RESUMO
BACKGROUND: Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. METHODS: Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. RESULTS: Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464). CONCLUSION: Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.
Assuntos
Tumor Carcinoide , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Gástricas , Síndrome de Zollinger-Ellison , Celulas Tipo Enterocromafim , Gastrinas , HumanosRESUMO
BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.
Assuntos
Neoplasias Gastrointestinais/cirurgia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Alemanha , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Neuroendocrine Neoplasia of the digestive tract Abstract. Neuroendocrine neoplasia are a rare and heterogenous tumor entity with long median survival even in metastatic situation. Surgery is the key therapeutic option although a wide range of other therapies are available in metastatic situation. Milestones in classification and grading were achieved by the European Neuroendocrine Tumor Society (ENETS) leading to practical guidelines and WHO- and TNM-classification comparable to the colorectal carcinoma. These new guidelines enable the handling of a rare and complex tumor entity.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Trato Gastrointestinal/patologia , Humanos , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , PrognósticoRESUMO
To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/genética , Neoplasias Colorretais/genética , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Gástricas/genética , Idoso , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Éxons/genética , Feminino , Seguimentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Oximas/farmacologia , Oximas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosforilação/genética , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Análise Serial de Tecidos , Vemurafenib/farmacologiaRESUMO
BACKGROUND/AIMS: Neuroendocrine tumors of the small intestine (SI-NETs) exhibit an increasing incidence and high mortality rate. Until now, no fundamental molecular event has been linked to the tumorigenesis and progression of these tumors. Only the loss of chromosome 18 (Chr18) has been shown in up to two thirds of SI-NETs, whereby the significance of this alteration is still not understood. We therefore performed the first comprehensive study to identify Chr18-related events at the genetic, epigenetic and gene/protein expression levels. METHODS: We did expression analysis of all seven putative Chr18-related tumor suppressors by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Next-generation exome sequencing and SNP array analysis were performed with five SI-NETs with (partial) loss of Chr18. Finally, we analyzed all microRNAs (miRNAs) located on Chr18 by qRT-PCR, comparing Chr18+/- and Chr18+/+ SI-NETs. RESULTS: Only DCC (deleted in colorectal cancer) revealed loss of/greatly reduced expression in 6/21 cases (29%). No relevant loss of SMAD2, SMAD4, elongin A3 and CABLES was detected. PMAIP1 and maspin were absent at the protein level. Next-generation sequencing did not reveal relevant recurrent somatic mutations on Chr18 either in an exploratory cohort of five SI-NETs, or in a validation cohort (n = 30). SNP array analysis showed no additional losses. The quantitative analysis of all 27 Chr18-related miRNAs revealed no difference in expression between Chr18+/- and Chr18+/+ SI-NETs. CONCLUSION: DCC seems to be the only Chr18-related tumor suppressor affected by the monoallelic loss of Chr18 resulting in a loss of DCC protein expression in one third of SI-NETs. No additional genetic or epigenetic alterations were present on Chr18.
Assuntos
Aberrações Cromossômicas , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Proteínas de Transporte/metabolismo , Ciclinas/metabolismo , Receptor DCC , Elonguina , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Intestinais/patologia , Masculino , Tumores Neuroendócrinos/patologia , Fosfoproteínas/metabolismo , Receptores de Superfície Celular/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
OBJECTIVE: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. METHODS: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. RESULTS: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). CONCLUSIONS: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions.
Assuntos
Neoplasias Brônquicas/complicações , Neoplasias Brônquicas/epidemiologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Neoplasia Endócrina Múltipla Tipo 1/epidemiologia , Adulto , Idoso , Neoplasias Brônquicas/diagnóstico por imagem , Neoplasias Brônquicas/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico por imagem , Neoplasia Endócrina Múltipla Tipo 1/patologia , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Tomografia Computadorizada de EmissãoRESUMO
The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.
Assuntos
Biomarcadores Tumorais/análise , Insulinoma/patologia , Proteínas de Neoplasias/biossíntese , Neoplasias Pancreáticas/patologia , Proteômica/métodos , Adulto , Idoso , Cromatografia Líquida , Eletroforese em Gel Bidimensional , Feminino , Humanos , Imuno-Histoquímica , Insulinoma/metabolismo , Insulinoma/mortalidade , Estimativa de Kaplan-Meier , Masculino , Microdissecção , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Espectrometria de Massas por Ionização por Electrospray , Análise Serial de TecidosRESUMO
BACKGROUND: Myelodysplastic syndromes (MDS) present with a normo- or hyperplastic bone marrow in most cases. We aimed at a characterization of patients with different types of cellularity. METHODS: We assessed marrow cellularity both by histology and cytology in 1270 patients and analyzed hematologic, cytogenetic, and prognostic parameters accordingly. RESULTS: The concordance of the assessment of cellularity differed dramatically between histology and cytology as only 36.5% were described as hypocellular by both methods (P < 0.0005) (hypocellular 16.4%, normocellular 23.3%, hypercellular 60.3%). There were no major differences with regard to hematopoietic insufficiency. The presence of fibrosis was associated to hypercellular bone marrow. Median survival differed from 38 months in hypocellular, 42 months in normocellular, and 25 months in hypercellular MDS (P < 0.0005). AML progression rates were 33% for hypercellular MDS after 2 yr, whereas hypo- and normocellular had a progression rate of 19% after 2 yr (P = 0.018). IPSS and IPSS-R were able to identify different risk groups within all three cellularity groups. CONCLUSION: Based on our data, hypocellular patients obviously do not present as a separate entity, as there were no striking differences with regard to cytogenetics and WHO types. Assessment of cellularity should be performed by histopathology.
Assuntos
Medula Óssea/patologia , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Progressão da Doença , Feminino , Testes Hematológicos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , PrognósticoRESUMO
INTRODUCTION: Liver metastases of GEP-NETs are a known major prognostic factor with a strong effect on patients' survival. To date, various treatment options are available, whereas surgery remains the only curative option. Because large liver resections often cannot be performed due to insufficient remnant liver volume, a special operative technique, "cherry picking" (multiple nonanatomic liver resections), can be used as a tissue-preserving procedure. METHODS: Of 91 patients with various GEP-NETs, 16 patients were identified with synchronous or metachronous multifocal, bilobular liver metastases (>10). All were treated with "cherry picking." Patient records were reviewed retrospectively and clinical data and pathology results were analyzed. RESULTS: Mean survival after primary tumour resection was 82.8 versus 41.2 months after liver surgery. All 16 patients are still alive. Mean recurrence-free survival after primary tumour operation was 49.8 versus 24.6 months after liver surgery. Complications of cherry picking included two postoperative biliary leakages and three small hepatic abscesses (conservative/interventional approach 25 % (n = 4), surgical approach 6.25 % (n = 1). There was no postoperative mortality. Initial hormonal symptoms (5/16 patients) completely disappeared postoperatively in 2 patients and were significantly decreased in 3 patients. CONCLUSIONS: The tissue-preserving surgical technique "cherry picking" has developed due to improved imaging techniques and increased knowledge in liver anatomy, which has helped to make this approach safer and easier. Highly selected patients with multiple bilobular liver metastases of GEP-NET can benefit from this special surgical approach, also applicable for recurrent metastases.
Assuntos
Neoplasias Gastrointestinais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Glutathione peroxidase 4 (GPx4), an abundant selenoenzyme, is ubiquitously expressed in a tissue-, cell- and differentiation-dependent manner, and it is localized in cytoplasmic, mitochondrial, and nuclear cellular compartments. Here, we report cytoplasmic and nuclear localization of GPx4 in Caco-2 intestinal epithelial cells. Enterocytic differentiation of Caco-2 cells triggers an increase in GPx4 mRNA and protein levels, mediated by enhanced promoter activity. We identified a combined cAMP response element (CREB) and CCAAT/enhancer binding protein (C/EBP) site as critical for the differentiation-triggered GPx4 promoter activity. Induction of GPx4 correlated with C/EBPα transcript levels during differentiation, suggesting a role of C/EBPα as regulator of enterocytic GPx4 expression. Consistent with the in vitro results, GPx4 protein was detected in cytoplasmic and nuclear compartments of enterocytes in human intestinal epithelia. GPx4 is uniformly expressed in colonic crypts and is differentially expressed along the crypt-to-villus axis in the small intestine with a more pronounced expression of GPx4 in the upper villi, which contain fully differentiated enterocytes. These data suggest that intestinal GPx4 expression is modulated by the enterocytic differentiation program, and the results support a direct role of nuclear GPx4 in the (selenium-dependent) prevention of oxidative damage in the gastrointestinal tract.
Assuntos
Diferenciação Celular/fisiologia , Núcleo Celular/enzimologia , Citoplasma/enzimologia , Enterócitos/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Glutationa Peroxidase/biossíntese , Elementos de Resposta/fisiologia , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Células CACO-2 , Enterócitos/citologia , Trato Gastrointestinal/enzimologia , Glutationa Peroxidase/genética , Humanos , Oxirredução , Fosfolipídeo Hidroperóxido Glutationa PeroxidaseRESUMO
Introduction Invasive breast cancer with neuroendocrine differentiation is a rare subtype of breast malignancy. Due to frequent changes in the definition of these lesions, the correct diagnosis, estimation of exact prevalence, and clinical behaviour of this entity may be challenging. The aim of this study was to evaluate the prevalence, clinical features, and outcomes in a large cohort of patients with breast cancer with neuroendocrine differentiation. Patients Twenty-seven cases of breast cancer with neuroendocrine differentiation have been included in this analysis. Twenty-one cases were identified by systematic immunohistochemical re-evaluation of 465 breast cancer specimens using the neuroendocrine markers chromogranin A and synaptophysin, resulting in a prevalence of 4.5%. A further six cases were identified by a review of clinical records. Results Median age at the time of diagnosis was 61 years. 70% of patients had T2â-â4 tumors and 37% were node-positive. The most common immunohistochemical subtype was HR-positive/HER2-negative (85%). 93% were positive for synaptophysin and 48% for chromogranin A. Somatostatin receptor type 2A status was positive in 12 of 24 analyzed tumors (50%). Neuroendocrine-specific treatment with somatostatin analogues was administered in two patients. The 5-year survival rate was 70%. Conclusions Breast cancer with neuroendocrine differentiation is mostly HR-positive/HER2-negative and the diagnosis is made at a higher TNM stage than in patients with conventional invasive breast carcinoma. Moreover, breast cancer with neuroendocrine differentiation was found to be associated with impaired prognosis in several retrospective trials. Due to somatostatin receptor 2A expression, somatostatin receptor-based imaging can be used and somatostatin receptor-targeted therapy can be offered in selected cases.
RESUMO
ABSTRACT: The presence of primary neuroendocrine tumors in the liver is still a matter of controversy. We present a case of a somatostatin-receptor-positive mass of the liver in the 68Ga-DOTATOC PET/CT. No other primary tumor was found after conventional imaging, endoscopically, and after liver-segment resection. Immunohistochemically, a constellation of findings was found to be compatible with a primary neuroendocrine neoplasm of the liver.
Assuntos
Neoplasias Hepáticas/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Idoso , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Octreotida/análogos & derivados , Compostos OrganometálicosRESUMO
Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan-Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC (p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC (p = 0.42) as well as in SCLC demonstrating a shift from low to high expression (p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.
RESUMO
BACKGROUND: Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1. METHODS: Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization. RESULTS: The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set. CONCLUSIONS: The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.
Assuntos
Adenoma/patologia , Glucagon/metabolismo , Neoplasias Pancreáticas/patologia , Adenoma/genética , Adenoma/metabolismo , Adulto , Inibidor de Quinase Dependente de Ciclina p27/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
A role of sphingolipids for inflammatory bowel disease and cancer is evident. However, the relative and separate contribution of sphingolipid deterioration in inflammation versus carcinogenesis for the pathophysiology of colitis-associated colon cancer (CAC) was unknown and therefore examined in this study. We performed isogenic bone marrow transplantation of inducible sphingosine-1-phosphate (S1P) lyase knockout mice to specifically modulate sphingolipids and associated genes and proteins in a compartment-specific way in a DSS/AOM mediated CAC model. 3D organoid cultures were used in vitro. S1P lyase (SGPL1) knockout in either immune cells or tissue, caused local sphingolipid accumulation leading to a dichotomic development of CAC: Immune cell SGPL1 knockout (I-SGPL-/-) augmented massive immune cell infiltration initiating colitis with lesions and calprotectin increase. Pathological crypt remodeling plus extracellular S1P-signaling caused delayed tumor formation characterized by S1P receptor 1, STAT3 mRNA increase, as well as programmed cell death ligand 1 expression, accompanied by a putatively counter regulatory STAT1S727 phosphorylation. In contrast, tissue SGPL1 knockout (T-SGPL-/-) provoked immediate occurrence of epithelial-driven tumors with upregulated sphingosine kinase 1, S1P receptor 2 and epidermal growth factor receptor. Here, progressing carcinogenesis was accompanied by an IL-12 to IL-23 shift with a consecutive development of a Th2/GATA3-driven, tumor-favoring microenvironment. Moreover, the knockout models showed distinct lymphopenia and neutrophilia, different from the full SGPL1 knockout. This study shows that depending on the initiating cellular S1P source, the pathophysiology of inflammation-induced cancer versus cancer-induced inflammation develops through separate, discernible molecular steps.
Assuntos
Aldeído Liases/fisiologia , Carcinogênese , Colite/etiologia , Neoplasias do Colo/complicações , Inflamação/etiologia , Aldeído Liases/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Células Cultivadas , Colite/genética , Colite/patologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Inflamação/genética , Lisofosfolipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.
Assuntos
Neoplasias Duodenais/patologia , Predisposição Genética para Doença , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Somatostatina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Duodenais/metabolismo , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/patologia , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/metabolismo , Paraganglioma/metabolismo , Paraganglioma/patologia , Prognóstico , Somatostatinoma/metabolismo , Somatostatinoma/patologia , SíndromeRESUMO
BACKGROUND: Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary. DESIGN: One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively. RESULTS: Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors. CONCLUSIONS: Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.
Assuntos
Biomarcadores Tumorais/análise , Proteínas de Homeodomínio/análise , Tumores Neuroendócrinos/química , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patologia , Fator de Transcrição CDX2 , Proteínas de Ligação a DNA/análise , Neoplasias Gastrointestinais/química , Neoplasias Gastrointestinais/patologia , Humanos , Imuno-Histoquímica , Proteínas com Homeodomínio LIM , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Sensibilidade e Especificidade , Fatores de TranscriçãoRESUMO
Persistent hyperinsulinemic hypoglycemia in adults is usually caused by solitary benign insulinomas. Nesidioblastosis, a term that has been used to designate a functional disorder of the beta cells, is a rare cause of persistent hyperinsulinemic hypoglycemia in adults, but seems to have increased in frequency. The histopathologic criteria for adult nesidioblastosis are similar to those used for the diagnosis of the diffuse form of congenital hyperinsulinism in infants and include beta-cell hypertrophy, islet hyperplasia, and an increase in the beta-cell mass. However, the degree and extent of these features vary much more from patient to patient than in newborns. The cause of adult nesidioblastosis is not known, but the recently observed association with gastric bypass surgery in obese patients suggests that a reactive process possibly unmasks or induces a defect in the beta cell, resulting in its hyperfunction.
Assuntos
Nesidioblastose/etiologia , Nesidioblastose/patologia , Adulto , Previsões , Humanos , Células Secretoras de Insulina/patologia , Nesidioblastose/diagnóstico , Nesidioblastose/genética , Nesidioblastose/terapiaRESUMO
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
RESUMO
Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired preclinical research in NET. Herein, we establish and characterize a lymph node-derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared with existing NET cell lines BON and QGP-1. In vivo growth was assessed in a xenograft mouse model. The neuroendocrine identity of NT-3 was verified by expression of multiple NET-specific markers, which were highly expressed in NT-3 compared with BON and QGP-1. In addition, NT-3 expressed and secreted insulin. Until now, this well-differentiated phenotype is stable since 58 passages. The proliferative labeling index, measured by Ki-67, of 14.6% ± 1.0% in NT-3 is akin to the original tumor (15%-20%), and was lower than in BON (80.6% ± 3.3%) and QGP-1 (82.6% ± 1.0%). NT-3 highly expressed somatostatin receptors (SSTRs: 1, 2, 3, and 5). Upon subcutaneous transplantation of NT-3 cells, recipient mice developed tumors with an efficient tumor take rate (94%) and growth rate (139% ± 13%) by 4 weeks. Importantly, morphology and neuroendocrine marker expression of xenograft tumors resembled the original human tumor.Implications: High expression of somatostatin receptors and a well-differentiated phenotype as well as a slow growth rate qualify the new cell line as a relevant model to study neuroendocrine tumor biology and to develop new tumor treatments. Mol Cancer Res; 16(3); 496-507. ©2018 AACR.