotopic liver transplantation (OLT). Despite this, surgical resection is still the primary treatment modality to achieve cure. This review focuses on the surgical management of PanNETs.
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Affiliation(s)
- Michael E Johnston
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michela M Carter
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Gregory C Wilson
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Syed A Ahmad
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sameer H Patel
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Management of Pancreatic and Duodenal Neuroendocrine Tumors. Updates Surg 2018. [DOI: 10.1007/978-88-470-3955-1_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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15
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Ridtitid W, Al-Haddad MA. Endoscopic Ultrasound Imaging for Diagnosing and Treating Pancreatic Cysts. Gastrointest Endosc Clin N Am 2017; 27:615-642. [PMID: 28918802 DOI: 10.1016/j.giec.2017.06.004] [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] [Indexed: 02/04/2023]
Abstract
Cystic pancreatic lesions are increasingly diagnosed owing to the abundant use of cross-sectional imaging. Given their malignant potential, true pancreatic cysts should be considered for resection or periodic follow-up. Cystic lesions of the pancreas (CLPs) require further evaluation and management. Therefore, it is important to establish a solid diagnosis at the time of detection. Endoscopic ultrasound examination is the imaging modality of choice. Fine needle aspiration provides fluid for cytologic, biochemical, and molecular assays to classify lesions and predict biological behavior. This review provides an overview of the diagnosis and management of various types of commonly encountered true CLPs.
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Affiliation(s)
- Wiriyaporn Ridtitid
- Division of Gastroenterology and Hepatology, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
| | - Mohammad A Al-Haddad
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 550 North University Boulevard, Suite 4100, Indianapolis, IN 46202, USA.
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Sharma A, Mukewar S, Vege SS. Clinical Profile of Pancreatic Cystic Lesions in von Hippel-Lindau Disease: A Series of 48 Patients Seen at a Tertiary Institution. Pancreas 2017; 46:948-952. [PMID: 28697137 DOI: 10.1097/mpa.0000000000000875] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Little is known about the association between pancreatic cystic lesions (PCLs) with von Hippel-Lindau disease (VHLD). In this study, we describe the clinical presentation, type of PCLs, and risk for malignancy in PCLs in VHLD. METHODS Patients given a diagnosis of both VHLD and PCLs were identified from electronic medical records at Mayo Clinic, Rochester, MN, from January 1, 2000, to January 1, 2016. Various demographic, clinical, and radiologic variables were recorded. RESULTS Forty-eight patients were identified with PCLs and VHLD. Most were female (73%), and mean (standard deviation) age was 35.9 (14.2) years. Most (92%) were asymptomatic. PCLs included simple cysts (n = 34, 69%), serous cystadenoma (n = 14, 29%), branch duct intraductal papillary neoplasm (n = 5, 10%), and cystic neuroendocrine tumors (n = 2, 4%). Eight (19%) had mixed PCLs. Cyst aspiration was performed in 8 (53%) patients who underwent EUS, and all were negative for malignancy. At a median follow-up of 84 months, no PCL-associated cancers were seen. CONCLUSIONS Simple cyst is the most common type of PCL found in VHL disease; however, other PCLs were also seen with no malignancy potential. Branch duct intraductal papillary mucinous neoplasms were present in 10%, and this association was not hitherto reported.
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Affiliation(s)
- Ayush Sharma
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Satoh K, Sadowski SM, Dieckmann W, Quezado M, Nilubol N, Kebebew E, Patel D. 18F-FDG PET/CT Volumetric Parameters are Associated with Tumor Grade and Metastasis in Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease. Ann Surg Oncol 2016; 23:714-721. [PMID: 27638678 DOI: 10.1245/s10434-016-5541-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of prognosis. OBJECTIVE The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. METHODS Sixty-two patients with VHL-associated PNETs prospectively underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). MTV, TLG, and maximum standardized uptake value (SUVmax) were measured using a semi-automatic method. Surgically resected PNETs were classified according to 2010 World Health Organization tumor grade classification. MTV, TLG, and SUVmax were analyzed by metastatic disease and tumor grade using the Mann-Whitney test. RESULTS A total of 88 PNETs were identified by CT and 18F-FDG PET/CT, 10 of which were non-FDG-avid. Histologic grading was available for 20 surgical patients. Patients with metastatic PNETs had a higher TLG (median 25.9 vs. 7.7 mean SUV [SUVmean]*mL; p = 0.0092) compared with patients without metastasis, while patients with grade 2 PNETs had a higher MTV (median 6.9 vs. 2.6 mL; p = 0.034) and TLG (median 41.2 vs. 13.1 SUVmean*mL; p = 0.0035) compared with patients with grade 1 PNETs. No difference in tumor size or SUVmax was observed between the groups. CONCLUSIONS Patients with metastatic PNETs have a higher TLG compared with patients without metastasis. Grade 2 PNETs have a higher MTV and TLG compared with grade 1 PNETs. Tumor size and SUVmax were not associated with grade. Volumetric parameters on 18F-FDG PET/CT may be useful in detecting higher grade PNETs with a higher malignant potential that may need surgical intervention.
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Affiliation(s)
- Kei Satoh
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samira M Sadowski
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - William Dieckmann
- PET Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Martha Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Naris Nilubol
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Electron Kebebew
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Dhaval Patel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Findeis-Hosey JJ, McMahon KQ, Findeis SK. Von Hippel-Lindau Disease. J Pediatr Genet 2016; 5:116-23. [PMID: 27617152 PMCID: PMC4918695 DOI: 10.1055/s-0036-1579757] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/10/2015] [Indexed: 01/01/2023]
Abstract
Von Hippel-Lindau disease is an autosomal dominant syndrome which occurs secondary to germline mutations in the VHL tumor suppressor gene, located on chromosome 3. Clinically von Hippel-Lindau disease is characterized by an increased risk of developing simple visceral cysts, most commonly in the pancreas and kidneys, in addition to an increased risk of developing neoplasms, often with clear cell features, in a multitude of organ systems. The most common neoplasms are cerebellar and retinal hemangioblastomas, adrenal pheochromocytomas, clear cell renal cell carcinomas, pancreatic neuroendocrine tumors, pancreatic serous cystadenomas, and endolymphatic sac tumors. These lesions most commonly present during adulthood; however, screening and surveillance for the development of these lesions should begin in the pediatric years for patients with von Hippel-Lindau disease. In this review article, the genetics and most common neoplasms of von Hippel-Lindau disease are reviewed, with an eye towards implications for the pediatric patient.
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Affiliation(s)
- Jennifer J. Findeis-Hosey
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States
| | - Kelly Q. McMahon
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States
| | - Sarah K. Findeis
- The Pennsylvania State University School of Medicine and Dentistry, Hershey, Pennsylvania, United States
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Evaluation and management of pancreatic lesions in patients with von Hippel–Lindau disease. Nat Rev Clin Oncol 2016; 13:537-49. [PMID: 27030075 DOI: 10.1038/nrclinonc.2016.37] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Zou YU, Xu J, Zhang M. Long-term follow-up and clinical course of a rare case of von Hippel-Lindau disease: A case report and review of the literature. Oncol Lett 2016; 11:3273-3278. [PMID: 27123102 PMCID: PMC4841067 DOI: 10.3892/ol.2016.4387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 03/15/2016] [Indexed: 12/12/2022] Open
Abstract
von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic syndrome that increases susceptibility to a variety of benign and malignant neoplasms. It has been well documented that, despite complete excision of initial neoplasms, VHL patients may develop further lesions, in some cases many years after the initial diagnosis. Therefore, the varied and complex clinical manifestations and radiological findings of VHL are of interest. The current study is the first to describe a case of VHL disease with lateral ventricular hemangioblastomas and subsequent pancreatic neuroendocrine tumor, bilateral renal cysts and renal cell carcinoma. The complete clinical course, radiological findings, including ultrasound, computed tomography and magnetic resonance imaging (MRI), and associated pathological findings are presented. Radiology is critical in the accurate diagnosis, treatment and follow-up of VHL. Continuous close and long-term follow-up with radiological examination, particularly MRI, must be conducted in patients with VHL disease. To the best of our knowledge, the current case is a rare phenomenon that has not yet been described in the English literature.
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Affiliation(s)
- Y U Zou
- Department of Radiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Jingjing Xu
- Department of Radiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Minming Zhang
- Department of Radiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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Ayloo S, Molinari M. Pancreatic manifestations in von Hippel-Lindau disease: A case report. Int J Surg Case Rep 2016; 21:70-2. [PMID: 26945487 DOI: 10.1016/j.ijscr.2016.02.031] [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: 10/20/2015] [Revised: 02/18/2016] [Accepted: 02/19/2016] [Indexed: 10/22/2022] Open
Abstract
INTRODUCTION Pancreatic manifestations in Von Hippel-Lindau (VHL) disease can present as a multitude of forms, and their management can be challenging. PRESENTATION OF THE CASE A 66-year-old woman presented with increasing abdominal girth without other associated symptoms of nausea, vomiting, abdominal pain, weight-loss, and jaundice. Her medical and surgical histories were significant for type II diabetes, cerebral tumor resection, bilateral nephrectomies, and laser photocoagulation of retinal hemangiomas. Computed tomography (CT) of the abdomen showed a massive multi-cystic lesion in the pancreas and the patient was referred to our hepatopancreatic biliary center. DISCUSSION The findings on the subsequent cross-sectional MRI imaging signified pancreatic manifestations in VHL disease. CONCLUSION The management of VHL disease-associated benign pancreatic cystic lesions involves interval monitoring with cross-sectional imaging for malignant changes/development.
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Affiliation(s)
- Subhashini Ayloo
- Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Michele Molinari
- Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
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Park TY, Lee SK. In response to 'Pancreatic neuroendocrine tumors in von Hippel-Lindau disease', by Louis de Mestier & Pascal Hammel. Scand J Gastroenterol 2015; 50:1056-7. [PMID: 25794337 DOI: 10.3109/00365521.2015.1025239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Tae Young Park
- Department of Internal Medicine, Division of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea
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Park TY, Lee SK, Park JS, Oh D, Song TJ, Park DH, Lee SS, Seo DW, Kim MH. Clinical features of pancreatic involvement in von Hippel-Lindau disease: a retrospective study of 55 cases in a single center. Scand J Gastroenterol 2015; 50:360-7. [PMID: 25562111 DOI: 10.3109/00365521.2014.992364] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system and visceral organs. In this study, we describe clinical features of pancreatic involvement in VHL disease, of which there have been few reported studies to date. METHODS We reviewed medical records of 63 VHL patients, diagnosed at Asan Medical Center between January 1995 and December 2013. Demographic, genetic, and radiologic features, and the clinical course of VHL patients with pancreatic involvement were retrospectively analyzed. RESULTS Among the 63 VHL patients, 55 (87.4%) had VHL-associated pancreatic lesions (male: female, 31:24; median age at onset, 33 years; range, 12-67 years). These presented as single simple cysts (n = 5, 9.1%), multiple simple cysts (n = 14, 25.5%), serous cystadenoma (n = 29, 52.7%), or neuroendocrine tumors (NETs) (n = 17, 30.9%). Genetic tests were performed on 35 of the 55 patients (63.6%) and VHL gene mutations were observed in 28 of them (80%). Of the 55 patients, 11 received surgical treatment, 2 received endoscopic ultrasonography-guided ethanol ablation therapy as local treatment for NET, and 42 patients were followed regularly without intervention (20%, 3.6%, and 76.4%, respectively). CONCLUSION Pancreatic involvement in VHL disease is common, with a prevalence of 87.4%. Serial screening imaging studies for the early detection of VHL-associated NET are necessary in individuals at risk of VHL disease. A large-scale epidemiological study of VHL disease is needed to examine the natural course of the disease and the prognosis for pancreatic involvement.
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Affiliation(s)
- Tae Young Park
- Department of Internal Medicine, Division of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea
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Schmid S, Gillessen S, Binet I, Brändle M, Engeler D, Greiner J, Hader C, Heinimann K, Kloos P, Krek W, Krull I, Stoeckli SJ, Sulz MC, van Leyen K, Weber J, Rothermundt C, Hundsberger T. Management of von hippel-lindau disease: an interdisciplinary review. Oncol Res Treat 2014; 37:761-71. [PMID: 25531723 DOI: 10.1159/000369362] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 10/22/2014] [Indexed: 12/11/2022]
Abstract
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumour predisposition syndrome with an incidence of 1:36,000 newborns, the estimated prevalence in Europe is about 1-9/100,000. It is associated with an increased risk of developing various benign and malignant tumours, thus affecting multiple organs at different time points in the life of a patient. Disease severity and diversity as well as age at first symptoms vary considerably, and diagnostic delay due to failure of recognition is a relevant issue. The identification of a disease-causing VHL germline mutation subsequently allows family members at risk to undergo predictive genetic testing after genetic counselling. Clinical management of patients and families should optimally be offered as an interdisciplinary approach. Prophylactic screening programs are a cornerstone of care, and have markedly improved median overall survival of affected patients. The aim of this review is to give an overview of the heterogeneous manifestations of the VHL syndrome and to highlight the diagnostic and therapeutic challenges characteristic for this orphan disease. A comprehensive update of the underlying genetic and molecular principles is additionally provided. We also describe how the St. Gallen VHL multidisciplinary group is organised as an example of interdisciplinary cooperation in a tertiary hospital in Switzerland.
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Affiliation(s)
- Sabine Schmid
- Division of Haematology and Oncology, Cantonal Hospital St. Gallen, Switzerland
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Liang X, Hu F, Ma Z, Li N, Chen Y, Zhang J. Obstructive jaundice due to von Hippel-Lindau disease-associated pancreatic lesions: A case report. Oncol Lett 2014; 8:446-448. [PMID: 24959293 PMCID: PMC4063595 DOI: 10.3892/ol.2014.2098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 04/04/2014] [Indexed: 11/24/2022] Open
Abstract
von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic syndrome that may lead to pancreatic masses and obstructive jaundice. The present study describes the case of a 20-year-old male who suffered from obstructive jaundice due to VHL disease-associated pancreatic lesions whose primary symptom was dizziness, followed by the appearance of jaundice. Since the excision of the renal cell carcinomas was not possible, the patient also refused surgery to resect the pancreatic head mass. A metallic stent was placed at the stenosis site of the common bile duct. Percutaneous transhepatic cholangiography (PTCD) surgery was later performed following complete blockage of the stent, however, to date, the patient continues to rely on PTCD. VHL disease-associated pancreatic lesions are rarely the direct cause of mortality, however, obstructive jaundice due to these lesions may be lethal. Therefore, the treatment of patients with incurable renal or central nervous system tumors and obstructive jaundice presents a problem.
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Affiliation(s)
- Xiaoyu Liang
- Department of General Surgery, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Fanguo Hu
- Department of General Surgery, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Zhicheng Ma
- Department of General Surgery, Tianjin First Center Hospital, Tianjin 300192, P.R. China
| | - Nan Li
- Department of General Surgery, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Yan Chen
- Department of General Surgery, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Jie Zhang
- Department of General Surgery, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
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Igarashi H, Ito T, Nishimori I, Tamura K, Yamasaki I, Tanaka M, Shuin T. Pancreatic involvement in Japanese patients with von Hippel-Lindau disease: results of a nationwide survey. J Gastroenterol 2014; 49:511-6. [PMID: 23543325 DOI: 10.1007/s00535-013-0794-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 03/14/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND The frequency and prognosis of pancreatic endocrine tumors (PNET)/pancreatic cystic tumors (PCT) in Japanese patients with von Hippel-Lindau disease (VHL) are still open to question. METHODS We conducted the first nationwide epidemiological study of VHL disease in Japan to elucidate this question. Data on 377 VHL patients (PNET, 53; PCT, 152) were reported, and then their clinical characteristics were analyzed. RESULTS PNET was found in 14.1 % and PCT in 40.3 %; 4.5 % had both. The onset of PNET and PCT mostly occurred at 30-39 years of age (median ages, 34 and 33 years, respectively). Metastasis was observed in 7.5 % of PNET patients at diagnosis, and 64.2 % underwent surgery including enucleation, partial and total pancreatectomy, and bypass surgery. Two patients received non-surgical therapies. No PNET-related deaths were observed. In PCT patients, no metastasis was observed at diagnosis, and 9.2 % underwent surgery or drainage. According to the classification system without or with adrenal pheochromocytoma, the VHL patients studied herein were subdivided into 313 (83 %) with VHL type 1 and 64 (17 %) with VHL type 2; 29 (9.3 %) and 24 (37.5 %) patients had PNET with VHL type 1 and 2, suggesting that patients with VHL type 2 were significantly more related to PNET than those with VHL type 1 (P < 0.01). CONCLUSIONS This study showed no significant difference in the epidemiology of pancreatic involvement between Japanese and non-Japanese VHL patients. Concerning the prognosis, follow-up study is needed.
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Affiliation(s)
- Hisato Igarashi
- Department of Medicine and Bioreguratory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Chemometric evaluation of urinary steroid hormone levels as potential biomarkers of neuroendocrine tumors. Molecules 2013; 18:12857-76. [PMID: 24135941 PMCID: PMC6269673 DOI: 10.3390/molecules181012857] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/25/2013] [Accepted: 10/10/2013] [Indexed: 01/08/2023] Open
Abstract
Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL−1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1–300 ng mL−1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed.
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Addeo A, Bini R, Viora T, Bonaccorsi L, Leli R. Von Hippel-Lindau and myotonic dystrophy of Steinert along with pancreatic neuroendocrine tumor and renal clear cell carcinomal neoplasm: Case report and review of the literature. Int J Surg Case Rep 2013; 4:648-50. [PMID: 23774333 DOI: 10.1016/j.ijscr.2013.03.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 03/04/2013] [Accepted: 03/11/2013] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION Myotonic dystrophy of Steinert, DM1, is the most common adult muscular dystrophy and generally is not associated to development on multiple site neoplasm. Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome that is associated to tumors such as hemangioblastoma of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. No data exist in literature describing the coexistence of both DM1 and VHL. PRESENTATION OF CASE Herein we report a case of renal and pancreatic neoplasm in a young adult female affected by DM1 and VHL simultaneously. DISCUSSION DM1 is due to an unstable trinucleotide (CTG) expansion in the 30 antranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, located on chromosome 19q13.3. Several molecular mechanisms thought to be determining the classical DM phenotype have been shown. VHL disease is characterized by marked phenotypic variability and the most common tumors are hemangioblastomas of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. The pancreatic manifestations seen in patients with VHL disease are divided into 2 categories: pancreatic neuroendocrine tumor (PNET) as solid tumors, and cystic lesions, including a simple cyst and serous cystadenoma. The surgical approach for these cistic lesions is to consider as golden standard. Blansfield has proposed 3 criteria to predict metastatic disease of PNET in patients with VHL disease: (1) tumor size greater than or equal to 3cm; (2) presence of a mutation in exon 3; and (3) tumor doubling time less than 500d. If the patient has none of these criteria the patient could be followed with physical examination and radiological surveillance on a 2/3 years base.(4) If the patient has 1 criterion, the patient should be followed more closely every 6 months to 1 year. If the patient has 2 or 3 criteria, the patient should be considered for surgery given the high risk of future malignancy. Our patient owned only one criterion but in presence of a second malignant tumor. Our hypothesis for this rare findings is that both DM and VHL might be derived from genetic aberration and these might be linked to a major cancer susceptibility. As far as we know this is the first confirmed case of RCC and neuroendocrine pancreatic cancer occurring concurrently with VHL and, at the same time, DM1. According to this case report and the literature data a VHL should be ruled out in the presence of RCC presenting along with pancreatic cysts/tumor. CONCLUSION As far as we know this is the first confirmed case of RCC and neuroendocrine pancreatic cancer occurring concurrently with VHL and, at the same time, DM1. Our hypothesis for the unusual findings is that both DM and VHL derived from genetic aberration and these are linked to a major cancer susceptibility.
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Affiliation(s)
- A Addeo
- Department of Oncology, United Lincolnshire Hospital Trust, Lincoln, UK.
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Vortmeyer AO, Falke EA, Gläsker S, Li J, Oldfield EH. Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms. Acta Neuropathol 2013; 125:333-50. [PMID: 23400300 DOI: 10.1007/s00401-013-1091-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Revised: 01/25/2013] [Accepted: 01/26/2013] [Indexed: 02/06/2023]
Abstract
Patients with von Hippel-Lindau disease carry a germline mutation of the Von Hippel-Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.
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Affiliation(s)
- Alexander O Vortmeyer
- Department of Pathology, Yale University School of Medicine, 416A Lauder Hall 310 Cedar Street, New Haven, CT 06520, USA.
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Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. CHINESE JOURNAL OF CANCER 2012; 32:312-24. [PMID: 23237225 PMCID: PMC3845620 DOI: 10.5732/cjc.012.10295] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.
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Affiliation(s)
- Cynthia Ro
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Abstract
Pancreatic incidentalomas are defined as asymptomatic pancreatic lesions, discovered incidentally by imaging for an unrelated indication. They are being discovered with increasing frequency as the use of high quality cross sectional imaging is becoming more widespread. These lesions cover a wide spectrum of pathology from benign simple cysts through potentially malignant lesions such as intraductal papillary mucinous neoplasia, to frankly malignant adenocarcinoma. In this article we outline the incidence, imaging characteristics and natural history of the various incidental lesions with emphasis to neuroendocrine tumors. A diagnostic approach is also suggested, including the rational use of further imaging, serum biochemistry and the utility of ultrasound guided aspiration of cyst fluid if present. We examine several proposed classification systems and discuss the role of surgery, surveillance and prognosis.
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Affiliation(s)
- Xeily Zárate
- Department of Surgery, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico
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Sakorafas GH, Tsiotos GG, Korkolis D, Smyrniotis V. Individuals at high-risk for pancreatic cancer development: management options and the role of surgery. Surg Oncol 2012; 21:e49-58. [PMID: 22244849 DOI: 10.1016/j.suronc.2011.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 12/09/2011] [Accepted: 12/13/2011] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer (PC) is a highly lethal disease. Despite advances regarding the safety and long-term results of pancreatectomies, early diagnosis remains the only hope for cure. This necessitates the implementation of an intensive screening program (based mainly on modern imaging), which - given the incidence of PC - is not cost effective for the general population. However, this screening program is recommended for individuals at high-risk for PC development. Indications for screening include the following three clinical settings: hereditary cancer predisposition syndromes associated with PC, hereditary pancreatitis and familial pancreatic cancer syndrome. The aim of this strategy is to identify pre-invasive (precursor) lesions, which are curable. Surgery is recommended in the presence of recognizable lesion on imaging lesions. Partial (anatomic) pancreatectomy - depending on the location of the suspicious lesion - is the most widely accepted type of surgical intervention in this setting; occasionally, however, total pancreatectomy may be required, in carefully selected patients. Despite that experience still remains limited, there is evidence that this aggressive strategy allows early detection of neoplastic lesions, thereby improving the effectiveness of surgery and prognosis.
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Affiliation(s)
- George H Sakorafas
- Department of Surgery, Athens University, Medical School, Arkadias 19-21, Athens, Greece.
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Nielsen SM, Rubinstein WS, Thull DL, Armstrong MJ, Feingold E, Yip L, Tisherman SA, Carty SE. Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A. Fam Cancer 2011; 10:701-7. [PMID: 21713522 DOI: 10.1007/s10689-011-9465-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.
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Affiliation(s)
- Sarah M Nielsen
- Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA
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