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1.
Pancreas ; 51(8): 1056-1060, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607953

RESUMO

ABSTRACT: We report a father and his daughter who both had multiple somatostatinomas in the duodenal bulb without a known syndrome. The father, at age 68 years, was incidentally found to harbor 4 approximately 1.5-cm well-differentiated neuroendocrine tumors in the duodenal bulb. His preoperative somatostatin level was elevated. He underwent partial duodenectomy and regional lymph node dissection; one lymph node was positive for metastasis. One year postoperatively, a recurrence was found in the surgical bed; he was treated with octreotide for 2 years, which stabilized the recurrent tumor. Ten years postoperatively, the mucosa of his remaining duodenum was normal. His daughter, at age 53 years, was found to harbor multiple small neuroendocrine tumors in the duodenal bulb. Immunostaining of available specimens showed that the neuroendocrine tumors from the father and daughter both were strongly positive for somatostatin. Micronodules of somatostatin-expressing neuroendocrine cells were found in the parts of the specimens uninvolved with the tumors. Both patients exhibited no evidence of known syndromes associated with somatostatinoma. The daughter did not harbor mutations in 93 genes commonly found in genetic tumor syndromes. The 2 cases thus suggest a novel, autosomal dominant, genetic syndrome of familial duodenal somatostatinomatosis.


Assuntos
Neoplasias Duodenais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Somatostatinoma , Masculino , Humanos , Idoso , Pessoa de Meia-Idade , Neoplasias Duodenais/genética , Neoplasias Duodenais/complicações , Recidiva Local de Neoplasia , Duodeno/patologia , Somatostatinoma/diagnóstico , Somatostatinoma/genética , Somatostatinoma/complicações , Tumores Neuroendócrinos/patologia , Somatostatina/uso terapêutico , Neoplasias Pancreáticas/patologia
2.
Biochem Biophys Res Commun ; 525(4): 1032-1037, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32178873

RESUMO

Pancreatic neuroendocrine tumors (pNETs) occur due to the abnormal growth of pancreatic islet cells and predominantly develop in the duodenal-pancreatic region. Somatostatinoma is one of the pNETs associated with tumors of pancreatic δ cells, which produce and secrete somatostatin. Limited information is currently available on the pathogenic mechanisms of somatostatinoma. The large-conductance Ca2+-activated K+ (BKCa) channel is expressed in several types of cancer cells and regulates cell proliferation, migration, invasion, and metastasis. In the present study, the functional expression of the BKCa channel was examined in a human somatostatinoma QGP-1 cell line. In QGP-1 cells, outward currents were elicited by membrane depolarization at pCa 6.5 (300 nM) in the pipette solution and inhibited by the specific BKCa channel blocker, paxilline. Paxilline-sensitive currents were detected, even at pCa 8.0 (10 nM) in the pipette solution, in QGP-1 cells. In addition to the α and ß2-4 subunits of the BKCa channel, the novel regulatory γ1 subunit (BKCaγ1) was co-localized with the α subunit in QGP-1 cells. Paxilline-sensitive currents at pCa 8.0 in the pipette solution were reduced by the siRNA knockdown of BKCaγ1. Store-operated Ca2+ entry was smaller in BKCaγ1 siRNA-treated QGP-1 cells. The proliferation of QGP-1 cells was attenuated by paxilline or the siRNA knockdown of BKCaγ1. These results strongly suggest that BKCaγ1 facilitates the proliferation of human somatostatinoma cells. Therefore, BKCaγ1 may be a novel therapeutic target for somatostatinoma.


Assuntos
Cálcio/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Neoplasias Pancreáticas/metabolismo , Somatostatinoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Neoplasias Pancreáticas/genética , Bloqueadores dos Canais de Potássio/farmacologia , RNA Interferente Pequeno , Somatostatinoma/genética
3.
Pediatr Blood Cancer ; 67(4): e28096, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876082

RESUMO

We report an index case of a male patient who presented with all clinical manifestations of Pacak-Zhuang syndrome, including early-age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings. Sequencing analysis detected an EPAS1 mutation in all tumors tested, but not in the germline.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Oftalmopatias Hereditárias/genética , Neoplasias Primárias Múltiplas/genética , Policitemia/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias Duodenais/genética , Humanos , Masculino , Mutação , Glomos Para-Aórticos/patologia , Paraganglioma/genética , Feocromocitoma/genética , Somatostatinoma/genética , Síndrome , Adulto Jovem
4.
Eur J Endocrinol ; 179(4): 219-228, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30299890

RESUMO

Objective: Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas; however, their prognosis differs significantly upon their proliferative state, which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods: MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of five miRNAs on an independent validation cohort of 63 primary PanNEN samples. Cox proportional hazards survival regression models were fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results: Nineteen miRNAs displayed differential expression between tumor grades. The altered expression of three out of five chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were upregulated in more proliferative PanNENs compared to Grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b of primary PanNENs predicted worse progression-free and overall survival; however, multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions: The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.


Assuntos
MicroRNAs/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Simulação por Computador , Intervalo Livre de Doença , Feminino , Gastrinoma/genética , Gastrinoma/patologia , Perfilação da Expressão Gênica , Humanos , Insulinoma/genética , Insulinoma/patologia , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Somatostatinoma/genética , Somatostatinoma/patologia , Taxa de Sobrevida
6.
Artigo em Inglês | MEDLINE | ID: mdl-24781045

RESUMO

UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Paraganglioma/genética , Policitemia/genética , Somatostatinoma/genética , Carcinogênese/genética , Humanos , Mutação , Paraganglioma/tratamento farmacológico , Policitemia/congênito , Policitemia/tratamento farmacológico , Somatostatinoma/tratamento farmacológico , Síndrome
7.
Blood ; 121(13): 2563-6, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23361906

RESUMO

Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain-of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2α and increased expression of hypoxia-related genes.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mutação , Oxigênio/metabolismo , Neoplasias Pancreáticas/genética , Paraganglioma/genética , Policitemia/genética , Somatostatinoma/genética , Neoplasias Abdominais/genética , Neoplasias Abdominais/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Feminino , Células HeLa , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutação/fisiologia , Neoplasias Pancreáticas/metabolismo , Paraganglioma/metabolismo , Filogenia , Policitemia/metabolismo , Somatostatinoma/metabolismo
9.
N Engl J Med ; 367(10): 922-30, 2012 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-22931260

RESUMO

Hypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression. However, mutations in genes encoding α subunits of hypoxia-inducible factors (HIF-α) have not previously been identified in any cancer. Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2α (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of whom had polycythemia. The two mutations were associated with increased HIF-2α activity and increased protein half-life.


Assuntos
Neoplasias Abdominais/genética , Neoplasias das Glândulas Suprarrenais/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Paraganglioma/genética , Policitemia/etiologia , Somatostatinoma/genética , Neoplasias Abdominais/complicações , Adolescente , Neoplasias das Glândulas Suprarrenais/complicações , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Hidroxilação , Mutação , Neoplasias Pancreáticas/genética , Paraganglioma/sangue , Paraganglioma/complicações , Somatostatinoma/complicações , Transcrição Gênica , Regulação para Cima
10.
Endocr Pathol ; 20(3): 177-81, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19488862

RESUMO

A 36-year-old male with neurofibromatosis type 1 (NF-1) presented with symptoms of obstructive jaundice. Imaging showed a periampullary mass, which on endoscopic retrograde cholangiopancreatography biopsy proved to be a somatostatinoma. A Whipple's procedure was performed and a somatostatinoma of the duodenum was confirmed. In addition, the patient had a gastrointestinal stromal tumor (GIST) of the jejunum with accompanying hyperplasia of interstitial cells of Cajal. The somatostatinoma was histologically characteristic with pseudoglandular and solid patterns together with psammoma bodies and lymphovascular invasion. The GIST did not display mutations in c-kit or platelet-derived growth factor receptor genes. The novel finding in this case was the presence of several vessels in the submucosa and muscularis propria of the duodenum displaying prominent intimal hyperplasia and in keeping with so-called neurofibromatosis-associated vasculopathy. These abnormal vessels were within and close to the somatostatinoma only and were not found away from the tumor. It is thought that the vasculopathy is related to NF-1 with abnormal neurofibromin possibly playing a role.


Assuntos
Vasos Sanguíneos/patologia , Neoplasias Duodenais/patologia , Tumores do Estroma Gastrointestinal/patologia , Neoplasias do Jejuno/patologia , Neurofibromatose 1/patologia , Somatostatinoma/patologia , Adulto , Neoplasias Duodenais/irrigação sanguínea , Neoplasias Duodenais/genética , Neoplasias Duodenais/cirurgia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Neoplasias do Jejuno/genética , Neoplasias do Jejuno/cirurgia , Masculino , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Neurofibromatose 1/genética , Neurofibromatose 1/cirurgia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-kit/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Somatostatinoma/irrigação sanguínea , Somatostatinoma/genética , Somatostatinoma/cirurgia
11.
Orv Hetil ; 147(5): 195-200, 2006 Feb 05.
Artigo em Húngaro | MEDLINE | ID: mdl-16509219

RESUMO

The pathogenesis, diagnosis and therapy of tumours originating from the endocrine pancreas represent one of the most exciting challenges of contemporary medicine. Some of these tumours appear as part of four hereditary syndromes (multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 and tuberous sclerosis) that are all inherited as autosomal dominant traits and result from mutations of tumour suppressor genes. Considering its clinical relevance, MEN1 appears to be the most important among these four syndromes. Tumours of the endocrine pancreas develop in 30-80% of patients carrying mutations of the MEN1 gene. Gastrinomas are the most frequent functioning tumours in MEN1 patients, followed by insulinomas, whereas other tumors e.g. glucagonoma, VIP-oma, GRF-oma and somatostatinoma occur very rarely. Tumours of the endocrine pancreas are infrequent in patients suffering from VHL, neurofibromatosis and tuberous sclerosis. In this review article, the authors present a synopsis of tumours of the endocrine pancreas related to these hereditary syndromes underlining the clinical characteristics, diagnostical and therapeutical possibilities.


Assuntos
Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Gastrinoma/diagnóstico , Gastrinoma/genética , Glucagonoma/genética , Humanos , Insulinoma/diagnóstico , Insulinoma/genética , Programas de Rastreamento , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neurofibromatose 1/complicações , Neoplasias Pancreáticas/prevenção & controle , Somatostatinoma/genética , Esclerose Tuberosa/complicações , Vipoma/genética , Doença de von Hippel-Lindau/complicações
12.
Minerva Endocrinol ; 29(1): 19-24, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15258554

RESUMO

Somatostatin producing duodenal carcinoids are rare, comprising a mere 2% of small bowel carcinoids and 5-10% of all duodenal tumors. Since the 1st case described by Kaneko in 1979 more than 50 cases have been reported in the world literature. From these reports, it is gradually emerging that duodenal somatostatinomas may show a strong association with von Recklinhausen's neurofibromatosis (VRNF) as a distinct neuroendocrine syndrome. A case of a patient affected by VRNF associated with duodenal somatostatinoma with consequent obstructive jaundice is reported. The authors discuss the characteristics of these tumors and review the literature. A total of 27 patients with Von Recklinghausen's disease associated with immunohistologically proved duodenal somatostatinoma have been identified and compared with 29 duodenal somatostatinoma not associated with VRNF, and with 32 cases of pancreatic somatostatinomas.


Assuntos
Neoplasias Duodenais/genética , Neurofibromatose 1 , Somatostatinoma/genética , Adulto , Ampola Hepatopancreática/patologia , Colangiopancreatografia Retrógrada Endoscópica , Ducto Colédoco/patologia , Neoplasias Duodenais/complicações , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/cirurgia , Feminino , Humanos , Icterícia Obstrutiva/etiologia , Pancreaticoduodenectomia , Neoplasias Cutâneas/genética , Somatostatinoma/complicações , Somatostatinoma/diagnóstico , Somatostatinoma/cirurgia
13.
Intern Med ; 40(1): 38-43, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11201368

RESUMO

A female with von Hippel-Lindau (VHL) disease type 2A first presented with erythrocytosis at the age of 9 years. This patient revealed multiple paragangliomas at age 22. After the removal of tumors, a retinal hemangioblastoma developed. Our diagnosis of VHL disease type 2A was confirmed. Moreover, systemic examination showed a duodenal somatostatinoma. Frequent and long-term monitoring is important for patients with pheochromocytomas or paragangliomas, and a screening for VHL disease and other hereditary cancer syndromes is recommended. Recognition of neuroendocrine tumors as a manifestation of VHL disease permits earlier diagnosis and improves prognosis.


Assuntos
Neoplasias Duodenais/genética , Policitemia/genética , Somatostatinoma/genética , Doença de von Hippel-Lindau/patologia , Adulto , Anemia Hipocrômica/etiologia , Glicemia/análise , Catecolaminas/sangue , Catecolaminas/urina , Feminino , Teste de Tolerância a Glucose , Hemangioblastoma/genética , Humanos , Proteínas de Neoplasias/sangue , Paraganglioma/genética , Flebotomia/efeitos adversos , Gravidez , Descolamento Retiniano/etiologia , Neoplasias da Retina/genética , Somatostatina/sangue , Doença de von Hippel-Lindau/sangue , Doença de von Hippel-Lindau/classificação
14.
Genes Chromosomes Cancer ; 29(1): 83-7, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10918398

RESUMO

Comparative genomic hybridization (CGH) was used to investigate changes in DNA copy numbers in 25 paraffin-embedded samples of pancreatic endocrine tumors from 23 patients. Insulin was the dominant hormone in 12, glucagon in 7, somatostatin in 1, and pancreatic polypeptide in 2 tumors. One to 15 (mean, 8.1) changes in DNA copy numbers were observed in 22 of the 25 tumors. The most recurrent aberration, found in 68% of the tumors, involved gains in chromosome 7 with a minimal overlapping region at 7q11.2. Other frequent gains included chromosomes 19 (60%) and 14 (56%). Chromosome arm 20q was amplified in 48% of the cases with the minimal overlapping region of 20q11.1-13.1. The two most frequent DNA losses were found at 11q21-22 in 32% and at 11p13-15 in 24% of the cases. The amplified chromosomal regions contain several candidate genes that may be involved in islet cell tumorigenesis. The regions with most frequent losses are likely to contain still uncharacterized tumor suppressor genes. Wiley-Liss, Inc.


Assuntos
Aberrações Cromossômicas/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Carcinoma de Células das Ilhotas Pancreáticas/genética , Carcinoma de Células das Ilhotas Pancreáticas/patologia , Deleção Cromossômica , Feminino , Dosagem de Genes , Glucagonoma/genética , Glucagonoma/patologia , Humanos , Insulinoma/genética , Insulinoma/patologia , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Neoplasias Pancreáticas/patologia , Somatostatinoma/genética , Somatostatinoma/patologia
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