The Pheochromocytoma/Paraganglioma syndrome: an overview on mechanisms, diagnosis and management

ABSTRACT Pheochromocytomas/paragangliomas (PPGL) are rare, metastatic, and potentially fatal neuroendocrine tumors, often neglected because they present symptoms similar to other prevailing clinical conditions such panic syndrome, thyrotoxicosis, anxiety, hypoglycemia, etc., delaying diagnosis and treatment. The rate of diagnosis of PPGL has been increasing with the improvement in the measurement of catecholamine metabolites and the expanding availability of imaging procedures. Its essential genetic nature has been extensively investigated, comprising more than 20 genes currently related to PPGL and more new genes will probably be revealed. This overview will shed some light on the clinical, laboratory, topographical, genetic diagnosis, and management of PPGL.

STUDY OF CLINICAL AND LABORATORY PROFILE OF PATIENTS WITH ADRENAL MASS.

Aims and objectives: AIM of this study was to observe and correlate clinical and laboratory profile of patients with adrenal mass. The objective was to study clinical and laboratory profile of patients with adrenal mass with the secondary objective to establish the etiological diagnosis with adrenal mass Methods: This observational study was carried out at tertiary care government hospital in north India from Jul 2020 to June 2022. Based on prevalence 4.4 of the disease as per previous study sample size for 95% confidence level & 5% precision works out 43. The inclusion Criteria were patients detected to have adrenal mass or symptoms related with adrenal mass. The exclusion criteria were any pre-existing known malignancy other than adrenal gland. Subsequent to enrolment the demographic data, clinical data, laboratory data, hormonal assays and radiological data was recorded as per predesigned proforma. The adrenal CT imaging protocol consists of three phases together are used for calculating absolute percentage washout and/or relative percentage washout to differentiate lipid-poor adenomas from primary carcinoma and metastases. Results: The mean age was 39± 15.41. Majority of patients were males 35(77.8%). 86.7% subjects had no comorbidity, 7.9 % had HTN. 6.7% patients were noted to have clinical cushings whereas in 4.4% subject acanthosis nigricans and goiter was seen. On Overnight dexamethasone suppression test, 16/45 patients were observed with value higher than <2.01 ug/dl, similar was the case with low dose dexamethasone suppression test. There was a significant rise in the mean plasma free metanephrine and urinary metanephrine noted in 12/ 45 patients. The minimum size of adrenal mass detected in the USG abdomen was 2.5 cm. The minimum size of adrenal mass detected in the CT abdomen was 1.21 cm. There is a significant association noted between absolute percentage washout (APW) outcome and hormonal activity with p-value <0.001. Conclusion: 6.7 % had features of cushing's disease and 4.4 % had acanthosis nigricans. On hormonal assays elevated metanephrine levels were seen in 26% subjects. On hormonal assays of ONDST and LDDST 35.5 % subjects were seen with elevated levels. Other hormonal assays aldosterone, renin and ACTH were normal. CECT was sensitive to identify a small adrenal mass up to 0.633 cm. 34 % of adrenal mass were hyper functional and 2 % were found malignant in this study.

Establishment and verification validation of plasma free metanephrines measurement by chemiluminescence immunoassay / 中华检验医学杂志

Objective:To establish a chemiluminescence immunoassay method for free metanephrines measurement in plasma, and verify its performance.Methods:The samples (calibrator, plasma, and quality control sample) were extracted and acylated, the processed analyte samples were then competed with the immobilized specific antigens of metanephrine (MN), normetanephrine (NMN) respectively, to combine specific antibodies marked by Horseradish Peroxidase (HRP), the immobilized antigens-antibody-HRP immune reaction product was then formed through the immune reaction, which could be detected through measurement of HRP catalytic substrate luminescence. Performance verification was performed using specificity, sensitivity,precision,thermally accelerated stability, and accuracy metrics.Results:The established detection methods for MN and NMN have no obvious cross-reactions when detecting multiple structural analogs; the limit of blank, limit of detection and functional sensitivity of the MN detection reagent was 10.51, 21.15 and 25.76 ng/L, and the performance of the NMN detection reagent was 11.54, 28.43 and 31.29 ng/L; the coefficients of variation of the detection reagents for MN and NMN were 2.41%-5.38% and 1.61%-3.22% respectively; the accelerated stability test of the two detection reagents showed that the reagents could be stored stably for 1 year at 2-8 ℃; and the measurement results of this method can be traced to the mass spectrometer.Conclusion:In this study, a chemiluminescence immunoassay detection method for free metanephrines in plasma is successfully established.

Feocromocitoma y Paraganglioma: un reto más allá de la clínica / Pheochromocytoma and Paraganglioma: a Challenge beyond the Clinic

Resumen Los feocromocitomas y paragangliomas son tumores raros que se originan en las células cromafines. Tienen un amplio espectro clínico que va desde el hallazgo incidental hasta manifestaciones por la producción exagerada de catecolaminas. El diagnóstico bioquímico se realiza mediante medición de metanefrinas libres en plasma. El tratamiento ideal es la escisión quirúrgica completa previo bloqueo de receptores a y 6 adrenérgicos. En caso de enfermedad metastásica, las opciones de tratamiento sistêmico actuales son limitadas y con escasa tasa de respuesta. Está en investigación el uso de antiangiogénicos.

Abstract Pheochromocytomas and Paragangliomas are rare tumors, originated from the chromaffin cells. They have a broad clinical spectrum from incidental finding to full clinical manifestations explain to overproduction of catecholamines. The biochemistry diagnosis is made by the measurement of free Metanephrines in plasma. Complete surgical removal is the optimal treatment, previously having a y 6 adrenergic receptors blockage. In case of metastasic disease, treatment options are palliative, limited and with a low rate response; the use of antiangiogenic treatments is under investigation.

A rare case of bilateral adrenal pheochromocytoma with unusual presentation: the case report

Here we report a 25 years old male patient came to our emergency department with chief complaints of headache from 3 months, blurring of vision 7 days, abdominal pain 7 days, and vomiting from 2 days. Young male, with no known comorbidities, presented to our casualty with headache since, 3 months, episodic in nature, increased over the last 1 week, holocranial, gradually progressive in severity. last recorded Blood pressure outside was 220/120 mmHg and papilledema were noted on fundoscopy. USG abdomen and pelvis, CECT abdomen done and diagnosed to have bilateral adrenal pheochromocytoma. Patient underwent bilateral adrenalectomy was performed with good intra op BP control. Right adrenals were enlarged and shows multiple nodular lesions, left adrenal noted shows nodular lesions. Surgery remains the first line of management in malignant pheochromocytoma. Norepinephrine, epinephrine, and dopamine all act on their target receptors, which causes a physiological change in the body. Increase in catecholamines cause severe hypertension and multiple systemic complications like (cardiovascular, cerebrovascular events) and can lead to death if untreated.

Correlation of plasma level of MNs to blood lipid, blood glucose and blood pressure in patients with pheochromocytoma/paraganglioma / 解放军医学杂志

Objective To investigate the correlations of plasma methoxyadrenaline (MN) and methoxynorepinephrine (NMN) (collectively called MNs) to blood lipid, blood glucose and blood pressure in patients with pheochromocytoma (PCC) and paraganglioma (PGL) (collectively called PPGL). Methods The clinical data were retrospectively analyzed of 64 patients with pathologically confirmed PPGL in Chinese PLA General Hospital during Jan. 2017 to Jun. 2018. According to the tertiles plasma MN before operation, the 64 cases were divided into T1 (n=21), T2 (n=21) and T3 (n=22) group, and then were divided into T’1 (n=21), T’2 (n=21) and T’3 (n=22) group according to the tertiles plasma NMN before operation. The correlations were analyzed of plasma level of MNs to the blood lipid, blood glucose and blood pressure. Results The body mass index (BMI) value decreased significantly with the increase of plasma MNs level in patients with PPGL. With the increase of plasma NMN level, high density lipoprotein cholesterol (HDL-C) and systolic blood pressure (SBP) increased significantly (P<0.05). Pearson correlation analysis showed that the plasma MN was negatively correlated with BMI (r=-0.319, P=0.010), and positively correlated with the tumor diameter (r=0.268, P=0.032). The plasma NMN was negatively correlated with BMI (r=-0.353, P=0.004), and positively correlated with SBP, fasting blood glucose (FBG), total cholesterol (TG), HDL-C, and tumor diameter (r=0.256, 0.019, 0.047, 0.001 and 0.003, respectively. P<0.05). The multivariate linear regression analysis showed that the plasma MN was negatively correlated with BMI (β=0.09, P=0.004) and positively correlated with tumor diameter (β=0.04, P=0.016). Plasma NMN was negatively correlated with BMI (β=0.08, P=0.006), and positively correlated with SBP, FBG, TG, HDL-C, tumor diameter (β=0.01, 0.13, 0.18, 0.50 and 0.06, respectively. P<0.05). Conclusions The plasma MNs level is related to the regulation of blood lipid, blood sugar and blood pressure. Patients with high plasma MNs level before operation should pay more attention to the occurrence of hypertension and high FBG.

Update on Modern Management of Pheochromocytoma and Paraganglioma

Despite all technical progress in modern diagnostic methods and treatment modalities of pheochromocytoma/paraganglioma, early consideration of the presence of these tumors remains the pivotal link towards the best possible outcome for patients. A timely diagnosis and proper treatment can prevent the wide variety of potentially catastrophic cardiovascular complications. Modern biochemical testing should include tests that offer the best available diagnostic performance, measurements of metanephrines and 3-methoxytyramine in plasma or urine. To minimize false-positive test results particular attention should be paid to pre-analytical sampling conditions. In addition to anatomical imaging by computed tomography (CT) or magnetic resonance imaging, new promising functional imaging modalities of photon emission tomography/CT using with somatostatin analogues such as ⁶⁸Ga-DOTATATE (⁶⁸Ga-labeled DOTA(0)-Tyr(3)-octreotide) will probably replace ¹²³I-MIBG (iodine-123-metaiodobenzylguanidine) in the near future. As nearly half of all pheochromocytoma patients harbor a mutation in one of the 14 tumor susceptibility genes, genetic testing and counseling should at least be considered in all patients with a proven tumor. Post-surgical annual follow-up of patients by measurements of plasma or urinary metanephrines should last for at least 10 years for timely detection of recurrent or metastatic disease. Patients with a high risk for recurrence or metastatic disease (paraganglioma, young age, multiple or large tumors, genetic background) should be followed up lifelong.

Development of a LC-MS/MS method for the simultaneous determination of metanephrine and norepinephrine in human plasma / 中华检验医学杂志

Objective The aim of our study was to develop a robust LC-MS/MS method for determination of MN and NMN in blood plasma.Methods A liquid chromatography -tandem mass spectrometric ( LC-MS/MS) method was used, with signal linearity, lower limits of quantitation, precision and accuracy being evaluated.The study recruited 126 healthy volunteers, and MN and NMN in blood plasma were determined.At the same time samples from 21 patients ( 17 pheochromocytoma, 4 ectopic pheochromocytoma) , a hypertension group of 108 persons, and a control group of 84 persons were analyzed. A paired T test was used to compare the MN and NMN levels between the different groups.Results The performance characteristics for the method in terms of linearity, lower limits of quantitation, precision and accuracy were verified.Significant differences were found between the concentration levels of MN and NMN in the diseased and healthy groups.Conclusion A robust and reliable LC-MS/MS method for the determination of MN and NMN in blood plasma has been developed and was shown to be suitable for clinical application.

A 5-Year Prospective Follow-Up Study of Lipid-Rich Adrenal Incidentalomas: No Tumor Growth or Development of Hormonal Hypersecretion

BACKGROUND: Current guidelines for follow-up of adrenal incidentalomas are extensive and hampered by lack of follow-up studies. We tested the hypothesis that small lipid-rich adrenal incidentalomas, initially characterized by tumor size 20 mm for the patient with largest tumor growth and those with subclinical hypercortisolism. All patients had normal 24-hour urinary metanephrines and normetanephrines. Low attenuation (<10 HU) was demonstrated in 97% of 67 masses re-evaluated with unenhanced CT. CONCLUSION: None of the patients developed clinically relevant tumor growth or new subclinical hypercortisolism. Biochemical screening for pheochromocytoma in incidentalomas demonstrating <10 HU on unenhanced CT is not needed. For such incidentalomas <40 mm, it seems sufficient to perform control CT and screen for hypercortisolism after 5 years.

Feocromocitoma-paraganglioma: revisión de tema / Pheochromocytoma-paraganglioma: a review

Resumen: el feocromocitoma es una enfermedad poco frecuente, correspondiente a un tumor derivadode las células cromafines, originado en la médula de la glándula suprarrenal. Cuando este tumor se origina en los paraganglios el término correcto es paraganglioma. Las manifestaciones clínicas son variables y secundarias a la masa tumoral o a la producción exagerada de catecolaminas. Los síntomas originados por el crecimiento de la masa tumoral incluyen dolor abdominal, malestar epigástrico, obstrucción de estructuras cercanas como la vía biliar y los uréteres, y, cuando está localizado en otros sitios como el mediastino, disnea. Los síntomas secundarios a la hiperproducción de catecolaminas son diaforesis, palpitaciones, cefalea, crisis hipertensivas, hipertensión sostenida, constipación, náuseas, vómito y, en la forma más exagerada, crisis catecolaminérgicas. El diagnóstico se realiza mediante la medición de metanefrinas libres en orina de 24 horas o en plasma, y como alternativa se puede realizar medición de catecolaminas en orina de 24 horas. La medición de ácido vanilmandélico es poco sensible, lo mismo que la medición de catecolaminas en plasma, la cual no es recomendada. El tratamiento de esta enfermedad es quirúrgico. En aquellos pacientes con feocromocitomamaligno o paraganglioma se puede realizar una estrategia de observación activa y en quienes tengan progresión de la enfermedad el uso de quimioterapia o, según el grado de compromiso, el uso de metayodobencilguanidina marcada con yodo-131 es la terapia de elección. El uso de terapia molecular diana utilizando inhibidores de tirosina quinasa es un área de investigación activa.

Abstract: Pheochromocytoma is a rare disease, corresponding to a tumor originated in the chromaphincells, and located in the adrenal medulla. When the tumor is located in the paraganglia the appropriate term is paraganglioma. Clinical manifestations are variable and secondary to the tumoral local extension or to the overproduction of catecholamines. Symptoms secondary to local growth of the tumor includes abdominal pain, epigastric discomfort, obstruction of nearby structures such as biliary tree and ureters, and when is located in other regions such as the mediastinum, dyspnea. Symptoms secondary to overproduction of catecholamines are diaphoresis, headache, hypertensive emergencies, sustained hypertension, constipation, nausea, vomiting and, in the most extreme form, catecholaminergic crisis. Diagnosis is based on the measurement of free plasmatic or urinary metanephrines.As an alternative can be used 24 hours urinary catecholamines. The detection of vanillylmandelic acid and plasma catecholamines has poor sensibility and is no longer recommended. The treatment of this entity is surgical resection. In those patients with malignant pheochromocytoma or paraganglioma an observation and watch strategy can be used. If disease progression is detected, the use of chemotherapy or iodine-131-labeled meta-iodobenzylguanidine, according to the severity of compromise, is the next step. The use of targeted molecular therapies using tyrosine kinase inhibitoris an area under active research.

Feocromocitoma :presentación como síndrome coronario agudo: Reporte de un caso / Presentation of a pheochromocytoma as an acute coronary syndrome: Report of one case

The typical symptoms of pheochromocytoma are palpitations, sweating, headaches and hypertension. We report a 70-year-old female admitted to the hospital due to a sudden onset of precordial pain with electrocardiographic changes. After admission the patient evolved with recurrent chest pain accompanied by hypertensive paroxysms and a pheochromocytoma was suspected. Measurement of catecholamines and metanephrines confirmed the diagnosis and an abdominal magnetic resonance localized the tumor. The patient underwent surgery with successful removal of the pheochromocytoma and was discharged in good conditions.

Approach to the patient of pheochromocytoma: the diagnosis and treatment / 中华内分泌代谢杂志

A 34-year-old male patient with suspected pheochromocytoma was referred to our department for paroxysmal hypertension. Pheochromocytoma was confirmed by very high plasma nor-metanephrine ( NMN ) and metanephrine ( MN ). Contrast CT of the adrenal disclosed a 3.0 cm x 3.0 cm mass in the left adrenal. 18 F-FDG-PET-CT showed high uptake only in the left adrenal. When the patient's blood pressure was well controlled with 4 mg/d doxazosin for 2 weeks, surgery was then performed under laparoscopy. A round solid left adrenal pheochromocytoma was resected. After surgery, plasma MN and NMN levels returned to normal, and the patient was free of clinical symptoms with normal blood pressure. This patient has been followed 3 years with normal blood pressure, MN, and NMN levels, without tumor recurrence shown hy adrenal CT.

Diagnostic value of free plasma metanephrines for pheochromocytoma / 中华检验医学杂志

Objective To investigate the application value of free plasma metanephrines metanephrine(MN) and normetanephrine (NM) measured with enzyme immunoassay (EIA), NM in diagnosis of pheochromocytoma. Methods Histologically confirmed pheochromocytomas (n=30) and control patients with hypertension (n=51) were enrolled in the study. Blood tests for free plasma metanephrines(MN and NM) were performed with a commercially available EIA kit and the results were compared with [3] I-metaiedobenzyl guanidine (MIBG) whole body scan findings. Results The whole body scan was positive in all pheochromocytoma patients and negative in 15 control patients with 100% accuracy. The median values in the 2 groups were 59.3 ng/L and 33.7 ng/L (Z=-2. 440, P<0.05) for MN, 652.0 ng/L and 36. 3 ng/L (Z=-6.699, P<0.001) for NM, with 96. 7% (29/30) sensitivity, 86. 3% (44/51)specificity and 90.1% (73/81) accuracy for their combination ( either or both positive). There was no significantly statistical difference when compared with 13I-MIBG whole body scan findings (100. 0% ,P >0. 05). Conclusion The results show that the EIA method may be eligible as an alternative to HPLC for plasma metanephrines determination in the identification of pheochromocytoma.

Changes of Plasma NMN and MN During the Operation of Pheochromocytoma / 上海第二医科大学学报

Objective To study the changes of plasma normetanephrine(NMN) and metanephrine(MN) during the resection of adrenal pheochromocytoma. Methods Fourteen patients with adrenal pheocromocytoma and 9 patients with adrenal cortex tumor were recruited in our study. Blood samples were obtained at these time points: after anesthesia induction,the beginning of incision of skin, when exploring the tumor,resection of the tumor, and the end of anesthesia. The NMN and MN were determined by high performance liquid chromatogram (HPLC). Results NMN were obviously different among 5 time points in the patients with adrenal pheocromocytoma (P0.05). No significant difference was found between NMN and MN in the patients with adrenal cortex tumor. Conclusion NMN has markedly changed during the resection of adrenal pheochromocytoma, while MN has been relatively stable. The anesthesia induction and exploring of the tumor are the key of a successful operation. MN is the stable index in the diagnosis of adrenal pheochromocytoma.

Diagnostic Value of 24-hours Urinary Total Metanephrine As a Screening Test of Patients with Suspected Pheochromocytoma / 대한내분비학회지

BACKGROUND: A pheochromocytoma is a rare cause of secondary hypertension. Its diagnosis is important as the hypertension is usually curable by resection of the tumor, whereas the condition is potentially lethal if undetected. Biochemical confirmation of excessive catecholamine production is a prerequisite to a definitive diagnosis. Various studies from other countries have indicated that measuring of the urinary metanephrine, using a specific procedure, is the single most reliable screening test for all patients suspected of having a pheochromocytoma. However, the diagnostic value of urinary metanephrine has never been reported in Korea. We investigated the diagnostic value of 24-hours urinary metanephrine in patients with a suspected pheochromocytoma. METHODS: This was a retrospective evaluation study, which included 95 patients with sustained hypertension and paroxysmal symptoms, and 38 patients with asymptomatic adrenal incidentaloma at Seoul National University Hospital, between July 2000 and October 2002. We performed the 24- hour urinary total metanephrine test on all patients. The diagnosis of a pheochromocytoma was applied only when confirmed by pathological analysis of a resected specimen. The possibility of a pheochromocytoma was ruled out when all biochemical tests were normal, which were performed at least in duplicate, or there was no evidence of a mass in abdominal radiological studies or histological verification. We determined the upper reference limit for urinary metanephrine as 1.3mg/day and calculated the sensitivity and specificity of the 24-hour urinary metanephrine test. RESULTS: Seventeen patients were diagnosed with a pheochromocytoma. The total metanephrine measurement had sensitivities and specificities of 82.4 and 73.3% in all the patients, 90.9 and 66.7% in patients with hypertension and paroxysmal symptoms, and 66.7 and 90.6% in patients with adrenal incidentaloma, respectively. CONCLUSION: The urinary total metanephrine measurement had relatively lower sensitivities and specificities than in other countries(sensitivity: 83~100%, specificity: 80~98%). The sensitivity of urinary metanephrine was relatively high in patients with hypertension and paroxysmal symptoms, and the specificity was high in patients with an adrenal incidentaloma. We suggest that normetanephrine and metanephrine should be separately measured, and a reasonable upper reference limit be used. It may also be necessary to measure urinary metanephrine together with urinary catecholamine or VMA to improve the diagnostic value of the urinary metanephrine test.

Determination of metanephrine and normetanephrine by high-performance liquid chromatography with electrochemical detector and its diagnostic application for pheochromocytoma / 中华检验医学杂志

Objective To establish high-performance liquid chromatography with electrochemical detector(HPLC-ECD) method for the determination for metanephrine and normetanephrine in 24 h urine, and provide a superior test for the diagnostic of pheochromocytomas over plasma/urine catecholamine.Methods MCX solid-phase cartridge was used for extraction of metanephrine and normetanephrine,HPLC-ECD was used for their measurements.The intra-assay CVs,interassay CVs and recoveries of metanephrine and normetanephrine were also calculated.104 hypertensive patients without pheochromocytomas and 5 pheochromocytomas patients were selected in this study.The concentrations of metanephrine and normetanephrine were compared with the plasma and 24h urinary catecholamines concentrations.Results The intra-assay CV,inter-assay CV and recovery of metanephrine were 5.9%, 7.5%,91.1% respectively;the intra-assay CV,inter-assay CV and recovery of normetanephrine were 6.3%,6.6%,88.5%,respectively.The MN,NMN,plasma CA and urine CA of all pheochromocytomas patients were positive.MN and NMN were negative in controls,while plasma CA and urine CA are false positive in 15 patients and 14 patients in controls,respectively.Conclusions The study establish a fast and accurate method for quantification of metanephrine and normetanephrine in 24 h urine by HPLC-ECD.These findings also prove that it is the best biochemical assays for pheochromocytomas at present.

Familial non-hemolytic jaundice with conjugated and unconjugated hyperbilirubinemia

Ten jaundiced and sixty nine non-jaundiced members from two unrelated families were the subjects of this report. The jaundiced members showed qualitative and quantitative differences in the clinical and chemical expression of this disease. Excretory defects such as idiopathic hypercholesterolemia and asymptomatic PBI elevations were noted in jaundiced and non-jaundiced members. It was emphasized that this disease may manifest with various combinations of excretory defects for conjugated forms of bilirubin, iodopanoic acid (Telepaque), Bromsulfalein (BSP), liver pigment (? metanephrine glucuronide) and probably iodine and cholic acid. It was postulated that a protein carrier in the liver cytoplasma have binding sites for these substances. Variations of binding sites on these protein molecules result in different manifestations in affected members of a family or different families with this disease. It also show that they are not necessarily different syndromes. (Summary)