Pheochromocytoma/paraganglioma crisis: case series from a tertiary referral center for pheochromocytomas and paragangliomas

Pheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it is associated with a significant mortality rate of approximately 15%, recognizing the signs and symptoms and making the appropriate diagnosis are critical. For this purpose, we report the clinical course of the crisis in four out of a total of six patients with a PPGL crisis from a cohort of 199 PPGL patients of a single tertiary referral center for PPGL patients in the Netherlands diagnosed between 2002 and 2020. Successful treatment of a PPGL crisis demands prompt diagnosis, vigorous pharmacological therapy, and emergency tumor removal if the patient continues to deteriorate.Diabetes mellitus: pathophysiological changes and therap

Interleukin-6 producing pheochromocytoma/paraganglioma: case series from a tertiary referral centre for pheochromocytomas and paragangliomas

Introduction In addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder the diagnosis. Patients and methods We report the clinical course and subsequent treatment of IL-6 producing PPGL in three patients from a single tertiary referral centre for PPGL patients in the Netherlands. Conclusion PPGL combined with persistent elevated inflammatory markers, either in the presence or absence of pyrexia, raised suspicion of IL-6 overproduction in these three patients. Although surgical resection of the tumour is the only curative treatment option, our case series adds to the accumulating evidence that alpha-blockers might be effective in these patients.Diabetes mellitus: pathophysiological changes and therap

Health-related quality of life in adrenocortical carcinoma:Development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties

Germline DLST variants promote epigenetic modifications in pheochromocytoma-paraganglioma

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle.Objective/design: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines.Patients and Setting: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals.Results: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation.Conclusions: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.MTG

Circulating adrenomedullin and B-type natriuretic peptide do not predict blood pressure fluctuations during pheochromocytoma resection: a cross-sectional study

Background: Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. Methods: Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events. Results: A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P = 0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P = 0.013 and OR: 1.54, P = 0.017, respectively). Conclusions: plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.Diabetes mellitus: pathophysiological changes and therap

Screening in adrenal tumors

Clinical epidemiolog

Value of I-123-MIBG Scintigraphy in Paraganglioma

Aim: The aim of the study was to evaluate the current role of I-123-MIBG scintigraphy in the detection and follow-up of patients with paragangliomas. Materials and Methods: 117 patients were referred for diagnostic I-123-MIBG scintigraphy based on a strong clinical suspicion, positive familial history and genetic testing, or for follow-up of paragangliomas. I-123-MIBG images were analyzed and correlated with In-111-octreotide scintigraphy, CT or MRI results. Accuracy of the imaging method was calculated per patient and per tumor per site. Results: A total of 117 patients were referred for I-123-MIBG diagnostic imaging; 80 patients were diagnosed with paraganglioma; 66 patients had a single neuroendocrine tumor and 14 patients multiple tumors. The total number of all lesions in these patients was 172. I-123-MIBG scintigraphy demonstrated 65 lesions in 56 patients (overall sensitivity: 56.3%, specificity: 84%). Lesion-per-site analysis revealed that sensitivity and specificity significantly varied per tumor site (lowest sensitivity for the head and neck: 17.5% and lowest specificity for the abdomen: 87.5%). Hormones were elevated in 85 patients: 55 I-123-MIBG tumors were positive and 35 tumors were negative. In 16 patients (13.7%) with a genetic burden and a single neuroendocrine tumor, I-123-MIBG whole-body imaging was successful at detecting a second tumor. In 2 patients (1.7%) with paragangliomas, I-123-MIBG unexpectedly detected metastases, so the restaging was properly done. Conclusion: I-123-MIBG scintigraphy remains important in pheochromocytoma and functioning neuroendocrine tumors. The value of I-123-MIBG scintigraphy is high in familial syndromes with multiple neuroendocrine tumors at different sites, multifocal tumors, and relapsing and metastatic disease. Copyright (C) 2009 S. Karger AG, BaselDiabetes mellitus: pathophysiological changes and therap

Malignant pheochromocytoma and paraganglioma: management options

Purpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-131-MIBG, Y-90 and Lu-177-DOTATATE), chemotherapy and targeted therapy. Recent findings The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype.Diabetes mellitus: pathophysiological changes and therap

Insulin resistance in patients with type 1 diabetes assessed by glucose clamp studies: systematic review and meta-analysis

Clinical epidemiolog