Christina Pamporaki and Graeme Eisenhofer
Alejandro L Rosas, Anna A Kasperlik-Zaluska, Lucyna Papierska, Barbara Lee Bass, Karel Pacak and Graeme Eisenhofer
Pheochromocytoma crisis (PC) is a rare life-threatening endocrine emergency that may present spontaneously or can be unmasked by ‘triggers’, including certain medications that provoke the release of catecholamines by tumors. Several isolated cases of PC have been reported after administration of exogenous glucocorticoids; evidence that these drugs cause adverse events in patients with pheochromocytoma is mainly anecdotal.
We report four cases of PC most likely induced by glucocorticoids and review seven previous reports in the literature linking steroid administration to the development of PC.
In four new cases reported here, glucocorticoid administration was associated with a fatal outcome in one case, a pheochromocytoma multisystem crisis in another, and serious hypertensive crises in two others. Two patients had incidental adrenal masses and were undergoing high-dose dexamethasone suppression tests (DST).
Exogenous glucocorticoids may unpredictably trigger PC. Pheochromocytoma should be included in the differential diagnosis of any patient who develops a hypertensive crisis, cardiac failure, tachycardia, headache, and abdominal or chest pain after receiving exogenous glucocorticoids. Glucocorticoid induced PC is frequently associated with hemorrhagic pheochromocytoma. Although exogenous glucocorticoids cause serious complications unpredictably, they should be avoided or administered only if necessary and with caution in patients with known or suspected pheochromocytoma. During the investigation of incidental adrenal masses, pheochromocytoma should ideally be ruled out before administering glucocorticoids. However, no cases have been reported with 1 mg of dexamethasone when given as a DST in patients with pheochromocytoma; larger doses, as low as 2 mg of dexamethasone, may trigger a PC. A patient with pheochromocytoma presenting as an adrenal incidentaloma may also be at risk if exposed to glucocorticoids given as pre-treatment in case of allergy to contrast media.
Thanh-Truc Huynh, Karel Pacak, Frederieke M Brouwers, Mones S Abu-Asab, Robert A Worrell, MacClellan M Walther, Abdel G Elkahloun, David S Goldstein, Susannah Cleary and Graeme Eisenhofer
Objective: Phaeochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2) produce adrenaline, whereas those with von Hippel-Lindau (VHL) syndrome do not. This study assessed whether these distinctions relate to differences in expression of the transporters responsible for uptake and storage of catecholamines – the noradrenaline transporter and the vesicular monoamine transporters (VMAT 1 and VMAT 2).
Methods: Tumour tissue and plasma samples were obtained from 31 patients with hereditary phaeochromocytoma − 18 with VHL syndrome and 13 with MEN 2. We used quantitative PCR, Western blotting, electron microscopy, immunohistochemistry and measurements of plasma and tumour catecholamines to assess differences in expression of the transporters in noradrenaline-producing vs adrenaline-producing hereditary tumours. These differences were compared with those in a further group of 26 patients with non-syndromic phaeochromocytoma.
Results: Adrenaline-producing phaeochromocytomas in MEN 2 patients expressed more noradrenaline transporter mRNA and protein than noradrenaline-producing tumours in VHL patients. In contrast, there was greater expression of VMAT 1 in VHL than MEN 2 tumours, while expression of VMAT 2 did not differ significantly. These differences were associated with larger numbers of storage vesicles and higher tissue contents of catecholamines in MEN 2 than in VHL tumours. Differences in expression of the noradrenaline transporter were weaker, and those of VMAT 1 and VMAT 2 stronger, in noradrenaline and adrenaline-producing non-syndromic than in hereditary tumours.
Conclusions: The findings show that, in addition to differences in catecholamine biosynthesis, phaeochromocytomas in MEN 2 and VHL syndrome also differ in expression of the transporters responsible for uptake and vesicular storage of catecholamines.
Priya Kaji, Jorge A Carrasquillo, W Marston Linehan, Clara C Chen, Graeme Eisenhofer, Peter A Pinto, Edwin W Lai and Karel Pacak
Objective: [123/131I]metaiodobenzylguanidine (MIBG) scintigraphy is considered as the gold standard in the localization of pheochromocytoma. However, this method has less optimal sensitivity for the detection of pheochromocytoma associated with von Hippel–Lindau (VHL). Our preliminary results suggest that this is partially due to the low expression of cell membrane norepinephrine transporter system in VHL-related pheochromocytoma cells. Another probable cause may be the low affinity that [123/131I]MIBG has for these cells. Recently, 6-[18F]fluorodopamine ([18F]DA) positron emission tomography (PET) has been introduced as a novel functional imaging modality with high sensitivity for pheochromocytoma. Therefore, we investigated whether [18F]DA PET is more effective than [123/131I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma.
Materials and methods: In this study, we evaluated seven VHL patients in whom adrenal pheochromocytomas were confirmed by histopathology results. Adrenal pheochromocytomas were localized using computed tomography (CT), magnetic resonance imaging (MRI), [123/131I]MIBG scintigraphy and [18F]DA PET.
Results: [18F]DA PET localized pheochromocytoma in all the seven patients, as did in CT. In contrast, three out of the seven had negative results utilizing [123/131I]MIBG scintigraphy and one out of the six patients had negative MRI results.
Conclusions: [18F]DA PET was found to show more promising results when compared with [123/131I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma, with a 100% rate of localization. Thus, [18F]DA PET in conjunction with CT/MRI should be considered as an effective method for the proper localization of VHL-related adrenal pheochromocytoma.
Christina Pamporaki, Michael Bursztyn, Manja Reimann, Tjalf Ziemssen, Stefan R Bornstein, Fred C G J Sweep, Henri Timmers, Jacques W M Lenders and Graeme Eisenhofer
Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown.
In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations.
Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming.
There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations.
Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.
Mariko Sue, Victoria Martucci, Florina Frey, Jacques W M Lenders, Henri J Timmers, Mariola Pęczkowska, Aleksander Prejbisz, Brede Swantje, Stefan R Bornstein, Wiebke Arlt, Martin Fassnacht, Felix Beuschlein, Mercedes Robledo, Karel Pacak and Graeme Eisenhofer
Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations.
Design and methods
Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42±16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production.
Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours.
SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.
Laura Gieldon, Jimmy Rusdian Masjkur, Susan Richter, Roland Därr, Marcos Lahera, Daniela Aust, Silke Zeugner, Andreas Rump, Karl Hackmann, Andreas Tzschach, Andrzej Januszewicz, Aleksander Prejbisz, Graeme Eisenhofer, Evelin Schrock, Mercedes Robledo and Barbara Klink
Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1).
We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced.
Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients’ blood and tumor samples. Validation was carried out by Sanger sequencing.
Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified.
Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.
Dipti Rao, Mirko Peitzsch, Aleksander Prejbisz, Katarzyna Hanus, Martin Fassnacht, Felix Beuschlein, Christina Brugger, Stephanie Fliedner, Katharina Langton, Christina Pamporaki, Volker Gudziol, Anthony Stell, Andrzej Januszewicz, Henri J L M Timmers, Jacques W M Lenders and Graeme Eisenhofer
Measurements of plasma methoxytyramine, the O-methylated dopamine metabolite, are useful for detecting rare dopamine-producing pheochromocytomas and paragangliomas (PPGLs) and head and neck paragangliomas (HNPGLs), but utility for screening beyond that achieved using standard measurements of normetanephrine and metanephrine is unclear.
Evaluation of the additional utility of methoxytyramine compared to plasma normetanephrine and metanephrine for diagnosis of PPGLs and HNPGLs.
Comparative prospective study.
Comparison of mass spectrometric-based measurements of plasma methoxytyramine, normetanephrine and metanephrine in 1963 patients tested for PPGLs at six tertiary medical centers according to reference intervals verified in 423 normotensive and hypertensive volunteers.
Of the screened patients, 213 had PPGLs and 38 HNPGLs. Using an upper cut-off of 0.10 nmol/L for methoxytyramine, 0.45 nmol/L for metanephrine and age-specific upper cut-offs for normetanephrine, diagnostic sensitivity with the addition of methoxytyramine increased from 97.2% to 98.6% for patients with PPGLs and from 22.1% to 50.0% for patients with HNPGLs, with a small decrease in specificity from 95.9% to 95.1%. Addition of methoxytyramine did not significantly alter areas under receiver operating characteristic curves for patients with PPGLs (0.984 vs 0.991), but did increase (P < 0.05) areas for patients with HNPGLs (0.627 vs 0.801). Addition of methoxytyramine also increased the proportion of patients with PPGLs who showed highly positive predictive elevations of multiple metabolites (70.9% vs 49.3%).
While the benefit of additional measurements of plasma methoxytyramine for the detection of PPGLs is modest, the measurements do assist with positive confirmation of disease and are useful for the detection of HNPGLs.
Dirk Weismann, Mirko Peitzsch, Anna Raida, Aleksander Prejbisz, Maria Gosk, Anna Riester, Holger S Willenberg, Reiner Klemm, Georg Manz, Timo Deutschbein, Matthias Kroiss, Roland Därr, Martin Bidlingmaier, Andrzej Januszewicz, Graeme Eisenhofer and Martin Fassnacht
Reports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography–tandem mass spectrometric (LC–MS/MS) measurements of MNs to diagnose PPGLs.
In a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC–MS/MS, each in a specialized laboratory.
Plasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC–MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC–MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC–MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias.
The EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut-offs resulting in comparable diagnostic performance of EIA and LC–MS/MS assays.
Aikaterini Geroula, Timo Deutschbein, Katharina Langton, Jimmy Masjkur, Christina Pamporaki, Mirko Peitzsch, Stephanie Fliedner, Henri J L M Timmers, Stefan R Bornstein, Felix Beuschlein, Anthony Stell, Andrzej Januszewicz, Aleksander Prejbisz, Martin Fassnacht, Jacques W M Lenders and Graeme Eisenhofer
Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease.
Design and methods
Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n = 245) compared to without (n = 1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess the probability of disease and relationships to catecholamine excess.
Hyperhidrosis, palpitations, pallor, tremor and nausea were 30–90% more prevalent (P < 0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P < 0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to BMI, which was lower (P < 0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess.
This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease.