RESUMO
Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analysed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification was gNEN-1 (n = 86/60.6%), gNEN-2 (n = 7/4.9%), gNEN-3 (n = 24/16.9%) and gNEN-4 (n = 25/17.6%), while hypergastrinemia-associated gNEN-1 and -2 were all low-grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification, OS differed for early and advanced stages, while WHO grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs -4).
Assuntos
Neoplasias Intestinais/patologia , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Neoplasias Intestinais/classificação , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/classificação , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Taxa de SobrevidaRESUMO
Neuroendocrine neoplasms (NEN) represent a group of potentially malignant tumors, which can be located in every section of the gastrointestinal tract, the pancreas and the bronchopulmonary system. Gastroduodenal NENs have a relatively good prognosis in comparison to other subentities, e.g. pancreatic or ileojejunal NENs. In the stomach there are four different types of NENs, while in the duodenum there are five types and all vary in the malignant potential and the therapeutic approach. Due to the simple access endoscopic methods not only have diagnostic but also important therapeutic relevance in this subgroup. Lesions smaller than 1 cm can easily be resected with forceps or snare resection and for larger lesions up to 2 cm more invasive strategies, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are available. Important criteria in gastric NEN for the risk evaluation of endoscopic treatment alone are the size of the lesion, depth of invasion and the tumor biology, e.g. neuroendocrine tumor (NET) G1/G2 versus neuroendocrine carcinoma (NEC) G3. In duodenal NEN the aforementioned risk factors also apply and in addition only lesions outside the ampulla of Vater should be endoscopically resected whereas periampullary lesions need to be addressed surgically. As an individualized therapeutic approach the possibility of a combined endoscopic and laparoscopic resection technique exists. Follow-up endoscopic investigations are necessary, especially in gastric type 1 NENs, which have a tendency to relapse.
Assuntos
Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Duodenoscopia/métodos , Gastroscopia/métodos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Humanos , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Síndrome de Zollinger-Ellison/patologia , Síndrome de Zollinger-Ellison/cirurgiaAssuntos
Neoplasias Brônquicas/terapia , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Neoplasias Brônquicas/secundário , Europa (Continente) , Humanos , Neoplasias Intestinais/secundário , Tumores Neuroendócrinos/secundário , Neoplasias Pancreáticas/secundárioAssuntos
Neoplasias do Apêndice/terapia , Tumores Neuroendócrinos/terapia , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/epidemiologia , Neoplasias do Apêndice/patologia , Europa (Continente) , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologiaAssuntos
Neoplasias do Íleo/terapia , Neoplasias do Jejuno/terapia , Tumores Neuroendócrinos/terapia , Consenso , Europa (Continente) , Humanos , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/epidemiologia , Neoplasias do Íleo/patologia , Neoplasias do Jejuno/diagnóstico , Neoplasias do Jejuno/epidemiologia , Neoplasias do Jejuno/patologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologiaRESUMO
Neuroendocrine neoplasms (NEN) of the breast are specific tumor entities. According to the literature up to 5% of breast neoplasms are malignant epithelial neoplasms of the breast. They are defined by a neuroendocrine (NE) architecture and cytology combined with an expression of the neuroendocrine vesicle markers chromogranin A and/or synaptophysin. The diagnosis is supplemented by the receptor status and the proliferative activity. According to the World Health Organization (WHO) classification of 2012 the following groups of NEN are distinguished: (1) invasive breast carcinoma with NE differentiation, (2) well-differentiated neuroendocrine tumor (NET) and (3) poorly differentiated small cell carcinoma (NEC). This review article focuses on (1) the definition and basic principles of diagnostics, (2) the history, nomenclature and WHO classification from 2003 and 2012, (3) the frequency of breast NEN, (4) the hereditary background and functional activity, (5) the expression of receptors and (6) the possible clinical implications. In addition, the first results of a retrospective single center study (n = 465 patients with breast cancer over a time period of 4 years) on the frequency of NEN of the breast at the Breast Center of the University Hospital Düsseldorf are presented. In this study a frequency of 4.5% of NEN was found based on a diagnostic cut-off of > 50% Chromogranin A and/or synaptophysin positive tumor cells.
Assuntos
Neoplasias da Mama/patologia , Tumores Neuroendócrinos/patologia , Biomarcadores Tumorais/análise , Mama/patologia , Proliferação de Células , Cromogranina A/análise , Feminino , Humanos , Invasividade Neoplásica , Prognóstico , Sinaptofisina/análiseRESUMO
BACKGROUND: Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. PATIENTS AND METHODS: Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). CONCLUSION: The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.
Assuntos
Neoplasias do Sistema Digestório/diagnóstico , Neoplasias do Sistema Digestório/cirurgia , Hormônios Ectópicos/sangue , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/cirurgia , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Neoplasias do Sistema Digestório/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Prognóstico , Síndrome , Adulto JovemRESUMO
BACKGROUND: Somatostatin analogues (SSA) are widely used in the treatment of patients with functioning and non-functioning neuroendocrine tumours (NET). The aim of our investigation was to evaluate the antiproliferative effect of SSA in patients with pancreatic NET. METHODS: We retrospectively analysed records of 43 patients with pancreatic NET treated at our clinic with octreotide long-lasting release as a first-line therapy. The aim of our study was to investigate the overall best response according to the RECIST criteria, overall best response defined as disease control rate (SD+PR), response and disease control rate at 12 months, and time to tumour progression (TTP). RESULTS: The mean age (± SD) of the patients (16 female/27 male) at initial diagnosis was 54.7 ± 11.86 years. At the start of therapy, 39 of 43 patients were classified as stage IV according to ENETS-TNM. Tumours were graded, based on MiB-1/Ki67 staining, as G1 (n = 8), G2 (n = 30) or unknown (n = 5). The octreoscan was positive in 37 patients, negative in 2 and unknown in 4 cases. Nineteen patients had functioning tumours, 24 patients had non-functioning tumours. Median overall survival was 98 months, and median TTP was 13 months. Analysis of grading showed a statistically significant influence on TTP when comparing the median TTP for Ki67 >10% with Ki67 <5% (p = 0.009) and Ki67 5-10% (p = 0.036). CONCLUSION: SSA may be considered as a first-line treatment for antiproliferative purposes in metastatic NET of the pancreas. Patients with a proliferation index <10% displayed a more durable response compared to those with a higher proliferation index.
Assuntos
Antineoplásicos Hormonais/farmacologia , Proliferação de Células/efeitos dos fármacos , Tumores Neuroendócrinos/patologia , Octreotida/farmacologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Estudos RetrospectivosRESUMO
INTRODUCTION: The impact on the survival of bone metastases (BM) in patients with neuroendocrine tumor (NET) is a matter of debate. BM have a key role in causing symptoms and in decreasing patients' quality of life. Although the mechanisms of the development of BM are not completely clear, it is now well understood that the Receptor Activator of Nuclear factor Kappa-B-/Ligand (RANK/RANKL)/osteoprotegerin (OPG) pathway plays a relevant role. AIM: To characterize the RANK/RANKL/OPG pathway in patients affected with NET. PATIENTS AND METHODS: Two cohorts of 15 patients each were enrolled in the study; one cohort was affected with NET without BM and the second cohort was affected with NET with BM. The serum RANK/RANKL/OPG pathway was assessed in both the groups. RESULTS: Serum OPG levels and RANKL/OPG ratio were lower and higher, respectively, in NET patients harboring BM than in those without BM. During the ROC analysis, a cut-off value of 1071 pg/ml for OPG and 0.62 for RANKL/OPG ratio were able to significantly distinguish between the two groups. CONCLUSIONS: This study indicates that RANK/RANKL/OPG pathway is imbalanced in patients with NET harboring BM. Specific alterations of this pathway could predict an early development of BM.
Assuntos
Neoplasias Ósseas/sangue , Carcinoma Neuroendócrino/sangue , Neoplasias Intestinais/sangue , Neoplasias Pulmonares/sangue , Osteoprotegerina/genética , Neoplasias Pancreáticas/sangue , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Adulto , Idoso , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/secundário , Progressão da Doença , Diagnóstico Precoce , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/genética , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Ligante RANK/sangue , Curva ROC , Receptor Ativador de Fator Nuclear kappa-B/sangue , Transdução de Sinais , Análise de SobrevidaAssuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/radioterapia , Humanos , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Medicina de Precisão , Prognóstico , Radioterapia/métodos , Radioterapia Adjuvante , Somatostatina/análogos & derivadosAssuntos
Carcinoma Neuroendócrino/secundário , Carcinoma Neuroendócrino/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Carcinoma Neuroendócrino/patologia , Hepatectomia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Cuidados Paliativos/métodos , Pneumonectomia , Guias de Prática Clínica como Assunto , Prognóstico , Reoperação , Taxa de SobrevidaRESUMO
BACKGROUND: Chromosomal instability is observed in a wide spectrum of human cancer syndromes. However, to date, little is known of the characteristic genetic changes in sporadic neuroendocrine tumours of the gastroenteropancreatic system. AIMS AND METHOD: We have studied copy number aberrations (CNAs) in 26 sporadic neuroendocrine tumours of the enteropancreatic system (12 foregut and 14 midgut tumours) by comparative genomic hybridisation (CGH), allowing simultaneous evaluation of the entire tumour genome. RESULTS: Nearly all tumours (25/26; that is, 96%) showed chromosomal imbalances, including full chromosomal aneuploidies, losses and gains of chromosome arms, interstitial deletions, and amplifications. Whereas gains of chromosomes 4, 5, and 19 were found in both foregut and midgut tumours, gains of chromosomes 20q (58%), 19 (50%), as well as 17p (50%), and partial losses of chromosomes 1p (42%), 2q (42%), 3p, 4q, and 6q (25% each) were frequently observed only in foregut tumours. In contrast, midgut tumours displayed less CNAs. Gains were detected for chromosomes 17q and 19p (57%). Most frequent losses affected chromosomes 18 (43%) and 9p (21%). CONCLUSIONS: The results of our CGH analyses revealed new distinct candidate regions in the human genome associated with sporadic neuroendocrine tumours. Some of the genetic alterations were shared by foregut and midgut tumours while others discriminated between the two groups. Thus our results allude to the involvement of identical as well as discriminative genetic loci in tumorigenesis and progression of neuroendocrine neoplasms of the foregut and midgut. Based on these findings potential new candidate genes will be discussed.
Assuntos
Aberrações Cromossômicas/genética , Neoplasias Gastrointestinais/genética , Tumores Neuroendócrinos/genética , Hibridização de Ácido Nucleico , Neoplasias Pancreáticas/genética , Adolescente , Adulto , Idoso , Aneuploidia , Deleção Cromossômica , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The nature and biology of neuroendocrine cells and of tumors derived therefrom have been the subject of intense research using cell biological and molecular approaches. Diagnostic procedures for establishing the diagnosis of a neuroendocrine tumor have been improved through the development of new serological markers and imaging procedures. Histopathological diagnosis has been refined by the introduction of a broad spectrum of marker proteins for different subtypes of neuroendocrine neoplasms. The high receptor specificity of somatostatin analogues such as octreotide or lanreotide has made these drugs valuable tools in diagnosis and therapy, and some of the achievements made as well as future directions are reviewed in this article. Another substance in use for therapy of neuroendocrine tumors is interferon-a, whose signal transduction mechanism has been investigated considerably during the past several years. In addition to biotherapy with somatostatin analogues and/or interferon-a, chemotherapy is an accepted strategy in the treatment of advanced neuroendocrine tumor disease derived from the foregut. In this context, streptozotocin has caught some attention due to its somewhat selective toxicity against neuroendocrine tumor cells. Some recent studies on the role of the glucose transporter isoform GLUT2 may provide insight into streptozotocin's action. The multiple endocrine neoplasia type-1 gene has recently been cloned, sequenced and identified as a gene potentially involved in the development of the familial cancer syndrome of multiple endocrine neoplasia type 1 (MEN-1). Mutations of this putative tumor suppressor gene have been described, and the abundance of mutations in MEN-1-related tumors as well as sporadic neuroendocrine tumors at MEN-1 locations have been demonstrated. Whether determination of MEN-1 mutations will be valuable for clinical routine is under investigation.