Measurement Of Plasma Metanephrines Research Articles

PD03-05 PHEOCHROMOCYTOMA: IS THERE A ROLE FOR ULTRASONOGRAPHY IN THE SCREENING OF ADRENAL MASS IN HYPERTENSIVE PATIENTS?

You have accessJournal of UrologyCME1 Apr 2023PD03-05 PHEOCHROMOCYTOMA: IS THERE A ROLE FOR ULTRASONOGRAPHY IN THE SCREENING OF ADRENAL MASS IN HYPERTENSIVE PATIENTS? Bruno Di Domenico, Gabriel Simoes, Caio de Oliveira, Luiz Gustavo Brandao, Helena Lima, and Marcelo Lima Bruno Di DomenicoBruno Di Domenico More articles by this author , Gabriel SimoesGabriel Simoes More articles by this author , Caio de OliveiraCaio de Oliveira More articles by this author , Luiz Gustavo BrandaoLuiz Gustavo Brandao More articles by this author , Helena LimaHelena Lima More articles by this author , and Marcelo LimaMarcelo Lima More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003220.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Pheochromocytomas are catecholamine-producing tumors derivate from chromaffin cells. Their clinical presentation is variable, with arterial hypertension being the most frequent finding and paroxysms (headache, palpitations, and sweating) the most characteristic. Diagnosis is clinical, through the measurement of serum and/or urinary metanephrines and imaging methods. The great challenge is how to identify these patients. It is estimated that 0.1% of hypertensive patients have pheochromocytomas. The hypertension of these patients can be treated surgically by laparoscopic adrenalectomies. The objective of the study was to evaluate the use of ultrasonography as a screening test for pheochromocytoma in hypertensive patients. METHODS: The medical records of all patients who underwent adrenalectomy between 1999 and 2020 were reviewed. Only the patients with a pathologic diagnosis of pheochromocytoma were selected. RESULTS: A total of 29 laparoscopic adrenalectomies were performed in 25 patients, including four bilateral adrenalectomies. The average patient age was 40.2 years old (range 18-66). Ultrasonography was the first exam performed on twenty-nine hypertensive patients in the imaging investigation that showed adrenal masses with a mean diameter of 2.8 cm. After that, all patients underwent computed tomography scanning or magnetic resonance imaging, and meta-[131I]iodobenzylguanidine (131I-MIBG) whole-body scintigraphy before adrenalectomy. Measurements of plasma metanephrines and/or urinary catecholamines were high in all patients. Although abdominal ultrasonography usually has low sensitivity and specificity, it was fundamental to identifying patients with adrenal mass and proceeding with the investigation. CONCLUSIONS: Ultrasonography was an efficient method for screening investigation of pheochromocytoma in the hypertensive population and is considered a safe, low-cost and fast imaging exam. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e76 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bruno Di Domenico More articles by this author Gabriel Simoes More articles by this author Caio de Oliveira More articles by this author Luiz Gustavo Brandao More articles by this author Helena Lima More articles by this author Marcelo Lima More articles by this author Expand All Advertisement PDF downloadLoading ...

A Case of Adrenal Pheochromocytoma Presenting with Anxiety

Pheochromocytoma is a rare, neuroendocrine tumor secreting catecholamine, arising from chromaffin cells of the adrenal medulla. Also, very rare cause of secondary hypertension in pediatric age, and however, it is important to suspect. Presentation of this tumor is highly variable but the most common pediatric cases being persistent hypertension, tachycardia, sweating, and headache. In addition, anxiety, weight loss and recurrent hypertension may also appear among the clinical manifestations of the disease. The diagnosis requires measurement of plasma metanephrines, with imaging studies performed for localization and identification of metastatic lesions. The definitive management of hypertension is surgical. We present a case with pheochromocytoma that was previously diagnosed as anxiety due to tachycardia associated with hypertension.

Adrenocortical Tumors and Pheochromocytoma/Paraganglioma Initially Mistaken as Neuroblastoma-Experiences From the GPOH-MET Registry.

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis.

Quantitation of plasma metanephrines using isotope dilution liquid chromatography tandem mass spectrometry (ID-LC/MS/MS): a candidate reference measurement procedure and its application to evaluating routine ID-LC/MS/MS methods.

Accurate measurement of plasma metanephrines (MNs) including metanephrine (MN) and normetanephrine (NMN) is crucial for the screening and diagnosis in pheochromocytomas and paragangliomas (PPGLs). Although the number of laboratories using liquid chromatography tandem mass spectrometry (LC-MS/MS) method to measure MNs has been increasing rapidly, those laboratory-developed assays showed incomparable results. There are no reference measurement procedures (RMPs) or reference materials (RMs) for MNs in Joint Committee for Traceability in Laboratory Medicine (JCTLM), which hindered the standardization of MNs measurement. We established a candidate RMP (cRMP) based on isotope dilution liquid chromatography tandem mass spectrometry (ID-LC/MS/MS) method for plasma MNs measurement. Plasma samples were spiked with MN-D3 and NMN-D3 as internal standards; protein precipitation and ion-exchange solidphase extraction (SPE) were performed to extract samples, eventually analyzed by LC-MS/MS. The cRMP was applied to evaluate two routine ID-LC/MS/MS methods through split-sample comparisons. Fifty-three individual patient samples were determined by cRMP and two routine ID-LC/MS/MS methods; results were analyzed by ordinary linear regression and Bland-Altman plots. The cRMP exhibited desirable imprecision, with intra-run and total imprecision (coefficient variation, CV) for MN being 0.79-1.36% and 1.53-1.87% and for NMN being 1.10-1.34% and 1.15-1.64%. The analytical recoveries of MN and NMN ranged from 98.3 to 101.7% and from 98.5 to 101.9%, respectively. Significant calibrator biases and sample-specific deviations were observed in method comparison. An accurate, precise, and reliable cRMP for plasma MNs was developed, and RMs with value assigned following the cRMP would help minimize the calibration bias and improve the comparability of different measuring systems.

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine.

Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

Pheochromocytoma as the Etiology of Cushing Syndrome Through Paracrine ACTH Signaling

Abstract Introduction: Pheochromocytomas are rare catecholamine-secreting tumors of the adrenal medulla that may also secrete ACTH. There are approximately 100 cases of ACTH-producing pheochromocytomas reported in the peer reviewed literature, and they typically cause Cushing syndrome by significantly raising circulating ACTH levels. We report a pheochromocytoma causing apparent ACTH-independent Cushing syndrome by paracrine action of locally produced ACTH on ipsilateral adrenal cortex. Case: A 64-year-old female was referred for an incidentally discovered left adrenal mass. The mass was 4 cm and 37 Hounsfield units on non-contrast computed tomography, and the right adrenal gland was unremarkable. The patient’s history was notable for three years of resistant hypertension, and examination revealed stigmata of Cushing syndrome including moon facies, scattered bruises, and wide, pink striae. Three measurements of plasma metanephrines ranged from 3- to 4.5-fold elevated, and 24 h urine metanephrines were 5.2-fold elevated. Urine 24 h epinephrine was 2.7-fold elevated. Three 8 AM cortisol measurements on overnight dexamethasone suppression tests were 16.3–17.4 mcg/dL (< 1.8), and 8 AM dexamethasone on one test was 494 ng/dL (140–295). Two midnight salivary cortisol measurements were 0.348 and 0.416 mcg/dL (< 0.112), and 8 AM ACTH levels on two occasions were 6.8 and 7.9 pg/mL (7.2–63.3). After adrenergic blockade, the patient underwent left adrenalectomy. Her tumor stained for synaptophysin and chromogranin consistent with pheochromocytoma, and focal staining for ACTH was also observed. Hyperplasia of the adjacent adrenal cortex was present. Hypertension resolved after adrenalectomy, and the patient developed secondary adrenal insufficiency (8 AM cortisol and ACTH 1.0 mcg/dL [> 15] and 2.9 pg/mL, respectively). Discussion: There are five published reports of pheochromocytoma and subclinical hypercortisolemia due to paracrine ACTH or IL-6 activity on ipsilateral adrenal cortex, but this case is distinguished by the occurrence of overt Cushing syndrome. Our patient had ACTH < 10 pg/mL on two measurements, her pheochromocytoma showed focal staining for ACTH, and hyperplasia of adjacent adrenal cortex was observed. In contrast, median ACTH level was 5-6x above the upper limit of normal in a recent review of 95 cases of pheochromocytomas with Cushing syndrome due to ectopic ACTH secretion. If Cushing syndrome was due to bilateral adrenal hyperplasia independent of the patient’s pheochromocytoma, cortisol excess would not have resolved after unilateral adrenalectomy. Communication between cortical and medullary circulations through venous radicles provides a mechanism for ACTH produced by the patient’s pheochromocytoma to affect the function of adjacent cortex. This case demonstrates a novel mechanism by which ACTH from a pheochromocytoma can cause Cushing syndrome.

Single-centre study of the diagnostic performance of plasma metanephrines with seated sampling for the diagnosis of phaeochromocytoma/paraganglioma.

Background Measurement of plasma metanephrines is regarded as one of the best screening tests for phaeochromocytoma/paraganglioma. Current guidelines recommend that samples are ideally collected in the supine position after 30 min rest and interpreted using supine reference ranges, in order to optimize the diagnostic performance of the test. Current practice in our centre is to collect samples for plasma metanephrines from seated patients. The aim of the study was to determine, if seated sampling for plasma metanephrines provides acceptable diagnostic performance in our centre. Methods Clinical and laboratory data of 113 patients, gathered over a four-year period 2010-2014, were reviewed. All had undergone preoperative plasma metanephrines measurement and had postoperative histopathology confirmation or exclusion of phaeochromocytoma/paraganglioma. Results Of 113 patients included in the study, 40 had a histological diagnosis of phaeochromocytoma/paraganglioma. The remaining 73 patients had an alternative adrenal pathology. The diagnostic sensitivity of normetanephrine or metanephrine above the upper limit of our in-house seated reference range was 93%. However, excluding three cases of paraganglioma determined clinically and biochemically to be non-functional raised the sensitivity to 100%. Diagnostic specificity was 90%. Applying published supine reference ranges made no difference to diagnostic sensitivity in this group of patients but decreased diagnostic specificity to 75%. Conclusions While these data are derived from a relatively small study population, they demonstrate acceptable diagnostic performance for seated plasma metanephrines as a screening test for phaeochromocytoma/paraganglioma. These data highlight a high diagnostic sensitivity for plasma metanephrines with seated sampling in our centre.

Applying a new decision threshold to an old test: does the measurement of plasma metanephrines in patients fasting and supine improve diagnostic sensitivity?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma.

Reports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography-tandem mass spectrometric (LC-MS/MS) measurements of MNs to diagnose PPGLs. In a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC-MS/MS, each in a specialized laboratory. Plasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC-MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC-MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC-MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias. The EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut-offs resulting in comparable diagnostic performance of EIA and LC-MS/MS assays.

A novel method for the measurement of plasma metanephrines using online solid phase extraction-liquid chromatography tandem mass spectrometry.

Measurement of plasma metanephrine, normetanephrine and 3-methoxytyramine is useful in the diagnosis of phaeochromocytomas, but many assays require a large volume of plasma due to poor assay sensitivity, and often require lengthy sample preparation. Our aim was to develop a method for measurement of plasma metanephrines using a small sample volume with minimal hands-on preparation. Samples were deproteinised using 10 K spin filters prior to online solid phase extraction using a Waters Acquity UPLC Online SPE Manager (Waters, Manchester, UK) coupled to a Waters Xevo TQ-S mass spectrometer (Waters, Manchester, UK). The assay was validated and results compared to a previously published method. We achieved a limit of quantification of 37.5 pmol/L for metanephrine and 3-methoxytyramine and 75 pmol/L for normetanephrine using only 150 µL of sample. The assay was linear up to 30,000 pmol/L for all analytes and in a method comparison study results showed good agreement with a previously published LC-MS/MS assay. We have developed a simple method for measurement of plasma metanephrine, normetanephrine and 3-methoxytyramine using only 150 µL of sample. There is minimal hands-on sample preparation required and the assay is suitable for routine use in a clinical laboratory.

Detection of pheochromocytoma by enzyme immunoassay measurements of plasma metanephrines requires appropriately established upper cut-offs of reference intervals

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Measurements of plasma metanephrines by immunoassay versus LC-MS/MS for diagnosis of pheochromocytoma

Measurements of plasma metanephrines by immunoassay versus LC-MS/MS for diagnosis of pheochromocytoma

Seasonal variation of plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Background: Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. Objective: In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations. Methods: Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming. Results: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P!0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P!0.0001). These differences resulted in a twofold higher (PZ0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (PZ0.0010). Forearm warming increased blood flow and lowered (PZ0.0020) plasma normetanephrine concentrations. Conclusions: Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Clinical utility of chromogranin A in SDHx‐related paragangliomas

Measurement of plasma/urinary catecholamine metabolites--especially normetanephrine (NMN)--represents a gold standard in biochemical detection of succinate dehydrogenase subunit B (SDHB) and D (SDHD)-related pheochromocytomas (PHEO) and paragangliomas (PGL). This study was designed to assess diagnostic utility of chromogranin A (CgA) alone or in combination with NMN in patients with PHEO/PGL related to mutations in SDHB and SDHD. A retrospective study of SDHB and SDHD NIH patients' cohort, which included 41 patients with SDHB mutation-related PHEO/sPGL and 18 patients with either SDHD or SDHB mutation-related head and neck PGL (HNPGL) with both CgA and NMN measured at the time of diagnosis at NIH. In the SDHB group, CgA showed sensitivity of 73.2% and specificity of 95.9%, while for NMN they were 70.7% and 98.6%, respectively. Elevations in CgA and NMN were complementary in 92.7% of patients with proven tumors. Both tests performed well on receiver operating characteristic curve analysis. CgA levels were elevated in 76.9% of SDHB patients and in 80% of patients with metastatic disease and normal NMN levels. CgA values in patients with HNPGL were significantly lower than in patients with PHEO/sPGL. CgA is a valuable complementary biomarker in work-up of SDHB-related PHEO/sPGL. In combination with plasma NMN, CgA further enhances tumor detection by 22.0% with minimal loss in specificity. Although non-specific for PHEO/PGL, CgA may well supplement plasma NMN to facilitate diagnostic evaluation of SDHB-related PHEO/sPGL, especially where the measurement of plasma metanephrines could otherwise be delayed by decreased availability or cost restriction.

Seasonal variation in plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Higher plasma concentrations of catecholamines in winter than in summer have been established, but whether this impacts the plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. In this study, we examined seasonal variations in the plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming ('arterialization' of venous blood) on blood flow and measured concentrations. The measurements of the plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for the measurements of plasma metanephrines and forearm blood flow before and after forearm warming. There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, the plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations. The plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Genetics, Diagnosis, and Management of Medullary Thyroid Carcinoma and Pheochromocytoma/Paraganglioma

Medullary thyroid carcinoma (MTC) and pheochromocytoma/paraganglioma (PHEO/PGL) are rare neuroendocrine tumors. Because of the increased metastatic rates in certain genetic backgrounds, early diagnosis and treatment are essential to improved patient outcomes. Our objective was to summarize recent findings related to the genetics, diagnosis, and management of MTC and PHEO/PGL. A literature review was performed. MTC is primarily associated with mutations in the rearranged during transfection (RET) proto-oncogene. Determining the specific genetic mutation can guide patient management and screening. Early detection and appropriate surgical management of MTC is critical to prevent or limit metastatic spread, as treatment options for patients with metastatic disease are limited. PHEO/PGL also has a strong genetic component, with approximately 50% of cases linked to germline and somatic mutations in 15 genes. Although most PHEO/PGLs are benign, factors such as genetic background, size, tumor location, and high methoxytyramine levels are associated with higher rates of metastatic disease. The state-of-the-art diagnosis and localization of PHEO/PGLs is based on measurement of plasma metanephrines and methoxytyramine and functional imaging studies. For both PHEO/PGL and MTC, surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. As genetic testing becomes more widely available, the diagnosis of MTC and PHEO/PGL will be made earlier due to routine screening of at-risk patients. In addition, continued advances in basic science, diagnostic methods, and imaging techniques will improve understanding of the pathogenesis of these diseases and facilitate the introduction of novel treatment strategies for patients with metastatic disease.

Hipertensión arterial de díficil control asociada a masa abdominal

Palpation of an abdominal mass and the presence of difficult-to-control hypertension should make us consider the possible existence of a pheochromocytoma. Malignant pheochromocytoma accounts for 2-11% of neuroendocrine tumors, catecholamine producing tumors, in which the typical clinical triad is not always present because of the variety of their clinical presentations. Diagnosis is confirmed through the nondipper pattern in the ambulatory blood pressure monitoring (ABPM) study, the measurement of plasma metanephrines and chromogranin A, as well as the imaging tests. Pheochromocytomas have a bad prognosis, survival being less than 50% at 5 years. The main treatment is tumor excision. They are usually resistant to radiotherapy, and response to chemotherapy is minimum. Thus, the treatment approach is often mainly palliative.

Is there still a place for adrenal venous sampling in the diagnostic localization of pheochromocytoma?

Our objective is to outline the utility of adrenal venous sampling (AVS) with measurements of metanephrine to normetanephrine ratios for diagnostic localization of phaeochromocytoma in a patient with normal plasma levels of catecholamines. A 53-year-old-woman was referred for evaluation of recurrent pheochromocytoma following a right adrenalectomy 14 years earlier. Diagnosis of recurrent disease was established from elevations in plasma metanephrines with normal levels of catecholamines. Magnetic resonance imaging indicated two 1-2 cm masses in the right surgical bed and another 1-1.5 cm mass in the left adrenal. These masses were negative on (123)I-metaiodobenzylguanidine scintigraphy. There was no evidence of a hereditary syndrome. We, therefore, carried out two investigational approaches to identify the tumor masses. Hybrid positron emission tomography/computed tomography with (68)Ga-DOTATOC ((68)Ga-DOTATOC-PET/CT) confirmed the presence of recurrent disease in the right surgical bed and also suggested additional left adrenal involvement. Normal plasma catecholamines precluded the use of adrenal venous sampling (AVS) with catecholamine measurements. Hence, we performed AVS with measurements of plasma metanephrines, which were 4- to 7-fold higher in the left adrenal vein than in central venous plasma. We observed a reversal of the normally high metanephrine to normetanephrine ratio (mean value ± SD 5.28 ± 1.86; range 3.36-8.84, n = 13) to 0.73, establishing the presence of a left adrenal pheochromocytoma. Surgical pathology confirmed bilateral disease. This case highlights a scenario where a combination of (68)Ga-DOTATOC-PET/CT and AVS with measurement of the metanephrine to normetanephrine ratio was crucial for the preoperative assessment of a patient with bilateral pheochromocytoma.

A clinical overview of pheochromocytomas/paragangliomas and carcinoid tumors

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 nonoperable 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; nonresectable tumors are treated with somatostatin analogs or chemotherapy. Overall 5-year survival for patients with carcinoids is 67%.

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Findings from five independent studies - with close to 350 patients with pheochromocytoma and more than 2,500 in whom the tumor was excluded - indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98% and specificity of 92%. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing true- from false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with (131)I-labelled M-iodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.