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1
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Sun BL, Ding H, Sun X. Histopathologic and genetic distinction of well-differentiated grade 3 neuroendocrine tumor versus poorly-differentiated neuroendocrine carcinoma in high-grade neuroendocrine neoplasms. Am J Clin Pathol 2025:aqaf013. [PMID: 40037757 DOI: 10.1093/ajcp/aqaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/04/2025] [Indexed: 03/06/2025] Open
Abstract
OBJECTIVES The classification of neuroendocrine neoplasms has evolved significantly. In the current World Health Organization (WHO) classification, well-differentiated grade 3 neuroendocrine tumors (G3-NETs) are distinguished from poorly-differentiated neuroendocrine carcinomas (NECs) based on morphology despite using the same proliferation indices, which poses diagnostic challenges. This review aims to assist pathologists in making an accurate diagnosis, which is crucial for patient management as G3-NETs and NECs have different prognoses and chemotherapy responses. METHODS A literature review and meta-analyses were conducted to summarize current knowledge of G3-NETs and NECs, focusing on histopathologic and genetic characteristics. RESULTS Grade 3 neuroendocrine tumors and NECs are distinct entities with differences in histopathology, genetics, and clinical presentations. Grade 3 neuroendocrine tumors have a lower Ki-67 proliferation index and tumor mutational burden compared to NECs. Distinct gene mutations and pathways have been identified in G3-NETs and NECs, offering potential for developing a diagnostic gene panel. The 2022 WHO classification recognizes the use of immunohistochemistry for somatostatin receptors 2/5, TP53, Rb, Menin, P27, ATRX, and DAXX to distinguish G3-NETs and NECs. In particular, TP53 and ATRX immunohistochemistry may be useful in routine diagnostics. CONCLUSIONS Specific immunohistochemistry and genetic tests should be developed and incorporated into the classification to reliably distinguish G3-NETs from NECs.
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Affiliation(s)
- Belinda L Sun
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Hongxu Ding
- College of Pharmacy, University of Arizona, Tucson, AZ, United States
| | - Xiaoguang Sun
- Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ, United States
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2
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Zhang XY, Yu JF, Li Y, Li P. Periampullary duodenal neuroendocrine tumor in a patient with neurofibromatosis-1: A case report. World J Clin Oncol 2024; 15:1222-1231. [PMID: 39351464 PMCID: PMC11438844 DOI: 10.5306/wjco.v15.i9.1222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Patients with neurofibromatosis type 1 (NF1) are exposed to a higher risk of developing neuroendocrine tumors (NETs). Periampullary neuroendocrine neoplasms (NENs) in NF1 patients primarily affect the duodenum and periampullary region. CASE SUMMARY A 50-year-old male patient was admitted to our hospital due to progressive skin and scleral yellowing for over 6 months. An abdominal contrast-enhanced computed tomography scan revealed a tumor in the periampullary region, which measured 1.2 cm × 1.4 cm in size and showed a progressive enhancement. Magnetic resonance cholangiopancreatography indicated the dilation of intrahepatic and extrahepatic bile ducts. The patient was diagnosed with an ampullary tumor with the possibility of malignancy. A Whipple procedure was performed. Microscopically, the duodenum tumor was found to invade the mucosa, sphincter, and muscular layer of the duodenal papilla. Histologic hematoxylin and eosin staining confirmed the presence of duodenal G1 NET. Subsequently, a bibliometric analysis was performed to evaluate the state of NEN research. Publications about periampullary NENs showed an annual increase, with most of them focusing on the treatment and diagnosis of NENs. CONCLUSION This article reported a case of periampullary duodenal NET in a patient with NF1, and a bibliometric analysis was conducted.
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Affiliation(s)
- Xiao-Yu Zhang
- The First Central Hospital Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Jian-Fa Yu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Yang Li
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Ping Li
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People’s Hospital, Tianjin 300192, China
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3
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Lalvani S, Brown RM. Neurofibromatosis Type 1: Optimizing Management with a Multidisciplinary Approach. J Multidiscip Healthc 2024; 17:1803-1817. [PMID: 38680880 PMCID: PMC11055545 DOI: 10.2147/jmdh.s362791] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 04/09/2024] [Indexed: 05/01/2024] Open
Abstract
Neurofibromatosis Type I (NF1) is a complex genetic condition that affects multiple organ systems and presents a unique set of challenges for clinicians in its management. NF1 is a tumor predisposition syndrome that primarily affect the peripheral and central nervous systems via the impact of haploinsufficiency upon neural crest lineage cells including Schwann cells, melanocytes, fibroblasts, etc. NF1 can further lead to pathology of the skin, bones, visual system, and cardiovascular system, all of which can drastically reduce a patient's quality of life (QOL). This review provides a comprehensive examination of the many specialties required for the care of patients with Neurofibromatosis Type 1 (NF1). We delve into the pathogenesis and clinical presentation of NF1, highlighting its diverse manifestations and the challenges they pose in management. The review underscores the importance of a multidisciplinary approach to NF1, emphasizing how such an approach can significantly improve patient outcomes and overall QOL. Central to this approach is the role of the NF expert, who guides a multidisciplinary team (MDT) comprising healthcare professionals from many areas of expertise. The MDT collaboratively addresses the multifaceted needs of NF1 patients, ensuring comprehensive and personalized care. This review highlights the need for further investigation to optimize the workflow for NF1 patients in an MDT setting, and to improve implementation and efficacy.
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Affiliation(s)
- Shaan Lalvani
- Department of Neurology, The Mount Sinai Hospital, New York, NY, USA
| | - Rebecca M Brown
- Department of Neurology, The Mount Sinai Hospital, New York, NY, USA
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Fujiwara S, Koyamada N, Miyazawa K, Saiki Y, Horii A, Miyazaki S. Duodenal neuroendocrine tumor after bilateral breast cancer with type 1 neurofibromatosis: a case report. Surg Case Rep 2024; 10:28. [PMID: 38282102 PMCID: PMC10822824 DOI: 10.1186/s40792-024-01827-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 01/19/2024] [Indexed: 01/30/2024] Open
Abstract
BACKGROUND Young women with NF1 are at a high risk of developing breast cancer. Although they are at risk for abdominal tumors, such as gastrointestinal stromal tumors and neuroendocrine tumors, follow-up strategies for other tumors after breast cancer have not yet been established. Here, we present a case of duodenal neuroendocrine tumor found during follow-up after bilateral mastectomy for breast cancer with type 1 neurofibromatosis (NF1), for which pancreaticoduodenectomy (PD) and lymphadenectomy were performed. CASE PRESENTATION A 46-year-old woman with NF1 was referred to our hospital for treatment of a duodenal submucosal tumor. Her previous operative history included bilateral mastectomy for breast cancer: right total mastectomy and left partial mastectomy performed 9 and 5 years ago, respectively. Her daughter was confirmed to have NF1, but her parents were unclear. Although she had no recurrence or symptoms during the follow-up for her breast cancer, she wished to undergo 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) for systemic screening. FDG-PET demonstrated FDG accumulation in the duodenal tumor with a maximum standardized uptake value of 5.78. Endoscopy revealed a 20-mm-diameter tumor in the second duodenal portion, and endoscopic biopsy suggested a NET G1. We performed PD and lymphadenectomy for complete. She was doing well without recurrence and was followed up with PET tomography-computed tomography. CONCLUSIONS Early detection of gastrointestinal tumors is difficult, because most of them are asymptomatic. Gastrointestinal screening is important for patients with NF1, and PD with lymphadenectomy is feasible for managing duodenal neuroendocrine tumors, depending on their size.
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Affiliation(s)
- Sho Fujiwara
- Department of Surgery, Iwate Prefectural Chubu Hospital, 17-10 Murasakino, Kitakami, , Iwate, 024-8507, Japan.
- Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Miyagi, 980-8575, Japan.
- Department of Surgery, Columbia University Irving Medical Center, 622 West 168th St, New York, NY, 10032, USA.
| | - Nozomi Koyamada
- Department of Surgery, Iwate Prefectural Chubu Hospital, 17-10 Murasakino, Kitakami, , Iwate, 024-8507, Japan
| | - Koji Miyazawa
- Department of Surgery, Iwate Prefectural Chubu Hospital, 17-10 Murasakino, Kitakami, , Iwate, 024-8507, Japan
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-0872, Japan
| | - Yuriko Saiki
- Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Miyagi, 980-8575, Japan
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
- Office of Medical Education, Tohoku University School of Medicine, Sendai, Miyagi, 980-0872, Japan
| | - Akira Horii
- Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Shukichi Miyazaki
- Department of Surgery, Iwate Prefectural Chubu Hospital, 17-10 Murasakino, Kitakami, , Iwate, 024-8507, Japan
- Department of Surgery, South Miyagi Medical Center, Ogawara, Shibata, Miyagi, 989-1253, Japan
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Araujo-Castro M. Indications for genetic study in gastro-entero-pancreatic and thoracic neuroendocrine tumors. ENDOCRINOL DIAB NUTR 2023; 70 Suppl 1:63-73. [PMID: 36396595 DOI: 10.1016/j.endien.2022.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 04/03/2022] [Indexed: 11/16/2022]
Abstract
Gastro-entero-pancreatic (GEP-NET) and thoracic neuroendocrine tumours (NETs) are one of the most heritable groups of neoplasms in the body, being multiple endocrine neoplasia syndrome type 1 (MEN1), the genetic syndrome most frequently associated with this type of tumours. Moreover, Von Hippel Lindau syndrome, tuberous sclerosis, type 4 multiple neoplasia syndrome, and type 1 neurofibromatosis are associated with an increased risk of developing GEP-NETs. Another important aspect in GEP-NETs and thoracic NETs is the knowledge of the molecular background since the molecular profile of these tumours may have implications in the prognosis and in the response to specific treatments. This review summarizes the main indications for performing a genetic study in patients with GEP-NETs and thoracic NETs, and the methods used to carry it out. Moreover, it offers a description of the main hereditary syndromes associated with these NETs and their molecular background, as well as the clinical implications of the molecular profile.
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Affiliation(s)
- Marta Araujo-Castro
- Unidad de Neuroendocrinología, Departamento de Endocrinología y Nutrición, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Invesitigación Sanitaria (IRYCIS), Madrid, Spain; Departamento de Medicina, Universidad de Alcalá, Madrid, Spain.
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Ruggeri RM, Benevento E, De Cicco F, Fazzalari B, Guadagno E, Hasballa I, Tarsitano MG, Isidori AM, Colao A, Faggiano A. Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies. J Endocrinol Invest 2023; 46:213-234. [PMID: 36038743 DOI: 10.1007/s40618-022-01905-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/16/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
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Affiliation(s)
- R M Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico "Gaetano Martino" University Hospital, 98125, Messina, Italy.
| | - E Benevento
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - F De Cicco
- SSD Endocrine Disease and Diabetology, ASL TO3, Pinerolo, TO, Italy
| | - B Fazzalari
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - E Guadagno
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - I Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - M G Tarsitano
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - A M Isidori
- Gruppo NETTARE, Policlinico Umberto I, Università Sapienza, Rome, Italy
| | - A Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
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7
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Mohindroo C, McAllister F, De Jesus-Acosta A. Genetics of Pancreatic Neuroendocrine Tumors. Hematol Oncol Clin North Am 2022; 36:1033-1051. [PMID: 36154786 DOI: 10.1016/j.hoc.2022.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1, 1650 Orleans Street, CRB1 Rm 409, Baltimore, MD 21287.
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8
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Matas-Nadal C, Soria X, Gonzalez-Farré M, Baradad M, Tuset N, Rius Riu F, González M, Gatius S, Vilardell F, López-Ortega R, Martí RM. Abdominal tumors in patients with neurofibromatosis type I: Genotype-phenotype relationships. Eur J Med Genet 2022; 65:104609. [PMID: 36096471 DOI: 10.1016/j.ejmg.2022.104609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 08/15/2022] [Accepted: 09/06/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumors have been detected in 25% of the necropsies performed on NF1 patients, but have been reported only in 7% of NF1 patients in the largest series. Such data imply an important gap between the true presence of tumors and those diagnosed. Few genotype-phenotype relationships have been described but to date none referring to abdominal tumors. OBJECTIVES Evaluate retrospectively the efficacy of a regular and proactive follow-up of NF1 patients to early diagnose abdominal tumors and report their mutations. METHODS Cohort study performed between 2010 and 2020, with 43 NF1 adult patients followed at our Dermatology department. RESULTS Eight abdominal tumors were diagnosed in six patients, meaning that 14% of the followed patients developed an abdominal tumor. Five patients (83%) were asymptomatic. Five (83.3%) had a family history of NF1 with abdominal tumors (patients 1,2 and 3,4,5 were relatives). CONCLUSIONS Although currently gastrointestinal routine screening investigations for asymptomatic patients are not recommended in the guidelines, the family aggregation in our series suggests it should be considered a close follow-up of the relatives of a patient with an NF1-related abdominal tumor. Also, for the first time, two mutations [c.2041C > T (p.Arg681Ter) and c.4537C > T (p.Arg1513*)] have been associated with family aggregation of abdominal tumors in NF1 patients.
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Affiliation(s)
- C Matas-Nadal
- Dermatology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; IRB Lleida, Spain.
| | - X Soria
- Dermatology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; IRB Lleida, Spain
| | - M Gonzalez-Farré
- Dermatology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; University of Lleida, Spain
| | - M Baradad
- Dermatology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; IRB Lleida, Spain; University of Lleida, Spain
| | - N Tuset
- Medical Oncology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - F Rius Riu
- Endocrinology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - M González
- General Surgery Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - S Gatius
- IRB Lleida, Spain; Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - F Vilardell
- IRB Lleida, Spain; Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, Lleida, Spain; Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - R López-Ortega
- Laboratori Clínic ICS Lleida, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - R M Martí
- Dermatology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; IRB Lleida, Spain; Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; University of Lleida, Spain
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9
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Indicaciones de estudio genético en los tumores neuroendocrinos gastro-entero-pancreáticos y torácicos. ENDOCRINOL DIAB NUTR 2022. [DOI: 10.1016/j.endinu.2022.04.004] [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: 11/22/2022]
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10
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Abstract
Neurofibromatosis type (NF-1) is an autosomal dominant disorder characterized predominantly by neurocutaneous manifestations. Involvement of the gastrointestinal tract is uncommon but is associated with a significant risk of malignancy. There are a handful of case reports linking NF-1 with pancreatic neuroendocrine tumors; these include gastrin-secreting variants with the attendant Zollinger-Ellison syndrome. We present the case of a 52-year-old lady who presented with recurrent peptic ulceration and diarrhea. Serum gastrin levels were elevated and magnetic resonance imaging demonstrated the presence of a pancreatic lesion with multiple liver metastases. The lesion was moderately fludeoxyglucose avid on positron emission tomography-computed tomography. Endoscopic ultrasonography-guided sampling revealed the presence of synaptophysin positive neuroendocrine cells with positive gastrin immunostaining. A conservative approach was adopted, and the patient's symptoms improved on proton pump inhibitors. Zollinger-Ellison syndrome is an important condition, which should be kept in mind in the patient with NF-1 who presents with recurrent peptic ulceration and diarrhea. The emerging association between these 2 conditions is being examined on a cellular and immunohistochemical level.
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11
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Pancreatic Neuroendocrine Neoplasms: Updates on Genomic Changes in Inherited Tumour Syndromes and Sporadic Tumours Based on WHO Classification. Crit Rev Oncol Hematol 2022; 172:103648. [PMID: 35248713 DOI: 10.1016/j.critrevonc.2022.103648] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 02/19/2022] [Accepted: 02/28/2022] [Indexed: 12/16/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are the neuroendocrine neoplasms with greatest rate of increase in incidence. Approximately 10% of PanNENs arise as inherited tumour syndromes which include multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 4, von Hippel-Lindau syndrome, neurofibromatosis type1, tuberous sclerosis complex 1/2, Cowden syndrome, and Glucagon cell hyperplasia and neoplasia as well as familial insulinomatosis. In sporadic PanNENs, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes are associated with development and progression in pancreatic neuroendocrine tumours. The other changes are in VEGF pathway, Notch pathway, germline mutations in MUTYH, CHEK2, BRCA2, PHLDA3 as well as other genetic alterations. On the other hand, pancreatic neuroendocrine carcinomas share similar genetic alterations with ductal adenocarcinomas, e.g., TP53, RB1 or KRAS. In addition, microRNA and changes in immune microenvironment were noted in PanNENs. Updates on these genetic knowledges contribute to the development of management strategies for patients with PanNENs.
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12
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Nosé V, Gill A, Teijeiro JMC, Perren A, Erickson L. Overview of the 2022 WHO Classification of Familial Endocrine Tumor Syndromes. Endocr Pathol 2022; 33:197-227. [PMID: 35285003 DOI: 10.1007/s12022-022-09705-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2022] [Indexed: 12/16/2022]
Abstract
This review of the familial tumor syndromes involving the endocrine organs is focused on discussing the main updates on the upcoming fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. This review emphasizes updates on histopathological and molecular genetics aspects of the most important syndromes involving the endocrine organs. We describe the newly defined Familial Cancer Syndromes as MAFA-related, MEN4, and MEN5 as well as the newly reported pathological findings in DICER1 syndrome. We also describe the updates done at the new WHO on the syndromic and non-syndromic familial thyroid diseases. We emphasize the problem of diagnostic criteria, mention the new genes that are possibly involved in this group, and at the same time, touching upon the role of some immunohistochemical studies that could support the diagnosis of some of these conditions. As pathologists play an important role in identifying tumors within a familial cancer syndrome, we highlight the most important clues for raising the suspicious of a syndrome. Finally, we highlight the challenges in defining these entities as well as determining their clinical outcome in comparison with sporadic tumors. Instead of the usual subject review, we present the highlights of the updates on familial cancer syndromes by answering select questions relevant to practicing pathologists.
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Affiliation(s)
- Vania Nosé
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
| | | | - José Manuel Cameselle Teijeiro
- Clinical University Hospital Santiago de Compostela and Medical Faculty, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
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13
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Frey S, Mirallié E, Le Bras M, Regenet N. What Are the Place and Modalities of Surgical Management for Pancreatic Neuroendocrine Neoplasms? A Narrative Review. Cancers (Basel) 2021; 13:5954. [PMID: 34885063 PMCID: PMC8656750 DOI: 10.3390/cancers13235954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, although surgical treatment has long been suggested as the only treatment of pancreatic neuroendocrine neoplasms, its modalities are an evolving landscape. For selected patients (small, localized, non-functional panNENs), a "wait and see" strategy is suggested, as it is in the setting of multiple neuroendocrine neoplasia type 1, but the accurate size cut-off remains to be established. Parenchyma-sparring pancreatectomy, aiming to limit pancreatic insufficiency, are also emerging procedures, which place beyond the treatment of insulinomas and small non-functional panNENs (in association with lymph node picking) remains to be clarified. Furthermore, giving the fact that the liver is generally the only metastatic site, surgery keeps a place of choice alongside medical therapies in the treatment of metastatic disease, but its modalities and extensions are still a matter of debate. This narrative review aims to describe the current recommended surgical management for pancreatic NENs and controversies in light of the actual recommendations and recent literature.
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Affiliation(s)
- Samuel Frey
- Université de Nantes, Quai de Tourville, 44000 Nantes, France; (S.F.); (E.M.)
- L’institut du Thorax, Université de Nantes, CNRS, INSERM, CHU de Nantes, 44000 Nantes, France
- Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l’Appareil Digestif, CHU de Nantes, 44000 Nantes, France
| | - Eric Mirallié
- Université de Nantes, Quai de Tourville, 44000 Nantes, France; (S.F.); (E.M.)
- Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l’Appareil Digestif, CHU de Nantes, 44000 Nantes, France
| | - Maëlle Le Bras
- Endocrinologie, Diabétologie et Nutrition, L’institut du Thorax, CHU Nantes, 44000 Nantes, France;
| | - Nicolas Regenet
- Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l’Appareil Digestif, CHU de Nantes, 44000 Nantes, France
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14
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Chevalier B, Dupuis H, Jannin A, Lemaitre M, Do Cao C, Cardot-Bauters C, Espiard S, Vantyghem MC. Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations. Front Endocrinol (Lausanne) 2021; 12:678869. [PMID: 34025587 PMCID: PMC8134657 DOI: 10.3389/fendo.2021.678869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/15/2021] [Indexed: 11/13/2022] Open
Abstract
Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.
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Affiliation(s)
- Benjamin Chevalier
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
- University of Lille, Lille, France
| | - Hippolyte Dupuis
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
| | - Arnaud Jannin
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
- University of Lille, Lille, France
| | - Madleen Lemaitre
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
- University of Lille, Lille, France
| | - Christine Do Cao
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
| | - Catherine Cardot-Bauters
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
- University of Lille, Lille, France
- INSERM U1190, European Genomic Institute for Diabetes, Lille, France
| | - Marie Christine Vantyghem
- Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital, Lille, France
- University of Lille, Lille, France
- INSERM U1190, European Genomic Institute for Diabetes, Lille, France
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15
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Makita N, Kayahara M, Kano S, Munemoto M, Yagi Y, Onishi I, Kawashima A. A Case of Duodenal Neuroendocrine Tumor Accompanied by Gastrointestinal Stromal Tumors in Type 1 Neurofibromatosis Complicated by Life-Threatening Vascular Lesions. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e927562. [PMID: 33424018 PMCID: PMC7810287 DOI: 10.12659/ajcr.927562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Patient: Female, 45-year-old Final Diagnosis: Neuroendocrine tumor Symptoms: Bleeding Medication:— Clinical Procedure: Pancreaticoduodenectomy Specialty: General and Internal Medicine
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Affiliation(s)
- Naoki Makita
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Masato Kayahara
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Shunsuke Kano
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Masayoshi Munemoto
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Yasumichi Yagi
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Ichiro Onishi
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Atsuhiro Kawashima
- Department of Medical Laboratory, National Hospital Organization Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
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16
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Hissong E, Yantiss RK. Intraoperative Evaluation of the Gastrointestinal Tract. FROZEN SECTION PATHOLOGY 2021:15-48. [DOI: 10.1007/978-3-030-71308-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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17
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18
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Wang Y, Call J. Mutational Testing in Gastrointestinal Stromal Tumor. Curr Cancer Drug Targets 2020; 19:688-697. [PMID: 30914028 DOI: 10.2174/1568009619666190326123945] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/05/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
Targeted treatment has become a major modality in cancer management. Such cancer drugs are generally designed to treat tumors with certain genetic/genomic makeups. Mutational testing prior to prescribing targeted therapy is crucial in identifying who can receive clinical benefit from specific cancer drugs. Over the last two decades, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure to being identified as distinct gastrointestinal mesenchymal tumors with well-defined clinical and molecular characteristics, for which multiple lines of targeted therapies are available. Although the National Comprehensive Cancer Network (NCCN) strongly recommends mutational testing for optimal management of GIST, many GIST patients still have neither a mutation test performed or any mutation-guided cancer management. Here, we review the mutation-guided landscape of GIST, mutational testing methods, and the recent development of new therapies targeting GIST with specific mutations.
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Affiliation(s)
- Yu Wang
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
| | - Jerry Call
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
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19
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Balmer JC, Mikhaylov Y, Lewin DN, Mahvi DM, Ramsay Camp E. Synchronous Upper Intestinal Neurofibromas and Duodenal Periampullary Well-Differentiated Neuroendocrine Tumor Associated With Neurofibromatosis 1. Am Surg 2020; 87:128-130. [PMID: 32856931 DOI: 10.1177/0003134820945236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder associated with characteristic skin findings, as well as a fourfold increase in risk of malignancy. NF1 patient malignancies commonly include the central and peripheral nervous system, but these patients are also at high risk of developing gastrointestinal (GI) tumors. While most often these GI tumors are benign upper GI neurofibromas; clinicians should have a high suspicion for malignant tumors, degeneration into a malignant peripheral nerve sheath tumor or less common associated malignancies such as well-differentiated neuroendocrine tumor (formerly carcinoid tumor), when patients present with multiple GI tumors. Our patient underwent a Whipple for symptomatic neurofibromas associated with NF1 and was unexpectedly discovered to have a metastatic duodenal well-differentiated neuroendocrine tumor. The patient is a 66-year-old man with NF1 who presented with hematemesis and was found to have large gastric neurofibromas and an ampullary neurofibroma based on endoscopy and radiological imaging. Another ostensive neurofibroma was noted distally. A pancreatoduodenectomy was performed. Pathological examination identified the neurofibromas but the tumor measuring 1.4cm and arising from the minor duodenal papilla was, in fact, a synchronous well-differentiated neuroendocrine tumor metastatic to regional lymph nodes, consistent with pT2 pN1, Stage IIIB cancer. NF1 patients with multiple GI tumors are at an increased risk for malignancy. Therefore, a high index of suspicion for malignancy in any patient with NF1 presenting with gastrointestinal symptoms has implications for a surgeon, warranting not only a further diagnostic investigation, but also an appropriate surgical intervention and sampling for nodal spread. Because of the possibility of a simultaneous cancer, it is crucial to assess all suspicious tumors even if the masses appear endoscopically benign.
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Affiliation(s)
- Jacob C Balmer
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Yana Mikhaylov
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - David N Lewin
- Department of Pathology, Medical University of South Carolina, Charleston, SC, USA
| | - David M Mahvi
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - E Ramsay Camp
- Department of Surgery, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
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20
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Somatostatinoma and Neurofibromatosis Type 1-A Case Report and Review of the Literature. Diagnostics (Basel) 2020; 10:diagnostics10090620. [PMID: 32825782 PMCID: PMC7555390 DOI: 10.3390/diagnostics10090620] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.
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21
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Pulvirenti A, Pea A, Chang DK, Jamieson NB. Clinical and Molecular Risk Factors for Recurrence Following Radical Surgery of Well-Differentiated Pancreatic Neuroendocrine Tumors. Front Med (Lausanne) 2020; 7:385. [PMID: 32850899 PMCID: PMC7419466 DOI: 10.3389/fmed.2020.00385] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/22/2020] [Indexed: 12/29/2022] Open
Abstract
Well-differentiated pancreatic neuroendocrine tumors are increasingly diagnosed neoplasms. For localized disease, surgery is the first-line therapy and is curative in most cases. However, although recurrence is a rare event, it can still occur up to 10 years from surgery, worsening the prognosis. Many clinical and pathological factors have been associated with recurrence; however, it is currently unclear how to accurately discern patients at risk for relapse of disease from those that should be considered cured. In this review, we focus on clinical, pathological, and molecular factors associated with recurrence and discuss available prediction tools to assess the risk of recurrence following surgery.
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Affiliation(s)
- Alessandra Pulvirenti
- Unit of General and Pancreatic Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Antonio Pea
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - David K. Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Nigel B. Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
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22
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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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23
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Foiadelli T, Naso M, Licari A, Orsini A, Magistrali M, Trabatti C, Luzzi S, Mosconi M, Savasta S, Marseglia GL. Advanced pharmacological therapies for neurofibromatosis type 1-related tumors. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:101-114. [PMID: 32608378 PMCID: PMC7975824 DOI: 10.23750/abm.v91i7-s.9961] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/23/2020] [Indexed: 11/23/2022]
Abstract
Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most frequent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumorigenesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results.
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Affiliation(s)
- Thomas Foiadelli
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Matteo Naso
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Amelia Licari
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Alessandro Orsini
- Pediatric Neurology, Pediatric Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Italy.
| | - Mariasole Magistrali
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Chiara Trabatti
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
| | - Mario Mosconi
- Orthopaedic and Traumatology Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| | - Salvatore Savasta
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
| | - Gian Luigi Marseglia
- Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
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24
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Dare AJ, Gupta AA, Thipphavong S, Miettinen M, Gladdy RA. Abdominal neoplastic manifestations of neurofibromatosis type 1. Neurooncol Adv 2020; 2:i124-i133. [PMID: 32642738 PMCID: PMC7317050 DOI: 10.1093/noajnl/vdaa032] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome, with a wide clinicopathologic spectrum. It is defined by characteristic central nervous system, cutaneous and osseous manifestations, and by mutations in the NF1 gene, which is involved in proliferation via p21, RAS, and MAP kinase pathways. Up to 25% of NF1 patients develop intra-abdominal neoplastic manifestations including neurogenic (commonly plexiform neurofibromas and malignant peripheral nerve sheath tumors), interstitial cells of Cajal (hyperplasia, gastrointestinal stromal tumors), neuroendocrine, and embryonal tumors (rhabdomyosarcoma). Nonspecific symptoms, multifocal disease, or coexistence of 2 or more tumor types make patients challenging to diagnose and manage. Screening for intra-abdominal tumors in NF1 patients remains controversial, and currently no guidelines are established. Management decisions are complex and often informed by single-center experiences or case studies in the literature, though the field is rapidly evolving. Thus, NF1 patients should be followed in specialist centers familiar with their wide spectrum of pathology and with multidisciplinary care including specialized pathology and radiology. This review will (1) provide a contemporaneous synthesis of the literature and our multi-institutional clinical experiences with intra-abdominal neoplasms in NF1 patients, (2) present a classification framework for this heterogeneous group of disorders, and (3) outline approaches to screening, surveillance, diagnosis, and management.
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Affiliation(s)
- Anna J Dare
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Abha A Gupta
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Seng Thipphavong
- Department of Medical Imaging, Women's College Hospital, Toronto, Ontario, Canada
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute/Center for Cancer Research, Bethesda, Maryland, USA
| | - Rebecca A Gladdy
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
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25
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Abstract
Inherited syndromes are important to recognize in the setting of a pancreatic neuroendocrine tumor (PNET) as there are significant implications for the patient's medical management and opportunity for early detection of subsequent manifestations. Although most PNETs are sporadic, approximately 10% are due to an inherited syndrome, which include multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). The general hallmarks of a hereditary endocrine neoplasia predisposition syndrome include any one of the following: multiple primary tumors (in the same or different organs), rare tumors (prevalence of less than 1 in 1,000 people in the general population), earlier age of diagnosis (usually under the age of 40), characteristic pattern of disease in the individual or family (phenotype and inheritance pattern). These syndromes are monogenic (due to a single gene disorder), highly penetrant (with all carriers of the disease exhibiting at least part of the phenotype) and can display variable expressivity (where affected individuals may have different presentations and features of the disease). A thoughtful approach to management is required, even if the presenting symptom is resolved, as these syndromes often involve multi-organ disease with a lifelong risk for tumor development. Additionally, the natural history of tumors in the setting of a hereditary condition may be different than would be expected in a sporadic form of the disease. For example, in some circumstances the risk of metastatic disease is lower, and therefor longer observation is the preferred approach over early surgical intervention. The unique aspects to management, challenges in hereditary disease recognition and accurate diagnosis, and rarity of these syndromes are all reasons to support referral to high-volume centers with the experience and knowledge to treat patients with hereditary endocrine neoplasia syndromes.
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Affiliation(s)
- Jennifer L Geurts
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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26
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Gregório C, Rosset C, Alves LDS, Netto CBO, Machado SMDS, Bersch VP, Osvaldt AB, Ashton-Prolla P. Synchronous Periampullary Tumors in a Patient With Pancreas Divisum and Neurofibromatosis Type 1. Front Genet 2020; 11:395. [PMID: 32425982 PMCID: PMC7212385 DOI: 10.3389/fgene.2020.00395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/30/2020] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION In this study, we describe for the first time a Neurofibromatosis type 1 patient with pancreas divisum, multiple periampullary tumors and germline pathogenic variants in NF1 and CFTR genes. CASE REPORT A 62-year-old female NF1 patient presented with weakness, choluria, nausea, and diffuse abdominal pain to an emergency room service. Magnetic resonance imaging revealed an abdominal mass involving the periampullary region and pancreas divisum. After surgical resection, three synchronous neoplasms were detected including two ampullary tumors (adenocarcinoma of the major ampulla and a neuroendocrine tumor of the minor ampulla) and a gastrointestinal stromal tumor (GIST). Germline multigene panel testing (MGPT) identified two pathogenic heterozygous germline variants: NF1 c.838del and CFTR c.1210-34TG[12]T[5]. CONCLUSION This is the first report of a Neurofibromatosis type 1 patient with pancreas divisum and multiple periampullary tumors harboring pathogenic germline variants in NF1 and CFTR genes. The identification of two germline variants and a developmental anomaly in this patient may explain the unusual and more severe findings and underscores the importance of comprehensive molecular analyses in patients with complex phenotypes.
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Affiliation(s)
- Cleandra Gregório
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Clévia Rosset
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Laura da Silva Alves
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | - Vivian Pierri Bersch
- Serviço de Cirurgia do Aparelho Digestivo, Grupo de Vias Biliares e Pâncreas, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Grupo do Pâncreas, Serviço de Cirurgia do Aparelho Digestivo, Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Alessandro Bersch Osvaldt
- Serviço de Cirurgia do Aparelho Digestivo, Grupo de Vias Biliares e Pâncreas, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Programa de Pós-graduação em Medicina: Ciências Cirúrgicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Patricia Ashton-Prolla
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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27
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Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev 2020; 41:bnz004. [PMID: 31555796 PMCID: PMC7080342 DOI: 10.1210/endrev/bnz004] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
| | - Gregory Kaltsas
- 1st Department of Propaupedic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
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28
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Park EK, Kim HJ, Lee YH, Koh YS, Hur YH, Cho CK. Synchronous Gastrointestinal Stromal Tumor and Ampullary Neuroendocrine Tumor in Association with Neurofibromatosis Type 1: A Report of Three Cases. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:227-231. [PMID: 31650799 DOI: 10.4166/kjg.2019.74.4.227] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 11/03/2022]
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disorder. The pathogenesis of NF1 is suggested to be an alteration of the NF-1 gene, which normally functions as a tumor suppressor. A mutation of NF-1 causes the development of viable tumors in various sites. On the other hand, the synchronous manifestation of a gastrointestinal stromal tumor (GIST) and neuroendocrine tumor (NET) in the background of NF1 is extremely rare. This paper reports three cases treated with surgical intervention along with the long-term follow-up results. Three patients showed synchronous ampullary NET and GIST in association with NF1 supported by postoperative histopathologic analysis. Surgical treatments, such as pancreatoduodenectomy and local excision were applied. No recurrence occurred during the postoperative follow-up period of 10, 9, and 2.7 years. Synchronous GIST and NET in the background of NF1 is extremely rare, but the possible coexistence of other tumors in NF1 patients is relatively higher than that in the general population. Furthermore, both NETs and GISTs occurring in NF1 patients tend to be smaller in size compared to that in the general population. Therefore, when NF1 patients present with vague abdominal discomfort, close attention must be paid to identifying the coexistence of other neoplasms.
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Affiliation(s)
- Eun Kyu Park
- Department of Surgery, Chonnam National University Hospital, Gwangju, Korea
| | - Hee Joon Kim
- Department of Surgery, Chonnam National University Hospital, Gwangju, Korea
| | - Yun Ho Lee
- Department of Surgery, Chonnam National University Hospital, Gwangju, Korea
| | - Yang Seok Koh
- Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Young Hoe Hur
- Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Chol Kyoon Cho
- Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
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Huang Y, Chen G, Lin L, Jin X, Kang M, Zhang Y, Shi D, Chen K, Guo Q, Chen L, Wu D, Huang P, Chen J. Resection of GIST in the duodenum and proximal jejunum: A retrospective analysis of outcomes. Eur J Surg Oncol 2019; 45:1950-1956. [DOI: 10.1016/j.ejso.2019.05.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 04/29/2019] [Accepted: 05/02/2019] [Indexed: 01/10/2023] Open
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Poredska K, Kunovsky L, Prochazka V, Dolina J, Chovancova M, Vlazny J, Andrasina T, Eid M, Jabandziev P, Kysela P, Kala Z. Triple malignancy (NET, GIST and pheochromocytoma) as a first manifestation of neurofibromatosis type-1 in an adult patient. Diagn Pathol 2019; 14:77. [PMID: 31301733 PMCID: PMC6626625 DOI: 10.1186/s13000-019-0848-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 06/20/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Neurofibromatosis type-1 (NF1), also called von Recklinghausen disease, is a rare genetic disease which can lead to the development of benign or even malignant tumors. NF1 is mostly diagnosed in children or early adolescents who present with clinical symptoms. A curative therapy is still missing and the management of NF1 is based on careful surveillance. Concerning tumors which affect the gastrointestinal tract in patients with NF1, the most common is a gastrointestinal stromal tumor (GIST). CASE PRESENTATION We present a case of a 58-year-old adult patient with dyspeptic symptoms who was incidentally diagnosed with triple malignancy (pheochromocytoma, multiple GISTs of small intestine and an ampullary NET) as a first manifestation of NF1. The patient underwent surgical treatment (adrenalectomy and pancreaticoduodenectomy) with no complications and after 2 years remains in oncological remission. CONCLUSION NF1 is a rare genetic disease which can cause various benign or malignant tumors. The coincidence of GIST and NET is almost pathognomonic for NF1 and should raise a suspicion of this rare disorder in clinical practice.
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Affiliation(s)
- Karolina Poredska
- Department of Gastroenterology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Lumir Kunovsky
- Department of Gastroenterology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Vladimir Prochazka
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jiri Dolina
- Department of Gastroenterology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Miroslava Chovancova
- Department of Pathology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jakub Vlazny
- Department of Pathology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Tomas Andrasina
- Department of Radiology and Nuclear Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Michal Eid
- Department of Hematology, Oncology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Petr Jabandziev
- Department of Pediatrics, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Petr Kysela
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zdenek Kala
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Mafficini A, Scarpa A. Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 2019; 40:506-536. [PMID: 30657883 PMCID: PMC6534496 DOI: 10.1210/er.2018-00160] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
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Affiliation(s)
- Andrea Mafficini
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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Thavaraputta S, Graham S, Rivas Mejia AM, Lado-Abeal J. Duodenal somatostatinoma presenting as obstructive jaundice with the coexistence of a gastrointestinal stromal tumour in neurofibromatosis type 1: a case with review of the literature. BMJ Case Rep 2019; 12:12/1/bcr-2018-226702. [PMID: 30635305 DOI: 10.1136/bcr-2018-226702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatostatinomas are rare neuroendocrine tumours, mostly located in the pancreas or duodenum, with an estimated incidence of 1 in 40 million. Duodenal somatostatinomas (DSs) are usually found in association with neurofibromatosis type 1 (NF1), tuberous sclerosis and Von Hippel-Lindau syndrome. Gastrointestinal stromal tumours (GIST) have also been described in NF1, but the association with somatostatinoma is very uncommon. We report the case of a patient with NF1 who presented with obstructive jaundice due to multiple firm nodules around the ampulla of Vater. A pancreaticoduodenectomy was performed and revealed a 1 cm duodenal/ampullary mass which stained positive for somatostatin, together with a GIST also found on the duodenal wall. Despite its rarity, ampullary somatostatinomas should be considered in the differential diagnosis of biliary tract dilation in patients with NF1.
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Affiliation(s)
- Subhanudh Thavaraputta
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Suzanne Graham
- Department of Pathology, Texas Tech Univeristy Health Sciences Center, Lubbock, Texas, USA
| | - Ana M Rivas Mejia
- Division of Endocrinology, Department of Internal Medicine, Texas Tech University Health Science Center School of Medicine, Lubbock, Texas, USA
| | - Joaquin Lado-Abeal
- Division of Endocrinology, Department of Internal Medicine, Texas Tech University Health Science Center School of Medicine, Lubbock, Texas, USA
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Noë M, Pea A, Luchini C, Felsenstein M, Barbi S, Bhaijee F, Yonescu R, Ning Y, Adsay NV, Zamboni G, Lawlor RT, Scarpa A, Offerhaus GJA, Brosens LAA, Hruban RH, Roberts NJ, Wood LD. Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. Mod Pathol 2018; 31:1532-1538. [PMID: 29849115 PMCID: PMC6168403 DOI: 10.1038/s41379-018-0082-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/30/2018] [Accepted: 05/03/2018] [Indexed: 02/08/2023]
Abstract
Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms-neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole-exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.
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Affiliation(s)
- Michaël Noë
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Antonio Pea
- Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Matthäus Felsenstein
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stefano Barbi
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Feriyl Bhaijee
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Raluca Yonescu
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Ning
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Giuseppe Zamboni
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- Sacro Cuore Don Calabria Hospital, 37024, Negrar, Verona, Italy
| | - Rita T Lawlor
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Ralph H Hruban
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicholas J Roberts
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Popivanov G, Tabakov M, Mantese G, Cirocchi R, Piccinini I, D'Andrea V, Covarelli P, Boselli C, Barberini F, Tabola R, Pietro U, Cavaliere D. Surgical treatment of gastrointestinal stromal tumors of the duodenum: a literature review. Transl Gastroenterol Hepatol 2018; 3:71. [PMID: 30363779 DOI: 10.21037/tgh.2018.09.04] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 09/04/2018] [Indexed: 01/10/2023] Open
Abstract
Background Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumours in the digestive tract. The duodenal GIST (dGIST) is the rarest subtype, representing only 4-5% of all GIST, but up to 21% of the resected ones. The diagnostic and therapeutic management of dGIST may be difficult due to the rarity of this tumor, its anatomical location, and the clinical behavior that often mimic a variety of conditions; moreover, there is lack of consent for their treatment. This study has evaluated the scientific literature to provide consensus on the diagnosis of dGIST and to outline possible options for surgical treatment. Methods An extensive research has been carried out on the electronic databases MEDLINE, Scopus, EMBASE and Cochrane to identify all clinical trials that report an event or case series of dGIST. Results Eighty-six studies that met the inclusion criteria were identified with five hundred forty-nine patients with dGIST: twenty-seven patients were treated with pancreatoduodenectomy and ninety-six with only local resection (segmental/wedge resections); in four hundred twenty-six patients it is not possible identify the type of treatment performed (pancreatoduodenectomy or segmental/wedge resections). Conclusions dGISTs are a very rare subset of GISTs. They may be asymptomatic or may involve symptoms of upper GI bleeding and abdominal pain at presentation. Because of the misleading clinical presentation the differential diagnosis may be difficult. Tumours smaller than 2 cm have a low biological aggressiveness and can be followed annually by endoscopic ultrasound. The biggest ones should undergo radical surgical resection (R0). In dGIST there is no uniformly adopted surgical strategy because of the low incidence, lack of experience, and the complex anatomy of the duodenum. Therefore, individually tailored surgical approach is recommended. R0 resection with 1-2 cm clear margin is required. Lymph node dissection is not recommended due to the low incidence of lymphatic metastases. Tumor rupture should be avoided.
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Affiliation(s)
- Georgi Popivanov
- Military Medical Academy, Clinic of Endoscopic, Endocrine surgery and Coloproctology, Sofia, Bulgaria
| | - Mihail Tabakov
- University Hospital Sv. Ivan Rilski, Surgical Clinic, Sofia, Bulgaria
| | - George Mantese
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Roberto Cirocchi
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Irene Piccinini
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Vito D'Andrea
- Department of Surgical and Biomedical Sciences, University of Perugia, Italy
| | - Piero Covarelli
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Carlo Boselli
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Francesco Barberini
- Department of Surgical Sciences, The University of Rome "La Sapienza", Rome, Italy
| | - Renata Tabola
- Department and Clinic of Gastrointestinal and General Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Ursi Pietro
- Department of Surgical and Biomedical Sciences, University of Perugia, Italy
| | - Davide Cavaliere
- General Surgery and Surgical Oncology, Morgagni-Pierantoni Hospital, Forlì, Italy
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Xie R, Fu KI, Chen SM, Tuo BG, Wu HC. Neurofibromatosis type 1-associated multiple rectal neuroendocrine tumors: A case report and review of the literature. World J Gastroenterol 2018; 24:3806-3812. [PMID: 30197486 PMCID: PMC6127664 DOI: 10.3748/wjg.v24.i33.3806] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/12/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
Neurofibromatosis type 1 (NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiple rectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.
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Affiliation(s)
- Rui Xie
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi 563003, Guizhou Province, China
| | - Kuang-I Fu
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi 563003, Guizhou Province, China
- Department of Endoscopy, Kanma Memorial Hospital, Tokyo 3250046, Japan
| | - Shao-Min Chen
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi 563003, Guizhou Province, China
| | - Bi-Guang Tuo
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi 563003, Guizhou Province, China
| | - Hui-Chao Wu
- Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi 563003, Guizhou Province, China
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Lee JM, Lee JM, Hyun JJ, Choi HS, Kim ES, Keum B, Jeen YT, Chun HJ, Lee HS, Kim CD, Kim DS, Kim JY. Intraductal papillary bile duct adenocarcinoma and gastrointestinal stromal tumor in a case of neurofibromatosis type 1. World J Gastroenterol 2018; 24:537-542. [PMID: 29398874 PMCID: PMC5787788 DOI: 10.3748/wjg.v24.i4.537] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/13/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
We report our experience with a synchronous case of gastrointestinal stromal tumor (GIST) and intraductal papillary neoplasm of the bile duct (IPNB) in an elderly woman with neurofibromatosis type 1 (NF-1). A 72-year-old woman presented with a 2-mo history of right upper abdominal pain unrelated to diet and indigestion. Fourteen years earlier, she had been diagnosed with NF-1, which manifested as café au lait spots and multiple nodules on the skin. Computed tomography (CT) revealed a multilocular low-density mass with septation, and mural nodules in the right hepatic lobe, as well as a 1.7-cm-sized well-demarcated enhancing mass in the third portion of the duodenum. The patient subsequently underwent right hepatectomy and duodenal wedge resection. We present here the first report of a case involving a synchronous IPNB and GIST in a patient with NF-1. Our findings demonstrate the possibility of various tumors in NF-1 patients and the importance of diagnosis at an early stage
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Affiliation(s)
- Jung Min Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Jae Min Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Anam Hospital, Seoul 02841, South Korea
| | - Jong Jin Hyun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Eun Sun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Bora Keum
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yoon Tae Jeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Hoon Jai Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Hong Sik Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Chang Duck Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, South Korea
| | - Dong Sik Kim
- Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul 02841, South Korea
| | - Joo Young Kim
- Department of Pathology, Korea University College of Medicine, Seoul 02841, South Korea
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Seo Y, Jeong Y, Kim DY, Choi K, Kim ES, Moon SD, Han JH. A novel neurofibromatosis type 1 ( NF1) mutation in a patient with NF1 and pheochromocytoma. Korean J Intern Med 2018; 33:214-217. [PMID: 29172408 PMCID: PMC5768533 DOI: 10.3904/kjim.2015.256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Revised: 09/23/2015] [Accepted: 10/07/2015] [Indexed: 11/27/2022] Open
Affiliation(s)
- Yoorim Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Yeonjeong Jeong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Dong Yoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Kyueun Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Eun Sook Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
- Correspondence to Eun Sook Kim, M.D. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea Tel: +82-32-280-5175 Fax: +82-32-280-5683 E-mail:
| | - Sung Dae Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Je Ho Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
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Abstract
Neuroendocrine tumours (NETs) are a heterogenous group of tumours arising from neuroendocrine cells in several sites around the body. They include tumours of the gastroenteropancreatic system, phaeochromocytoma and paraganglioma and medullary thyroid cancer. In recent years, it has become increasingly apparent that a number of these tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing rapidly. Identifying which patients are likely to have a germline mutation enables clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. The institution of screening and surveillance programmes may in turn lead to a major shift in presentation patterns for some of these tumours. In this review, we examine the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and we outline which underlying conditions should be suspected. We also discuss what type of screening may be appropriate in a variety of situations.
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Affiliation(s)
- Triona O'Shea
- Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
| | - Maralyn Druce
- Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
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Tewari M, Swain JR, Dixit VK, Shukla HS. Molecular Aberrations in Periampullary Carcinoma. Indian J Surg Oncol 2017; 8:348-356. [DOI: 10.1007/s13193-017-0645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 03/15/2017] [Indexed: 11/29/2022] Open
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Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24:R315-R334. [PMID: 28710117 DOI: 10.1530/erc-17-0012] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.
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Affiliation(s)
- Annunziata Di Domenico
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | - Tabea Wiedmer
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | | | - Aurel Perren
- Institute of PathologyUniversity of Bern, Bern, Switzerland
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Abdessayed N, Gupta R, Mestiri S, Bdioui A, Trimech M, Mokni M. Rare triad of periampullary carcinoid, duodenal gastrointestinal stromal tumor and plexiform neurofibroma at hepatic hilum in neurofibromatosis type 1: a case report. BMC Cancer 2017; 17:579. [PMID: 28851321 PMCID: PMC5575842 DOI: 10.1186/s12885-017-3567-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 08/18/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Neurofibromatosis type 1 is a relatively common inherited disorder. Patients with neurofibromatosis type 1 are at high risk of developing neurogenic, neuroendocrine and mesenchymal intra-abdominal tumors. Although coexistence of multiple tumors of different types is frequent in neurofibromatosis type 1, simultaneous occurrence of abdominal tumors of three types in very rare. CASE PRESENTATION A 66-year-old lady with neurofibromatosis type 1 presented with painless progressive jaundice for six months. Laboratory investigations revealed iron deficiency anemia and conjugated hyperbilirubinemia. Tumor markers were normal. Abdominal computed tomography showed a 3 × 2 cm heterogenous mass in the periampullary region with mild dilation of the common bile duct and another 2 × 1.7 cm mass in the fourth portion of the duodenum. Endoscopic biopsy confirmed the diagnosis of periampullary carcinoid. At surgery, multiple small nodules were detected at the hepatic hilum. Frozen section suggested them to be neurofibromas. Patient underwent pancreatoduodenectomy and had uneventful recovery with no recurrence at two months. Microscopic examination of the resected specimen confirmed presence of three tumors: periampullary well differentiated neuroendocrine tumor, gastrointestinal stromal tumor of the fourth part of duodenum and plexiform neurofibroma at the hepatic hilum. CONCLUSION Patients of neurofibromatosis type 1 with abdominal symptoms should be treated with high index of clinical suspicion and thoroughly evaluated to rule out multiple tumors.
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Affiliation(s)
- Nihed Abdessayed
- Department of pathology, Farhat Hached Hospital, Avenue Farhat Hached, 4000 Sousse, Tunisia
- Research Lab: transfer in technology in anatomic pathology (LR12SP08), Sousse, Tunisia
| | - Rahul Gupta
- Department of HPB surgery, CARE hospital, Hyderabad, India
| | - Sarra Mestiri
- Department of pathology, Farhat Hached Hospital, Avenue Farhat Hached, 4000 Sousse, Tunisia
| | - Ahlem Bdioui
- Department of pathology, Farhat Hached Hospital, Avenue Farhat Hached, 4000 Sousse, Tunisia
| | - Mounir Trimech
- Department of pathology, Farhat Hached Hospital, Avenue Farhat Hached, 4000 Sousse, Tunisia
| | - Moncef Mokni
- Department of pathology, Farhat Hached Hospital, Avenue Farhat Hached, 4000 Sousse, Tunisia
- Research Lab: transfer in technology in anatomic pathology (LR12SP08), Sousse, Tunisia
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Fliedner SMJ, Shankavaram U, Marzouca G, Elkahloun A, Jochmanova I, Daerr R, Linehan WM, Timmers H, Tischler AS, Papaspyrou K, Brieger J, de Krijger R, Breza J, Eisenhofer G, Zhuang Z, Lehnert H, Pacak K. Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster. Neoplasia 2017; 18:567-76. [PMID: 27659016 PMCID: PMC5031903 DOI: 10.1016/j.neo.2016.07.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/22/2016] [Accepted: 07/25/2016] [Indexed: 01/06/2023] Open
Abstract
Recently, activating mutations of the hypoxia-inducible factor 2α gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs (n = 6) from 2 patients were compared with normal adrenal medullas (n = 8) and other hereditary pseudohypoxic PGLs (VHL: n = 13, SDHB: n = 15, and SDHD: n = 14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla (false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes.
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Affiliation(s)
- Stephanie M J Fliedner
- 1st Department of Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
| | - Uma Shankavaram
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Geena Marzouca
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Abdel Elkahloun
- Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ivana Jochmanova
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; 1st Department of Internal Medicine Medical Faculty of P. J. Šafárik University in Košice, Košice, Slovakia
| | - Roland Daerr
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - W Marston Linehan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Henri Timmers
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Konstantinos Papaspyrou
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Jürgen Brieger
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Ronald de Krijger
- Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands; Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands
| | - Jan Breza
- Department of Urology, Comenius University, Bratislava, Slovak Republic
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Zhengping Zhuang
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Hendrik Lehnert
- 1st Department of Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Karel Pacak
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Mixed mucinous adenocarcinoma and somatostatinoma of the ampulla of Vater associated with neurofibromatosis type 1. Pathology 2017; 49:553-555. [PMID: 28693748 DOI: 10.1016/j.pathol.2017.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 03/18/2017] [Accepted: 03/29/2017] [Indexed: 12/31/2022]
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ElGuindy YM, Javadi S, Menias CO, Jensen CT, Elsamaloty H, Elsayes KM. Imaging of secretory tumors of the gastrointestinal tract. Abdom Radiol (NY) 2017; 42:1113-1131. [PMID: 27878636 DOI: 10.1007/s00261-016-0976-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Gastrointestinal secretory tumors, or gastroenteropancreatic neuroendocrine tumors, encompass a wide array of endocrine cell tumors. The significance of these tumors lies in their ability to alter physiology through hormone production as we well as in their malignant potential. Functioning tumors may present earlier due to symptomatology; conversely, non-functioning tumors are often diagnosed late as they reach large sizes, causing symptoms secondary to local mass effect. Imaging aids in the diagnosis, staging, and prognosis and provides key information for presurgical planning. Although most of these tumors are sporadic, some are associated with important syndromes and associations, knowledge of which is critical for patient management. In this article, we provide an overview of secretory and neuroendocrine tumors of the GI tract and pancreas.
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Petr EJ, Else T. Genetic predisposition to endocrine tumors: Diagnosis, surveillance and challenges in care. Semin Oncol 2016; 43:582-590. [DOI: 10.1053/j.seminoncol.2016.08.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 08/10/2016] [Indexed: 02/07/2023]
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Pancreaticoduodenectomy in patients with type 1 Neurofibromatosis: Report of two cases and literature review. Int J Surg Case Rep 2016; 27:36-40. [PMID: 27529834 PMCID: PMC4987505 DOI: 10.1016/j.ijscr.2016.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Revised: 08/07/2016] [Accepted: 08/08/2016] [Indexed: 02/08/2023] Open
Abstract
Type 1 Neurofibromatosis is an autosomal disorder associated with gastrointestinal tumors in almost one quarter of the cases. The presence of synchronous malignant gastrintestinal tumor in patients with type 1 Neurofibromatosis is rarely reported in the literature. Patients with type 1 Neurofibromatosis with gastrointestinal complaints should be thoroughly evaluated to rule out malignancy. Optimal management of patients with synchronous neoplasms is single-stage surgical resection. Introduction Type 1 Neurofibromatosis (NF1) is one of the most common autosomal dominantly inherited multisystem disorders. It is associated with an increased risk of developing neurologic and gastrointestinal (GI) malignant neoplasms. The incidence of GI involvement is reported in 10–25% of patients. Less than 5% of NF1 patients with GI neoplasms manifest symptoms. The presence of synchronic gastrointestinal stromal and neuroendocrine tumors is rare in these patients. Presentation of cases The first case is a 37 year-old male patient with a history of abdominal pain for a few months. Imaging study showed a periampullary mass and a solid lesion at the third duodenal portion. He was submitted to a pancreatoduodenectomy and histological anaylisis showed two low-grade neuroendocrine tumors and a gastrointestinal stromal tumor. The second case is a 47 year-old female patient with a routine computed tomography scan showing a duodenal and a jejunal lesion. Duodenopancreatectomy was performed and histological analysis showed a neuroendocrine adenocarcinoma of the duodenum and two jejunal lesions compatible with GI tumors. Discussion GI symptoms such as jaundice, pain and bleeding in NF1 patients should prompt urgent admission Occasionally, associated gastrointestinal tumors may be incidentally found in asymptomatic NF1 patients. The presence of a periampullary or duodenal neoplasia such as neuroendocrine tumors should be evaluated. Conclusion Although rare, the synchronic presentation of gastrointestinal tumors in patients with NF1 should be ruled out since it can lead to higher morbidity and mortality rates. Single-stage surgical management is feasable and yields satisfactory results.
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Major and Minor Duodenal Papilla Neuroendocrine Tumors in Type 1 Neurofibromatosis: Case Report. J Gastrointest Cancer 2016; 49:71-74. [DOI: 10.1007/s12029-016-9854-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Somatostatinoma of the Ampulla: An Incidental Postoperative Finding Following Colorectal Cancer Resection. ACG Case Rep J 2016; 3:109-11. [PMID: 26958562 PMCID: PMC4748198 DOI: 10.14309/crj.2016.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/11/2015] [Indexed: 12/03/2022] Open
Abstract
Somatostatinoma of the gastrointestinal tract is a rare finding, especially arising from the ampulla of Vater. We present a man recently diagnosed with rectal adenocarcinoma who was found on imaging to have an ampullary mass. Histology and immunohistochemical staining of the biopsied tissue were consistent with a nonfunctioning somatostatinoma. The patient had neurofibromatosis, which have been reported in patients with ampullary somatostatinomas. Our case highlights the importance of gastrointestinal findings in those with underlying genetic conditions.
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49
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Luna IE, Monrad N, Binderup T, Boisen Thoegersen C, Hilsted L, Jensen C, Federspiel B, Knigge U. Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms: Twenty-Three Cases Evaluated according to the WHO 2010 Classification. Neuroendocrinology 2016; 103:567-77. [PMID: 26505735 DOI: 10.1159/000441605] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 10/08/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/OBJECTIVE Neuroendocrine neoplasms of the pancreas and duodenum with predominant or exclusive immunoreactivity for somatostatin (pdSOMs) are rare, and knowledge about tumour biology, treatment, survival and prognostic factors is limited. This study aims to describe clinical, pathological and biochemical features as well as treatment and prognosis of pdSOMs. DESIGN Twenty-three patients with pdSOM (9 duodenal, 12 pancreatic and 2 unknown primary tumours) were identified from our prospective neuroendocrine tumour database, and data according to the study aims were recorded. RESULTS Among the 9 patients with duodenal SOM, the male/female ratio was 4/5. All males and 1 female had neurofibromatosis type 1. Seven patients had stage 1A/B and 2 had stage 2B disease. The Ki-67 index was 1-5% (median 2%). Plasma somatostatin was elevated in the patients with 2B disease. Of the 14 patients with pancreatic SOM or an unknown primary tumour, the male/female ratio was 2/12. One male had multiple endocrine neoplasia type 1. Five had stage 1A/2B and 9 had stage 4. The Ki-67 index was 1-40% (median 7%). Plasma somatostatin was elevated in 7 patients. Patients reported symptoms related to the somatostatinoma syndrome, but none fulfilled the criteria for a full syndrome. Primary tumour in the pancreas, metastatic disease at diagnosis and higher tumour grade were all associated with significantly poorer survival. CONCLUSION None of the patients with pdSOM presented with the full somatostatinoma syndrome. Prognostic factors are localisation of the primary tumour, dissemination and tumour grade. A Ki-67 index of 5% may discriminate the course of the disease.
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Rogers A, Wang LM, Karavitaki N, Grossman AB. Neurofibromatosis Type 1 and pancreatic islet cell tumours: an association which should be recognized. QJM 2015; 108:573-6. [PMID: 23173186 DOI: 10.1093/qjmed/hcs203] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- A Rogers
- From the Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, University of Oxford, OX3 7LE, UK and Department of Histopathology, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK
| | - L M Wang
- From the Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, University of Oxford, OX3 7LE, UK and Department of Histopathology, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK
| | - N Karavitaki
- From the Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, University of Oxford, OX3 7LE, UK and Department of Histopathology, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK
| | - A B Grossman
- From the Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, University of Oxford, OX3 7LE, UK and Department of Histopathology, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK
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