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Clinical Endocrinology Nov 2017The outcomes of patients with metastatic phaeochromocytoma (PHEO) and paraganglioma (PGL) are unclear. We performed a systematic review and meta-analysis of baseline... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The outcomes of patients with metastatic phaeochromocytoma (PHEO) and paraganglioma (PGL) are unclear. We performed a systematic review and meta-analysis of baseline characteristics and mortality rates of patients with metastatic PHEO and PGL (PPGL).
DESIGN
Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Web of Science, and references of key articles were searched from inception to 2016.
PATIENTS
Studies comprised ≥20 patients with metastatic PPGL and reported baseline characteristics and follow-up data.
MEASUREMENTS
Reviewers extracted standardized data and assessed risk of bias using a modified Newcastle-Ottawa tool. Random-effects meta-analysis was used to pool event rates across studies.
RESULTS
Twenty retrospective noncomparative studies reported on 1338 patients with metastatic PHEO (685/1296, 52.9%) and PGL (611/1296, 47.1%), diagnosed at a mean age of 43.9 ± 5.2 years. Mean follow-up was 6.3 ± 3.2 years. Of 532 patients with reported data, 40.4% had synchronous metastases. Five-year (7 studies, n = 738) and 10-year (2 studies, n = 55) mortality rates for patients with metastatic PPGL were 37% (95% CI, 24%-51%) and 29% (95% CI, 17%-42%), respectively. Higher mortality was associated with male sex (RR 1.50; 95% CI, 1.11-2.02) and synchronous metastases (RR 2.43; 95% CI, 1.01-5.85).
CONCLUSIONS
Available low-quality evidence from heterogeneous studies suggests low mortality rates of patients with metastatic PPGL. Male sex and synchronous metastases correlated with increased mortality. The outcomes of patients with metastatic PPGL have been inadequately assessed, indicating the need for carefully planned prospective studies.
Topics: Adrenal Gland Neoplasms; Adult; Female; Humans; Male; Middle Aged; Mortality; Neoplasm Metastasis; Paraganglioma; Pheochromocytoma; Treatment Outcome
PubMed: 28746746
DOI: 10.1111/cen.13434 -
Frontiers in Endocrinology 2023Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry...
INTRODUCTION
Pheochromocytomas and paragangliomas (PCC/PGL) are rare neuroendocrine tumors and can secrete catecholamine. Previous studies have found that SDHB immunohistochemistry (IHC) can predict SDHB germline gene mutation, and SDHB mutation is closely associated with tumor progression and metastasis. This study aimed to clarify the potential effect of SDHB IHC as a predictive marker for tumor progression in PCC/PGL patients.
METHODS
We included PCC/PGL patients diagnosed in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from 2002 to 2014 for retrospective analysis and discovered that SDHB (-) staining patients had poorer prognoses. Then we examined SDHB protein expression by IHC on all tumors in the prospective series, which was composed of patients from 2015 to 2020 in our center.
RESULTS
In the retrospective series, the median follow-up was 167 months, and during follow-up, 14.4% (38/264) patients developed metastasis or recurrence, and 8.0% (22/274) patients died. Retrospective analysis revealed that 66.7% (6/9) of participants in the SDHB (-) group and 15.7% (40/255) of those in the SDHB (+) group developed progressive tumors (OR: 10.75, 95% CI: 2.72-52.60, P=0.001), and SDHB (-) was independently associated with poor outcomes after adjusting by other clinicopathological parameters (OR: 11.68, 95% CI: 2.58-64.45, P=0.002). SDHB (-) patients had shorter disease-free survival (DFS) and overall survival (OS) (P<0.001) and SDHB (-) was significantly associated with shorter median DFS (HR: 6.89, 95% CI: 2.41-19.70, P<0.001) in multivariate cox proportional hazard analysis. In the prospective series, the median follow-up was 28 months, 4.7% (10/213) patients developed metastasis or recurrence, and 0.5% (1/217) patient died. For the prospective analysis, 18.8% (3/16) of participants in the SDHB (-) group had progressive tumors compared with 3.6% (7/197) in the SDHB (+) group (RR: 5.28, 95% CI: 1.51-18.47, P=0.009), statistical significance remained (RR: 3.35, 95% CI: 1.20-9.38, P=0.021) after adjusting for other clinicopathological factors.
CONCLUSIONS
Our findings demonstrated patients with SDHB (-) tumors had a higher possibility of poor outcomes, and SDHB IHC can be regarded as an independent biomarker of prognosis in PCC/PGL.
Topics: Humans; Pheochromocytoma; Immunohistochemistry; Retrospective Studies; China; Paraganglioma; Prognosis; Adrenal Gland Neoplasms; Succinate Dehydrogenase
PubMed: 37008946
DOI: 10.3389/fendo.2023.1121397 -
Scientific Reports Jul 2023Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs)....
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.
Topics: Humans; Adrenal Gland Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Cytoplasm; Paraganglioma; Peripheral Nervous System Neoplasms; Pheochromocytoma
PubMed: 37463949
DOI: 10.1038/s41598-023-38606-8 -
The International Journal of... May 2021Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest... (Review)
Review
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.
Topics: Adrenal Gland Neoplasms; Animals; Electron Transport Complex II; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Metabolism, Inborn Errors; Mitochondria; Mitochondrial Diseases; Mutation; Paraganglioma; Pheochromocytoma; Reactive Oxygen Species; Succinate Dehydrogenase
PubMed: 33609747
DOI: 10.1016/j.biocel.2021.105949 -
Human Molecular Genetics Oct 2020Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though... (Review)
Review
Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the most frequently results from inactivating variants in genes encoding subunits of succinate dehydrogenase. Expanding knowledge of the genetics of PPGL has been translated into clinical practice by the provision of widespread testing for inherited PPGL. In this review, we explore how the molecular stratification of PPGL is being utilized to enable more personalized strategies for investigation, surveillance and management of affected individuals and their families. Translating recent genetic research advances into clinical service can not only bring benefits through more accurate diagnosis and risk prediction but also challenges when there is a suboptimal evidence base for the clinical consequences or significance of rare genotypes. In such cases, clinical, biochemical, pathological and functional imaging assessments can all contribute to more accurate interpretation and clinical management.
Topics: Adrenal Gland Neoplasms; Genetic Testing; Germ-Line Mutation; Humans; Paraganglioma; Pheochromocytoma; Precision Medicine; Signal Transduction; Succinate Dehydrogenase
PubMed: 33059362
DOI: 10.1093/hmg/ddaa201 -
European Annals of Otorhinolaryngology,... Sep 2014Surgery has been long considered to be the treatment of choice for glomus jugulare paragangliomas, as it is the only modality able to totally eradicate the tumour.... (Review)
Review
Surgery has been long considered to be the treatment of choice for glomus jugulare paragangliomas, as it is the only modality able to totally eradicate the tumour. However, despite considerable progress in interventional radiology and nerve monitoring, surgery is associated with an unacceptably high complication rate for a benign tumour, explaining the growing place of radiotherapy in the management of these tumours. This review of the literature confirms the efficacy of conformal radiotherapy with or without intensity modulation and stereotactic radiotherapy, which both achieve tumour control rates ranging from 90% to almost 100% of cases, but for different tumour volumes, almost constant stabilization or even improvement of symptoms, and a considerably lower rate of adverse effects than with surgery. However, radiotherapy remains contraindicated in the presence of intracranial invasion or extensive osteomyelitis. In the light of these results, together with the improved quality of life and a better knowledge of the natural history of this disease, many authors propose radiotherapy as first-line treatment for all glomus jugulare paragangliomas regardless of their size, particularly in patients with no preoperative deficits.
Topics: Glomus Jugulare; Humans; Paraganglioma; Radiotherapy
PubMed: 24908634
DOI: 10.1016/j.anorl.2014.01.003 -
Metabolism: Clinical and Experimental Sep 2020Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to...
BACKGROUND
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.
METHODS
Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N,N-diethylnorspermine (DENSPM) and N,N- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.
RESULTS
Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.
CONCLUSIONS
This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
Topics: Adrenal Gland Neoplasms; Animals; Biogenic Polyamines; Cell Line, Tumor; Humans; Male; Metabolomics; Mice; Mutation; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase; Xenograft Model Antitumor Assays
PubMed: 32562798
DOI: 10.1016/j.metabol.2020.154297 -
The Journal of Clinical Endocrinology... Sep 2021Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and...
CONTEXT
Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes.
OBJECTIVE
The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control.
DESIGN
A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1].
SETTING
Tertiary academic hospital.
PATIENTS
360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female.
MAIN OUTCOME MEASURES
The primary and secondary outcomes were weight and HbA1c, respectively.
RESULTS
On multivariable MEM, norepinephrine (P < 0.0005) negatively correlated with weight when all catecholamines and their derivatives were tried in the model, and normetanephrine (P < 0.0005) correlated when only metanephrines were included. In the surgical cohort (n = 272), normetanephrine decreased postoperatively and was inversely associated with weight (P < 0.0005). Elevated norepinephrine or normetanephrine at the study termination, indicative of metastatic and/or recurrent disease (MRD), correlated with weight loss. Norepinephrine and normetanephrine (P < 0.0005) directly correlated with HbA1c.
CONCLUSION
Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.
Topics: Adrenal Gland Neoplasms; Aged; Body Weight; Catecholamines; Cohort Studies; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Paraganglioma; Pheochromocytoma; Retrospective Studies; Risk Factors; United States
PubMed: 34089611
DOI: 10.1210/clinem/dgab401 -
Endocrine Jun 2017To determine the accuracy of biochemical tests for the diagnosis of pheochromocytoma and paraganglioma. (Review)
Review
Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review.
PURPOSE
To determine the accuracy of biochemical tests for the diagnosis of pheochromocytoma and paraganglioma.
METHODS
A search of the PubMed database was conducted for English-language articles published between October 1958 and December 2016 on the biochemical diagnosis of pheochromocytoma and paraganglioma using immunoassay methods or high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection for measurement of fractionated metanephrines in 24-h urine collections or plasma-free metanephrines obtained under seated or supine blood sampling conditions.
RESULTS
Application of the Standards for Reporting of Diagnostic Studies Accuracy Group criteria yielded 23 suitable articles. Summary receiver operating characteristic analysis revealed sensitivities/specificities of 94/93% and 91/93% for measurement of plasma-free metanephrines and urinary fractionated metanephrines using high-performance liquid chromatography or immunoassay methods, respectively. Partial areas under the curve were 0.947 vs. 0.911. Irrespective of the analytical method, sensitivity was significantly higher for supine compared with seated sampling, 95 vs. 89% (p < 0.02), while specificity was significantly higher for supine sampling compared with 24-h urine, 95 vs. 90% (p < 0.03). Partial areas under the curve were 0.942, 0.913, and 0.932 for supine sampling, seated sampling, and urine. Test accuracy increased linearly from 90 to 93% for 24-h urine at prevalence rates of 0.0-1.0, decreased linearly from 94 to 89% for seated sampling and was constant at 95% for supine conditions.
CONCLUSIONS
Current tests for the biochemical diagnosis of pheochromocytoma and paraganglioma show excellent diagnostic accuracy. Supine sampling conditions and measurement of plasma-free metanephrines using high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection provides the highest accuracy at all prevalence rates.
Topics: Adrenal Gland Neoplasms; Chromatography, High Pressure Liquid; Humans; Metanephrine; Paraganglioma; Pheochromocytoma; Sensitivity and Specificity; Specimen Handling; Tandem Mass Spectrometry
PubMed: 28405881
DOI: 10.1007/s12020-017-1300-y -
Endocrine Pathology Jun 2021Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although... (Review)
Review
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.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Humans; Immunohistochemistry; Paraganglioma; Pathology, Molecular; Pheochromocytoma
PubMed: 33768452
DOI: 10.1007/s12022-021-09675-0