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.
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.
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.
We suggest that nMAD.nNMT is a useful measure for identifying pheochromocytoma in a population with a low pre-test probability.
Pheochromocytoma; urinary metanephrines
Fractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.
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electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data.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.
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).
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.
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.
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.
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.
Adrenal tumour; catecholamines; ELISA; metanephrines; phaeochromocytoma
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.
The aim of this study was to compare the diagnostic performances of plasma free versus deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma.
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.
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).
Measurements of plasma free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma.
Phaeochromocytoma; diagnostic tests; free metanephrines; deconjugated metanephrines; normetanephrine; metanephrine
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.
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.
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.
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.
pheochromocytoma; paraganglioma; norepinephrine; epinephrine; dopamine; normetanephrine; metanephrine; methoxytyramine; von Hippel-Lindau syndrome; neurofibromatosis type 1; multiple endocrine neoplasia type 2; succinate dehydrogenase
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.
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.
adrenal incidentaloma; catecholamines; hypertension; pheochromocytoma; scintigraphy
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.
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.
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.
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.
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.
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.
Laparoscopic adrenalectomy; benign adrenal disorders; lesser morbidity
We report an unusual case of normotensive pheochromocytoma detected incidentally, presenting a pre-operative management problem.
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.
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.
Normotensive pheochromocytoma; adrenal incidentaloma; preoperative preparation
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.
Pheochromocytoma; Paraganglioma; Catecholamines; Metanephrines; Mitochondria; Oxidative Phosphorylation; Glycolysis
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.
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.
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%.
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.
paraganglioma; positron emission tomography; imaging; fluorodopamine; metanephrines
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%.
Pheochromocytomas; paragangliomas; radionuclide imaging; carcinoid tumors
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.
pheochromocytoma; paraganglioma; von Hippel-Lindau syndrome; mutation testing; germline mutations; loss of heterozygosity
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.
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.
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.
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.
Pheochromocytoma; Cocaine; Myocardial Infarction
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.
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.
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.
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.
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.
123I-MIBG; pheochromocytoma; paraganglioma; succinate dehydrogenase subunit B; catecholamines; metanephrines
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.
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.
To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate.
Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.
22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma.
Plasma catecholamine levels, blood pressure, and heart rate.
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.
The study lacked a placebo group, and the sample was relatively small.
Intravenous low-osmolar contrast–enhanced CT can safely be used in patients with pheochromocytoma who are not receiving α- or β-blockers.
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.
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).
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.
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.
pheochromocytoma; paraganglioma; metastases; methoxytyramine; dopamine; metanephrines; catecholamines; succinate dehydrogenase type B
We present the case of a 30-year-old woman, 33 weeks pregnant, whose pregnancy was complicated with the rare condition of pheochromocytoma-induced myocardial infarction. Alpha- and beta-adrenergic blockade was instituted immediately for control of hypertension and arrhythmias. Two weeks after myocardial infarction, fetal maturity was documented, and the patient underwent cesarean section delivery of a 6-lb, 6-oz baby girl. The delivery was followed immediately by excision of a 7- x 6- x 4.5-cm tumor, which was confirmed to be a pheochromocytoma by histologic examination. Her post-operative course was uneventful. Our case study and a review of the literature show that the key to successful fetal and maternal outcome is early diagnosis, which can be confirmed by 24-hour urine testing of catecholamine and metanephrine levels. If the tumor is diagnosed before 20 weeks' gestation, we recommend immediate surgical removal of the tumor and continuation of the pregnancy to term. The management of the patient who presents between 20 and 24 weeks' gestation will depend on the uterine size in terms of tumor access. After 24 weeks, the pregnancy should be carried to term, at which time delivery by cesarean section will be followed by tumor excision. Postoperative care should include appropriate cardiovascular investigation and ongoing serial measurements of urinary catecholamines.
Background: Mutations in genes coding for the mitochondrial complex II succinate dehydrogenase (SDH) subunits cause familial neural crest derived (NCD) tumours.
Methods: Index cases from six apparently unrelated families affected by NCD tumours were analysed for mutations in the SDHB, SDHC, and SDHD genes.
Results: The same nonsense germline heterozygous mutation (Q109X) in exon 4 of the SDHD gene was found in each of the six families. Overall, 43 heterozygotes were identified. These were evaluated for the presence of NCD tumours through radiological examination of the neck, thorax, and abdomen, and measurement of urinary metanephrines and plasma chromogranin A. A novel missense SDHD variant, T112I, which did not segregate with the Q109X mutation and was not associated with phenotypic manifestations, was observed in one of the families. Microsatellite analysis showed a common haplotype in all individuals heterozygous for the Q109X mutation, indicating a founder effect. Overall, 18 heterozygotes were clinically affected by at least one NCD tumour. Every affected patient inherited the germline mutation from the father, confirming SDHD maternal genomic imprinting. Penetrance of the paternally inherited mutation progressively increased from 33% to 83% at 30 and 60 years, respectively. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumours variably associated or not with paragangliomas or phaeochromocytomas. Loss of heterozygosity was observed in tumour cells isolated by laser capture microdissection.
Conclusions: This study shows that a single founder SDHD mutation is present in an area of central Italy and that this mutation is associated with widely variable interfamilial and intrafamilial expressivity.
Aim—To evaluate the effects of low dose
fentanyl infusion analgesia on behavioural and neuroendocrine stress
response and short term outcome in premature infants ventilated for
hyaline membrane disease.
METHODS—Twenty seven ventilated preterm infants
were randomly assigned to receive a mean fentanyl infusion of 1.1 (0.08 SE) µg/kg/h for 75 (5) hours, and 28 untreated infants were
considered a control group. A behavioural sedation score was used to
assess the infants' behaviour. Urinary metanephrine and the
normetanephrine:creatinine molar ratio were determined at 0, 24, 48 and
72 hours. Outcome data and ventilatory indexes were recorded for each infant.
RESULTS—The fentanyl group showed significantly
lower behavioural stress scores and O2 desaturations than
controls and lower urinary concentrations of metanephrine and
normetanephrine at 24, 48,72 hours. The two groups showed no
significant difference in ventilatory variables or short term outcome.
CONCLUSIONS—A short course of low dose fentanyl
infusion reduces behavioural sedation scores, O2
desaturations and neuroendocrine stress response in preterm ventilated infants.