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Endocrine Dec 2023Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild,... (Review)
Review
Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.
Topics: Humans; Insulin Resistance; Pheochromocytoma; Sodium-Glucose Transporter 2 Inhibitors; Insulin; Diabetic Ketoacidosis; Norepinephrine; Adrenal Gland Neoplasms; Diabetes Mellitus, Type 2
PubMed: 37731140
DOI: 10.1007/s12020-023-03492-7 -
The Lancet. Digital Health Sep 2023Pheochromocytomas and paragangliomas have up to a 20% rate of metastatic disease that cannot be reliably predicted. This study prospectively assessed whether the...
BACKGROUND
Pheochromocytomas and paragangliomas have up to a 20% rate of metastatic disease that cannot be reliably predicted. This study prospectively assessed whether the dopamine metabolite, methoxytyramine, might predict metastatic disease, whether predictions might be improved using machine learning models that incorporate other features, and how machine learning-based predictions compare with predictions made by specialists in the field.
METHODS
In this machine learning modelling study, we used cross-sectional cohort data from the PMT trial, based in Germany, Poland, and the Netherlands, to prospectively examine the utility of methoxytyramine to predict metastatic disease in 267 patients with pheochromocytoma or paraganglioma and positive biochemical test results at initial screening. Another retrospective dataset of 493 patients with these tumors enrolled under clinical protocols at National Institutes of Health (00-CH-0093) and the Netherlands (PRESCRIPT trial) was used to train and validate machine learning models according to selections of additional features. The best performing machine learning models were then externally validated using data for all patients in the PMT trial. For comparison, 12 specialists provided predictions of metastatic disease using data from the training and external validation datasets.
FINDINGS
Prospective predictions indicated that plasma methoxytyramine could identify metastatic disease at sensitivities of 52% and specificities of 85%. The best performing machine learning model was based on an ensemble tree classifier algorithm that used nine features: plasma methoxytyramine, metanephrine, normetanephrine, age, sex, previous history of pheochromocytoma or paraganglioma, location and size of primary tumours, and presence of multifocal disease. This model had an area under the receiver operating characteristic curve of 0·942 (95% CI 0·894-0·969) that was larger (p<0·0001) than that of the best performing specialist before (0·815, 0·778-0·853) and after (0·812, 0·781-0·854) provision of SDHB variant data. Sensitivity for prediction of metastatic disease in the external validation cohort reached 83% at a specificity of 92%.
INTERPRETATION
Although methoxytyramine has some utility for prediction of metastatic pheochromocytomas and paragangliomas, sensitivity is limited. Predictive value is considerably enhanced with machine learning models that incorporate our nine recommended features. Our final model provides a preoperative approach to predict metastases in patients with pheochromocytomas and paragangliomas, and thereby guide individualised patient management and follow-up.
FUNDING
Deutsche Forschungsgemeinschaft.
Topics: United States; Humans; Pheochromocytoma; Retrospective Studies; Prospective Studies; Cross-Sectional Studies; Paraganglioma; Adrenal Gland Neoplasms; Machine Learning
PubMed: 37474439
DOI: 10.1016/S2589-7500(23)00094-8 -
Endocrine Oncology (Bristol, England) Jan 2023Metyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological...
OBJECTIVE
Metyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological and metabolic parameters and changes in endocrine function associated with metyrosine administration should be validated in comparison to surgery. This study was performed to confirm the effects of metyrosine on the physiological, metabolic, and endocrinological functions of patients with pheochromocytoma/paraganglioma in the perioperative period.
DESIGN
This retrospective cohort study was performed at a single university hospital.
METHODS
We included ten patients with pheochromocytoma/paraganglioma who received oral metyrosine after α-blocker therapy and consecutive surgeries. Urinary catecholamine metabolite levels and other clinical parameters were evaluated before and after metyrosine administration, and 1 week after surgery.
RESULTS
The mean age was 53.1 ± 16.1 years. Of the ten participants (four men and six women), nine had pheochromocytoma and one had paraganglioma. The median maximum metyrosine dose was 750 mg/day. Urinary catecholamine metabolite levels significantly decreased in a dose-dependent manner after metyrosine administration. Both systolic and diastolic blood pressure significantly decreased after metyrosine and surgical treatment. Metyrosine administration significantly improved insulin sensitivity, although surgery improved the the basal insulin secretion. Additionally, serum prolactin and thyroid-stimulatory hormone levels were significantly increased by metyrosine treatment, whereas plasma renin activity was decreased.
CONCLUSIONS
Metyrosine significantly reduced catecholamines in patients with pheochromocytoma/paraganglioma and ensured the safety of the surgery. Adjustment of metyrosine administration may make surgical pretreatment more effective in achieving stabilized blood pressure and improving glucose metabolism. Endocrine parameters may manifest as the systemic effects of metyrosine administration.
PubMed: 37822367
DOI: 10.1530/EO-23-0006 -
Problemy Endokrinologii Nov 2023This review article contains a summary of modern aspects of preoperative preparation, surgical treatment, and follow-up of patients with adrenal pheochromocytomas. The... (Review)
Review
This review article contains a summary of modern aspects of preoperative preparation, surgical treatment, and follow-up of patients with adrenal pheochromocytomas. The main component of preoperative preparation is the use of alpha-blockers. The need to prescribe them to all patients is increasingly disputed, especially for patients without severe hypertension. An increasing number of publications demonstrate positive results of treatment without the use of alpha-blockers, advocating an individual approach and the use of the drug according to certain indications. Minimally invasive endoscopic techniques of adrenalectomy have become widespread in surgical treatment. They are represented by laparoscopic and retroperitonescopic technic, including using their single-port modifications. The earliest possible intersection of the central vein in the past was considered the most important aspect of adrenalectomy for pheochromocytoma, currently, due to the development of surgical techniques and anesthesiological manuals, this has ceased to be a mandatory rule of successful surgery. Despite the significant influence of the intersection of this vessel on intraoperative hemodynamics, surgical tactics with its later intersection have their own justifications and do not lead to a deterioration in treatment results. The standard volume of surgical intervention for pheochromocytomas is total adrenalectomy, however, in the presence of hereditary syndromes, such as multiple endocrine neoplasia type 2 syndrome, neurofibomatosis type 1, von Hippel-Lindau syndrome, it is possible to perform cortical-sparing adrenalectomy.
Topics: Humans; Pheochromocytoma; von Hippel-Lindau Disease; Adrenal Gland Neoplasms; Multiple Endocrine Neoplasia Type 2a; Adrenalectomy; Syndrome
PubMed: 37968950
DOI: 10.14341/probl13283 -
Laboratory Investigation; a Journal of... Sep 2023Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis...
Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis occurs. Although recent phase 2 clinical trials of immune checkpoint inhibitors in the treatment of PPGL have preliminarily shown promising results, the fundamentals of immunotherapy for PPGL have not yet been established. In the early research, using bulk RNA sequencing of tumor samples from 7 PPGL patients, we found that PPGL tumor tissues exhibited high PD-L1 mRNA expression compared with adjacent normal adrenal medulla tissues, and this was related to T-cell exhaustion biomarkers. To further validate the association, in this study (n = 60), we first stratified all PPGL samples according to PD-L1 expression as determined by immunohistochemical staining, and then subjected 23 fresh PPGL tumor samples from the cohort to a quantitative polymerase chain reaction (n = 16), flow cytometry (n = 7), and multiplex-immunofluorescence staining. Subsequently, we evaluated the pathological manifestations of all 60 PPGL tumor samples and analyzed the correlation among PD-L1 expression, adverse pathological behavior, various clinicopathological data, and genotypes in PPGL. The results showed that PD-L1-positive expression correlated with the exhaustion of tumor-infiltrating T cells, preoperative abnormal elevation of plasma norepinephrine, high Ki67 index, and adverse pathological behavior in PPGL but not with genetic mutation or metastatic disease, possibly due to the limitation of the small number of patients with metastatic disease (n = 4) in the study cohort. In conclusion, our findings reveal that PD-L1 expression is associated with T-cell exhaustion and adverse pathological behavior in PPGL. These results are expected to provide a new theoretical basis and clinical guidance for the treatment of PPGL.
Topics: Humans; Pheochromocytoma; B7-H1 Antigen; T-Cell Exhaustion; Paraganglioma; Adrenal Gland Neoplasms; Lymphocytes, Tumor-Infiltrating
PubMed: 37406931
DOI: 10.1016/j.labinv.2023.100210 -
Cureus Sep 2023This report presents the case of a 45-year-old man with a history of episodic headaches, palpitations, and sweating for the past six months. His blood pressure on...
This report presents the case of a 45-year-old man with a history of episodic headaches, palpitations, and sweating for the past six months. His blood pressure on admission was 170/100 mmHg. The patient was diagnosed with pheochromocytoma confirmed by elevated levels of plasma catecholamines and metanephrines. CT imaging revealed a 3 cm mass in the left adrenal gland with evidence of local invasion into the surrounding tissues. The patient underwent a laparoscopic adrenalectomy and was discharged on the third postoperative day with normal blood pressure. Histopathological examination confirmed the diagnosis of pheochromocytoma. The patient was followed for six months postoperatively with the resolution of symptoms and no evidence of tumor recurrence on imaging. Recurrence involves complex environment-gene interactions that are poorly understood. The diagnosis of pheochromocytoma could take several weeks to several years mainly because the symptoms are nonspecific and episodic. Although sudden death is rare, the debilitations associated with pheochromocytoma are often multisystemic with cardiovascular, emotional, and metabolic components. This case report highlights the importance of early diagnosis, appropriate management, and follow-up for pheochromocytoma.
PubMed: 37727845
DOI: 10.7759/cureus.45490 -
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 -
Journal of the Endocrine Society Jul 2023In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to...
CONTEXT
In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases.
OBJECTIVE
This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients.
METHODS
In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected.
RESULTS
Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and genotype, despite a familial clustering in one-third of patients.
CONCLUSION
The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed.
PubMed: 37409183
DOI: 10.1210/jendso/bvad083 -
Medical Sciences (Basel, Switzerland) Jun 2023Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased... (Review)
Review
Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 37489462
DOI: 10.3390/medsci11030046