Diagnosis Of Pheochromocytomas And Paragangliomas Research Articles

8332 Genotype/Phenotype Profile Of Pheochromocytoma/Paraganglioma Patients In A Single Tertiary Referral Center Of South Texas

Abstract Disclosure: V. Desai: None. M.A. Escobar Vasco: None. C. Estrada-Zuniga: None. B. Landry: None. H. Gonzalez-Cantu: None. D. Pruthi: None. F. Tozzi: None. J. Ferrell: None. M. Kitano: None. C. Solis-Herrera: None. J.M. Bruder: None. S. Raghunathan: None. P.L. Dahia: None. Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Nearly 40% of patients with PPGLs have a heritable germline mutation and around 30% carry somatic mutations in one of >20 known susceptibility genes. 15-20% of cases can progress to metastatic disease. Recently, ethnic differences have been suggested in PPGLs and support further evaluation of ethnically diverse cohorts which can offer guidance for surveillance and patient care. Goal: The objective of this study is to identify genetic and clinical features of patients with a diagnosis of PPGL in predominant ethnic groups located in a single tertiary referral center of South Texas that is a designated Pheo-Para Alliance Clinical and Research Center of Excellence. Methods: Medical records were utilized to obtain demographic and clinical data, including age at diagnosis, gender, ethnicity, family history, tumor location, metastasis, clinical disease vs. carrier status, and genotype from patients enrolled in an IRB-approved repository. Results: 62 index patients who were diagnosed with PPGL or had a pathogenic germline mutation with no clinical disease were enrolled between 2006 to 2023. Patients were predominantly Caucasian (n=30/59, 50.8%) and Hispanic (n=24/59, 40.6%). In the Hispanic group, twenty-one were diagnosed with PPGL and three were asymptomatic carriers. This group had an average age of 38.3 years (range, 13-77), 85.7% had pheochromocytomas (11.1% were bilateral), 14.3% were metastatic, 16.7% had a positive family history, and 65% had an identifiable germline mutation. The most commonly mutated genes in Hispanics were VHL (n=5), SDHx (n=5), and EPAS1 (n=3). In the Caucasian group, thirty patients were diagnosed with PPGL and three were asymptomatic carriers. The average age for Caucasians was 46.4 years (range, 19-80). 23% had a positive family history, 66.7% had pheochromocytoma, 22.2% had metastatic disease, and 77.3% had a germline mutation. The most common genotype in Caucasians was SDHx (n=12) followed by NF1 (n=4). Conclusion: In this PPGL cohort, Hispanic patients tended to be younger at diagnosis, have lower proportion of SDH germline mutations and higher frequency of somatic mutations compared to Caucasians. This preliminary observation should inform further investigation into PPGL genotype-phenotype associations across ethnic groups toward improving surveillance and patient care. Presentation: 6/2/2024

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications.Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset.In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled.SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0–246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309–0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410–0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877–0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396–0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405–0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274–0.718]; P = .001) were associated with a reduced risk of death.SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Pitfalls in the Diagnostic Evaluation of Pheochromocytomas.

Pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumors arising from chromaffin cells, present a significant diagnostic challenge due to their clinical rarity and polymorphic symptomatology. The clinical cases demonstrate the importance of an integrated approach that combines clinical assessment, biochemical testing, and imaging to distinguish PPGLs from mimicking conditions, such as obstructive sleep apnea and interfering medication effects, which can lead to false-positive biochemical results. Although a rare condition, false-negative metanephrine levels can occur in pheochromocytomas, but imaging findings can give some clues and increase suspicion for a pheochromocytoma diagnosis. This expert endocrine consult underscores the critical role of evaluating preanalytical conditions and pretest probability in the biochemical diagnosis of PPGLs. Moreover, a careful differentiation of PPGLs from similar conditions and careful selection and interpretation of diagnostic tests, with focus on understanding and reducing false positives to enhance diagnostic accuracy and patient outcomes, is crucial.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Clinical diagnosis of pheochromocytoma and paraganglioma-induced secondary hypertension through UPLC-MS/MS analysis of plasma catecholamines and their metabolites.

This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced secondary hypertension using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n=79) and a PPGL without hypertension (n=76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC-MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL-induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p<.05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p<.05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL-induced secondary hypertension.

SAT310 Single Institution Retrospective Case Cohort Of Adult Cyanotic Congenital Heart Disease And Associated Pheochromocytoma And Paraganglioma

Abstract Disclosure: R.B. Jones: None. B. Bennett: None. D. Cohen: Consulting Fee; Self; Novartis Pharmaceuticals, Consultant, Medtronic, Consultant, Recor, Consultant. Grant Recipient; Self; Medtronic, Research Support, Recor, Research Support. Other; Self; Metavention, DSMB. Introduction: Improved management for patients with cyanotic congenital heart disease (CCHD) has led to prolonged lifespan and a noticeable increase in patients with CCHD presenting with pheochromocytoma and paraganglioma (PPGL). PPGL susceptibility genes including VHL, SDH(x), FH, EPAS1 have been connected to a common signaling pathway that activates hypoxia-inducible factors (HIF). 4 of 5 patients with CCHD and PPGL were reported to have a somatic gain-of-function mutation in EPAS1 encoding HIF-2α. One hypothesis is that the hypoxic environment positively selects for cells with gain-of-function mutations predisposing patients to develop PPGL even when environment is no longer hypoxic. PPGL was diagnosed 13-53 years after surgical correction of CCHD in these patients. We report a case series on 9 CCHD/PPGL patients treated at our institution. Objective: To describe a cohort of patients with CCHD who developed PPGLs. Methods: A retrospective chart review of patients with CCHD treated for PPGL at our institution was performed describing demographics, CCHD and related treatments, symptoms of PPGL and Hct/SpO2 at diagnosis, tumor size, catecholamine biochemistries, imaging and genetic analysis when available. Results: Four of 9 patients were female. Average age of diagnosis of PPGL was 30.7 years (SD 9.6 years, range 15-47 years). CCHD anomalies included Tetralogy of Fallot (2), hypoplastic right ventricle (2) and hypoplastic left ventricle (2). Most surgeries to correct CCHD were performed within days of life; the latest reported surgical procedure was at age 12, 1 patient had a subsequent heart transplant. Patients experienced hot flashes (5), arrhythmias (4), hypertension (4), abdominal pain and nausea (2), headaches (1) and asymptomatic (1). Hct and SpO2 ranged from 38%-53% and 85%-99% respectively. Three patients had multiple PPGLs; 2 had metastatic or recurrent PPGL. Metanephrines at diagnosis ranged from normal to 23x the upper limit of normal (ULN). Catecholamines ranged from normal to 16x ULN. Location of PPGL included 6 mediastinal and abdominal paraganglioma (PGLs), 5 head and neck PGLs, and 3 pheochromocytomas. Tumor size ranged from 9-65mm at maximum diameter on pathology. 7/9 patients had germline mutation testing; one SDHB mutation, one SDHA mutation of undetermined significance, and one BARD1 mutation were identified. Conclusions: The extended timeframe between onset of cyanosis and development of PPGL supports long term regular monitoring of CCHD patients to detect PPGL. We suggest screening with plasma metaneprines and catecholamines at age 15 and every 3-5 years after.

Biochemical Assessment of Pheochromocytoma and Paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances.

Biomarker identification of immune-related genes in pheochromocytoma and paraganglioma.

Although we have a good understanding of the diagnosis and treatment of pheochromocytoma and paraganglioma (PPGL), the underlying pathogenesis and molecular pathways of PPGL need to be further studied. This study aimed to use bioinformatics to analyze the role of immune-related genes (IRGs) in the pathogenesis of PPGL. GSE19422 and GSE60459 microarray data were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the "limma" package in R, and genes overlapping with IRGs were screened using the "VennDiagram" package. A protein-protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the core genes were identified by Cytoscape, followed by enrichment analysis and receiver operating characteristic (ROC) curve analysis to evaluate the diagnostic efficacy of the core genes. In addition, the level of immune cell infiltration of PPGL was analyzed and the target drug of the core gene was predicted. A total of 1,105 DEGs were identified from the 2 datasets, of which 94 were IRGs, suggesting that the occurrence of PPGL involved immune-related pathways. Through PPI and Cytoscape, a total of 2 core genes: fibroblast growth factor 2 (FGF2), FYN proto-oncogene (FYN), and vascular cell adhesion molecule 1 (VCAM1) were identified, and the ROC curve showed that these 3 core genes had good efficacy in the diagnosis of PPGL, and more than 50 potential therapeutic drugs could be predicted based on these 3 core genes. Subsequent immunoinfiltration analysis showed that mast cells activated were significantly elevated in patients with PPGL, negatively correlated with macrophages M2, and positively correlated with the level of dendritic cells activated. This study found that immunity is closely related to the occurrence of PPGL, and that FGF2, FYN, and VCAM1 may be potential biomarkers and therapeutic targets of PPGL.

PS-C22-5: PLASMA METANEPHRINES PROVIDE GREATER SPECIFICITY THAN URINARY METANEPHRINES IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA: A PROSPECTIVE TRIAL

Introduction: Pheochromocytoma and paraganglioma (PPGL), and obstructive sleep apnea (OSA) are important secondary causes of hypertension. Both plasma and urinary metanephrines have high diagnostic sensitivity and specificity for diagnosis of PPGL. Patients with OSA have increased nocturnal catecholamine release, which can lead to increased metanephrines production over 24 hours. We hypothesized that morning plasma metanephrines have a higher diagnostic accuracy than 24-hour urinary metanephrines in patients with OSA. Methods: We recruited patients undergoing polysomnography for suspected OSA. Plasma and 24-hour urinary metanephrines were measured. Patients with elevated metanephrines had repeated measurements of metanephrines, imaging and follow-up, to diagnose, or exclude, PPGL. Results: Seventy-six patients completed polysomnography and biochemical testing, of which 68 had OSA. One patient had a PPGL, while PPGL was excluded in the remaining patients. At baseline, OSA patients were more likely to have falsely-elevated urinary (17 of 67, 25.4%), than falsely-elevated plasma metanephrines (2 of 67, 2.9%) (P &lt; 0.01). Seven patients had normal metanephrines on repeat testing. Nine patients with persistently elevated metanephrines underwent abdominal imaging: six patients had no PPGL, one had lipid-rich adrenal adenomas, one had indeterminate adrenal adenoma, and one had bladder tumor. This final patient with biopsy-proven bladder PPGL had marginally-elevated urinary metanephrines, but false-negative plasma metanephrines, due to the small tumor size. Falsely-elevated urine metanephrines were more common in patients with severe OSA (13 of 3, 38.2%), compared to moderate OSA (1 of 13, 7.7%) and mild OSA (3 of 20, 15%), P &lt; 0.01. Falsely-elevated plasma and urine metanephrines were all due to elevation of normetanephrine, while metanephrine was normal in all patients. Declines in metanephrines were observed only in patients with OSA treated with continuous positive pressure ventilation, while those untreated had no improvements. Conclusion: In patients with OSA, metanephrines measured in plasma provide better specificity than those measured in urine for the diagnosis of PPGL. However, one patient with a small PPGL was missed by plasma metanephrines.

Hemodynamics in Patients With Pheochromocytoma or Paraganglioma Undergoing Non-neuroendocrine Operations.

Surgical resection of pheochromocytoma and paraganglioma (PPGL) may be associated with excessive hemodynamic variability. Whether hemodynamic variability occurs in patients with undiagnosed PPGL undergoing unrelated, non-neuroendocrine, operations is unknown. We identified patients who underwent non-neuroendocrine surgical procedures up to 5y before pathologic diagnosis of PPGL. For each PPGL, two non-PPGL patients were matched based on sex, age, type, and year of operation. Electronic medical records were reviewed for intraoperative blood pressures, heart rates, and hemodynamic variability was assessed with range (maximum-minimum), standard deviation, coefficient of variation, and average real variability. Thirty-seven PPGL patients underwent operations preceding the diagnosis of PPGL: 25 pheochromocytomas, 11 paragangliomas, and one metastatic pheochromocytoma. Median interquartile range tumor size at diagnosis was 35mm (23 to 60). The time from index operation to PPGL diagnosis was ≤12mo in 21 (56.8%) patients. In 23 (62.2%) patients, the subsequently diagnosed PPGL was functional. Fifteen (40.5%) PPGL and 20 (27.0%) control patients were preoperatively treated for hypertension (P=0.149). Maximum intraoperative systolic BP was >180mmHg for 4 (10.8%) PPGL patients and 3 (4.1%) controls (P=0.219). Two PPGL patients had intraoperative systolic BP >230mmHg. No significant differences were found with all other measures of intraoperative hemodynamic variability. Similarly, in secondary analysis there was no significant difference in intraoperative hemodynamic variability between biochemically active PPGL and their respective controls. Patients with undiagnosed PPGL undergoing a wide variety of non-neuroendocrine operations had intraoperative hemodynamic variability comparable to non-PPGL patients undergoing the same type of procedures.

Proneuropeptide Y and neuropeptide Y metabolites in healthy volunteers and patients with a pheochromocytoma or paraganglioma

Neuropeptide Y (NPY1-36) is a vasoconstrictor peptide co-secreted with catecholamines by sympathetic nerves, the adrenal medulla, and neoplasms such as pheochromocytomas and paragangliomas (PPGLs). It is produced by the intracellular cleavage of proNPY and metabolized into multiple fragments with distinct biological activities. NPY immunoassays for PPGL have a diagnostic sensitivity ranging from 33 to 100%, depending on the antibody used.We have validated a multiplex micro-UHPLC-MS/MS assay for the specific and sensitive quantification of proNPY, NPY1-39, NPY1-37, NPY1-36, NPY2-36, NPY3-36, NPY1-35, NPY3-35, and the C-flanking peptide of NPY (CPON) (collectively termed NPYs), and determined the NPYs reference intervals and concentrations in 32 PPGL patients before, during, and after surgery.Depending on the peptide measured, NPYs were above the upper reference limit (URL) in 20% to 67% of patients, whereas plasma free metanephrine and normetanephrine, the gold standard for PPGL, were above the URL in 40% and 87% of patients, respectively. Age, sex, tachycardia, and tumor localization were not correlated with NPYs. Plasma free metanephrines performed better than NPYs in the detection of PPGL, but NPYs may be a substitute for an early diagnosis of PPGL for patients that suffer from severe kidney impairment or receiving treatments that interfere with catecholamine reuptake.

Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma.

Catecholamine-producing tumors of childhood include most notably neuroblastoma, but also pheochromocytoma and paraganglioma (PPGL). Diagnosis of the former depends largely on biopsy-dependent histopathology, but this is contraindicated in PPGL where diagnosis depends crucially on biochemical tests of catecholamine excess. Such tests retain some importance in neuroblastoma though continue to largely rely on measurements of homovanillic acid (HVA) and vanillylmandelic acid (VMA), which are no longer recommended for PPGL. For PPGL, urinary or plasma metanephrines are the recommended most accurate tests. Addition of methoxytyramine to the plasma panel is particularly useful to identify dopamine-producing tumors and combined with normetanephrine also shows superior diagnostic performance over HVA and VMA for neuroblastoma. While use of metanephrines and methoxytyramine for diagnosis of PPGL in adults is established, there are numerous pitfalls for use of these tests in children. The establishment of pediatric reference intervals is particularly difficult and complicated by dynamic changes in metabolites during childhood, especially in infants for both plasma and urinary measurements, and extending to adolescence for urinary measurements. Interpretation of test results is further complicated in children by difficulties in following recommended preanalytical precautions. Due to this, the slow growing nature of PPGL and neglected consideration of the tumors in childhood the true pediatric prevalence of PPGL is likely underappreciated. Earlier identification of disease, as facilitated by surveillance programs, may uncover the true prevalence and improve therapeutic outcomes of childhood PPGL. For neuroblastoma there remain considerable obstacles in moving from entrenched to more accurate tests of catecholamine excess.

Study of stability and interference for catecholamines and metanephrines, 3-methoxytyramine: key point of an accurate diagnosis for pheochromocytoma and paraganglioma

Background Accurate diagnosis of pheochromocytoma and paraganglioma (PPGLs) is highly dependent on the detection of metanephrines and catecholamines. However, the systematic investigation on influencing factors including specimen (plasma or whole blood), anticoagulant, storage conditions, and interference factors need further confirmation. Methods Blood with heparin-lithium or EDTA-K2 were collected, stability of epinephrine (EPI), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN), 3-methoxytyramine (3-MT) in whole blood and plasma at room temperature and 4 °C for different storage times, stability of plasma MN, NMN and 3-MT at −20 °C and −80 °C were investigated. Plasma with hemoglobin (1 g/L, 2 g/L, 3 g/L, 4 g/L, 6 g/L), TG (<5 mmol/L, 5–8 mmol/L, >8 mmol/L) were prepared. Results EPI, NE, DA were prone to degrade at room temperature, samples should be centrifuged at 4 °C. EPI and NE were stable in whole blood at 4 °C for 4 h and in plasma for 2 h. For MN, NMN, 3-MT, plasma can be stable at room temperature and 4 °C for at least 6 h, which is better than whole blood; there was no significant difference when stored at −20 °C and −80 °C for 7 days. Heparin-lithium had a slight advantage over EDTA-K2. EPI, NE, DA should not be performed when Hb > 1 g/L or TG > 5 mmol/L. MN, NMN, 3-MT should not be performed when Hb > 2 g/L, whereas TG had no interference. Conclusions According to the actual clinical application scenario, this study provided a reliable basis for the accurate diagnosis of PPGLs.

Diagnostic Accuracy of Salivary Metanephrines in Pheochromocytomas and Paragangliomas

Measurements of plasma free metanephrines are recommended for diagnosing pheochromocytomas and paragangliomas (PPGL). Metanephrines can be detected in saliva with LC-MS/MS with sufficient analytical sensitivity and precision. Because collecting saliva is noninvasive and less cumbersome than plasma or urine sampling, we assessed the diagnostic accuracy of salivary metanephrines in diagnosing PPGL. This 2-center study included 118 healthy participants (44 men; mean age: 33 years (range: 19--74 years)), 44 patients with PPGL, and 54 patients suspected of PPGL. Metanephrines were quantified in plasma and saliva using LC-MS/MS. Diagnostic accuracy; correlation between plasma and salivary metanephrines; and potential factors influencing salivary metanephrines, including age, sex, and posture during sampling, were assessed. Salivary metanephrines were significantly higher in patients with PPGL compared with healthy participants (metanephrine (MN): 0.19 vs 0.09 nmol/L, P < 0.001; normetanephrine (NMN): 2.90 vs 0.49 nmol/L, P < 0.001). The diagnostic sensitivity and specificity of salivary metanephrines were 89% and 87%, respectively. Diagnostic accuracy of salivary metanephrines was 88%, with an area under the ROC curve of 0.880. We found a significant correlation between plasma and salivary metanephrines (Pearson correlation coefficient: MN, 0.86, P < 0.001; NMN, 0.83, P < 0.001). Salivary NMN concentrations were higher when collected in a seated position compared with supine (P < 0.001) and increased with age (P < 0.001). Salivary metanephrines are a promising tool in the biochemical diagnosis of PPGL. Salivary metanephrines correlate with plasma free metanephrines and are increased in patients with PPGL. At this time, however, salivary metanephrines cannot replace measurement of plasma free metanephrines.

Pheochromocytoma and Paraganglioma in Pregnancy: a New Era.

Pheochromocytoma and paraganglioma (PPGL) in pregnancy is a rare entity and management of these patients is fraught with uncertainty. Our objective is to review current literature and discuss diagnosis and management of these patients. Outcomes of PPGL in pregnancy have improved in recent years. The greatest risk for adverse maternal and fetal outcomes is the diagnosis of PPGL after delivery. Alpha- and beta-adrenergic blockade is well tolerated and is associated with less adverse outcomes. Antepartum surgery is not associated with improved maternal or fetal outcomes. Biochemical testing and cross-sectional imaging should be performed prior to conception for patients with a known germline variant associated with PPGL. Medical therapy should be initiated when PPGL is diagnosed in pregnancy. Antepartum surgery should be reserved for special circumstances. Case detection testing in high-risk patients can identify PPGL before pregnancy.

Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.

Giant Adrenal Pheochromocytoma Presenting With Stroke

Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from the adrenal medulla or from paravertebral ganglia of the sympathetic chain(1). The tumours commonly produce one or more catecholamines: epinephrine, norepinephrine, and dopamine leading to a classic triad of presentation with pounding headache, profuse sweating, and palpitations occurs in spells; However, one in 10 patients may be completely asymptomatic and the diagnosis of PPGL is frequently missed(2). Care Report: A 29 years old African female presented with one-month history of throbbing headache, palpitations, profuse sweating, and unintentional weight loss. Her previous medical history and family history was unremarkable. She was found to have accelerated hypertension and a small lacunar infarct and some suspected subarachnoid hemorrhage on MRI head but was clinically silent. Investigation for secondary causes of hypertension revealed high metanephrine in urine and her imaging showed giant adrenal mass suggestive of pheochromocytoma.CT Abdomen of large left adrenal necrotic solid mass lesion with heterogenous enhancement of its solid components measuring 6.5 x 6.1 x 7 cm in maximum AP, TR and CC dimensions respectively.She was scheduled for open resection and left adrenalectomy after approximatly10 day and was treated with high-sodium diet, alpha blockers, and beta blockers perioperatively. Histopathology examination revealed Pheochromocytoma measuring 8 x 7 x 5 cm with diffuse growth >10% of tumor volume with central necrosis; PASS =4, which has malignant potential. She recovered well post operatively and required no further antihypertensive therapy or hormonal replacement, follow up hormonal profile and imaging with Iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy were negative for remnants or metastasis,further evaluation with gallium DOTATATE PET CT and molecular genetic testing was considered, but it was not available. Conclusion: Pheochromocytoma is a rare cause of secondary hypertension with a variable clinical presentation. Episodes of tumoral catecholamine release, are thought to be responsible for the high prevalence of cardiovascular emergencies, such as myocardial infarction, heart failure, and stroke as a complication of hypertensive crisis. Timely diagnosis and treatment are crucial to prevent life-threatening complications.

Changes in Clinical Presentation and Perioperative Management of Pheochromocytomas and Paragangliomas: A Four-Decade Experience in a Academic Center

Objective: Latin American reports on pheochromocytomas and paragangliomas (PPGL) are scarce. Recent studies have shown changes in both clinical presentation and management of these patients. We aimed to assess the main characteristics of PPGL patients in a single academic center over the last four decades. Experimental design: Cohort study. Patients and methods: Demographic, clinical, biochemical, genetic and perioperative data from 105 PPGL patients were retrospectively and prospectively collected over the 1980–2019 period. Patients were categorized into four groups (14 patients in the 1st, 25 patients in the 2nd, 27 patients in the 3th and 39 patients in the 4th decade) according to the date of diagnosis. Results: The mean age at diagnosis was 46±19 years, and the tumor size was 5.3±2.2 cm, female gender was 63%, bilateral tumor of 15%, paragangliomas 9% and metastatic disease in 15%. The aforementioned parameters remained stable across the four decades. During the study period we observed significant increases in doxazosin dosing (2.7±2.6 mg vs. 8.0±4.5 p<0.003) and laparoscopic procedures (28% vs. 84% p<0.001) along with a decrease in the length of hospital stay (10.0±8.9 vs. 3.8±1.7 days p=0.007). Among the 24 genetic tests performed, we identified 59% germline mutations. The most frequent mutations were RET (18%) and SDHX (18%), followed by VHL (14%), MAX (5%) and NF1 (4%). Notably, in the last decade we observed a dramatic increase in the proportion of incidental PPGL diagnosis (0% vs. 53% p<0.001) and genetic testing analyses (0 vs. 19 p<0.001). When comparing incidental diagnosis (n=25) versus clinically suspicious cases(n=50), incidentalomas had fewer adrenergic symptoms (38 vs. 62%; p<0.001), and lower rates of hypertension (64 vs. 80%; p=0.01), hypertension crises (28 vs. 44%; p=0.02), functionality (79 vs. 100%; p=0.01) and total catecholamines and/or metanephrine levels (8.4 vs. 12.5 fold above the upper normal limit; p=0.04). Conclusions: The implementation of a multidisciplinary program increased diagnosis and genetic testing and also optimized anesthesia and surgical procedure, translating into a notorious improvement in perioperative outcomes. In addition, we observed a change in the clinical presentation of PPGL in recent decades with amarked increase in incidental cases, which highlights the importance of early diagnosis and treatment.

Acute cardiac complications and subclinical myocardial injuries associated with pheochromocytoma and paraganglioma

BackgroundCatecholamine excess arising from pheochromocytomas and paragangliomas (PPGLs) can cause a wide spectrum of cardiac manifestations, including acute cardiac complications (ACCs) and subclinical myocardial injuries (SMIs). In this study, we aimed to conduct a comprehensive analysis of ACCs and SMIs in a large cohort of patients with PPGLs.MethodsWe retrospectively analyzed the clinical data of consecutive patients with PPGLs admitted between January 2013 and July 2020 (n = 189). The prevalence of ACCs and SMIs and characteristics of patients identified with ACCs and SMIs were investigated. Moreover, comparisons were performed between patients with and without ACCs.ResultsFourteen patients (7.4%) fulfilled the criteria for ACCs, including nine (4.8%) who presented with Takotsubo-like cardiomyopathy, four (2.1%) with heart failure with preserved ejection fraction, and finally one (0.5%) with catecholamine-induced cardiomyopathy. Compared to those without ACCs (n = 175), patients with ACCs had a higher prevalence of epinephrine-producing PPGLs (81.8% vs 33.9%, P = 0.006) and were more likely to show invasive behavior (61.5% vs 27.3%, P = 0.022) or hemorrhage/necrosis (53.9% vs 17.4%, P = 0.005) on histology. The apical sparing pattern (5/7, 71.4%) was the dominant impairment pattern of longitudinal strain (LS) for patients displaying Takotsubo-like cardiomyopathy. In patients without cardiac symptoms, a fairly high proportion (21/77, 27.3%) of patients who underwent screening for troponin and/or natriuretic peptide and/or echocardiography had SMIs.ConclusionsOne in every fourteen PPGL patients presented with ACCs, and in the patients with Takotsubo-like cardiomyopathy, the apical sparing pattern was the primary impairment pattern of LS. Additionally, nearly one-third of patients without symptoms had SMIs. The diagnosis of PPGLs should be considered in patients with acute reversible cardiomyopathy, especially in those exhibiting an apical sparing pattern of LS.

Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force.

Pheochromocytoma and paraganglioma (PPGLs) are rare catecholamine-secreting neuroendocrine tumors but can be life-threatening. Although most PPGLs are benign, approximately 10% have metastatic potential. Approximately 40% cases are reported as harboring germline mutations. Therefore, timely and accurate diagnosis of PPGLs is crucial. For more than 130 years, clinical, molecular, biochemical, radiological, and pathological investigations have been rapidly advanced in the field of PPGLs. However, performing diagnostic studies to localize lesions and detect metastatic potential can be still challenging and complicated. Furthermore, great progress on genetics has shifted the paradigm of genetic testing of PPGLs. The Korean PPGL task force team consisting of the Korean Endocrine Society, the Korean Surgical Society, the Korean Society of Nuclear Medicine, the Korean Society of Pathologists, and the Korean Society of Laboratory Medicine has developed this position statement focusing on the comprehensive and updated diagnosis for PPGLs.