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2.
Cancer Genet ; 256-257: 110-114, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107390

RESUMO

We report a novel case of multiple paragangliomas in a patient who was identified with pathogenic variants in both NF1 and SDHD genes. The proband is a man with known familial NF1 disease, diagnosed clinically in childhood. Multiple head and neck paragangliomas (HNPGL) were found during investigations for acute left sided neurological symptoms, in the region of his known plexiform neurofibroma. He was referred for genetic counselling. He underwent surgery to remove a left carotid body tumor (CBT). A pheochromocytoma and paraganglioma gene panel was tested. Blood and HNPGL tumor DNA were analyzed by whole exome sequencing. In addition to the NF1 truncating variant c.5107delA, p.(Ser1703AlafsTer7), the SDHD truncating pathogenic variant c.3G > A, p.(Met1?) was found. Tumor sequencing showed no LOH of SDHD or NF1, but monoallelic loss of 11p15 and 11q12.2-q12.3 was observed. Co-occurrence of pathogenic variants in multiple cancer susceptibility genes is rare but possible, identified by the increased use of panel testing. This is the first description of a patient presenting with NF1 and SDHD dual pathology, with HNPGL development due to SDHD. This case illustrates the central role of genetic sequencing in PPGLs and the strong genotype-phenotype correlations of different genes.


Assuntos
Mutação em Linhagem Germinativa/genética , Neoplasias de Cabeça e Pescoço/genética , Neurofibromina 1/genética , Paraganglioma/genética , Succinato Desidrogenase/genética , Adulto , Sequência de Bases , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Humanos , Masculino , Paraganglioma/diagnóstico por imagem , Paraganglioma/patologia , Linhagem
4.
Genes Genet Syst ; 96(2): 55-69, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34039789

RESUMO

The pathogenesis of pheochromocytoma and paraganglioma (PCPG) catecholamine-producing tumors is exceedingly complicated. Here, we sought to identify important genes affecting the prognosis and survival rate of patients suffering from PCPG. We analyzed 95 samples obtained from two microarray data series, GSE19422 and GSE60459, from the Gene Expression Omnibus (GEO) repository. First, differentially expressed genes (DEGs) were identified by comparing 87 PCPG tumor samples and eight normal adrenal tissue samples using R language. The GEO2R tool and Venn diagram software were applied to the Database for Annotation, Visualization and Integrated Discovery (DAVID) to analyze Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO). We further employed Cytoscape with the Molecular Complex Detection (MCODE) tool to make protein-protein interactions visible for the Search Tool for Retrieval of Interacting Genes (STRING). These procedures resulted in 30 candidate DEGs, which were subjected to Kaplan-Meier analysis and validated by Gene Expression Profiling Interactive Analysis (GEPIA) to determine their influence on overall survival rate. Finally, we identified ALDH3A2 and AKR1B1, two genes in the glycerolipid metabolism pathway, as being particularly enriched in PCPG tumors and correlated with T and B tumor-infiltrating immune cells. Our results suggest that these two DEGs are closely associated with the prognosis of malignant PCPG tumors.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/metabolismo , Redes Reguladoras de Genes , Humanos , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Mapas de Interação de Proteínas , Análise de Sobrevida , Transcriptoma
5.
Eur J Endocrinol ; 185(1): 179-191, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983135

RESUMO

Objective: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. Design and methods: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. Results: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. Conclusions: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Espectrometria de Massas/métodos , Metaboloma , Paraganglioma/patologia , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Animais , Estudos de Coortes , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Células PC12 , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Prognóstico , Ratos , Análise Serial de Tecidos/métodos
6.
Aging (Albany NY) ; 13(7): 9976-9990, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33795528

RESUMO

Pheochromocytoma and paraganglioma (PCPG) is a rare neuroendocrine tumor. This study aims to identify vital prognostic genes which were associated with PCPG tumor microenvironment (TME). We downloaded transcriptome data of PCPG from TCGA database and calculated the immune scores and stromal scores by using the ESTIMATE algorithm. DEGs related to TMB were then identified. We conducted WGCNA to further extract the TME-related modules. GO, KEGG pathway analysis, and PPI network were performed. Survival analysis was conducted to identify the hub genes associated with the prognosis of PCPG. A total of 150 PCPG samples were included in this study. We obtained 1507 and 2067 DEGs based on immune scores and stromal scores, respectively. WGCNA analysis identified the red module and brown module were correlated with immune sores while the turquoise module and red module were significantly associated with stromal scores. Functional enrichments analysis revealed that 307 TME-related genes were correlated with the inflammation or immune response. Survival analysis showed that three TME-relate genes (ADGRE1, CCL18, and LILRA6) were associated with PCPG prognosis. These three hub genes including ADGRE1, CCL18, and LILRA6 might be involved in the progression of PCPG and could serve as potential biomarkers and novel therapeutic targets.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/genética , Paraganglioma/genética , Feocromocitoma/genética , Microambiente Tumoral/genética , Neoplasias das Glândulas Suprarrenais/patologia , Proteínas de Ligação ao Cálcio/genética , Quimiocinas CC/genética , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Paraganglioma/mortalidade , Paraganglioma/patologia , Feocromocitoma/mortalidade , Feocromocitoma/patologia , Prognóstico , Receptores Acoplados a Proteínas G/genética , Receptores Imunológicos/genética , Taxa de Sobrevida , Transcriptoma
7.
Am J Surg Pathol ; 45(9): 1264-1273, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826547

RESUMO

Alpha-inhibin expression has been reported in pheochromocytomas and paragangliomas (PPGLs). We analyzed alpha-inhibin immunohistochemistry in 77 PPGLs (37 pheochromocytomas [PCCs] and 40 paragangliomas) and correlated the results with catecholamine profile, tumor size, Ki-67 labeling index, succinate dehydrogenase B subunit and carbonic anhydrase IX (CAIX) staining, and genetic pathogenesis. PPGLs were classified as pseudohypoxic cluster 1 disease with documented VHL mutation or SDHx mutation or biochemical phenotype, whereas NF1-driven and RET-driven PPGLs and those with a mature secretory (adrenergic or mixed adrenergic and noradrenergic) phenotype were classified as cluster 2 disease. The Cancer Genome Atlas data on INHA expression in PPGLs was examined. Alpha-inhibin was positive in 43 PPGLs (56%). Ki-67 labeling indices were 8.07% and 4.43% in inhibin-positive and inhibin-negative PPGLs, respectively (P<0.05). Alpha-inhibin expression did not correlate with tumor size. Alpha-inhibin was expressed in 92% of SDHx-related and 86% of VHL-related PPGLs. CAIX membranous staining was found in 8 of 51 (16%) tumors, including 1 SDHx-related PCC and all 5 VHL-related PCCs. NF1-driven and RET-driven PPGLs were negative for alpha-inhibin and CAIX. Alpha-inhibin was expressed in 77% of PPGLs with a pseudohypoxia signature, and 20% of PPGLs without a pseudohypoxia signature (P<0.05). PPGLs with a mature secretory phenotype were negative for CAIX. The Cancer Genome Atlas data confirmed higher expression of INHA in cluster 1 than in cluster 2 PPGLs. This study identifies alpha-inhibin as a highly sensitive (90.3%) marker for SDHx/VHL-driven pseudohypoxic PPGLs. Although CAIX has low sensitivity, it is the most specific biomarker of VHL-related pathogenesis. While alpha-inhibin cannot replace succinate dehydrogenase B subunit immunohistochemistry for detection of SDHx-related disease, it adds value in prediction of cluster 1 disease. Importantly, these data emphasize that alpha-inhibin is not a specific marker of adrenal cortical differentiation, as it is also expressed in PCCs.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Inibinas/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/metabolismo , Anidrase Carbônica IX/metabolismo , Humanos , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Sensibilidade e Especificidade
8.
Am J Clin Pathol ; 156(4): 691-699, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-33880513

RESUMO

OBJECTIVES: Biochemical testing of urinary metanephrines is useful in the diagnosis and monitoring of pheochromocytoma and paragangliomas. We investigated the feasibility of mixture decomposition (ie, indirect) methods in verifying clinically derived reference intervals for urinary deconjugated metanephrine metabolites. METHODS: Urinary 24-hour metanephrine and normetanephrine excretion results were extracted from our data warehouse and intervals were estimated by the modern variant of the Hoffmann method, maximum likelihood estimation (MLE), and gamma mixture model using R software. RESULTS: Hoffmann, MLE, and gamma mixture models provided metanephrine and normetanephrine intervals that closely matched those derived from clinical studies. However, three-component MLE and gamma models were required for normetanephrine in adult women because the Hoffmann method was not suitable. Some data transformations caused blending of the mixed distributions and subsequent widening of the reference interval estimation, emphasizing the importance of careful data transformation for Hoffmann and MLE analyses. Gamma mixture models gave overall good agreement without the need for data transformation. CONCLUSIONS: Indirect methods have utility in verifying reference intervals in 24-hour urine specimens collected by patients. We emphasize the benefits of applying multiple decomposition methods to corroborate findings and careful application of data transformation when using Gaussian-based models.


Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Metanefrina/urina , Normetanefrina/urina , Paraganglioma/urina , Feocromocitoma/urina , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia , Valores de Referência , Estudos Retrospectivos , Adulto Jovem
9.
J Clin Endocrinol Metab ; 106(8): e2900-e2906, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33846745

RESUMO

CONTEXT: False-positive results are common for pheochromocytoma/paraganglioma (PPGL) real-world screening. OBJECTIVE: Determine the correlation between screening urine and seated plasma metanephrines in outpatients where PPGL was absent, compared to meticulously prepared and supine-collected plasma metanephrines with age-adjusted references. DESIGN: Retrospective cohort study. SETTING: Databases from a single-provider provincial laboratory (2012-2018), a validated PPGL registry, and a manual chart review from a specialized endocrine testing unit. PATIENTS: PPGL registry data excluded known PPGL cases from the laboratory database. Outpatients having both urine and plasma metanephrines <90 days apart. METHODS: The correlation between urine and seated plasma measures along with the total positivity rate. All cases of plasma metanephrines drawn in the endocrine unit were reviewed for test indication and test positivity rate. RESULTS: There were 810 non-PPGL pairs of urine and plasma metanephrines in the laboratory database; 46.1% of urine metanephrines were reported high. Of seated outpatient plasma metanephrines drawn a median of 5.9 days later, 19.2% were also high (r = 0.33 and 0.50 for normetanephrine and metanephrine, respectively). In contrast, the meticulously prepared and supine collected patients (n = 139, 51% prior high urine metanephrines) had <3% rate of abnormal high results in patients without known PPGL/adrenal mass. CONCLUSIONS: There was a poor-to-moderate correlation between urine and seated plasma metanephrines. Up to 20% of those with high urine measures also had high seated plasma metanephrines in the absence of PPGL. Properly prepared and collected supine plasma metanephrines had a false-positive rate of <3% in the absence of known PPGL/adrenal mass.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Metanefrina/sangue , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Adolescente , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Humanos , Masculino , Programas de Rastreamento , Metanefrina/urina , Pessoa de Meia-Idade , Paraganglioma/sangue , Paraganglioma/patologia , Paraganglioma/urina , Feocromocitoma/sangue , Feocromocitoma/patologia , Feocromocitoma/urina , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
10.
Endocr Pathol ; 32(2): 228-244, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33768452

RESUMO

Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/análise , Imuno-Histoquímica/métodos , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Paraganglioma/genética , Paraganglioma/patologia , Patologia Molecular/métodos , Feocromocitoma/genética , Feocromocitoma/patologia
11.
J Clin Endocrinol Metab ; 106(6): e2393-e2401, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33693908

RESUMO

CONTEXT: Treatment of pheochromocytoma and paraganglioma (PPGL) requires preintervention titration of alpha- and beta-adrenergic blockade, but patients may still be at risk for complications from catecholamine excess. Metyrosine decreases catecholamine production, making it an attractive therapeutic adjunct for select patients. EVIDENCE ACQUISITION: A systematic literature review was performed (Ovid Medline and Scopus databases) on December 17, 2019, including studies with humans and original data. Studies with 10 or more patients on metyrosine for PPGL were included. Studies were screened for overlapping populations, and the most comprehensive study was included. The references of included studies were reviewed for additional data. Patient data from our institution between 2000 and 2015 were also reviewed. EVIDENCE SYNTHESIS: Metyrosine is well tolerated when used for a short course and can improve intraoperative outcomes in PPGL. Metyrosine should be considered when a difficult PPGL resection is expected (eg, pericardiac paraganglioma, abdominal paraganglioma with great vessel involvement), a large release of catecholamines is anticipated (eg, ablative therapy, chemotherapy), or when standard alpha- and beta-adrenergic blockade are not tolerated or cannot adequately control hypertension. Side effects are generally mild and self-limited, with sedation in a majority of patients. Extrapyramidal side effects are rare but can limit use of metyrosine. Because of its expense and limited availability, metyrosine use should be carefully planned and timed in relation to surgery. CONCLUSIONS: Metyrosine is a safe addition to traditional alpha- and beta-adrenergic blockade and should be considered in those patients with PPGL at high risk for acute release of catecholamines.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Paraganglioma/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , alfa-Metiltirosina/uso terapêutico , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/etiologia , Paraganglioma/complicações , Paraganglioma/epidemiologia , Paraganglioma/patologia , Feocromocitoma/complicações , Feocromocitoma/epidemiologia , Feocromocitoma/patologia , alfa-Metiltirosina/efeitos adversos
12.
Int J Biochem Cell Biol ; 134: 105949, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33609747

RESUMO

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.


Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/enzimologia , Mitocôndrias/enzimologia , Doenças Mitocondriais/enzimologia , Paraganglioma/enzimologia , Feocromocitoma/enzimologia , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/genética
13.
Thorac Cancer ; 12(7): 1115-1117, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33569902

RESUMO

Paragangliomas in the diaphragm are extremely rare. We report the case of a 27-year-old woman with a nonfunctioning paraganglioma protruding superiorly from the right diaphragm. The patient underwent an anterior thoracotomy, and a supradiaphragmatic tumor (70 mm in diameter), which compressed the inferior vena cava and the right hepatic vein, was completely resected by combined partial resection of the right diaphragm and pericardium. To our knowledge, this is the first report of a paraganglioma situated both on the diaphragm and close to the inferior vena cava and hepatic vein. KEY POINTS.


Assuntos
Paraganglioma/diagnóstico , Cavidade Torácica/patologia , Adulto , Feminino , Humanos , Paraganglioma/patologia
14.
J Clin Endocrinol Metab ; 106(5): e1937-e1952, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33462603

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior. EVIDENCE ACQUISITION: Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review. DATA SYNTHESIS: To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. CONCLUSIONS: Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.


Assuntos
Neoplasias Abdominais/secundário , Neoplasias das Glândulas Suprarrenais/patologia , Paraganglioma/patologia , Feocromocitoma/secundário , Neoplasias Abdominais/terapia , Neoplasias das Glândulas Suprarrenais/terapia , Animais , Humanos , Paraganglioma/terapia , Feocromocitoma/terapia
15.
Future Oncol ; 17(10): 1131-1141, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506713

RESUMO

Pheochromocytomas and paragangliomas (PPG) are rare cancers arising from the adrenal medulla (pheochromocytoma) or autonomic ganglia (paraganglioma). They have highly variable biological behavior. Most PPG express high-affinity norepinephrine transporters, allowing active uptake of the norepinephrine analog, 131iodine-metaiodobenzylguanidine (131I-MIBG). Low-specific-activity forms of 131I-MIBG have been used since 1983 for therapy of PPG. High-specific-activity 131I-MIBG therapy improves hypertension management, induces partial radiological response or stable disease, decreases biochemical markers of disease activity and is well tolerated by patients. This drug, approved in the USA in July 2018, is the first approved agent for patients with unresectable, locally advanced or metastatic PPG and imaging evidence of metaiodobenzylguanidine uptake, who require systemic anticancer therapy.


Assuntos
3-Iodobenzilguanidina/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Paraganglioma/patologia , Paraganglioma/radioterapia , Feocromocitoma/patologia , Feocromocitoma/radioterapia , Gerenciamento Clínico , Humanos , Estadiamento de Neoplasias , Resultado do Tratamento
16.
Endocr Pathol ; 32(1): 134-153, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33433885

RESUMO

Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype-phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype-phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/genética , Feocromocitoma/patologia , Predisposição Genética para Doença , Genômica , Genótipo , Humanos
18.
J Clin Endocrinol Metab ; 106(2): 459-471, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33180916

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle. OBJECTIVE/DESIGN: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines. PATIENTS AND SETTING: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals. RESULTS: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation. CONCLUSIONS: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.


Assuntos
Aciltransferases/genética , Neoplasias das Glândulas Suprarrenais/patologia , Metilação de DNA , Epigênese Genética , Mutação em Linhagem Germinativa , Paraganglioma/patologia , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Biomarcadores/análise , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Paraganglioma/genética , Feocromocitoma/genética , Prognóstico , Adulto Jovem
19.
Ann Nucl Med ; 35(1): 92-101, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33135123

RESUMO

OBJECTIVE: The primary aim of this study was to evaluate the long-term outcome of 177Lu-DOTATATE PRRT in terms of clinical, biochemical and imaging response rates, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in 131I-metaiodobenzylguanidine (MIBG) negative progressive/symptomatic locally advanced or metastatic paragangliomas (PGL). The secondary aims of this study were to determine clinical toxicity of 177Lu-DOTATATE and association of PFS with various variables. MATERIALS AND METHODS: 131I-MIBG negative PGL with progressive/symptomatic locally advanced or metastatic disease that underwent 177Lu-DOTATATE PRRT from 2012 to 2019 in our institute were evaluated. Standard dose activity of 5.55-7.4 GBq per cycle of 177Lu-DOTATATE was administered in somatostatin receptor (SSTR) positive PGL. Post-PRRT response was evaluated under three broad categories: (a) symptomatic, (b) biochemical, and (c) imaging (molecular and anatomic imaging). The PFS and OS since first 177Lu-DOTATATE cycle were determined. Associations of PFS with various variables were also investigated. The clinical toxicities of 177Lu-DOTATATE in PGL were determined. RESULTS: Amongst a total of 9 PGL patients, response to 177Lu-DOTATATE was seen in six patients, two patients, four patients and three patients on symptomatic, biochemical, molecular and anatomical based imaging response evaluation categories respectively with DCR of 67%. The median PFS and OS were not reached at a median follow-up of 40 months. Estimated PFS rate of 63% (95% CI 30-96%) and OS rate of 65% (95% CI 32-97%) were noticed at 40 months. Significant association of PFS was found for site of PGL (non-HNPGL), total cumulative dose of PRRT (> 22.2 GBq), and number of PRRT cycles patient received (≥ 4cycles). 177Lu-DOTATATE was well tolerated without acute catecholamine crisis, nephrotoxicity or bone marrow suppression of any grade or high-grade (grade ≥ 2) hematological toxicities. CONCLUSION: Our study showed favorable results with minimal low-grade and easily manageable side effects of 177Lu-DOTATATE in patients of PGL. Thus, 177Lu-DOTATATE may be considered as promising therapeutic option in 131I-MIBG negative and SSTR positive subset of PGL cases. However, further prospective study in a large number of patients is required for validation of our study results.


Assuntos
3-Iodobenzilguanidina , Progressão da Doença , Octreotida/análogos & derivados , Compostos Organometálicos/uso terapêutico , Paraganglioma/diagnóstico por imagem , Paraganglioma/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores de Peptídeos/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Octreotida/uso terapêutico , Paraganglioma/patologia
20.
J Endocrinol Invest ; 44(1): 15-25, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32602077

RESUMO

BACKGROUND: Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5-26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines. AIM: The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs. RESULTS: Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using 90Y or 177Lu-DOTATATE, could be a promising therapy. In addition, high specific 131I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable 131I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials. CONCLUSIONS: The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Paraganglioma/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Animais , Gerenciamento Clínico , Humanos , Paraganglioma/patologia , Feocromocitoma/patologia , Prognóstico
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