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1.  Measurement of urinary metanephrines to screen for pheochromocytoma in an unselected hospital referral population 
Clinical chemistry  2006;52(11):2060-2064.
Background
Despite the rarity of pheochromocytoma, the dangers of uncontrolled severe hypertension and the very effective surgical treatment of this condition mean that diagnosis is important. Urinary or plasma catecholamines or catecholamine-derivatives are commonly used to screen for pheochromocytomas prior to imaging. This study investigates whether derived measures obtained from 24-hour urinary metanephrine results, patient age and sex can better predict tumors in populations with a low pre-test probability.
Methods
This study takes a pragmatic approach by retrospectively studying the outcomes of an unselected population referred for urinary metanephrine testing (1819 patients) to a tertiary hospital laboratory, and investigates the usefulness of some simple derivative measures for detecting pheochromocytoma. Urinary 24-hour excretion of metanephrine, normetanephrine and 3-methoxytyramine were normalized by dividing by an age- and sex- specific reference range. The ability of products of these normalized measures to predict pheochromocytomas was assessed, compared to a gold standard of biopsy-confirmed tumor.
Results
The normalized product of urinary metanephrine and normetanephrine excretion (nMAD.nNMT) proved to be a highly sensitive (100%) and specific (99.1%) measure yielding a positive predictive value 82%. Receiver-operator characteristic curves were not improved by including the normalized 3-methoxytyramine concentrations in the product. nMAD.nNMT gave higher sensitivity and specificity than either test alone.
Conclusion
We suggest that nMAD.nNMT is a useful measure for identifying pheochromocytoma in a population with a low pre-test probability.
doi:10.1373/clinchem.2006.070805
PMCID: PMC2640466  PMID: 16990424
Pheochromocytoma; urinary metanephrines
2.  A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma 
Background
Fractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.
Methods
We aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted.
Results
Limitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%–100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%–100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07).
Conclusion
Negative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.
doi:10.1186/1472-6823-4-2
PMCID: PMC459231  PMID: 15225350
3.  The role of urinary fractionated metanephrines in the diagnosis of phaeochromocytoma 
Background & objectives:
Plasma and urinary metanephrines are used as screening tests for the diagnosis of phaeochromocytoma. The recommended cut-off levels are not standardized. This study was conducted to identify a cut-off level for 24 h urinary fractionated metanephrines viz. metanephrine (uMN) and normetanephrine (uNMN) using enzyme immunoassay for the diagnosis of phaeochromocytoma.
Methods:
Consecutive patients suspected to have phaeochromocytoma were included in the study. uMN and uNMN in 24 h urinary sample were measured using a commercial ELISA kit.
Results:
Overall, 72 patients were included over a period of 18 months. Twenty patients had histopathologically confirmed phaeochromocytoma and in 52 patients phaeochromocytoma was ruled out. Using the upper limit of normal stated by the assay manufacturer as the cut-off, uMN >350 μg/day had a low sensitivity and uNMN >600 μg/day had a poor specificity. By increasing the cut-off value of uNMN to twice the upper limit, specificity increased significantly without much loss in sensitivity. Combining uMN and uNMN using a cut-off twice the upper limit improved the diagnostic performance - sensitivity (95%); specificity (92.3%); positive predictive value (PPV - 82.6%); negative predictive value (NPV - 98%). In subsets of patients with a variable pretest probability for phaeochromocytoma, the PPV correlates well with the occurred of these tumors decreased, while the NPV remained at 100 per cent.
Interpretation & conclusions:
ELISA is a simple and reliable method for measuring uMN and uNMN. The test has a good NPV and can be used as an initial screening test for ruling out phaeochromocytoma. Each hospital will have to define the cut-off value for the assay being used, choosing a proper control population.
PMCID: PMC3657855  PMID: 23563375
Adrenal tumour; catecholamines; ELISA; metanephrines; phaeochromocytoma
4.  Plasma free versus deconjugated metanephrines for diagnosis of phaeochromocytoma 
Clinical endocrinology  2013;79(4):476-483.
Summary
Background
Diagnosis of phaeochromocytoma is commonly performed by measurements of plasma free normetanephrine and metanephrine. Plasma deconjugated normetanephrine and metanephrine have been proposed as alternative equivalent, but easier to measure biomarkers.
Objective
The aim of this study was to compare the diagnostic performances of plasma free versus deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma.
Methods
The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow up. Measurements were performed using liquid chromatography with electrochemical detection.
Results
Median plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (p<0.001) difference than that for the 10-fold higher levels of plasma deconjugated normetanephrine. In contrast, relative increases of plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, p=0.002) and specificity (93 vs 89%, p=0.012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0.986 vs 0.965, p<0.001).
Conclusion
Measurements of plasma free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma.
doi:10.1111/cen.12191
PMCID: PMC3762922  PMID: 23461656
Phaeochromocytoma; diagnostic tests; free metanephrines; deconjugated metanephrines; normetanephrine; metanephrine
5.  Measurements of Plasma Methoxytyramine, Normetanephrine and Metanephrine as Discriminators of Different Hereditary forms of Pheochromocytoma 
Clinical chemistry  2011;57(3):411-420.
BACKGROUND
Pheochromocytomas are rare catecholamine–producing tumors derived in at least 30% of cases from mutations in 9 tumor-susceptibility genes identified to date. Testing of multiple genes at considerable expense is often undertaken before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine and methoxytyramine, the O-methylated metabolites of catecholamines, might help distinguish different hereditary forms of the tumor.
METHODS
Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome and 59 with mutations of succinate dehydrogenase (SDH) type B or D genes.
RESULTS
In contrast to patients with VHL and SDH mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDH mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL and SDH mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases.
CONCLUSIONS
The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily utilized tool to guide cost-effective genotyping of underlying disease-causing mutations.
doi:10.1373/clinchem.2010.153320
PMCID: PMC3164998  PMID: 21262951
pheochromocytoma; paraganglioma; norepinephrine; epinephrine; dopamine; normetanephrine; metanephrine; methoxytyramine; von Hippel-Lindau syndrome; neurofibromatosis type 1; multiple endocrine neoplasia type 2; succinate dehydrogenase
6.  Pheochromocytoma: An Uncommon Presentation of an Asymptomatic and Biochemically Silent Adrenal Incidentaloma 
Pheochromocytomas are rare tumours originating from the chromaffin tissue. The clinical manifestations are variable and are not specific; as a result, pheochromocytomas often imitate other diseases. The diagnosis is usually established by biochemical studies, i.e., the measurement of catecholamines or their metabolites in urine or plasma, followed by radiographic and scintigraphic studies for localisation. Surgical removal of the tumour is the preferred treatment. We report a 30-year-old woman presenting with an adrenal incidentaloma that was 7.6 × 5.3 × 4.8 cm in size on an abdominal computed tomography scan. Investigations for adrenal hormones, including a low-dose dexamethasone suppression test, plasma aldosterone level, 24-hour urinary metanephrine and vanillylmandelic acid levels, and plasma metanephrine level were all within the normal ranges. During the surgical resection, the patient had a hypertensive spell. Surgery was postponed, and the blood pressure was adequately controlled with α blockers, followed by β blockers. After 2 weeks, the surgery was followed by a pathological biopsy that confirmed the pheochromocytoma diagnosis.
PMCID: PMC3431738  PMID: 22973143
adrenal incidentaloma; catecholamines; hypertension; pheochromocytoma; scintigraphy
7.  Updated and New Perspectives on Diagnosis, Prognosis, and Therapy of Malignant Pheochromocytoma/Paraganglioma 
Journal of Oncology  2012;2012:872713.
Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion, SDHB mutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis.
doi:10.1155/2012/872713
PMCID: PMC3407645  PMID: 22851969
8.  Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends 
Background
Neurofibromatosis Type 1(NF-1) has autosomal dominant inheritance with complete penetrance, variable expression and a high rate of new mutation. Pheochromocytoma occurs in 0.1%-5.7% of patients with NF-1.
Case presentation
We present the case of a 37-year-old patient with laparoscopically resected pheochromocytoma. He was investigated for hypertension, flushing and ectopic heart beat. Abdominal CT and MRI revealed a mass measuring 8 × 4 cm in the right adrenal gland. The diagnosis of pheochromocytoma was confirmed by elevated 24-hour urine levels of VMA, metanephrines and catecholamines as well as positive MIBG scan. The patient presented with classic clinical features of NF-1, which was confirmed by pathologic evaluation of an excised skin nodule. The patient underwent laparoscopic right adrenalectomy through a transabdominal approach and was discharged on the second postoperative day, being normotensive. The patient is normotensive without antihypertensive therapy 11 years after the procedure.
Conclusion
Nowadays in the era of laparoscopy, patients with pheochromocytoma reach the operating theatre easier than in the past. Despite, the feasibility and oncological efficacy of the laparoscopic approach to the adrenals, continued long term follow-up is needed to establish the minimally invasive technique as the preferred approach. Furthermore, these patients should be further investigated for other neoplasias and stigmata of other neurocutaneous syndromes, taking into account the association of the familial pheochromo-cytoma with other familial basis inherited diseases.
doi:10.1186/1477-7819-8-14
PMCID: PMC2848134  PMID: 20219130
9.  Advances in Biochemical Screening for Phaeochromocytoma using Biogenic Amines 
Biochemical testing for phaeochromocytoma is performed in diagnostic laboratories using a variety of tests with plasma, serum or 24-hour urine collections. These tests include catecholamines and their methylated metabolites - the metanephrines, either individually or in combination with their sulfated metabolites. High-performance liquid chromatography (HPLC) continues to be the dominant analytical method for biogenic amine quantitation. Chromatographic techniques are changing, with improvements in sample preparation procedures, column technology and more specific analyte detection using tandem mass spectrometry. Enrolments in quality assurance programs indicate that there are still many more laboratories in Australasia analysing urinary catecholamines than metanephrines. Nevertheless, clinical evidence and expert opinion favour metanephrines as the analytes with highest sensitivity for the detection of phaeochromocytoma. Practical issues such as better chemical stability and easier specimen collection also favour metanephrines over catecholamines. For these reasons, it is likely that laboratories increasingly will replace urine catecholamine testing with either plasma or urine metanephrines. However in interpreting positive results, the need remains to consider issues such as pre-test probability and use of potentially interfering medications.
PMCID: PMC2643090  PMID: 19224007
10.  Laparoscopic adrenalectomy: A single center experience 
AIMS:
To evaluate the efficacy and safety of laparoscopic adrenalectomy in benign adrenal disorders.
METHODS AND MATERIAL:
Since July 2007, twenty patients have undergone laparoscopic adrenalectomy for various benign adrenal disorders at our institution. Every patient underwent contrast enhanced CT-abdomen. Serum corticosteroid levels were conducted in all, and urinary metanephrines, normetanephrines and VMA levels were performed in suspected pheochromocytoma. All the patients underwent laparoscopic adrenalectomy via the transperitoneal approach.
RESULTS:
The patients were in the age range of 18-57 years, eleven males and nine females, seven right, eleven left, two bilateral. The mean operative time was 150 minutes (120-180), mean hospital stay four days (3-5), mean intraoperative blood loss 150 ml and mean post-operative analgesic need was for 36 (24-72) hours. One out of twenty-two laparoscopic operations had to be converted into open adrenalectomy due to intra-operative complications.
CONCLUSIONS:
Laparoscopic adrenalectomy is a safe, effective and useful procedure without any major post-operative complication and is the gold standard for all benign adrenal disorders.
doi:10.4103/0972-9941.72595
PMCID: PMC2992657  PMID: 21120066
Laparoscopic adrenalectomy; benign adrenal disorders; lesser morbidity
11.  Renal hilar paraganglioma: A case report 
World Journal of Radiology  2014;6(1):15-17.
Paragangliomas are extra-adrenal pheochromocytomas that derive from chromaffin cells and arise along the sympathetic paraganglia in the body. In the majority of cases, they are secretory tumors and most commonly present with palpitations. Plasma metanephrines are the standard screening tests for making the diagnosis which is confirmed by pathology. Imaging plays a very important role in establishing the diagnosis. However, there is no specific feature on imaging for paragangliomas; the vascularity of the tumor should show as hyper-enhancing lesions but this is not always the case. The diagnostic value of PET is yet a matter of debate. We present a very rare case of a paraganglioma arising at the renal hilum, splaying the renal artery and vein and causing vascular compromise to the left kidney. The patient presented with an atypical presentation of unrelenting fever that was followed by acute colicky pain. Based on imaging and blood metanephrine levels, the diagnosis of paraganglioma was made. Resection of the tumor was achieved and the patient is now asymptomatic.
doi:10.4329/wjr.v6.i1.15
PMCID: PMC3936207  PMID: 24578788
Renal; Hilar; Paraganglioma; Pheochromocytoma; Imaging
12.  A CLINICAL OVERVIEW OF PHEOCHROMOCYTOMAS/PARAGANGLIOMAS AND CARCINOID TUMORS 
Nuclear medicine and biology  2008;35(Suppl 1):S27-S34.
Pheochromocytomas/paragangliomas are rare tumors, most are sporadic. Biochemical proof of disease is better with measurement of plasma metanephrines and less cumbersome than determinations in urine; its implementation is expanding. Anatomical imaging with computed tomography or magnetic resonance imaging should be followed by functional (nuclear medicine) imaging: chromaffin-tumor-specific methods are preferred. Treatment is surgical; for non-operable disease other options are available. Overall 5-year survival is 50%.
Carcinoid tumors derive from serotonin-producing enterochromaffin cells in the fore-, mid- or hindgut. Biochemical screening (and follow-up) is done with measurements of 5-hydroxyindoloacetic acid in urine. For most carcinoids functional imaging is better than other modalities in localizing primary tumors. Surgery is the treatment of choice; non-resectable tumors are treated with somatostatin analogs or chemotherapy. Overall 5-year survival for patients with carcinoids is 67%.
doi:10.1016/j.nucmedbio.2008.04.007
PMCID: PMC2597413  PMID: 18707631
Pheochromocytomas; paragangliomas; radionuclide imaging; carcinoid tumors
13.  Adrenal incidentaloma: A case of pheochromocytoma with sub-clinical Cushing's syndrome 
Adrenal incidentalomas (AIs) are a cluster of different pathologies, but AIs with dual functional aspects are very rare. We report a case of AI with the evidence of both pheochromocytoma and sub-clinical Cushing's syndrome. A 42-year-old female patient presented with the history of abdominal pain. Abdominal computed tomography revealed right adrenal mass suggestive of pheochromocytoma. On endocrine evaluation, she admitted history of intermittent headache and palpitations for 4 years and was on treatment for hypertension and diabetes. There were no signs and symptoms suggestive of Cushing's syndrome. The laboratory data demonstrated 10 times raised 24-h urinary fractionated metanephrines with non-suppressible serum cortisol after 2-day low-dose dexamethasone suppression test. She underwent right-sided adrenalectomy with subsequent resolution of both pheochromocytoma and hypercortisolism. Patient was discharged in good clinical condition.
doi:10.4103/2230-8210.119587
PMCID: PMC3830320  PMID: 24251174
Adrenal incidentaloma; Cushing's syndrome; pheochromocytoma
14.  A case of normotensive pheochromocytoma with management dilemma 
Introduction:
We report an unusual case of normotensive pheochromocytoma detected incidentally, presenting a pre-operative management problem.
Case Note:
A 40-year-old lady with vague abdominal symptoms was initially discovered with a left adrenal incidentaloma by ultrasound abdomen, which was also revealed in computed tomography (CT). After exclusion of all the causes with possible necessary investigations, pheochromocytoma was confirmed with elevated 24 hour urinary metanephrine and normetanephrine. Her blood pressure was in low to normotensive range all throughout. She was attempted to be prepared with combined alpha and beta blockade but could not tolerate this regimen due to symptomatic hypotension. Subsequently, surgical preparation was planned cautiously with alpha-adenergic blockade only. With intensive monitoring, she underwent uneventful left adrenalectomy, and surgical pathology was consistent with pheochromocytoma.
Conclusion:
This case illustrates an unusual presentation of normotensive pheochromocytoma as adrenal incidentaloma. Pre-operative preparation in these patients can be achieved with alpha-adrenergic blockade, adequate hydration, and liberal salt intake.
doi:10.4103/2230-8210.104097
PMCID: PMC3603081  PMID: 23565433
Normotensive pheochromocytoma; adrenal incidentaloma; preoperative preparation
15.  PHEOCHROMOCYTOMA: A CATECHOLAMINE AND OXIDATIVE STRESS DISORDER 
Endocrine regulations  2011;45(2):65-90.
The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla — an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called “attacks” or “spells”. Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations.
Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto-oncogene activation, tumor suppressor gene inactivation, DNA damage, and genomic instability. Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development. In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development. Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift). This phenomenon, also called the Warburg effect, is well demonstrated by a positive [18F]-fluorodeoxyglycose positron emission tomography scan. Microarray studies, genome-wide association studies, proteomics and protein arrays, metabolomics, transcriptomics, and bioinformatics approaches will remain powerful tools to further uncover the pathogenesis of these tumors and their unique markers, with the ultimate goal to introduce new therapeutic options for those with metastatic or malignant pheochromocytoma and paraganglioma. Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell. Targeting the mTORC, IGF-1, HIF and other pathways, topoisomerases, protein degradation by proteosomes, balancing the activity of protein kinases and phosphatases or even synchronizing the cell cycle before any exposure to any kind of therapy will soon become a reality. Facing such a reality today will favor our chances to “beat” this disease tomorrow.
PMCID: PMC3414427  PMID: 21615192
Pheochromocytoma; Paraganglioma; Catecholamines; Metanephrines; Mitochondria; Oxidative Phosphorylation; Glycolysis
16.  Use of 6-[18F]-fluorodopamine positron emission tomography as first-line investigation for the diagnosis and localization of non-metastatic and metastatic pheochromocytoma 
Clinical endocrinology  2008;71(1):11-17.
Summary
Objective
Imaging modalities available for the localization of pheochromocytoma (PHEO) include computed tomography (CT), magnetic resonance imaging (MRI), [123I]-or [131I]-labeled metaiodobenzylguanidine (123/131I-MIBG) scintigraphy and 6-[18F]-fluorodopamine (18F-FDA) positron emission tomography (PET). Our aim was to investigate the yield of 18F-FDA PET versus biochemical testing and other imaging techniques to establish the diagnosis and location of PHEO.
Patients and measurements
The study included 99 consecutive patients (35 M, 64 F, mean±SD age 46.4±13.4 years), who underwent 18F-FDA PET, biochemical testing (plasma catecholamines and free metanephrines) and CT and/or MRI. The majority (78%) also underwent 123/131I-MIBG.
Results
26 patients had non-metastatic PHEO, 34 patients had metastatic PHEO, and PHEO was ruled out in 39 patients. Investigations to rule out or confirm PHEO yielded the following sensitivity/specificity: plasma metanephrines 97/95%, 18F-FDA 92/90%, 123I-MIBG 83/100%, 123/131I-MIBG 70/100%, CT 100/41%, MRI 98/60%. Sensitivities for localizing non-metastatic PHEO on a per-lesion base were: CT 97%, MRI 92%, 18F-FDA 78%, 123I-MIBG 78% and 123/131I-MIBG 76%. Sensitivities for detecting metastases on a per-patient base were: CT and MRI 100%, 18F-FDA 97%, 123I-MIBG 85%, and 123/131I-MIBG 65%.
Conclusion
For tumor localization, 18F-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with non-metastatic PHEO, but metastases are better detected by 18FFDA PET than by 123/131I-MIBG.
doi:10.1111/j.1365-2265.2008.03496.x
PMCID: PMC2713382  PMID: 19138315
paraganglioma; positron emission tomography; imaging; fluorodopamine; metanephrines
17.  Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution 
Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.
doi:10.1055/s-0032-1304662
PMCID: PMC3501345  PMID: 22438210
pheochromocytoma; paraganglioma; von Hippel-Lindau syndrome; mutation testing; germline mutations; loss of heterozygosity
18.  Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity 
PLoS ONE  2011;6(6):e21006.
Background
Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity.
Methodology/Principal Findings
We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities.
Conclusions/Significance
Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.
doi:10.1371/journal.pone.0021006
PMCID: PMC3118816  PMID: 21701596
19.  Acute Myocardial Infarction Secondary to Catecholamine Release Owing to Cocaine Abuse and Pheochromocytoma Crisis 
Abstract
Most pheochromocytomas are not suspected clinically while a high percentage of them are curable with surgery. We present the case of an adult cocaine-addicted male patient with an underlying pheochromocytoma and repeated myocardial infarctions. Computed tomography showed a left round adrenal mass, also high 24-hour urine levels of catecholamines and metanephrines were detected from urinalysis. The patient was given alpha and beta blockers, moreover a laparoscopic left adrenalectomy was performed. Cocaine can block the reuptake of noradrenaline, leading to increasing its concentration and consequently its effects as well, and induce local or diffuse coronary vasoconstriction in normal coronary artery segments per se, cocaine can also trigger pheochromocytoma crisis, and therefore, cardiac complications such as myocardial infarction due to these additive effects are intended to occur. For this reason, in the presence of typical clinical manifestations of pheochromocytoma, such as sustained or paroxysmal hypertension, headache, sweating, tachycardia and abdominal pain, probable association of this tumor in patients with cocaine abuse and associated cardiac complications must be ruled out.
doi:10.5812/ijem.6562
PMCID: PMC3693650  PMID: 23853620
Pheochromocytoma; Cocaine; Myocardial Infarction
20.  Pheochromocytoma Presenting as Acute Heart Failure Leading to Cardiogenic Shock and Multiorgan Failure 
Case Reports in Medicine  2011;2011:596354.
Pheochromocytoma is an endocrine tumor classically presenting with headache, paroxysmal hypertension, and palpitations. We discuss the case of a young male, presenting with acute heart failure and cardiogenic shock requiring stabilization with an intra-aortic balloon pump and a combination of ionotropes and vasopressors. Pheochromocytoma was diagnosed by CT scan, as well as urine and plasma metanephrines. After pretreatment with phenoxy-benzamine, the patient underwent adrenalectomy with subsequent cardiovascular stabilization and full recovery. Unfortunately, pheochromocytoma often remains undiagnosed. Given the ample diagnostic tools and good prognosis when treated suitably, the diagnosis should be entertained early in patients, presenting with unexplained cardiovascular compromise.
doi:10.1155/2011/596354
PMCID: PMC3099218  PMID: 21629811
21.  False-Negative 123I-MIBG SPECT Is Most Commonly Found in SDHB-Related Pheochromocytoma or Paraganglioma with High Frequency to Develop Metastatic Disease 
Endocrine-related cancer  2012;19(1):83-93.
Objective
The purpose of this study was to present the characteristics and outcome of patients with proven pheochromocytoma or paraganglioma who had false-negative 123I-MIBG SPECT.
Methods
Twenty one patients with false-negative 123I-MIBG SPECT, (6 males, 15 females) aged 13–55 years (mean 40.9 years) were included. We classified them according to the stage of the disease as non-metastatic or metastatic at the time of false-negative 123I-MIBG SPECT study, the location and size of the tumor, plasma and urinary catecholamine and metanephrine levels, genetic mutations, and outcome in terms of occurrence and progression of metastases and death.
Results
Thirteen patients were evaluated for metastatic tumors while 8 others were seen for non-metastatic disease. All primary tumors and multiple metastatic foci did not show avid 123I-MIBG uptake regardless of the tumor diameter. The majority of patients had extra-adrenal tumors with hypersecretion of normetanephrine or norepinephrine. SDHB mutation was present in 52% (n=11) of cases, RET mutation in 4% (n=1), and the rest were apparently sporadic. Twenty four percent (n=5) had metastatic disease on initial presentation. Fourteen patients were followed-up for 3–7 years. From them, 71% (n=10) had metastatic disease and majority had SDHB mutation. Nine are still alive while 5 (4 were SDHB) died due to metastatic disease.
Conclusion
A false-negative 123I-MIBG SPECT is frequently related to metastatic tumors and usually due to SDHB mutations with unfavourable prognosis. We, therefore, recommend that patients with false-negative 123I-MIBG SPECT be tested for SDHB mutations and to undergo more regular and close follow-up.
doi:10.1530/ERC-11-0243
PMCID: PMC3420013  PMID: 22167067
123I-MIBG; pheochromocytoma; paraganglioma; succinate dehydrogenase subunit B; catecholamines; metanephrines
22.  Biochemical tests for diagnosis of phaeochromocytoma: urinary versus plasma determinations. 
Fifteen patients with hypertension due to phaeochromocytoma and 35 controls with essential hypertension were studied to assess the diagnostic value of urinary and plasma biochemical determinations in phaeochromocytoma. In every case of phaeochromocytoma the urinary concentration of vanillylmandelate, metanephrines, or adrenaline plus noradrenaline was diagnostic of the disease irrespective of whether the patient was normotensive or hypertensive at the time. Plasma determinations of adrenaline and noradrenaline, however, gave falsely negative results on three occasions. These findings suggest that urinary biochemical determinations--particularly of metanephrines--are more reliable than plasma catecholamine measurements as a test for phaeochromocytoma. The test is particularly useful in patients with intermittent hypertension.
PMCID: PMC1504668  PMID: 6783201
23.  Brief Communication: Radiographic Contrast Infusion and Catecholamine Release in Patients With Pheochromocytoma 
Annals of internal medicine  2009;150(1):27-32.
Background
Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis.
Objective
To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate.
Design
Prospective study.
Setting
Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.
Participants
22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma.
Measurements
Plasma catecholamine levels, blood pressure, and heart rate.
Results
Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non–statistically significant after adjustment for use of α- and β-blockers.
Limitation
The study lacked a placebo group, and the sample was relatively small.
Conclusion
Intravenous low-osmolar contrast–enhanced CT can safely be used in patients with pheochromocytoma who are not receiving α- or β-blockers.
PMCID: PMC3490128  PMID: 19124817
24.  Chromogranin A and the α -subunit of glycoprotein hormones in medullary thyroid carcinoma and phaeochromocytoma 
British Journal of Cancer  2001;84(6):808-812.
Using specific immunoradiometric assays, we evaluated the clinical usefulness of chromogranin A and the α-subunit of glycoprotein hormones in neuroendocrine tumours of neuroectodermic origin. The serum α-subunit of glycoprotein hormones was only slightly increased in 2 out of 44 medullary thyroid carcinoma or phaeochromocytoma patients with increased calcitonin or 24-hour urinary metanephrine levels. Serum chromogranin A was increased in 12 of 45 (27%) medullary thyroid carcinoma patients with an elevated calcitonin level and in 4 of 16 medullary thyroid carcinoma patients (25%) with an undetectable calcitonin level, in 5 of 7 phaeochromocytoma patients with increased urinary catecholamine and metabolite excretion, and in 2 of 3 patients with a non-functioning phaeochromocytoma. During follow-up, the course of chromogranin A was found to parallel that of tumour burden and/or 24-hour urinary metanephrine in 5 phaeochromocytoma patients. We conclude that chromogranin A measurement is not recommended for the diagnosis of medullary thyroid carcinoma patients. It may be useful in patients with functioning and non-functioning phaeochromocytomas as a follow-up marker. In neuroendocrine tumour patients with elevated calcitonin secretion, the serum α-subunit of glycoprotein hormone measurement may help differentiate medullary thyroid carcinoma or phaeochromocytoma patients from other endodermal-derived neuroendocrine tumour patients in whom it is frequently elevated. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1677
PMCID: PMC2363821  PMID: 11259096
chromogranin A; α-subunit of glycoprotein hormones; medullary thyroid carcinoma; phaeochromocytoma; neuroendocrine tumours
25.  Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumor size, location and SDHB mutation status 
European Journal of Cancer  2011;48(11):1739-1749.
Summary
Background
There are currently no reliable biomarkers for malignant pheochromocytomas and paragangliomas (PPGLs). This study examined whether measurements of catecholamines and their metabolites might offer utility for this purpose.
Methods
Subjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumor. Eighteen catecholamine-related analytes were examined in relation to tumor location, size and mutations of succinate dehydrogenase subunit B (SDHB).
Results
Receiver-operating characteristic curves indicated that plasma methoxytyramine, the O-methylated metabolite of dopamine, provided the most accurate biomarker for discriminating patients with and without metastases. Plasma methoxytyramine was 4.7-fold higher in patients with than without metastases, a difference independent of tumor burden and the associated 1.6- to 1.8-fold higher concentrations of norepinephrine and normetanephrine. Increased plasma methoxytyramine was associated with SDHB mutations and extra-adrenal disease, but was also present in patients without SDHB mutations and metastases or those with metastases secondary to adrenal tumors. High risk of malignancy associated with SDHB mutations reflected large size and extra-adrenal locations of tumors, both independent predictors of metastatic disease. A plasma methoxytyramine above 0.2 nmol/L or a tumor diameter above 5 cm indicated increased likelihood of metastatic spread, particularly when associated with an extra-adrenal location.
Interpretation
Plasma methoxytyramine is a novel biomarker for metastatic PPGLs that together with SDHB mutation status, tumor size and location provide useful information to assess the likelihood of malignancy and manage affected patients.
doi:10.1016/j.ejca.2011.07.016
PMCID: PMC3372624  PMID: 22036874
pheochromocytoma; paraganglioma; metastases; methoxytyramine; dopamine; metanephrines; catecholamines; succinate dehydrogenase type B

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