Curr Hypertens Rep (2014) 16:442 DOI 10.1007/s11906-014-0442-z

SECONDARY HYPERTENSION: NERVOUS SYSTEM MECHANISMS (J BISOGNANO, SECTION EDITOR)

Diagnosis and Management of Pheochromocytoma: A Practical Guide to Clinicians Joseph M. Pappachan & Diana Raskauskiene & Rajagopalan Sriraman & Mahamood Edavalath & Fahmy W. Hanna

Published online: 3 May 2014 # Springer Science+Business Media New York 2014

Abstract Pheochromocytomas (PCCs) are rare catecholamine producing neuroendocrine tumors. The majority of these tumors (85 %) arise from the adrenal medulla. Those arising from the extra-adrenal neural ganglia are called paragangliomas (PGLs). Paroxysmal hypertension with sweating, headaches and palpitation are the usual presenting features of PCCs/ PGLs. Gene mutations are reported in 32–79 % of cases, making genetic screening mandatory in all the cases. The malignancy rates are 10–15 % for PCCs and 20–50 % for PGLs. Measurement of plasma or 24–hour urinary fractionated metanephrines is the best biochemical diagnostic test. Computed tomography or magnetic resonance imaging has high sensitivity (90–100 %) and reasonable specificity (70–90 %) for the anatomical localization. The functionality is assessed by different radionuclide imaging modalities such as metaiodobenzylguanidine (MIBG) scintigraphy, positron emission tomography or single photon emission computed tomography. The only modality of curative treatment is tumor excision. Proper peri-operative management improves the surgical outcomes. Annual follow up with clinical and biochemical assessment is recommended in all the cases after treatment. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking This article is part of the Topical Collection on Secondary Hypertension: Nervous System Mechanisms J. M. Pappachan (*) : D. Raskauskiene Department of Endocrinology, Walsall Manor Hospital, West Midlands WS2 9PS, UK e-mail: [email protected] R. Sriraman Department of Endocrinology, Lincoln County Hospital, Lincoln, UK M. Edavalath : F. W. Hanna Department of Endocrinology, University Hospital of North Staffordshire, Stoke-on-Trent ST4 6QG, UK

surgery, chemotherapy, radiotherapy, molecular agents like sunitinib and everolimus, radionuclide agents and different ablation procedures may be useful in the palliation of inoperable/metastatic disease. An update on the diagnostic evaluation and management of PCCs and PGLs is presented here. Keywords Pheochromocytomas (PCCs), Paragangliomas (PGLs) . Hypertension . Adrenal incidentaloma . Fractionated metanephrines

Introduction Pheochromocytomas (PCCs) are rare neuroendocrine tumors secreting catecholamines, which are very powerful vasoactive hormones. They account for 0.2 % to 0.6 % of cases of hypertension in the community [1]. Approximately 85 % of PCCs arise from the adrenal medulla and the remainder originate from the extra-adrenal autonomic neural ganglia which are known as paragangliomas (PGLs) [2]. The estimated annual incidence of PCCs/PGLs is 2 to 8 per million [3]. These neoplasms arise from the cromaffin tissues derived from the embryonic neural crest cells that give rise to the autonomic neural ganglia and adrenal medulla, and are considered to be neuroendocrine tumors. The genetic aspects, clinico-pathologic behavior, therapeutic strategies and follow up management of these tumors pose significant challenges to clinicians, and this review is to outline an update on the diagnostic evaluation and management of PCCs and PGLs.

Clinical Presentation The clinical presentation of these tumors varies considerably from individual to individual. In the recent years, PCCs are

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increasingly being diagnosed during the work up of adrenal incidentalomas detected by abdominal imaging performed for other reasons [1, 4, 5, 6••]. Asymptomatic adrenal mass was the initial presentation in 25 % of the cases in a recent series from the United States [7]. However, about 50 % of PCCs are diagnosed only at autopsy because many of these tumors remain clinically silent during life [5, 6••]. The symptoms when present, are related to the secretion of catecholamines by PCCs/ PGLs. The catecholamine surge may be episodic and many cases present with paroxysmal symptoms. The classical clinical picture is that of episodic hypertension, tachycardia, diaphoresis, headache and the feeling of anxiety or panic attacks. These episodes are related to catecholamine excess produced by the tumor. Unexplained orthostatic hypotension on a background of paroxysmal or refractory hypertension may be an important diagnostic clue that may help clinicians to suspect these tumors [8]. Some of the cases may present with severe ventricular dysfunction and dilated cardiomyopathy (catecholaminergic cardiomyopathy) [2, 7–10]. Hypertensive crisis, hyperglycemia, acute coronary syndromes, dangerous cardiac arrhythmias, acute left ventricular failure, stroke, aortic dissection, hemodynamic collapse and sudden death are some of the other well-recognized clinical manifestations of PCCs and PGLs.

Pathophysiology The release of catecholamines (epinephrine, norepinephrine and dopamine) into the circulation causes most of the clinical and pathological manifestations of PCCs/ PGLs. The αadrenergic effects of catecholamines produce intense vasospasm and hypertension, whereas the β-adrenergic effects produce vasodilatation, diaphoresis and tachycardia. Severe orthostatic hypotension with syncopal episodes in occasional cases may be related to the intense α-adrenergic mediated vasoconstriction with volume contraction, or β-adrenergic mediated skeletal muscle vasodilatation [2]. The paroxysmal nature of catecholamine release results in the characteristic episodic symptoms and signs in many cases of PCCs/ PGLs. The catecholamine release is usually intermittent (sometimes continuous) and spontaneous, although tumor manipulation from abdominal palpation/ surgery, straining, exercise, different medications (dopamine receptor antagonists such as metochlopramide, β-adrenergic blockers, sympathomimetics, monoamine oxidase inhibitors and corticosteroids), and intravenous contrasts can result in massive surge of these hormones into the circulation that can result in a clinical emergency known as a pheochromocytoma crisis. Recurrent episodes of catecholamine surge result in myocyte necrosis with inflammatory cell infiltration and hemorrhage, and the repetitive events of ventricular stunning in some patients with PCC may lead on to severe (but reversible)

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catecholaminergic cardiomyopathy [8]. Contraction-band necrosis is the histological hallmark of this condition. The prevalence of acute catecholaminergic cardiomyopathy in PCCs/ PGLs can be as high as 11 % [11]. Although most cases of PCCs/ PGLs are benign, about 10 % to 15 % of PCCs, and 20 % to 50 % of PGLs can be malignant [12, 13••, 14]. The only histological features suggestive of malignancy are local tumor invasion or distant metastasis that may occur even many years after surgical resection of the primary neoplasm [6••, 15]. The World Health Organization defines malignant PCCs/ PGLs as the presence of metastases at sites where chromaffin tissue is not normally present [3]. Metastasis commonly occurs to the lymph nodes, liver, lungs and bones. Malignant potential is found to be higher in PCCs with size >5 cm, PGLs and familial cases with mutations of succinate dehydrogenase subunit B (SDHB) [12, 13••]. The patients with four inherited genetic tumour syndromes are particularly more prone to develop PCCs and PGLs. They are, multiple endocrine neoplasia type 2A and 2B (MEN-2A & B), Von Hippel-Lindau syndrome (VHL) and neurofibromatosis type 1 (NF1) [2]. Increasing prevalence of mutations in other susceptibility genes causing PCCs/ PGLs have been reported in the recent years. The reports from different regions of the world showed that 32–79 % of cases were associated with mutations [16–18]. Therefore, many authorities recommend genetic testing in all the cases of PCCs/ PGLs. Table 1 lists the genes identified to date and their molecular functions [19•]. Genetic testing helps in the prognostication of the disease, to plan screening for tumour relapse and for counselling the families of index cases.

Table 1 Susceptibility genes identified to date in the causation of pheochromocytomas (PCCs) and paragangliomas (PGLs) Gene

Molecular function

NF1 RET VHL

GTPase Tyrosine kinase receptor Ubiquitin ligase activity

SDHA

Succinate dehydrogenase subunit of mitochondrial respiratory chain Succinate dehydrogenase subunit of mitochondrial respiratory chain Succinate dehydrogenase subunit of mitochondrial respiratory chain Succinate dehydrogenase subunit of mitochondrial respiratory chain Co-factor for succinate dehydrogenase complex Transmembrane protein Transcription factor GTPase Tumour suppressor

SDHB SDHC SDHD SDHAF2 TMEM127 MAX H-RAS EPAS1

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Diagnostic Evaluation Although the classic triad of symptoms of PCCs/ PGLs are episodic headaches, sweating and palpitations in association with hypertension [7], this clinical picture is seen only in a minority of cases. The patient population who needs to be screened for the disease is shown in Table 2. A proper clinical history and thorough examination may help to identify some of the genetic syndromes described above.

Laboratory Tests Because the diagnosis of PCCs/ PGLs relies primarily upon the evidence of catecholamine over-production, biochemical testing should be performed in all symptomatic cases, the patients with adrenal incidentalomas and those who have a hereditary risk factor for developing these tumors. The catecholamines are metabolized within the chromaffin cells to metanephrines, an intra-tumoral process that occurs independently of catecholamine release by these tumors [20••, 21]. Therefore, the measurements of fractionated metanephrines (normetanephrine and metanephrine measured separately) in

Table 2 The disease states or conditions where screening for pheochromocytomas (PCCs) and paragangliomas (PGLs) should be considered. MEN – multiple endocrine neoplasia, VHL – Von Hippel-Lindau disease, SDHB – succinate dehydrogenase subunit B, SDHD – succinate dehydrogenase subunit D Disease/condition

Prevalence of PCCs/ PGLs

MEN type 2A

About 50 %.[2]

MEN type 2B

About 50 %.[2]

VHL

10-20 %.[2]

Neurofibromatosis type 1

About 2 %.l [2]

SDHB mutation

52 %.[19]

SDHD mutation

29 %.

First degree relatives of the above diseases Adrenal incidentaloma

4 %. [1]

Resistant hypertension

0.5 %.

Unexplained heart failure



Paroxysmal headaches, palpitations, sweating and panic attacks in association with hypertension Patients developing hypertensive crisis during surgery or general anaesthesia Patients with hypertension triggered by betablockers, monoamine oxidase inhibitors, micturition/ changes in abdominal pressure Orthostatic hypotension in a hypertensive patient [20••]



New onset diabetes mellitus in a young and lean individual with hypertension [20••]

– – – –

the plasma or urine specimens provide a better diagnostic sensitivity than the measurement of plasma/ urine catecholamines [22, 23]. Among the hormone assays, plasma free metanephrines have the highest sensitivity and specificity (99 % and 89 %, respectively) for the diagnosis of PCCs/ PGLs [21]. A raised plasma free metanephrine level ≥4 times above the upper reference limit of normal indicates almost 100 % probability of the tumor [20••, 21, 24]. The reported sensitivity and specificity for urinary metanephrines are lower (97 % and 69 %, respectively). The sensitivity and specificity of plasma and urinary catecholamine assays are 84 % and 81 %, and 86 % and 88 %, respectively. The urinary vanillyl-mandelic acid assay has a lower sensitivity of 68 % although the reported specificity has been higher at 95 % [24]. The low sensitivity of this test makes it less useful in clinical practice. Several drugs such as the sympathomimetic agents (including ephedrine, levodopa, amphetamine, nicotine), labetalol, sotalol, acetaminophen, buspirone, mesalamine, sulphasalazine, methyldopa and antidepressants, and several food items (especially caffeinated beverages) can interfere with the biochemical assays, and, therefore, caution should be exercised while performing and interpreting these tests [20••]. Blood sampling should be performed in a supine position after about 30 minutes of rest. Food, caffeinated beverages, strenuous physical activity and smoking should not be allowed for about 12 hours prior to the blood tests [20••, 21]. When the plasma/ urinary metanephrine levels are only marginally elevated (

Diagnosis and management of pheochromocytoma: a practical guide to clinicians.

Pheochromocytomas (PCCs) are rare catecholamine producing neuroendocrine tumors. The majority of these tumors (85 %) arise from the adrenal medulla. T...
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