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Journal of Clinical Ultrasound : JCU Jan 2023To analyze the correlation between catecholamines and echocardiographic parameters in patients with pheochromocytoma and paraganglioma (PPGL).
PURPOSE
To analyze the correlation between catecholamines and echocardiographic parameters in patients with pheochromocytoma and paraganglioma (PPGL).
METHODS
Sixty-six patients who underwent surgical resection of pathologically proven PPGL from January 2016 to June 2019 were examined. Echocardiographic parameters were compared between patients with elevated catecholamine concentrations and those with normal concentrations.
RESULTS
The percentage of patients with elevation of any catecholamine (NE, DA, or E, and their metabolites) did not significantly differ between patients with normal and abnormal left ventricular ejection function (LVEF) or diastolic function (LVDF). E wave deceleration time (EDT) was significantly lower in patients with elevation of any catecholamine than in those with normal concentrations (p = 0.024). EDT was significantly lower in patients with elevated NE and its metabolites than in patients with normal NE concentration (p = 0.004). After adjusting for gender and age, EDT was significantly negatively correlated with elevated NE and its metabolites in regression analysis (B-value, -39.853; p = 0.023) and correlation analysis (r = -0.349; p = 0.004).
CONCLUSION
NE and its metabolites may have an impact on left ventricular diastolic function, which can be reflected by EDT. EDT was negatively correlated with elevated NE and its metabolites.
Topics: Humans; Pheochromocytoma; Catecholamines; Paraganglioma; Echocardiography; Adrenal Gland Neoplasms; Ventricular Dysfunction, Left
PubMed: 36054716
DOI: 10.1002/jcu.23290 -
Internal Medicine (Tokyo, Japan) Nov 2021
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma
PubMed: 34024860
DOI: 10.2169/internalmedicine.7413-21 -
Journal of Veterinary Internal Medicine Jan 2023Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs).
BACKGROUND
Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs).
HYPOTHESIS/OBJECTIVES
To report RIs for plasma, urinary and salivary concentrations of free metanephrines and to determine the diagnostic performance of plasma free normetanephrine (pNMN) and metanephrine (pMN) concentrations in dogs with PCC, hypercortisolism (HC), and nonadrenal illness (NAI).
ANIMALS
Eighty healthy dogs, 11 PCC dogs, 25 HC dogs, 6 NAI dogs.
METHODS
Plasma, urine, and saliva were collected prospectively from healthy dogs, and free metanephrine concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, medical records of dogs that had plasma free metanephrine concentrations measured by LC-MS/MS between 2018-2021 were studied retrospectively.
RESULTS
The RIs for free metanephrines in plasma, urine and saliva are reported. Dogs with PCC had significantly higher pNMN than dogs with HC (P < .001) and NAI (P = .002). The PCC dogs had significantly higher pMN than HC dogs (P < .001), but not higher than NAI dogs (P = .29). Using the upper reference limit, pNMN (>3.56 nmol/L) showed high sensitivity (100%, 95% confidence interval [CI]: 72-100) and specificity (94%, 95% CI: 79-99) for diagnosis of PCC, whereas pMN (>2.49 nmol/L) showed moderate sensitivity (73%, 95% CI: 39-94) and high specificity (94%, 95% CI: 79-99).
CONCLUSIONS AND CLINICAL IMPORTANCE
With establishment of these RIs, biochemical testing for PCC in dogs can be substantially improved. Measurement of pNMN is superior to pMN in dogs with PCC.
Topics: Dogs; Animals; Metanephrine; Pheochromocytoma; Chromatography, Liquid; Retrospective Studies; Tandem Mass Spectrometry; Normetanephrine; Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Dog Diseases
PubMed: 36637037
DOI: 10.1111/jvim.16624 -
Frontiers in Endocrinology 2023Pheochromocytomas (PCC)/paragangliomas (PGL) are catecholamine (CA) -secreting neuroendocrine tumors, which are known as PPGL due to their histological and... (Review)
Review
Pheochromocytomas (PCC)/paragangliomas (PGL) are catecholamine (CA) -secreting neuroendocrine tumors, which are known as PPGL due to their histological and pathophysiological similarities. In addition to the typical triad of paroxysmal headache, palpitation, and sweating, PPGL may also be accompanied by symptoms and signs involving multiple organs and systems such as the cardiovascular system, digestive system, endocrine system, and nervous system. Currently, surgical resection is the first choice for PPGL. Safe and effective surgical management of complicated PPGL is the goal of clinical work. In this paper, we discuss this hot issue based on complicated PPGL cases, aiming to share our experience of the surgical management strategy of PPGL.
Topics: Humans; Pheochromocytoma; Paraganglioma; Adrenal Gland Neoplasms; Neuroendocrine Tumors; Catecholamines
PubMed: 37152961
DOI: 10.3389/fendo.2023.1129622 -
Frontiers in Endocrinology 2022Adrenal hemorrhage is a rare, usually life-threating complication. The most common neoplasm resulting in spontaneous adrenal bleeding is pheochromocytoma and it accounts...
BACKGROUND
Adrenal hemorrhage is a rare, usually life-threating complication. The most common neoplasm resulting in spontaneous adrenal bleeding is pheochromocytoma and it accounts for nearly 50% of cases. Currently, the recommendations for the diagnosis and management of patients with adrenal bleeding due to pheochromocytoma are unavailable.
MATERIALS AND METHODS
We performed a database search for all pheochromocytoma patients, diagnosed and treated from 2005 to 2021 in tertiary endocrinology center. 206 patients were identified, 183 with complete data were included in the analysis. We investigated clinicopathological characteristics, treatment and outcomes of hemorrhagic pheochromocytoma cases and characterize our approach to perioperative diagnosis and medical management. Finally our experiences and data from previously published articles concerning adrenal hemorrhage were analyzed to propose a diagnostic and therapeutic algorithm for hemorrhagic pheochromocytomas.
RESULTS
In the whole group, seven patients (4 men and 3 women) with adrenal bleeding were found, (3.8%). Median patient's age was 49 years (range: 36-78 years). The most common manifestation of adrenal bleeding was acute abdominal pain (5/7). Two patients developed shock. Hormonal assessment was performed in five patients, based on 24-hour urinary fractionated metanephrines with urinary 3-methoxytyramine. Normetanephrine was elevated in all patients, metanephrine and 3-methoxytyramine - in four cases (4/5). Most patients (6/7) had symptoms suggesting pheochromocytoma before hemorrhage - most commonly paroxysmal hypertension (4/7). One patient died, before the diagnosis of adrenal bleeding was made. Diagnostic imaging performed in six out of seven patients revealed adrenal tumor, with median largest diameter equal to 7.4 cm (range: 5-11 cm). Five patients had elective surgery, in one case an urgent surgery was performed. In all cases the diagnosis of pheochromocytoma was confirmed in postoperative histopathology or in autopsy. The perioperative survival rate was 85.7%.
CONCLUSIONS
Diagnosis of pheochromocytoma should be always considered in patients with adrenal bleeding, especially with accompanying abdominal pain, hemodynamic shock and previous history of pheochromocytoma-associated symptoms. Lack of proper diagnosis of pheochromocytoma before surgery is associated with an additional perioperative risk. To improve the decision making in this life-threatening clinical situation, based on our results and literature data, we proposed a diagnostic and treatment algorithm.
Topics: Abdominal Pain; Adrenal Gland Neoplasms; Adult; Aged; Algorithms; Female; Hemorrhage; Humans; Male; Middle Aged; Pheochromocytoma
PubMed: 35992110
DOI: 10.3389/fendo.2022.908967 -
Frontiers in Endocrinology 2023Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
Topics: Humans; Pheochromocytoma; Citric Acid Cycle; Ketoglutaric Acids; Paraganglioma; Adrenal Gland Neoplasms; Mutation; Succinates; Succinic Acid; Signal Transduction; Fumarates; Dioxygenases; Tumor Microenvironment
PubMed: 37867526
DOI: 10.3389/fendo.2023.1274239 -
Frontiers in Endocrinology 2023To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence...
PURPOSE
To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease).
METHODS
This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection.
RESULTS
A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence.
CONCLUSION
The recurrence of PPGLs occurred more frequently in patients with mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.
Topics: Humans; Pheochromocytoma; Normetanephrine; Neoplasm Recurrence, Local; Paraganglioma; Adrenal Gland Neoplasms; Brain Neoplasms; Neoplasms, Second Primary
PubMed: 38155946
DOI: 10.3389/fendo.2023.1279828 -
Asian Journal of Surgery Jan 2022This study aimed to evaluate management and prognosis in children with pheochromocytoma who were treated at an Egyptian tertiary center.
OBJECTIVE
This study aimed to evaluate management and prognosis in children with pheochromocytoma who were treated at an Egyptian tertiary center.
METHODS
The authors conducted an 8-year retrospective analysis for 17 patients who were presented from January 2013 to January 2021. Clinical criteria, operative details, and follow-up data were assessed. Overall (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method. An event was assigned with the occurrence of recurrence or metachronous disease, or death.
RESULTS
Median age at diagnosis was 14 years (range: 6-17.5 years). Ten patients (58.8%) were males and seven (41.2%) were females. Hypertension-related symptoms were the main presentations in 15 patients (88%). None of the included children underwent genetic testing. Sixteen patients (94%) had unilateral tumors (right side: 12), whereas only one was presented with bilateral masses. The median tumor size was 7 cm (range: 4-9 cm). Metastatic workup did not reveal any metastatic lesions. All patients underwent open adrenalectomy, and clinical manifestations were completely resolved after surgery. Adjuvant therapy was not administered to any patient. There were no deaths or relapses at a median follow-up time of 40 months, whilst two children had metachronous disease after primary resection. Both were managed by adrenal-sparing surgery, and they achieved a second complete remission thereafter. Five-year OS and EFS were 100% and 88%, respectively.
CONCLUSIONS
Complete surgical resection achieves excellent clinical and survival outcomes for pheochromocytoma in children. Meticulous, long-term follow-up is imperative for early detection of metachronous disease to facilitate adrenal-sparing surgery. Genetic assessment for patients and their families is essential; however, it was not available at our institution.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Child; Female; Humans; Male; Neoplasm Recurrence, Local; Pheochromocytoma; Retrospective Studies; Treatment Outcome
PubMed: 34325990
DOI: 10.1016/j.asjsur.2021.07.029 -
Cell Reports Sep 2023The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells....
The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.
Topics: Humans; Animals; Mice; Pheochromocytoma; Germ-Line Mutation; Adrenal Gland Neoplasms; Mutation; Ubiquitination; Proto-Oncogene Proteins c-ret; Membrane Proteins
PubMed: 37659079
DOI: 10.1016/j.celrep.2023.113070 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Aug 2021To explore the surgical strategy and experience of reoperation for pheochromocytoma and paraganglioma which is very challenging.
OBJECTIVE
To explore the surgical strategy and experience of reoperation for pheochromocytoma and paraganglioma which is very challenging.
METHODS
The clinical data of 7 patients with pheochromocytoma and paraganglioma who underwent reoperation in Department of Urology, Peking University Third Hospital from August 2016 to February 2021 were analyzed retrospectively. There were 4 males and 3 females, with an average age of (44.1±11.5) years (28-60 years), 6 cases on the right side and 1 case on the left side. The causes of the operations included: (1) 2 cases of tumor recurrence after resection; (2) The primary operations failed to completely remove the tumors in 3 cases, because the tumors were large and closely related to blood vessels. (3) Pheochromocytoma and paraganglioma wasn't diagnosed before primary operation, therefore, drug preparation wasn't prepared. Two cases were interrupted by severe blood pressure fluctuations during the primary operations. Imaging evaluation, catecholamine biochemical examination and adequate adrenergic α receptor blockers were administrated in all the cases. The surgical approaches included open transperitoneal surgery in 4 cases, robot-assisted laparoscopy in 1 case and retroperitoneal laparoscopy in 2 cases. The innovative techniques included mobilization of the liver, inferior vena cava transection and anastomosis, and transection of left renal vein.
RESULTS
The average tumor size was (8.0±3.2) cm (3.6-13.9 cm). The median interval between the reoperation and the primary operation was 9 months (IQR: 6, 19 months). The median operation time was 407 min (IQR: 114, 430 min) and the median blood loss was 1 500 mL (IQR: 20, 3 800 mL). Operations of 5 cases were performed successfully, and 1 case failed only by exploration during the operation. One case died perioperatively. There were 5 cases of intraoperative blood transfusion, the median transfusion volume of red blood cells was 800 mL (IQR: 0, 2 000 mL). One case experienced postoperative lymphorrhagia, and recovered after conservative treatment. The renal function was normal in 2 cases after resection and anastomosis of inferior vena cava or transection of left renal vein. The average postoperative hospital stay was (7.2±3.3) d (4-13 d). The median follow-up time of 6 patients was 33.5 months (IQR: 4.8, 48.0 months). The case who failed in the reoperation still survived with tumor and there was no recurrence in the rest of the patients.
CONCLUSION
The reoperation of pheochromocytoma and paraganglioma, which can not be resected in the primary operation or recurred postoperatively, is difficult with high risk of hemorrhage, and there is a risk of failure and perioperative death. Different surgical approaches and strategies need to be adopted based on the different situation.
Topics: Adrenal Gland Neoplasms; Adult; Female; Humans; Laparoscopy; Male; Middle Aged; Neoplasm Recurrence, Local; Paraganglioma; Pheochromocytoma; Reoperation; Retrospective Studies
PubMed: 34393247
DOI: 10.19723/j.issn.1671-167X.2021.04.029