Diagnosis and Management of Pheochromocytomas and Paragangliomas: A Guide for the Clinician.

OBJECTIVE: The aim of this review was to provide a practical approach for clinicians regarding the diagnosis and management of pheochromocytomas and paragangliomas (PPGLs). METHODS: A literature search of PubMed was carried out using key words, including pheochromocytoma, paraganglioma, treatment, diagnosis, screening, and management. The discussion of diagnosis and management of PPGL is based on the evidence available from prospective studies when available and mostly from cohort studies, cross-sectional studies, and expert consensus. RESULTS: PPGL are neuroendocrine tumors arising from the chromaffin cells of adrenal medulla and sympathetic and parasympathetic ganglia, respectively. PPGL can be localized or metastatic, and they may secrete catecholamines, causing a variety of symptoms and potentially catastrophic and lethal complications if left untreated. The rarity of these tumors along with heterogeneous clinical presentation often poses challenges for the diagnosis and management. PPGL can be associated with several familial syndromes which are important to recognize. CONCLUSION: The last few years have witnessed an exponential growth in the knowledge around PPGL. This review aims at providing a comprehensive discussion of current concepts for clinicians regarding clinical presentation, diagnostic tools, and management strategies for PPGL.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

PURPOSE: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. METHODS: A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. RESULTS: Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens. CONCLUSION: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

Pheochromocytoma/Paraganglioma: Is This a Genetic Disorder?

Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia which often over-secrete catecholamines leading to cardiovascular morbidity and even mortality. These unique tumors have the highest heritability of all solid tumor types with up to 35-40% of patients with PCC/PGL having a germline predisposition. PURPOSE OF REVIEW: To review the germline susceptibility genes and clinical syndromes associated with PCC/PGL. RECENT FINDINGS: There are over 12 PCC/PGL susceptibility genes identified in a wide range of pathways. Each gene is associated with a clinical syndrome with varying penetrance for both primary and metastatic PCC/PGL and often includes increased risk for additional tumors besides PCC/PGL. Patients with sporadic or hereditary PCC/PGL should be monitored for life given the risk of multiple primary tumors, recurrence, and metastatic disease. All patients with PCC/PGL should be referred for consideration for clinical genetic testing given the high heritability of disease.

Chromaffin cell biology: inferences from The Cancer Genome Atlas.

Pheochromocytomas and paragangliomas (PCC/PGLs) are rare neuroendocrine tumors that are unusually diverse in metabolic profiles, in classes of molecular alterations and across a large number of altered genes. The Cancer Genome Atlas (TCGA) comprehensively profiled the molecular landscape of PCC/PGLs and identified novel genomic alterations and a new molecular classification of PCC/PGLs. In this review, we discuss the significant clinico-molecular findings of this integrated profiling study. We then review the molecular data of the TCGA cohort centering around known markers of sympathoadrenal cell lineage to better understand chromaffin cell biology. This analysis adds a new layer, that of chromaffin cell type, onto the published molecular classifications and in doing so provides inferences about underlying chromaffin cell biology and diversity.

Preoperative Metyrosine Improves Cardiovascular Outcomes for Patients Undergoing Surgery for Pheochromocytoma and Paraganglioma.

BACKGROUND: The goal of preoperative pharmacotherapy for pheochromocytoma (PCC) and paraganglioma (PGL) resection is to minimize intraoperative hemodynamic instability and perioperative cardiovascular complications, but no standard preoperative regimen exists. Historically, treatment used metyrosine and phenoxybenzamine (MP). The recent metyrosine shortage required that phenoxybenzamine alone (PA) be used for treatment. The authors examined their experience to determine the impact of preoperative metyrosine treatment on patient outcomes. METHODS: A retrospective cohort study investigated patients who underwent initial PCC/PGL resection (2000-2014). The primary outcome was intraoperative hemodynamics, measured by heart rate (HR) and systolic blood pressure (SBP). The secondary outcomes included perioperative complications and cardiovascular-specific complications (CVC). Univariate analysis was performed, and adjusted risk differences were estimated after confounding was taken into account. RESULTS: Of 174 patients, 142 (81.6 %) were in the MP group. The MP and PA patients had comparable intraoperative use of antihypertensives (83.9 vs 78.1 %; p = 0.443), vasopressors (74.6 vs 87.5 %; p = 0.120), and fluid resuscitation (mean, 24.4 vs 24.8 ml/min; p = 0.761). Although the perioperative complication rate did not differ significantly between the MP and PA groups (respectively 23.4 vs 34.4 %; p = 0.198), the PA patients had a 15.8 % higher rate of CVC even after controlling for confounders (p = 0.034). Compared with the MP patients, the PA patients had significantly more hemodynamic instability intraoperatively, with a greater range in HR (7.4 bpm; p = 0.034) and SBP (14.8 mmHg; p = 0.020). CONCLUSIONS: In this study, preoperative metyrosine improved intraoperative hemodynamic stability and decreased CVC rates in patients undergoing PCC/PGLresection. These data suggest that the addition of preoperative metyrosine may improve operative outcomes.

Patient-reported burden associated with pheochromocytoma/paraganglioma diagnosis.

Pheochromocytoma and paragangliomas (PPGLs) originate from the chromaffin cells of the adrenal medulla or neural crest progenitors outside the adrenal gland, respectively. The estimated annual incidence of PPGL is between 2.0 and 8.0/million adults. Minimal data exist on the impact of PPGL from the patient's perspective. Therefore, a survey was adapted from a previously published study on gastroenteropancreatic neuroendocrine tumors to explore the voice of patients with PPGL and learn ways to improve clinical care while understanding the current gaps to direct future research. A self-reported online survey was available to patients with PPGL and those with genetic predisposition even without PPGL from June to July 2022. Survey questions captured sociodemographic and clinical characteristics, the diagnostic workup, treatment and monitoring, quality and access to care, and financial impact. Here, we report the most relevant findings on patient experience of disease burden following diagnosis. A total of 270 people responded, the majority of whom were from the USA (79%), Caucasian (88%), and female (81%). The results of this survey highlight the burden of disease on a patient's daily life, resulting in moderate to severe financial distress, increased travel time to specialized facilities resulting in loss of work and wages, and significant delays in care. Respondents reported being unheard and unacknowledged. With a median time to diagnosis just over 2 years, the physical, mental, and emotional toll are substantial. Increasing access to PPGL specialists and centers could lead to faster diagnoses and better management, which may reduce the burden on both patients and healthcare centers.

E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.

Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG had distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations were associated with metastatic PCPG and these tumours had an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG had quiet genomes with some rare co-operative driver events observed, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies were also detected - MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identified features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.

Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing.

BACKGROUND: Pheochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumors that, although rare, are an important cause of secondary hypertension because of the high morbidity and mortality. PCC/PGL are still thought of as the "tumor of tens," with 10 % being hereditary; however, recent population based studies suggest that up to 32 % of patients have a germline mutation in one of the known common susceptibility genes (including NF1, VHL, RET, SDHB, SDHD, and SDHC). Despite this, most patients in the United States are not referred for clinical genetic testing by their physicians. We aimed to examine the mutation prevalence in a clinic-based population in the United States. METHODS: We performed a retrospective chart review of 139 consecutive patients with PCC/PGL from the medical genetics clinic at the hospital of the University of Pennsylvania from January 2004 through February 2012. RESULTS: We found a 41 % overall mutation detection rate. Twenty-six percent of the cohort had a mutation in the SDHB or SDHD genes. Of patients with at least one PGL tumor outside the adrenal gland, 53 % had an identified mutation. CONCLUSIONS: Forty-one percent of the cohort had a heritable mutation. The most commonly mutated gene was SDHB, which carries the highest risk of malignancy. These data, together with American Society of Clinical Oncology guidelines suggesting that genetic testing be performed if the risk of a hereditable mutation is at least 10 % or if it will affect medical management, strongly suggest that all patients with PCC/PGL should undergo clinical genetic testing.