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Phaeochromocytomas and paragangliomas (PPGLs) are revealed by acute cardiovascular complications involving end-organ damage in up to 20% of cases, a presentation associated with particularly high risk for mortality. Among such cases, PPGLs should be considered in patients with unexplained left ventricular failure, multi-organ failure, hypertensive crises or shock. The diagnosis of PPGL commonly relies on measurements of metanephrines in plasma or urine. However, acute critical illness is usually associated with sympathoadrenal activation. Thus, levels of metanephrines in patients in an acute emergency or intensive care setting, whether treated or not with vasoactive drugs, usually cannot be used to reliably diagnose PPGL. Delays in provision of diagnostic test results, particularly when these require 24-h urine collections, may also be incompatible for any need for rapid decisions on patient management or therapeutic interventions. The acute emergency situation therefore represents one exception to the rule where imaging studies to search for a PPGL may be undertaken without biochemical evidence of a catecholamine-producing tumour., (© 2015 John Wiley & Sons Ltd.)

Background: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest., Aim: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines., Methodology: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3., Results: The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU)., Conclusions: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU., (© 2014 John Wiley & Sons Ltd.)

Objective: To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine., Design and Methods: Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant)., Results: Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97·5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1·29 vs 0·79 nmol/l), metanephrine (0·49 vs 0·41 nmol/l) and methoxytyramine (0·42 vs 0·18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%)., Conclusions: High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5·7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions., (© 2013 John Wiley & Sons Ltd.)

Objective: Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making., Design and Patients: We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers., Measurement and Results: The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0·7-2·8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma., Conclusions: A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description., (© 2013 John Wiley & Sons Ltd.)

Unlabelled: A diagnosis of bilateral pheochromocytoma warrants exclusion of hereditary pheochromocytoma., Objective: To describe the first case of a bilateral pheochromocytoma associated with V804M mutation in the RET proto-oncogene., Patients: The index case was a 54-year-old man with bilateral adrenal masses discovered during a CT scan performed for other reasons., Measurements: Genetic analysis included exons 8-11 and 13-17 in the RET proto-oncogene, all four exons and flanking intronic regions in the SDHD gene, all eight exons and flanking intronic regions in the SDHB, and all three exons in the VHL gene., Results: Investigations revealed elevated urinary metanephrines (32.3 micromol/day), and laparoscopic bilateral adrenalectomy confirmed bilateral pheochromocytomas. A heterozygous V804M mutation in exon 14 of the RET was found in the index case and in four relatives. Total thyroidectomy, performed in four of five affected members in this kindred, disclosed a medullary thyroid carcinoma in the index case and in a 50-year-old woman, and nodular C-cell hyperplasia in the other two subjects., Conclusions: This clinical case suggests that individuals carrying the germline V804M mutation should be screened annually for the presence of pheochromocytoma.

Background: There are limitations to currently available biochemical tests for pheochromocytoma. Our objective was to evaluate the diagnostic efficacy of a novel tandem mass spectrometry assay for the measurement of fractionated urinary metanephrines in patients suspected to have a pheochromocytoma. We also developed clinically based cut-offs for positivity of this measurement., Methods: We examined the medical records of 506 patients (including 102 patients with a catecholamine-producing tumour) who underwent measurement of 24-h urinary fractionated metanephrines using tandem mass spectrometry as well as adrenal imaging at Mayo Clinic, Rochester. The cut-offs for positivity were defined as follows: total metanephrines (sum of the metanephrine fractions) 5163 nmol/day, normetanephrine fraction 4001 nmol/day, metanephrine fraction 1531 nmol/day. Receiver operating characteristic (ROC) curves were constructed., Results: The diagnostic efficacy was as follows: normetanephrine fraction sensitivity 87.3% [(95% confidence interval (CI) 79.4-92.4%], specificity 95.0% (92.5-96.8); metanephrine fraction sensitivity 56.9% (47.2-66.1), specificity 95.0% (92.5-96.8); elevation of either normetanephrine or metanephrine fraction sensitivity 97.1% (91.7-99.0) and specificity 91.1% (87.9-93.5). Areas under the ROC curves (AUCs) were 0.972 (95% CI 0.955-0.990) for the normetanephrine fraction, 0.800 (0.741-0.858) for the metanephrine fraction, 0.991 (0.985-0.996) for total metanephrines, and 0.991 (0.985-0.996) for a regression-derived ROC curve incorporating both the metanephrine and normetanephrine fractions., Conclusion: Measurement of 24-h urinary fractionated metanephrines by a tandem mass spectrometry assay appears to be an effective biochemical technique in the investigation of pheochromocytoma.

Objective: Chromogranin A (CgA) is the most accurate general marker of neuroendocrine tumours. Supranormal CgA concentrations have been recorded in patients with tumours of neuroectodermal origin such as phaeochromocytoma and paraganglioma., Design: The present study was performed to assess the role of CgA determination in the management of patients with phaeochromocytoma, in comparison with urinary catecholamines and their metabolites., Patients: The patients studied included 22 cases with phaeochromocytoma at initial presentation or at relapse some years after surgical cure or during follow-up of a malignant phaeochromocytoma. Seventeen patients were evaluated before and after surgical removal of phaeochromocytoma. To assess the specificity of the hormonal parameters, 20 subjects were enrolled as controls; they were from a group of patients referred to our observation for possible phaeochromocytoma and who were subsequently proven not to have the disease., Results: Urinary epinephrine and norepinephrine were supranormal in 82% and 77% of patients, respectively. Urinary metanephrines and normetanephrines were supranormal in 84% and 89% of patients, respectively. The combination of urinary metanephrine and normetanephrine had a sensitivity of 100% in identifying a phaeochromocytoma. CgA was supranormal in 91% of patients. Combining the results of CgA and urinary catecholamines (epinephrine and norepinephrine), the sensitivity for diagnosis of phaeochromocytoma was 100%. Urinary catecholamines, metabolites (metanephrine and normetanephrine) and CgA levels in patients with malignant phaeochromocytoma did not differ significantly from those of patients with benign lesions. In most cases, CgA normalized after surgery., Conclusions: Our results indicate that CgA is a good marker of phaeochromocytoma; measurement of CgA could have a role in the follow-up of patients operated on for phaeochromocytoma.

Objective: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period., Results: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully., Conclusion: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Objective: We have identified a large kindred with multiple endocrine neoplasia 2A (MEN 2A) due to a mutation at RET codon 609 that results in a cysteine to serine substitution, a mutation previously identified in only one case in the literature. We characterized the clinical phenotype of the kindred and the biochemical mechanism of this new mutation., Patients and Design: The index case, a 42-year-old woman, presented with pheochromocytoma. We screened 29 family members for the presence of the mutation. Of the 15 mutation-positive family members, 11 agreed to undergo further evaluation by physical examination, calcium and pentagastrin-stimulated calcitonin levels, measurement of urinary metanephrines, adrenal imaging and serum calcium levels. Biochemical characterization of the mutation was by transient transfection of human neuroblastoma cells and Western blot analysis., Results: This kindred demonstrated an inheritance pattern consistent with autosomal dominant pheochromocytoma. Strikingly, no clinically evident case of medullary thyroid cancer (MTC) was observed among mutation-positive family members. Thyroidectomy in six cases revealed C-cell hyperplasia in all and microscopic MTC in two cases. Transfection experiments using human neuroblastoma cells showed that the mutant RET, unlike the wild-type receptor, is constitutively phosphorylated in the absence of ligand, and thus resembles other previously characterized MEN 2A mutations., Conclusions: The identification of a new mutation causing a MEN 2A phenotype that features pheochromocytoma and the surprising absence of clinically apparent MTC has significant implications for carriers of this mutation and provides further insights into the genotype-phenotype correlation in MEN 2A.

Objectives: To assess the impact of [(131)I]meta-iodobenzylguanidine ((131)MIBG) scintigraphy on the management of phaeochromocytoma., Design and Patients: Between 1982 and 2002, 83 patients with histologically proven phaeochromocytoma or paraganglioma were investigated using (131)MIBG scintigraphy. Seventeen of these patients, with a hereditary form of the disease, presented with 23 phaeochromocytomas [three neurofibromatosis type 1 (NF1), five von Hippel-Lindau disease (VHL), eight multiple endocrine neoplasia type 2A (MEN2A) and one type 2B (MEN2B)]., Results: MIBG uptake was observed in 44/54 sporadic phaeochromocytomas (sensitivity 81.5%), 14/23 familial phaeochromocytomas (60.9%), 3/6 paragangliomas and 4/6 malignant phaeochromocytomas. No significant correlations were found between the degree of tracer uptake, tumour size and urinary metanephrine levels. No patients undergoing surgery for sporadic phaeochromocytoma had a second tumour located. Nine of 54 sporadic phaeochromocytomas had normal or mildly elevated urinary metanephrine levels (< 1.5 greater than normal). In eight of these patients, (131)MIBG was positive and confirmed the diagnosis of phaeochromocytoma. In malignant phaeochromocytomas (n = 6), MIBG demonstrated additional lesions not detected with computed tomography (CT) and/or magnetic resonance imaging (MRI) in three cases. The MIBG findings in the group with apparently sporadic paragangliomas (n = 6) were negative in four cases and failed to detect a cervical lesion in one multifocal paraganglioma., Conclusion: (131)MIBG was useful in confirming the diagnosis in phaeochromocytomas with low levels of catecholamine secretion. It contributed little to the management of patients when used as a means of screening for multifocality in sporadic phaeochromocytoma, or the management of patients with familial phaeochromocytoma. However, MIBG can be an informative method of investigation when dealing with malignant/ectopic forms, although the sensitivity of MIBG is lower in this group of patients.

Objective: Somatostatin receptors are present on human phaeochromocytomas. Catecholamine concentrations may decrease following short-term administration of somatostatin agonists to patients with phaeochromocytomas. We carried out a prospective study on 10 patients with malignant or recurrent phaeochromocytomas to examine the clinical and hormonal effects of three monthly intramuscular injections of 20 mg slow-release octreotide., Design and Measurements: Patients underwent somatostatin receptor scintigraphy using 111In-pentetreotide before slow-release octreotide was administered. The patients' symptoms, blood pressure, blood glucose concentrations, glycosylated haemoglobin concentra-tions, plasma insulin and noradrenaline concentrations, and the levels of two putative markers of tumour burden, urinary metanephrine excretion and plasma chromogranin A concentration, were recorded before the first injection and 28 days after the third injection., Results: Slow-release octreotide did not significantly alter symptoms, blood pressure, blood glucose concentrations, plasma catecholamine and chromogranin A concentrations or metanephrine excretion. Median glycosylated haemoglobin concentrations increased from 5.3% to 6.0% (P = 0.03). Patients whose tumours took up 111In- pentetreotide did not differ from those whose tumours did not after slow-release octreotide treatment in terms of symptoms, blood pressure, blood glucose, plasma catecholamine and chromogranin A concentrations or metanephrine excretion., Conclusion: Our data suggest that slow-release octreotide is of limited value for the long-term treatment of patients with malignant or recurrent benign phaeochromocytomas.

Objectives: Phaeochromocytoma may be either sporadic or part of a familial cancer syndrome. We have investigated whether there are differences between sporadic and MEN 2A phaeochromocytomas., Design: A retrospective study. We analysed age at presentation, sex, mode of presentation, clinical data, laboratory and imaging techniques, treatment, pathology and follow-up., Patients: Forty-six patients diagnosed with phaeochromocytoma between 1979 and 1995 (23 sporadic and 23 familial) at the Hospital Universitario Virgen de la Arrixaca (Murcia, Spain), a tertiary referral centre., Results: Mean age at presentation was 47 +/- 16 years for sporadic and 38 +/- 11 years for familial phaeochromocytoma (P < 0.05). The most common clinical feature and the presenting feature in cases of isolated phaeochromocytoma was hypertension. Of the MEN 2A patients, 52% were asymptomatic at diagnosis and only 35% presented with hypertension. Levels of adrenaline, noradrenaline, dopamine and metanephrines in a 24-hour urine connection confirmed the diagnosis in 95% of the isolated and 91% of the familial phaeochromocytomas. Computed tomography located 100% of the sporadic and 76% of the familial phaeochromocytomas (P < 0.02). All the MEN 2A phaeochromocytomas were bilateral compared with none of the sporadic phaeochromocytomas (P < 0.001). All the patients with familial phaeochromocytoma underwent bilateral adrenalectomy. The patients with sporadic phaeochromocytoma had the affected gland or the tumour, if extraadrenal, removed., Conclusions: In comparing sporadic and MEN 2A phaeochromocytoma we found differences in age at presentation, mode of presentation, clinical data, duration of clinical features, imaging findings bilaterality and type of surgical treatment required.

Objective: We report clinical, biochemical, morphological and histological data of phaeochromocytoma in 40 French families and in apparently sporadic cases of multiple endocrine neoplasia (MEN) type 2 A (medullary thyroid carcinoma, phaeochromocytoma, with or without hyperparathyroidism)., Design: This retrospective study was obtained from cases registered by the 'Groupe d'Etudes des Tumeurs à Calcitonine' from 1968 to 1990. We analysed the cases having sufficiently precise data on phaeochromocytoma with Pigas Software., Patients: Characteristics of phaeochromocytoma in 100 patients with MEN 2 A were reviewed. Phaeochromocytoma was bilateral in 51%. The disease was inherited in 94 patients from 40 families (40 probands, 54 relatives), and was apparently sporadic in six., Results: In this series, diagnostic circumstances were highly suggestive of phaeochromocytoma in 39.8% of the cases, whereas in 43.2%, diagnosis was made through systematic investigations of patients, either before (27.3%) or after (13.6%) thyroidectomy, or after discovery of hyperparathyroidism (2.3%). Fifteen per cent of patients were detected by family screening. Sudden death occurred in 8.9%, malignant phaeochromocytoma in 3%, and ectopic tissue in 4% of the cases. Urinary metanephrines appeared to be the most sensitive screening test. The extent of clinical symptoms was not associated with a particular hormonal pattern. Bilateral adrenalectomy was performed in 60% (in one step in 50%, in two steps in 10%). In these patients, bilateral histological lesions were observed in 92.5%. Simultaneous diagnosis for adrenal and thyroid disease was made in 73.4%, but phaeochromocytoma may be diagnosed before (9.6%) or after (17%) medullary thyroid carcinoma, with an interval greater than 2 years in 25 cases., Conclusion: Owing to variable clinical symptoms of phaeochromocytoma in these 100 cases of MEN 2 A, systemic biological adrenal assay is required. The search for phaeochromocytoma in medullary thyroid carcinoma (and vice versa) has to be systematically performed, even in apparently sporadic cases. Screening for phaeochromocytoma must be repeated for years, owing to the frequency of bilateral adrenal disease.