Portrait of a series of patients with pheochromocytoma/paraganglioma from a reference center in Brazil: Relevance of prior background features

Portrait of a series of patients with pheochromocytoma/paraganglioma from a reference center in Brazil: Relevance of prior background features | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Portrait of a series of patients with pheochromocytoma/paraganglioma from a reference center in Brazil: Relevance of prior background features José Viana Lima, Nilza M. Scalissi, Suzan M. Goldman, Claudio E. Kater This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5312717/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Context : Pheochromocytomas (Pheo) and paragangliomas (PGL) (PPGL) are catecholamine-producing tumours, whose functionality is confirmed by elevated plasma (Pl) and/or 24-h urinary (Ur) metanephrines (MN). Objective/Design : We review clinical, hormonal, and imaging aspects of 116 patients studied prospectively: 93 Pheo, 22 PGL, and one Pheo plus PGL. Results : Twenty-five % PPGL were discovered incidentally. Systemic arterial hypertension (SAH) was present in 81% (43% on stage 3), whereas 9.5% were prehypertensiveand 9.5%, normotensive. SAH plus paroxysms occurred in 31 (33%) patients, being exclusively sustained in the remaining; 26 (28%) had resistant SAH. Orthostatic hypotension was present in 65% of patients. Pl/Ur MN and normetanephrine (NMN) were compared to those of a positive (56 functioning PPGL) and a negative control group (654 subjects with normal MN/NMN). Total and fractionated Ur MN were elevated in 94% PPGL patients. Cut-off values of 885 mcg/24-h for Ur MN, and of 1.5 nmol/L for Pl MN identified functioning lesions with 100%/100% sensitivity and 93%/97% specificity, respectively. MRI detected 56% Pheo on the right side,25% on the left, and 19% bilateral; 13 of 23 PGL (56.5%) were retroperitoneal and 10 (43.5%), cervical. Right-side Pheo were larger (5.8 cm) than left-side ones (3.7 cm), but retroperitoneal (6.5 cm) and neck PGL (6.9 cm) were similar in size. Tumour size positively correlated with total Ur MN. Conclusions : in this large cohort of PPGL patients we highlighted relevant aspects of SAH, the frequentlyoverlooked manifestation of orthostatic hypotension, common incidental presentation, and significant tumour size/hormonal production correlation. Hypertension orthostatic hypotension pheochromocytoma paraganglioma adrenal incidentaloma metanephrines Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction/Background Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare catecholamine-producing tumours of the adrenal medulla and extra-adrenal chromaffin tissue, respectively. PGL usually develops from the sympathetic paraganglia of the chest and abdomen. Both are derived from ectodermal neural crest cells and are grouped under the term Pheo/PGL (PPGL) syndrome [1]. More than 40% of the PGLs from this cohort are head and neck tumours from parasympathetic origin. Recently, the WHO recommended the single name paraganglioma to designate both adrenal and extra-adrenal pheochromocytomas [2,3]. The world-wide incidence of PPGL is between 500 and 1,600 cases per year, with an equal sex distribution and the highest frequency in the 4th and 5th decades of life. PPGL has a prevalence of 0.1 to 0.6% among the hypertensive population [4–6]. Approximately 50% of PPGLs manifests clinically as sustained arterial hypertension that is usually accompanied by paroxysms (headache, palpitation, and sweating) and refractoriness to antihypertensive medications. Up to 10% of PPGLs may be found as adrenal incidentalomas. [7] With more genetic discoveries and detection tools, hereditary syndromes will become more common, whereas sporadic disease was the rule in the past [6–11]. Laboratory confirmation is based on elevated levels of plasma and/or urinary fractionated metanephrines. Plasma and urinary catecholamines can also be used, but are less sensitive, as is urinary vanillylmandelic acid (VMA), which was used in the past [12–17]. The imaging location of unilateral or bilateral Pheo and cervical (head and neck), thoracic, and pelvic PGL can be achieved by both CT and MRI, which may be functionally complemented by scintigraphy with 131 I-mIBG (meta-iodobenzylguanidine) and 68 Ga-DOTATATE (DOTA-octreotate) [6,9,14,18–21]. This article will focus on the major clinical, hormonal, and imaging aspects of a large series of PPGL patients studied in a single endocrine reference center in São Paulo, state of São Paulo, Brazil. Patients and methods Study population . From 2001 to 2019, we prospectively studied 137 patients ranging in age from 12 to 82 years in whom a diagnosis of Pheo and/or PGL was clinically considered and later confirmed by (i) hormonal assessment, (ii) specific imaging procedures, (iii) genetic evaluation for germline variants, (iv) surgery, and (v) pathological examination. Twenty-one patients were later excluded: 18 declined further participation, and three were under 14 years, the limit age per our protocol. The remaining 116 were 75 females (64.7%) and 41 males, with a median age of 45 years (ranging from 14 to 79 years). All patients were referred for investigation to the Adrenal and Hypertension Outpatient Clinic of the Division of Endocrinology and Metabolism, at EPM/UNIFESP mainly owing to: 1) systemic arterial hypertension (SAH; 81%) forevaluation of a possible secondary form of hypertension; 2) the existence of first-degree relatives with a previous positive genetic screening for PPGL (26.7%); 3) the presence of an adrenal incidentaloma or any suspicious adrenal or extra-adrenal mass (23.4%); and other reasons (11.2%). Control groups . To analyse and compare values of plasma and urinary metanephrines, we used two control groups, both extracted from an uncharacterized database registry of a commercial laboratory (Fleury Group, São Paulo, Brazil), after formal authorization: one consisted of data from patients with elevated plasma and/or urinary metanephrines in whom a diagnosis of PPGL was unequivocally established ( positive control group ); the other comprised data from a large cohort of subjects who had been evaluated for different disorders and included a panel of plasma and/or urinary metanephrines that were all normal. None of those patients were diagnosed with a PPGL at that time ( negative control group ). Positive controls were 56 subjects: 33 females (58.9%) and 23 males ranging in age from 26 to 82 years (median of 54). Fifty of them had Pheo and six had PGL. They were all “functioning” PPGL (hormone-secreting) by definition. The negative control were 654 subjects: 412 females (63%) and 242 males ranging in age from 16 to 82 years (median of 51). All had plasma and urinary metanephrines within the Fleury laboratory’s reference ranges. Non-functioning PPGL could not be excluded in them. All 116 patients from this study cohort (and/or their parents or liable) signed a written informed consent form for all investigational procedures and therapeutic decisions, which were previously approved by the Committee of Ethics in Clinical Research of the Institution. Patients from the positive and negative control groups were individually investigated by their respective physicians. Authorization to use the biochemical data employed in this manuscript, plus sex, age and information that led to the final diagnosis, was provided by the responsible Board of Directors of Fleury Group without personal patient identification. Study design . The following data were obtained from all patients at the time of admission: sex and age, height and weight (and body mass index, BMI), systolic and diastolic blood pressures and heart rate (HR) (average of two resting and seated office measurements), specific signs and symptoms of the disease (e.g., sustained hypertension and/or paroxysms, tachyarrhythmia, orthostatic hypotension, cardiogenic shock), impaired glucose tolerance (prediabetes or diabetes mellitus), presence of comorbidities, family history of PPGL and specific conditions suggesting the presence of germline pathogenic variants (PVs, see below), and current or past use of antihypertensive medications. We used the 2020 Brazilian Guidelines of Hypertension to define and grade the patient’s arterial hypertension [22]. Conditions suggesting the presence of germline PVs were as presented elsewhere [23–25]. Laboratory evaluation Urinary and blood collections . All patients clinically suspected underwent hormonal evaluation directed towards the hormonal detection of PPGL. Up to 2014, we employed 24-h urinary collections to measure 1) catecholamine excretion: norepinephrine [NE], epinephrine [E], and dopamine [Dp], and 2) fractionated metanephrines: normetanephrine [NMN], metanephrine [MN], and 3-methoxy-tyramine [3MT]. In addition, we simultaneously withdrew blood to measure plasma catecholamines (NE, E, and Dp). From 2014 on, as per the Endocrine Society's PPGL Guideline [9], we started measuring plasma NMN and MN in addition to 24-h urinary metanephrines and discontinued urinary and plasma catecholamines. Hormonal measurements : We measured plasma catecholamines, 24-h urinary catecholamines and metanephrines, and VMA by high-performance liquid chromatography (HPLC) using the Chromsystem Commercial Kit . [Chromsystems Instruments & Chemicals, GmbH] Plasma metanephrines were determined by HPLC coupled to tandem mass spectrometry (LC-MS/MS) through an in-house method developed and validated at the Fleury Group in 2010 [unpublished], in consonance with other protocol [26]. Radiological/Imaging evaluation We performed the following imaging procedures, as indicated and available: 1) abdominal (adrenal) and pelvic computerized tomography (CT) and/or magnetic resonance imaging (MRI); 2) cervical and/or chest MRI for patients with a suspected head/neck or thoracic tumor; 3) 131 I-mIBG full body scintigraphy; and 4) 18 FDG and/or 68 Ga-DOTATATE or DOTATOC PET-CT. We analysed the following CT and MRI data: topography, size, and characteristics of the lesion. Not all biochemical and imaging diagnostic procedures were necessary for each patient. We requested specific hormonal and topographic tests only for diagnostic purposes, mainly 24-h urinary NMN/MN and adrenal MRI or CT and/or 131 I-mIBG and 18 FDG PET-CT, whenever necessary and available. Statistical analysis For statistical purposes, all nondetectable values were arbitrarily considered equal to the limit of sensitivity for the assay divided by the square root of 2 [27]. We performed parametric and nonparametric statistical tests according to the nature of the variable, which were tested for normality by the Kolmogorov‒Smirnov test. Descriptive analysis included absolute (n) and relative (%) frequencies and bar graphs of qualitative variables and summary measures (mean, standard deviation, median, minimum, and maximum). Inferential analysis included the association test using Chi-square or Fisher's exact test and the logistic regression-stepwise forward method and ROC curve analysis to evaluate possible cutoff points for quantitative variables, complemented by calculation of sensitivity and specificity. Cut-off points were established by ROC curve analysis as recommended [28]. P < 0.05 was significant. Results Among the 116 PPGL patients in the present series, 102 were index cases (probands), and 14 were relatives from 8 families. Anthropometry and clinical presentation ( Table 1 ) Table 1 depicts anthropometric and clinical features of the 116 PPGL patients, separated into Pheo (n = 94) and PGL (n = 22). Among the 94 Pheo patients, one also had a neck PGL (thus, in table 3 and Fig. 3 , total PGL are 23). The sex ratio was approximately 2 F:1 M. PGL patients were younger (35.5 vs. 45 years, p < 0.01) and comprised significantly more subjects ≤ 20 years of age than Pheo (18.2% vs. 6.4%; p < 0.01). Median BMI and heart rate were similar between groups. Virtually all Pheo (98.9%) (including the one combined with a neck PGL) and 59.1% of PGL were functioning lesions, in the sense that they produced excessive catecholamines that resulted in clinical manifestations. At presentation, 64.7% of the patients had two clinical manifestations, 25% had only one, and 13.8% had three or more. The most common clinical feature was SAH in its various forms. Blood pressure Table 1 show the results related to hypertension. SAH was present in 94 of the 116 PPGL patients (81%), whereas 11 (9.5%) were prehypertensive and 11 (9.5%) had normal blood pressure. Among the 94 hypertensive patients, 28 (29.8%) were in stage 1, 25 (26.6%) were in stage 2, and 41 (43.6%) were in stage 3. Stage 3 SAH prevailed over stages 1 and 2 in the whole PPGL group, especially among the PGL patients. Overall, systolic and diastolic blood pressure (BP) were higher in hypertensive PGL than in Pheo, albeit not significantly. High BP was found alone in 29 (37.2%) hypertensive PPGL patients (29 Pheo) and was accompanied by paroxysms in the remaining 31 (32.9%) (29 Pheo). Hypertension that was difficult to control (resistant SAH) was present in 26 (27.7%) PPGL patients (20 Pheo) and was mostly found as paroxysmal and combined hypertension. Seventy-five (64.7%) patients (65 Pheo) had orthostatic hypotension, six of whom (8%, all Pheo) did not have hypertension of any form (all genetic [cluster 2], hormonally secretory, and generally smaller in size). The estimated median time since first diagnosis of SAH (with or without paroxysms) was 24 mo. (ranging from 1 to 480 mo.). Hormonal presentation Urinary and plasma metanephrines (Table 2 , Fig. 1 ) With the large negative control population (n = 654) as reference, we defined our own reference ranges for total and fractionated 24-h urinary and plasma MN as follows (results in mean ± SEM, and [range]): 24-h urinary NMN: 214.8 ±4.0 mcg/24 h [15–784]; MN: 81.9 ±1.6 mcg/24 h [3.5–326], and total metanephrines: 296.7 ±4.7 mcg/24 h [33–878]. Plasma NMN: 0.45 ±0.01 nmol/L [0.14-1.0] and MN: 0.18 ±0.01 nmol/L [0.14–0.6), and total metanephrines: 0.63 ±0.01 nmol/L [0.28–1.5]. As shown in Table 2 , 88 PPGL patients from the present study and, especially, 56 from the positive control group had significantly higher levels of NMN, MN, and total MN than the negative controls. The individual values of 24-h urinary MN from these subjects are shown in Fig. 1 . A cut-off value of 885 mcg/24 h for total urinary MN, determined by ROC curve analysis, had 100% sensitivity and 92.5% specificity at separating functioning from nonfunctioning PPGL (study cases and positive controls vs. negative controls). In fact, 67.4% of the 24-h urinary total MN values were above 885 mcg/24 h in the subgroup of functioning PPGL from this study and the positive control groups, compared to none in the negative controls (Fig. 1 ). Table 2 also shows that plasma metanephrines (NMN and MN) from the study group (n = 20) and the positive control group (n = 56) were significantly higher than those from the negative control group (p < 0.01). A cut-off value of 1.5 nmol/L for total plasma MN determined by ROC curve analysis had 100% sensitivity and 97.3% specificity to separate functioning from nonfunctioning PPGL lesions (study cases and positive controls vs. negative controls). Urinary and plasma catecholamines The following results were obtained for 24-h urinary catecholamines from 13 patients with Pheo and two with PGL: epinephrine: 906 ±216 mcg/24 h (800; range: 70 − 2,500); norepinephrine: 1,275 ±263 mcg/24 h (900; range: 100-3,900); and dopamine: 360 ±123 mcg/24 h (250; range: 70 − 2,000). Figure 3 depicts all the individual values. None of the PPGL patients had detectable values for plasma epinephrine, whereas plasma norepinephrine was 2,373 ±221 pg/mL (2,500; range: 900-3,500) and dopamine was 215 ±42 (180; range: 28–500). Topographic distribution and tumor size (Fig. 2 ) Most PPGL patients (93.9%) were initially imaged by MRI instead of CT (given the ease of performing it in our service). 53 Pheo (56.4%) were located on the right side, 23 (24.5%) on the left, and 18 (19.2%) were bilateral. Among the 23 PGL, 13 (56.5%) were retroperitoneal and 10 (43.5%) were cervical. The Pheo located on the right side were significantly larger than those on the left (including the bilateral ones) (median of 5.8 vs. 3.7 cm, respectively) (p < 0.01). Retroperitoneal and neck PGL had similar sizes (medians of 6.5 and 6.9 cm, respectively). The individual sizes of all PPGL lesions are depicted in Fig. 2 . Note that 70% of all 117 PPGL lesions were larger than 3 cm in diameter (and 61% were larger than 4 cm). High signal intensity on the T2-weighted sequence was observed in 108 of the 109 patients (99.1%) who underwent MRI. Among the 11 PPGL patients who underwent CT imaging, all typically had pre-contrast attenuation values above 10 HU, above 20 HU in the portal phase, and a contrast washout < 60%. Metanephrines and tumor size (Fig. 3 ) A significant positive correlation was observed between tumour size (largest diameter, in cm) and total urinary MN (in mcg/24 h) for 91 functioning PPGL (74 Pheo and 17 PGL): r = 0.27; p < 0.01 (Fig. 3 ). Nonfunctioning PPGL, especially head and neck PGL, presented 24-h urinary MN within the normal range. Discussion PPGL is a rare neuroendocrine tumour that is potentially metastatic and fatal if this diagnosis is not promptly suspected, and treatment is not started soon. Its incidence has been increasing recently due to improvements in the measurement of catecholamine metabolites and a greater demand for imaging tests. Unfortunately, there is still a significant diagnostic delay, some only coming post-mortem [2,3]. This diagnostic delay was confirmed in our population sample: most patients took two or more years to seek medical assistance, and one of them took almost 40 years to be diagnosed. Hence, major complications related to hypertension are to be expected. PPGL is a relevant diagnostic possibility in the investigation of secondary and/or resistant forms of SAH, regardless of the presence of paroxysms. Clinical scores are available to help define an individual’s risk of having PPGL. Features such as hyperhidrosis, palpitations, pallor, tremors, and nausea are 30–90% more prevalent in the PPGL population than in other hypertensive patients. These characteristics plus a heart rate above 85 bpm and BMI < 25 kg/m 2 guarantee scores close to the maximum of 7 points, a score that makes PPGL 5.8 times more likely than lower scores do [15]. The main manifestation in our patients that led to the suspicion of PPGL was sustained SAH. Other common ones were paroxysms, genetic screening, difficult-to-control SAH and adrenal incidentalomas, consistent with the medical literature [8,14,20]. When first investigated, most patients were already taking two or more classes of antihypertensive drugs. Orthostatic hypotension was a mostly relevant finding, often associated with SAH but also found in normotensive patients who were initially referred for genetic screening or evaluation of adrenal incidentaloma. This finding is important in the initial evaluation, as it is often present whether the individual has SAH or not. Normotensive and prehypertensive patients (almost 20% of our sample) were referred for evaluation of PPGL due to a positive family history or presence of adrenal incidentaloma (22%), as has been reported [20,23–25,29,30]. Investigation of PPGL is recommended for recent-onset diabetes mellitus in a young, lean, hypertensive patient since catecholamine excess favours hepatic gluconeogenesis and less degranulation of insulin by pancreatic beta cells [14]. Eighteen percent of our patients had impaired glucose tolerance, raising the question whether diagnosis and treatment of PPGL could change some subjects’ DM history, even leading to a "cure". Plasma free MN are considered the gold standard for the diagnosis of functioning PPGL, with slight superiority over 24-h urinary fractionated MN. In the past, the combination of urinary MN with plasma/urinary catecholamines was recommended because of its lowest false negative rate; however, plasma MN alone is diagnostically better than any of the combined tests. Negative plasma MN virtually excludes functional PPGL, but in its absence, 24-h urinary MN can replace them. Thus, the current laboratory diagnosis of PPGL must include plasma and/or 24-h urinary MN [6–10,14,16,31]. Both our PPGL study patients and the positive control group presented very high values of 24-h urinary and plasma MN compared to our large reference negative control group, even when nonfunctioning PPGL (especially those located in the neck) were included. The cut-off value of 885 mcg/24 h had a sensitivity and specificity of 100% and 92.5%, respectively, for total urinary MN. Thus, 24-h urinary MN alone is likely a sensitive and good marker of PPGL functionality, useful for screening patients for the disease. Plasma MN values twice above the upper limit of normal are strongly suggestive of PPGL, whereas values between 1X and 2X are considered suspect, requiring diagnostic complementation with 24-h urinary MN and/or chromogranin A measurement and/or a suppression test with clonidine. Based on our findings and others, we suggest a simple and direct algorithm (Fig. 4 ) to diagnose functioning PPGL. The measurement of 3-methoxy-tyramine can help in the diagnosis of PPGL, especially in dopamine-producing, metastatic, and neck PGL [14]. The topographic diagnosis of PPGL should initially be made with CT of the adrenals and pelvis, whereas MRI would be reserved for specific cases such as carriers of PV in PPGL-related genes, intracardiac and head/neck PGL, pregnant women, children, tumour recurrence and metastatic PPGL. Both imaging procedures have good sensitivity and specificity for the diagnosis of PPGL. The characteristics of PPGL on CT are attenuation values in the pre-contrast phase greater than 10 HU, usually above 20, with a contrast washout < 60% and high signal intensity (“light-bulb” bright) on the T2-sequence and out-of-phase sequence of MRI, with no loss of signal [8,9,13]. The ready availability of MRI over CT in our group prompted us to study 109 of our 116 patients with MRI at first, which was able to identify the high signal intensity on T2 in 108 of them; seven of the patients who underwent adrenal/pelvis CT had characteristics of a nonadenomatous lesion. The tumour diameter in our patients was mostly in the range of 5 to 6 cm. We identified three micro-pheochromocytomas (the smallest measuring 3 mm in diameter), none of hereditary origin, whose images disclosed only adrenal thickening, but their adrenergic clinical picture was exuberant; increased hormonal levels were detected in all during adrenergic episodes. The largest Pheo in our series was 24 cm in diameter and was initially suspected to be a primary adrenocortical carcinoma. We found a significant positive correlation between tumour size and total 24-h urinary MN. Functioning PPGL with a diameter greater than 5 cm tend to produce total urinary MN above 1,000 mcg/24 h. In summary, we present the clinical, hormonal, and imaging picture of a representative cohort of PPGL patients studied in a single reference center in São Paulo, Brazil, whose data mostly agree with other series reported worldwide. Of note, nearly 25% of the Pheo were discovered incidentally. Sustained SAH was present in more than 80% of cases (especially PGL patients), mostly severe and treatment-resistant and typically accompanied by paroxysms. Two-thirds of patients had orthostatic hypotension, an important but generally overlooked diagnostic clue. Diagnostic confirmation of a functioning PPGL strongly relies on the finding of elevated metanephrines (plasma and/or 24-urinary), complemented by chromogranin A and/or a clonidine test, as necessary. MRI was particularly valuable to identify PPGL and to investigate patients with germline variants: the right adrenal gland was more frequently affected than the left, and bilateral masses were present in 20% of cases. The average mass diameter was 5–6 cm, and the larger the mass, the more marked its total urinary metanephrine excretion. Although uncommon, the diagnosis of PPGL should be considered in young, lean, treatment-resistant hypertensive patients with an impaired glucose tolerance or new-onset diabetes mellitus. Declarations Declaration of interest There is no conflict of interest that could be perceived as prejudicing the impartiality of this research. Author Contribution A) Jose Viana Lima Junior: carried out data collection, clinical consultations with patients, collected blood tests, performed genetic analysis on patients, clinical monitoring of patients, performed statistical analysis and wrote the paper.B) Nilza Maria Scalissi: contributed by referring some patients for evaluation at UNIFESP-EPM Hospital and contributed to the discussion part of the paper.C) Suzan M. Goldman: contributed by analyzing all the PGL localization images and contributed to the discussion part of the paperD) Claudio Elias Kater: contributed to all the work guided by data collection, discussion of clinical cases, preparation of the paper and statistical analysis. Acknowledgments We thank Erica S. Souza de Araujo and Pamela M. 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(68)Ga-DOTATATE and (18)F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility, patterns and heterogeneity. Cancer Imaging. 2016;16:22. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89:479-91. Mozley PD, Kim CK, Mohsin J, Jatlow A, Gosfield E 3rd, Alavi A. The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med. 1994;35:1138-44. Barroso WKS, Rodrigues CIS, Bortolotto LA, Mota-Gomes MA, Brandão AA, Feitosa ADM, et al. Brazilian Guidelines of Hypertension – 2020. Arq Bras Cardiol. 2021;116(3):516-658. Lima Jr. JV, Scalissi NM, Oliveira KC, Lindsey SC, Olivati C, Ferreira EN, et al. Germline genetic variants in pheochromocytoma/paraganglioma: Single-center experience at São Paulo, Brazil. Endocrine Oncol. 2023;3:e220091. Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, et al. Clinical predictors, and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009;15:6378-85. Gimenez-Roqueplo AP, Robledo M, Dahia PLM. Update on the genetics of paragangliomas. Endocr Relat Cancer. 2023;30(4):e220373. Eisenhofer G, Peitzsch M, McWhinney BC. Impact of LC-MS/MS on the laboratory diagnosis of catecholamine-producing tumors. Trends Analyt Chem. 2016;84:106-116. Kater CE, Irony I, Biglieri EG, Faiçal S. Continuous adrenocorticotropin administration in hypopituitarism produces asynchronous increases of deoxy-corticosterone and 11-deoxycortisol relative to other reduced zona fasciculata steroids. J Clin Endocrinol Metab. 1990;71(2):305-10. Unal I. Defining an optimal cut-point value in ROC analysis: An alternative approach. Comput Math Methods Med. 2017;3762651. doi: 10.1155/2017/3762651. Epub 2017 May 31. Buffet A, Burnichon N, Favier J, Gimenez-Roqueplo A-P. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2020;34(2):1-14. Cascón A, Calsina B, Monteagudo M, Mellid S, Díaz-Talavera A, Currás-Freixes et al. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol. 2023; 70(3):e220167. Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillylmandelic acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2007;92:4602-8. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2ClinicalpaperONE0602241.docx Table3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5312717","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369318842,"identity":"d1537b4f-9c13-4394-ac27-7eeb3c2a552b","order_by":0,"name":"José Viana Lima","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYDACZjBpwQNkHWBgMJAD8diI0SIB1MKWANRiTIQWCJAAYh4DIEGEFoPjzM8e/GCQkNFtP/NNuqDAQE5+dgPb4wp8Wg6zmRv2AB1mdiZ3m/QMAwNjgzsH2A3P4NEi2cxgBvQIUMsBoBYegz+JGyQS2CQb8Gph/yb5B6Tl/JtnQC0G9fNnENDCz8xjJg225UYOG0hLAsMNwlrKpGUMQFqeGVsDtRhuuHOw3RCfFjb+49sk31TY2JudT354m+ePgbz87OZjD/FpgQADZI4EI2ENaECCVA2jYBSMglEw3AEAlUc90Qyzl8YAAAAASUVORK5CYII=","orcid":"","institution":"Federal University of São Paulo Medical School (EPM/UNIFESP)","correspondingAuthor":true,"prefix":"","firstName":"José","middleName":"Viana","lastName":"Lima","suffix":""},{"id":369318843,"identity":"7fbb3ce0-b74e-45d6-a16c-7cf6ddba30c4","order_by":1,"name":"Nilza M. Scalissi","email":"","orcid":"","institution":"Santa Casa de São Paulo School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nilza","middleName":"M.","lastName":"Scalissi","suffix":""},{"id":369318845,"identity":"a7041d3f-5716-4987-a4d4-3cb3ee929fdc","order_by":2,"name":"Suzan M. Goldman","email":"","orcid":"","institution":"Federal University of São Paulo Medical School (EPM/UNIFESP)","correspondingAuthor":false,"prefix":"","firstName":"Suzan","middleName":"M.","lastName":"Goldman","suffix":""},{"id":369318846,"identity":"ae42392e-c488-4b87-be7d-87f5fab4fdc9","order_by":3,"name":"Claudio E. Kater","email":"","orcid":"","institution":"Federal University of São Paulo Medical School (EPM/UNIFESP)","correspondingAuthor":false,"prefix":"","firstName":"Claudio","middleName":"E.","lastName":"Kater","suffix":""}],"badges":[],"createdAt":"2024-10-22 14:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5312717/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5312717/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":68690178,"identity":"b2d12fbf-853f-45a1-9d91-e7fa42214b1e","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":215150,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual values of total and fractionated 24-h urinary metanephrines from 89 patients with PPGL and 56 positive controls (see text for explanation). Shaded areas represent the normal ranges (minimum and maximum values from the negative control group). Note thesemilogarithmic scale; horizontal bars denote means. Boxed numbers atop each series represent the percentage of values above the upper limit of normal (ULN).\u003c/p\u003e","description":"","filename":"Figure11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/e2d0e31c161867f52bbdff13.jpg"},{"id":68690185,"identity":"b92f318c-cd28-4530-93b4-2a47c5e5121d","added_by":"auto","created_at":"2024-11-11 05:39:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":448000,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual location and size of lesions from 116 PPGL patients. Size is the largest diameter (in cm) obtained by CT or MRI. Horizontal bars denote means. Boxed numbers atop each series represent percentages of total PPGL.\u003c/p\u003e","description":"","filename":"Figure12.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/901d0e2b71db25365081a0c1.jpg"},{"id":68690181,"identity":"d279b14b-5814-4f54-ad1f-83d8a36ebdbc","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":267105,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between lesion size (largest diameter, in cm) and 24-h urinary excretion of total metanephrines from 89 patients with PPGL. Represented are either unilateral pheochromocytomas or the larger lesion of the bilateral ones.\u003c/p\u003e","description":"","filename":"Figure13.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/36452a43aba720477a1e6401.jpg"},{"id":68690184,"identity":"4844dccb-8289-4f29-87fa-a63af5fb287f","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":192383,"visible":true,"origin":"","legend":"\u003cp\u003eSuggested algorithm for laboratory investigation of functioning pheochromocytoma/paraganglioma (PPGL). \u003csup\u003e1\u003c/sup\u003e Measured by HPLC coupled with tandem mass spectrometry (LC-MS/MS); \u003csup\u003e2 \u003c/sup\u003eULN= upper limit of normal; \u003csup\u003e3 \u003c/sup\u003eMeasured by HPLC or LC-MS/MS.\u003c/p\u003e","description":"","filename":"Figure14.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/e474e819ae99ce4ce3288a2b.jpg"},{"id":68690183,"identity":"41cc293a-848c-4d09-93d2-ee7747556651","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":247902,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure15.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/7047c8b79400933b6a2f267e.jpg"},{"id":68690182,"identity":"9c00d013-48f6-4789-9a05-4e5390107545","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":155689,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure16.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/f2291a9ca37bf39b23bce78a.jpg"},{"id":75589381,"identity":"71fcb6f0-70e8-4d45-b3ab-f72fe47efd23","added_by":"auto","created_at":"2025-02-06 06:54:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2047334,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/6a4eb1c4-1663-40c5-8f4b-082df63d7215.pdf"},{"id":68690177,"identity":"d46cb24e-f74c-4399-a4d8-4c3ea5bf4de4","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":20719,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/443e94f361224d30d3b913d1.docx"},{"id":68690179,"identity":"1dd46959-c99a-4beb-9a8a-280dee4e9bed","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20000,"visible":true,"origin":"","legend":"","description":"","filename":"Table2ClinicalpaperONE0602241.docx","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/9bfaa18826a642f747ca1225.docx"},{"id":68690180,"identity":"0ea76994-927e-40a7-9a13-0ec7e0d38aad","added_by":"auto","created_at":"2024-11-11 05:39:35","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18006,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-5312717/v1/1665470ec08ea2cf85606142.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Portrait of a series of patients with pheochromocytoma/paraganglioma from a reference center in Brazil: Relevance of prior background features","fulltext":[{"header":"Introduction/Background","content":"\u003cp\u003ePheochromocytomas (Pheo) and paragangliomas (PGL) are rare catecholamine-producing tumours of the adrenal medulla and extra-adrenal chromaffin tissue, respectively. PGL usually develops from the sympathetic paraganglia of the chest and abdomen. Both are derived from ectodermal neural crest cells and are grouped under the term Pheo/PGL (PPGL) syndrome [1]. More than 40% of the PGLs from this cohort are head and neck tumours from parasympathetic origin. Recently, the WHO recommended the single name paraganglioma to designate both adrenal and extra-adrenal pheochromocytomas [2,3].\u003c/p\u003e \u003cp\u003eThe world-wide incidence of PPGL is between 500 and 1,600 cases per year, with an equal sex distribution and the highest frequency in the 4th and 5th decades of life. PPGL has a prevalence of 0.1 to 0.6% among the hypertensive population [4\u0026ndash;6].\u003c/p\u003e \u003cp\u003eApproximately 50% of PPGLs manifests clinically as sustained arterial hypertension that is usually accompanied by paroxysms (headache, palpitation, and sweating) and refractoriness to antihypertensive medications. Up to 10% of PPGLs may be found as adrenal incidentalomas. [7] With more genetic discoveries and detection tools, hereditary syndromes will become more common, whereas sporadic disease was the rule in the past [6\u0026ndash;11].\u003c/p\u003e \u003cp\u003eLaboratory confirmation is based on elevated levels of plasma and/or urinary fractionated metanephrines. Plasma and urinary catecholamines can also be used, but are less sensitive, as is urinary vanillylmandelic acid (VMA), which was used in the past [12\u0026ndash;17]. The imaging location of unilateral or bilateral Pheo and cervical (head and neck), thoracic, and pelvic PGL can be achieved by both CT and MRI, which may be functionally complemented by scintigraphy with \u003csup\u003e131\u003c/sup\u003eI-mIBG (meta-iodobenzylguanidine) and \u003csup\u003e68\u003c/sup\u003eGa-DOTATATE (DOTA-octreotate) [6,9,14,18\u0026ndash;21].\u003c/p\u003e \u003cp\u003eThis article will focus on the major clinical, hormonal, and imaging aspects of a large series of PPGL patients studied in a single endocrine reference center in S\u0026atilde;o Paulo, state of S\u0026atilde;o Paulo, Brazil.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy population\u003c/span\u003e. From 2001 to 2019, we prospectively studied 137 patients ranging in age from 12 to 82 years in whom a diagnosis of Pheo and/or PGL was clinically considered and later confirmed by (i) hormonal assessment, (ii) specific imaging procedures, (iii) genetic evaluation for germline variants, (iv) surgery, and (v) pathological examination. Twenty-one patients were later excluded: 18 declined further participation, and three were under 14 years, the limit age per our protocol. The remaining 116 were 75 females (64.7%) and 41 males, with a median age of 45 years (ranging from 14 to 79 years). All patients were referred for investigation to the Adrenal and Hypertension Outpatient Clinic of the Division of Endocrinology and Metabolism, at EPM/UNIFESP mainly owing to: 1) systemic arterial hypertension (SAH; 81%) forevaluation of a possible secondary form of hypertension; 2) the existence of first-degree relatives with a previous positive genetic screening for PPGL (26.7%); 3) the presence of an adrenal incidentaloma or any suspicious adrenal or extra-adrenal mass (23.4%); and other reasons (11.2%).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eControl groups\u003c/span\u003e. To analyse and compare values of plasma and urinary metanephrines, we used two control groups, both extracted from an uncharacterized database registry of a commercial laboratory (Fleury Group, S\u0026atilde;o Paulo, Brazil), after formal authorization: one consisted of data from patients with elevated plasma and/or urinary metanephrines in whom a diagnosis of PPGL was unequivocally established (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003epositive control group\u003c/span\u003e); the other comprised data from a large cohort of subjects who had been evaluated for different disorders and included a panel of plasma and/or urinary metanephrines that were all normal. None of those patients were diagnosed with a PPGL at that time (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003enegative control group\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePositive controls were 56 subjects: 33 females (58.9%) and 23 males ranging in age from 26 to 82 years (median of 54). Fifty of them had Pheo and six had PGL. They were all \u0026ldquo;functioning\u0026rdquo; PPGL (hormone-secreting) by definition.\u003c/p\u003e \u003cp\u003eThe negative control were 654 subjects: 412 females (63%) and 242 males ranging in age from 16 to 82 years (median of 51). All had plasma and urinary metanephrines within the Fleury laboratory\u0026rsquo;s reference ranges. Non-functioning PPGL could not be excluded in them.\u003c/p\u003e \u003cp\u003eAll 116 patients from this study cohort (and/or their parents or liable) signed a written informed consent form for all investigational procedures and therapeutic decisions, which were previously approved by the Committee of Ethics in Clinical Research of the Institution. Patients from the positive and negative control groups were individually investigated by their respective physicians. Authorization to use the biochemical data employed in this manuscript, plus sex, age and information that led to the final diagnosis, was provided by the responsible Board of Directors of Fleury Group without personal patient identification.\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy design\u003c/span\u003e. The following data were obtained from all patients at the time of admission: sex and age, height and weight (and body mass index, BMI), systolic and diastolic blood pressures and heart rate (HR) (average of two resting and seated office measurements), specific signs and symptoms of the disease (e.g., sustained hypertension and/or paroxysms, tachyarrhythmia, orthostatic hypotension, cardiogenic shock), impaired glucose tolerance (prediabetes or diabetes mellitus), presence of comorbidities, family history of PPGL and specific conditions suggesting the presence of germline pathogenic variants (PVs, see below), and current or past use of antihypertensive medications. We used the 2020 Brazilian Guidelines of Hypertension to define and grade the patient\u0026rsquo;s arterial hypertension [22].\u003c/p\u003e \u003cp\u003eConditions suggesting the presence of germline PVs were as presented elsewhere [23\u0026ndash;25].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory evaluation\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eUrinary and blood collections\u003c/span\u003e. All patients clinically suspected underwent hormonal evaluation directed towards the hormonal detection of PPGL. Up to 2014, we employed 24-h urinary collections to measure 1) catecholamine excretion: norepinephrine [NE], epinephrine [E], and dopamine [Dp], and 2) fractionated metanephrines: normetanephrine [NMN], metanephrine [MN], and 3-methoxy-tyramine [3MT]. In addition, we simultaneously withdrew blood to measure plasma catecholamines (NE, E, and Dp). From 2014 on, as per \u003cem\u003ethe Endocrine Society's PPGL Guideline\u003c/em\u003e [9], we started measuring plasma NMN and MN in addition to 24-h urinary metanephrines and discontinued urinary and plasma catecholamines.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHormonal measurements\u003c/span\u003e: We measured plasma catecholamines, 24-h urinary catecholamines and metanephrines, and VMA by high-performance liquid chromatography (HPLC) using the \u003cem\u003eChromsystem Commercial Kit\u003c/em\u003e. [Chromsystems Instruments \u0026amp; Chemicals, GmbH]\u003c/p\u003e\u003cp\u003ePlasma metanephrines were determined by HPLC coupled to tandem mass spectrometry (LC-MS/MS) through an in-house method developed and validated at the Fleury Group in 2010 [unpublished], in consonance with other protocol [26].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRadiological/Imaging evaluation\u003c/h3\u003e\n\u003cp\u003eWe performed the following imaging procedures, as indicated and available: 1) abdominal (adrenal) and pelvic computerized tomography (CT) and/or magnetic resonance imaging (MRI); 2) cervical and/or chest MRI for patients with a suspected head/neck or thoracic tumor; 3) \u003csup\u003e131\u003c/sup\u003eI-mIBG full body scintigraphy; and 4) \u003csup\u003e18\u003c/sup\u003eFDG and/or \u003csup\u003e68\u003c/sup\u003eGa-DOTATATE or DOTATOC PET-CT.\u003c/p\u003e \u003cp\u003eWe analysed the following CT and MRI data: topography, size, and characteristics of the lesion.\u003c/p\u003e \u003cp\u003eNot all biochemical and imaging diagnostic procedures were necessary for each patient. We requested specific hormonal and topographic tests only for diagnostic purposes, mainly 24-h urinary NMN/MN and adrenal MRI or CT and/or \u003csup\u003e131\u003c/sup\u003eI-mIBG and \u003csup\u003e18\u003c/sup\u003eFDG PET-CT, whenever necessary and available.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor statistical purposes, all nondetectable values were arbitrarily considered equal to the limit of sensitivity for the assay divided by the square root of 2 [27]. We performed parametric and nonparametric statistical tests according to the nature of the variable, which were tested for normality by the Kolmogorov‒Smirnov test. Descriptive analysis included absolute (n) and relative (%) frequencies and bar graphs of qualitative variables and summary measures (mean, standard deviation, median, minimum, and maximum). Inferential analysis included the association test using Chi-square or Fisher's exact test and the logistic regression-stepwise forward method and ROC curve analysis to evaluate possible cutoff points for quantitative variables, complemented by calculation of sensitivity and specificity. Cut-off points were established by ROC curve analysis as recommended [28]. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 116 PPGL patients in the present series, 102 were index cases (probands), and 14 were relatives from 8 families.\u003c/p\u003e\n\u003cp\u003e\u003cspan type=\"Underline\" name=\"Emphasis\"\u003eAnthropometry and clinical presentation\u003c/span\u003e (\u003cspan type=\"Underline\" name=\"Emphasis\"\u003eTable\u0026nbsp;1\u003c/span\u003e)\u003c/p\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" name=\"Emphasis\"\u003eTable\u0026nbsp;1\u003c/span\u003e depicts anthropometric and clinical features of the 116 PPGL patients, separated into Pheo (n\u0026thinsp;=\u0026thinsp;94) and PGL (n\u0026thinsp;=\u0026thinsp;22). Among the 94 Pheo patients, one also had a neck PGL (thus, in table 3 and Fig. \u003cspan\u003e3\u003c/span\u003e, total PGL are 23). The sex ratio was approximately 2 F:1 M. PGL patients were younger (35.5 vs. 45 years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and comprised significantly more subjects\u0026thinsp;\u0026le;\u0026thinsp;20 years of age than Pheo (18.2% vs. 6.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Median BMI and heart rate were similar between groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eVirtually all Pheo (98.9%) (including the one combined with a neck PGL) and 59.1% of PGL were functioning lesions, in the sense that they produced excessive catecholamines that resulted in clinical manifestations. At presentation, 64.7% of the patients had two clinical manifestations, 25% had only one, and 13.8% had three or more. The most common clinical feature was SAH in its various forms.\u003c/p\u003e\n\u003ch3\u003eBlood pressure\u003c/h3\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" name=\"Emphasis\"\u003eTable\u0026nbsp;1\u003c/span\u003e show the results related to hypertension. SAH was present in 94 of the 116 PPGL patients (81%), whereas 11 (9.5%) were prehypertensive and 11 (9.5%) had normal blood pressure. Among the 94 hypertensive patients, 28 (29.8%) were in stage 1, 25 (26.6%) were in stage 2, and 41 (43.6%) were in stage 3. Stage 3 SAH prevailed over stages 1 and 2 in the whole PPGL group, especially among the PGL patients. Overall, systolic and diastolic blood pressure (BP) were higher in hypertensive PGL than in Pheo, albeit not significantly.\u003c/p\u003e\n \u003cp\u003eHigh BP was found alone in 29 (37.2%) hypertensive PPGL patients (29 Pheo) and was accompanied by paroxysms in the remaining 31 (32.9%) (29 Pheo). Hypertension that was difficult to control (resistant SAH) was present in 26 (27.7%) PPGL patients (20 Pheo) and was mostly found as paroxysmal and combined hypertension. Seventy-five (64.7%) patients (65 Pheo) had orthostatic hypotension, six of whom (8%, all Pheo) did not have hypertension of any form (all genetic [cluster 2], hormonally secretory, and generally smaller in size).\u003c/p\u003e\n \u003cp\u003eThe estimated median time since first diagnosis of SAH (with or without paroxysms) was 24 mo. (ranging from 1 to 480 mo.).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eHormonal presentation\u003c/h2\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" name=\"Emphasis\"\u003eUrinary and plasma metanephrines\u003c/span\u003e (Table \u003cspan\u003e2\u003c/span\u003e, Fig. \u003cspan\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003eWith the large negative control population (n\u0026thinsp;=\u0026thinsp;654) as reference, we defined our own reference ranges for total and fractionated 24-h urinary and plasma MN as follows (results in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM, and [range]): 24-h urinary NMN: 214.8 \u0026plusmn;4.0 mcg/24 h [15\u0026ndash;784]; MN: 81.9 \u0026plusmn;1.6 mcg/24 h [3.5\u0026ndash;326], and total metanephrines: 296.7 \u0026plusmn;4.7 mcg/24 h [33\u0026ndash;878]. Plasma NMN: 0.45 \u0026plusmn;0.01 nmol/L [0.14-1.0] and MN: 0.18 \u0026plusmn;0.01 nmol/L [0.14\u0026ndash;0.6), and total metanephrines: 0.63 \u0026plusmn;0.01 nmol/L [0.28\u0026ndash;1.5].\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan\u003e2\u003c/span\u003e, 88 PPGL patients from the present study and, especially, 56 from the positive control group had significantly higher levels of NMN, MN, and total MN than the negative controls. The individual values of 24-h urinary MN from these subjects are shown in Fig. \u003cspan\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eA cut-off value of 885 mcg/24 h for total urinary MN, determined by ROC curve analysis, had 100% sensitivity and 92.5% specificity at separating functioning from nonfunctioning PPGL (study cases and positive controls vs. negative controls). In fact, 67.4% of the 24-h urinary total MN values were above 885 mcg/24 h in the subgroup of functioning PPGL from this study and the positive control groups, compared to none in the negative controls (Fig. \u003cspan\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eTable \u003cspan\u003e2\u003c/span\u003e also shows that plasma metanephrines (NMN and MN) from the study group (n\u0026thinsp;=\u0026thinsp;20) and the positive control group (n\u0026thinsp;=\u0026thinsp;56) were significantly higher than those from the negative control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). A cut-off value of 1.5 nmol/L for total plasma MN determined by ROC curve analysis had 100% sensitivity and 97.3% specificity to separate functioning from nonfunctioning PPGL lesions (study cases and positive controls vs. negative controls).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eUrinary and plasma catecholamines\u003c/h3\u003e\n\u003cp\u003eThe following results were obtained for 24-h urinary catecholamines from 13 patients with Pheo and two with PGL: epinephrine: 906 \u0026plusmn;216 mcg/24 h (800; range: 70\u0026thinsp;\u0026minus;\u0026thinsp;2,500); norepinephrine: 1,275 \u0026plusmn;263 mcg/24 h (900; range: 100-3,900); and dopamine: 360 \u0026plusmn;123 mcg/24 h (250; range: 70\u0026thinsp;\u0026minus;\u0026thinsp;2,000). Figure \u003cspan\u003e3\u003c/span\u003e depicts all the individual values.\u003c/p\u003e\n\u003cp\u003eNone of the PPGL patients had detectable values for plasma epinephrine, whereas plasma norepinephrine was 2,373 \u0026plusmn;221 pg/mL (2,500; range: 900-3,500) and dopamine was 215 \u0026plusmn;42 (180; range: 28\u0026ndash;500).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTopographic distribution and tumor size\u003c/strong\u003e (Fig. \u003cspan\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eMost PPGL patients (93.9%) were initially imaged by MRI instead of CT (given the ease of performing it in our service). 53 Pheo (56.4%) were located on the right side, 23 (24.5%) on the left, and 18 (19.2%) were bilateral. Among the 23 PGL, 13 (56.5%) were retroperitoneal and 10 (43.5%) were cervical.\u003c/p\u003e\n\u003cp\u003eThe Pheo located on the right side were significantly larger than those on the left (including the bilateral ones) (median of 5.8 vs. 3.7 cm, respectively) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Retroperitoneal and neck PGL had similar sizes (medians of 6.5 and 6.9 cm, respectively). The individual sizes of all PPGL lesions are depicted in Fig. \u003cspan\u003e2\u003c/span\u003e. Note that 70% of all 117 PPGL lesions were larger than 3 cm in diameter (and 61% were larger than 4 cm).\u003c/p\u003e\n\u003cp\u003eHigh signal intensity on the T2-weighted sequence was observed in 108 of the 109 patients (99.1%) who underwent MRI. Among the 11 PPGL patients who underwent CT imaging, all typically had pre-contrast attenuation values above 10 HU, above 20 HU in the portal phase, and a contrast \u003cem\u003ewashout\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;60%.\u003c/p\u003e\n\u003cp\u003e\u003cspan type=\"BoldUnderline\" name=\"Emphasis\"\u003eMetanephrines and tumor size\u003c/span\u003e (Fig. \u003cspan\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eA significant positive correlation was observed between tumour size (largest diameter, in cm) and total urinary MN (in mcg/24 h) for 91 functioning PPGL (74 Pheo and 17 PGL): r\u0026thinsp;=\u0026thinsp;0.27; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 (Fig. \u003cspan\u003e3\u003c/span\u003e). Nonfunctioning PPGL, especially head and neck PGL, presented 24-h urinary MN within the normal range.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePPGL is a rare neuroendocrine tumour that is potentially metastatic and fatal if this diagnosis is not promptly suspected, and treatment is not started soon. Its incidence has been increasing recently due to improvements in the measurement of catecholamine metabolites and a greater demand for imaging tests. Unfortunately, there is still a significant diagnostic delay, some only coming post-mortem [2,3].\u003c/p\u003e \u003cp\u003eThis diagnostic delay was confirmed in our population sample: most patients took two or more years to seek medical assistance, and one of them took almost 40 years to be diagnosed. Hence, major complications related to hypertension are to be expected.\u003c/p\u003e \u003cp\u003ePPGL is a relevant diagnostic possibility in the investigation of secondary and/or resistant forms of SAH, regardless of the presence of paroxysms. Clinical scores are available to help define an individual\u0026rsquo;s risk of having PPGL. Features such as hyperhidrosis, palpitations, pallor, tremors, and nausea are 30\u0026ndash;90% more prevalent in the PPGL population than in other hypertensive patients. These characteristics plus a heart rate above 85 bpm and BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e guarantee scores close to the maximum of 7 points, a score that makes PPGL 5.8 times more likely than lower scores do [15].\u003c/p\u003e \u003cp\u003eThe main manifestation in our patients that led to the suspicion of PPGL was sustained SAH. Other common ones were paroxysms, genetic screening, difficult-to-control SAH and adrenal incidentalomas, consistent with the medical literature [8,14,20]. When first investigated, most patients were already taking two or more classes of antihypertensive drugs. Orthostatic hypotension was a mostly relevant finding, often associated with SAH but also found in normotensive patients who were initially referred for genetic screening or evaluation of adrenal incidentaloma. This finding is important in the initial evaluation, as it is often present whether the individual has SAH or not.\u003c/p\u003e \u003cp\u003eNormotensive and prehypertensive patients (almost 20% of our sample) were referred for evaluation of PPGL due to a positive family history or presence of adrenal incidentaloma (22%), as has been reported [20,23\u0026ndash;25,29,30].\u003c/p\u003e \u003cp\u003eInvestigation of PPGL is recommended for recent-onset diabetes mellitus in a young, lean, hypertensive patient since catecholamine excess favours hepatic gluconeogenesis and less degranulation of insulin by pancreatic beta cells [14]. Eighteen percent of our patients had impaired glucose tolerance, raising the question whether diagnosis and treatment of PPGL could change some subjects\u0026rsquo; DM history, even leading to a \"cure\".\u003c/p\u003e \u003cp\u003ePlasma free MN are considered the gold standard for the diagnosis of functioning PPGL, with slight superiority over 24-h urinary fractionated MN. In the past, the combination of urinary MN with plasma/urinary catecholamines was recommended because of its lowest false negative rate; however, plasma MN alone is diagnostically better than any of the combined tests. Negative plasma MN virtually excludes functional PPGL, but in its absence, 24-h urinary MN can replace them. Thus, the current laboratory diagnosis of PPGL must include plasma and/or 24-h urinary MN [6\u0026ndash;10,14,16,31].\u003c/p\u003e \u003cp\u003eBoth our PPGL study patients and the positive control group presented very high values of 24-h urinary and plasma MN compared to our large reference negative control group, even when nonfunctioning PPGL (especially those located in the neck) were included. The cut-off value of 885 mcg/24 h had a sensitivity and specificity of 100% and 92.5%, respectively, for total urinary MN. Thus, 24-h urinary MN alone is likely a sensitive and good marker of PPGL functionality, useful for screening patients for the disease.\u003c/p\u003e \u003cp\u003ePlasma MN values twice above the upper limit of normal are strongly suggestive of PPGL, whereas values between 1X and 2X are considered suspect, requiring diagnostic complementation with 24-h urinary MN and/or chromogranin A measurement and/or a suppression test with clonidine. Based on our findings and others, we suggest a simple and direct algorithm (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) to diagnose functioning PPGL. The measurement of 3-methoxy-tyramine can help in the diagnosis of PPGL, especially in dopamine-producing, metastatic, and neck PGL [14].\u003c/p\u003e \u003cp\u003eThe topographic diagnosis of PPGL should initially be made with CT of the adrenals and pelvis, whereas MRI would be reserved for specific cases such as carriers of PV in PPGL-related genes, intracardiac and head/neck PGL, pregnant women, children, tumour recurrence and metastatic PPGL. Both imaging procedures have good sensitivity and specificity for the diagnosis of PPGL. The characteristics of PPGL on CT are attenuation values in the pre-contrast phase greater than 10 HU, usually above 20, with a contrast washout\u0026thinsp;\u0026lt;\u0026thinsp;60% and high signal intensity (\u0026ldquo;light-bulb\u0026rdquo; bright) on the T2-sequence and out-of-phase sequence of MRI, with no loss of signal [8,9,13].\u003c/p\u003e \u003cp\u003eThe ready availability of MRI over CT in our group prompted us to study 109 of our 116 patients with MRI at first, which was able to identify the high signal intensity on T2 in 108 of them; seven of the patients who underwent adrenal/pelvis CT had characteristics of a nonadenomatous lesion. The tumour diameter in our patients was mostly in the range of 5 to 6 cm. We identified three micro-pheochromocytomas (the smallest measuring 3 mm in diameter), none of hereditary origin, whose images disclosed only adrenal thickening, but their adrenergic clinical picture was exuberant; increased hormonal levels were detected in all during adrenergic episodes. The largest Pheo in our series was 24 cm in diameter and was initially suspected to be a primary adrenocortical carcinoma.\u003c/p\u003e \u003cp\u003eWe found a significant positive correlation between tumour size and total 24-h urinary MN. Functioning PPGL with a diameter greater than 5 cm tend to produce total urinary MN above 1,000 mcg/24 h.\u003c/p\u003e \u003cp\u003eIn summary, we present the clinical, hormonal, and imaging picture of a representative cohort of PPGL patients studied in a single reference center in S\u0026atilde;o Paulo, Brazil, whose data mostly agree with other series reported worldwide. Of note, nearly 25% of the Pheo were discovered incidentally. Sustained SAH was present in more than 80% of cases (especially PGL patients), mostly severe and treatment-resistant and typically accompanied by paroxysms. Two-thirds of patients had orthostatic hypotension, an important but generally overlooked diagnostic clue. Diagnostic confirmation of a functioning PPGL strongly relies on the finding of elevated metanephrines (plasma and/or 24-urinary), complemented by chromogranin A and/or a clonidine test, as necessary. MRI was particularly valuable to identify PPGL and to investigate patients with germline variants: the right adrenal gland was more frequently affected than the left, and bilateral masses were present in 20% of cases. The average mass diameter was 5\u0026ndash;6 cm, and the larger the mass, the more marked its total urinary metanephrine excretion. Although uncommon, the diagnosis of PPGL should be considered in young, lean, treatment-resistant hypertensive patients with an impaired glucose tolerance or new-onset diabetes mellitus.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of interest\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThere is no conflict of interest that could be perceived as prejudicing the impartiality of this research.\u003c/span\u003e \u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA) Jose Viana Lima Junior: carried out data collection, clinical consultations with patients, collected blood tests, performed genetic analysis on patients, clinical monitoring of patients, performed statistical analysis and wrote the paper.B) Nilza Maria Scalissi: contributed by referring some patients for evaluation at UNIFESP-EPM Hospital and contributed to the discussion part of the paper.C) Suzan M. Goldman: contributed by analyzing all the PGL localization images and contributed to the discussion part of the paperD) Claudio Elias Kater: contributed to all the work guided by data collection, discussion of clinical cases, preparation of the paper and statistical analysis.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe thank Erica S. Souza de Araujo and Pamela M. Lima do Livramento (Fleury Group) for their assistance in analysing patient samples and Jos\u0026eacute; de S\u0026aacute;, Rosa Paula Mello Biscolla and Maria Izabel Chiamolera for the analysis of the database.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAdler JT, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS, et al. Pheochromocytoma: current approaches and future directions. Oncologist. 2008;13:779-93.\u003c/li\u003e\n\u003cli\u003eSutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc. 1981;56(6):354-60.\u003c/li\u003e\n\u003cli\u003eAl Subhi AR, Boyle V, Elston MS. Systematic review: Incidence of pheochromocytoma and paraganglioma over 70 years. J Endocr Soc. 2022; 6(9):1-9.\u003c/li\u003e\n\u003cli\u003eRindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol. 2022;33(1):115-54.\u003c/li\u003e\n\u003cli\u003eMete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol. 2022;33(1):90-114.\u003c/li\u003e\n\u003cli\u003eNeumann HPH, Young Jr WF, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381(6):552-65. \u003cbr /\u003e 7- Aggarwal S, Prete A, Chortis V, Asia M, Sutcliffe RP, Arlt W, et al. Pheochromocytomas most commonly present as adrenal incidentalomas: A large tertiary center experience. J Clin Endocrinol Metab. 2023;109(1):e389-e396.\u003c/li\u003e\n\u003cli\u003eBravo EL, Tagle R. Pheochromocytoma: State-of-the-art and future prospects. Endocr Rev. 2003;24(4):539-53.\u003c/li\u003e\n\u003cli\u003eLenders JWM, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo A-P, Grebe SKG, Murad MH, et al. Endocrine Society. Pheochromocytoma and paraganglioma: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-42.\u003c/li\u003e\n\u003cli\u003eLima Jr. JV, Kater CE. The pheochromocytoma/paraganglioma syndrome: An overview on mechanisms, diagnosis and management. Int Braz J Urol. 2023;49(3):307-19.\u003c/li\u003e\n\u003cli\u003eBenn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, et al. Clinical presentation and penetrance of pheochromocytoma/ paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827-36.\u003c/li\u003e\n\u003cli\u003eAlgeciras-Schimnich A, Preissner CM, Young WF Jr, Singh RJ, Grebe SK. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J Clin Endocrinol Metab. 2008;93:91-5.\u003c/li\u003e\n\u003cli\u003eEisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab. 1998;83:2175-85.\u003c/li\u003e\n\u003cli\u003eGarcia-Carbonero R, Matute Teresa F, Mercader-Cidoncha E, MitjavilaCasanovas M, Robledo M, Tena I, et al. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clin Transl Oncol. 2021:23(10):1995-2019.\u003c/li\u003e\n\u003cli\u003eGeroula A, Deutschbein T, Langton K, Masjkur J, Pamporaki C, Peitzsch M, et al. Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol. 2019;181:409-20.\u003c/li\u003e\n\u003cli\u003eLenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287:1427-34.\u003c/li\u003e\n\u003cli\u003eN\u0026ouml;lting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 2022;43:199-239. Erratum in: Endocr Rev. 2021 Dec 14; Erratum in: Endocr Rev. 2021 Dec 14;\u003c/li\u003e\n\u003cli\u003eAntonio K, Valdez MMN, Mercado-Assis L, Ta\u0026iuml;eb D, Pacak K. Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging, and therapeutic options. Gland Surg. 2020;9(1):105-23.\u003c/li\u003e\n\u003cli\u003eChang CA, Pattison DA, Tothill RW, Kong G, Akhurst TJ, Hicks RJ, et al. (68)Ga-DOTATATE and (18)F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility, patterns and heterogeneity. Cancer Imaging. 2016;16:22.\u003c/li\u003e\n\u003cli\u003eIlias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89:479-91.\u003c/li\u003e\n\u003cli\u003eMozley PD, Kim CK, Mohsin J, Jatlow A, Gosfield E 3rd, Alavi A. The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med. 1994;35:1138-44.\u003c/li\u003e\n\u003cli\u003eBarroso WKS, Rodrigues CIS, Bortolotto LA, Mota-Gomes MA, Brand\u0026atilde;o AA, Feitosa ADM, et al. Brazilian Guidelines of Hypertension \u0026ndash; 2020. Arq Bras Cardiol. 2021;116(3):516-658.\u003c/li\u003e\n\u003cli\u003eLima Jr. JV, Scalissi NM, Oliveira KC, Lindsey SC, Olivati C, Ferreira EN, et al. Germline genetic variants in pheochromocytoma/paraganglioma: Single-center experience at S\u0026atilde;o Paulo, Brazil. Endocrine Oncol. 2023;3:e220091.\u003c/li\u003e\n\u003cli\u003eErlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, et al. Clinical predictors, and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009;15:6378-85.\u003c/li\u003e\n\u003cli\u003eGimenez-Roqueplo AP, Robledo M, Dahia PLM. Update on the genetics of paragangliomas. Endocr Relat Cancer. 2023;30(4):e220373.\u003c/li\u003e\n\u003cli\u003eEisenhofer G, Peitzsch M, McWhinney BC. Impact of LC-MS/MS on the laboratory diagnosis of catecholamine-producing tumors. Trends Analyt Chem. 2016;84:106-116.\u003c/li\u003e\n\u003cli\u003eKater CE, Irony I, Biglieri EG, Fai\u0026ccedil;al S. Continuous adrenocorticotropin administration in hypopituitarism produces asynchronous increases of deoxy-corticosterone and 11-deoxycortisol relative to other reduced zona fasciculata steroids. J Clin Endocrinol Metab. 1990;71(2):305-10.\u003c/li\u003e\n\u003cli\u003eUnal I. Defining an optimal cut-point value in ROC analysis: An alternative approach. Comput Math Methods Med. 2017;3762651. doi: 10.1155/2017/3762651. Epub 2017 May 31.\u003c/li\u003e\n\u003cli\u003eBuffet A, Burnichon N, Favier J, Gimenez-Roqueplo A-P. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2020;34(2):1-14.\u003c/li\u003e\n\u003cli\u003eCasc\u0026oacute;n A, Calsina B, Monteagudo M, Mellid S, D\u0026iacute;az-Talavera A, Curr\u0026aacute;s-Freixes et al. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol. 2023; 70(3):e220167.\u003c/li\u003e\n\u003cli\u003eBoyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillylmandelic acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2007;92:4602-8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hypertension, orthostatic hypotension, pheochromocytoma, paraganglioma, adrenal incidentaloma, metanephrines","lastPublishedDoi":"10.21203/rs.3.rs-5312717/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5312717/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eContext\u003c/strong\u003e: Pheochromocytomas (Pheo) and paragangliomas (PGL) (PPGL) are catecholamine-producing tumours, whose functionality is confirmed by elevated plasma (Pl) and/or 24-h urinary (Ur) metanephrines (MN).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective/Design\u003c/strong\u003e: We review clinical, hormonal, and imaging aspects of 116 patients studied prospectively: 93 Pheo, 22 PGL, and one Pheo plus PGL.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Twenty-five % PPGL were discovered incidentally. Systemic arterial hypertension (SAH) was present in 81% (43% on stage 3), whereas 9.5% were prehypertensiveand 9.5%, normotensive. SAH plus paroxysms occurred in 31 (33%) patients, being exclusively sustained in the remaining; 26 (28%) had resistant SAH. Orthostatic hypotension was present in 65% of patients. Pl/Ur MN and normetanephrine (NMN) were compared to those of a positive (56 functioning PPGL) and a negative control group (654 subjects with normal MN/NMN). Total and fractionated Ur MN were elevated in 94% PPGL patients. Cut-off values of 885 mcg/24-h for Ur MN, and of 1.5 nmol/L for Pl MN identified functioning lesions with 100%/100% sensitivity and 93%/97% specificity, respectively. MRI detected 56% Pheo on the right side,25% on the left, and 19% bilateral; 13 of 23 PGL (56.5%) were retroperitoneal and 10 (43.5%), cervical. Right-side Pheo were larger (5.8 cm) than left-side ones (3.7 cm), but retroperitoneal (6.5 cm) and neck PGL (6.9 cm) were similar in size. Tumour size positively correlated with total Ur MN.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: in this large cohort of PPGL patients we highlighted relevant aspects of SAH, the frequentlyoverlooked manifestation of orthostatic hypotension, common incidental presentation, and significant tumour size/hormonal production correlation.\u003c/p\u003e","manuscriptTitle":"Portrait of a series of patients with pheochromocytoma/paraganglioma from a reference center in Brazil: Relevance of prior background features","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-11 05:39:30","doi":"10.21203/rs.3.rs-5312717/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c133752-e4ac-4daf-a86e-538244a43647","owner":[],"postedDate":"November 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-06T06:54:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-11 05:39:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5312717","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5312717","identity":"rs-5312717","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}