Skip to content

Pheochromocytoma

Chapter 399 | Harrison's 22e

KEY CLINICAL POINTS

  • See source text for full details

RAW CONTENT

[PAGE 3073] 3073 CHAPTER 399 Fleseriu M et al: Consensus on diagnosis and management of Cushing’s diagnosis as an incidentaloma. About ~0.1% of hypertensive patients disease: A guideline update. Lancet Diabetes Endocrinol 9:847, 2021. harbor a pheochromocytoma. The mean age at diagnosis is ~40 years, Hahner S et al: Adrenal insufficiency. Nat Rev Dis Primers 7:19, 2021. although the tumors can be detected from early childhood, particularly Merke DP et al: Modified-release hydrocortisone in congenital adre- when genetically determined, until late in life. The classic “rule of tens” nal hyperplasia. J Clin Endocrinol Metab 106:e2063, 2021. for pheochromocytomas states that ~10% are bilateral, 10% are extra- Prete A et al: Prevention of adrenal crisis: Cortisol responses to major adrenal, and 10% are metastatic. stress compared to stress dose hydrocortisone delivery. J Clin Endo- ETIOLOGY AND PATHOGENESIS crinol Metab 105:2262, 2020. PPGLs are well-vascularized tumors that arise from cells derived from Prete A et al: Cardiometabolic disease burden and steroid excretion the sympathetic (e.g., adrenal medulla or sympathetic trunk) or para- in benign adrenal tumors: A cross-sectional multicenter study. Ann sympathetic (e.g., carotid body, glomus tympanicum, glomus jugulare, Intern Med 175:325, 2022. glomus vagale) paraganglia (Fig. 399-1). The name pheochromocytoma Wu X et al: [11C]metomidate PET-CT versus adrenal vein sampling for reflects the formerly used black-colored staining caused by chromaffin diagnosing surgically curable primary aldosteronism: a prospective, oxidation of catecholamines. The World Health Organization (WHO) within-patient trial. Nat Med 29:190, 2023. applies the term pheochromocytoma to adrenal tumors (usually secret- ing) and the term paraganglioma to tumors at all other sites including head and neck, thoracic, extra-adrenal retroperitoneal, and pelvic sites. The etiology of sporadic PPGLs is unknown. However, 25–33% of patients have an inherited condition, including germline mutations in the classically recognized RET (rearranged during transfection), VHL, NF1 (neurofibromatosis type 1), SDHB, SDHC, and SDHD (subunits 399 Pheochromocytoma of SDH) genes or in the more recently recognized SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated Frederic Castinetti, factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate dehydro- Hartmut P. H. Neumann genase), HIF1 α and HIF2 α (hypoxia-inducible factor), MDH2 (malate dehydrogenase), KIF1B β (kinesin family member), IDH1, (isocitrate dehydrogenase 1), SLC25A11 (oxoglutarate/malate), H-RAS (trans- forming protein p21), and DNMTA3 (DNA methyltransferase 3 alpha) Pheochromocytomas and paragangliomas (PPGLs) are catecholamine- genes. Biallelic gene inactivation, a characteristic of tumor-suppressor producing tumors derived from the sympathetic or parasympathetic genes, has been demonstrated for the VHL, NF1, SDHx, TMEM127, nervous system. These tumors may arise sporadically or be inherited MAX, FH, PDH1, PDH2, MDH2, and KIF1B β genes. In contrast, RET as features of multiple endocrine neoplasia type 2 (MEN 2), von is a protooncogene, and mutations activate receptor tyrosine kinase Hippel–Lindau (VHL) disease, or several other pheochromocy- activity. Succinate dehydrogenase (SDH) is an enzyme of the Krebs toma-associated syndromes. The diagnosis of pheochromocytomas cycle and the mitochondrial respiratory chain. The VHL protein is a identifies a potentially correctable cause of hypertension, and their component of a ubiquitin E3 ligase. VHL mutations reduce protein removal can prevent hypertensive crises that can be lethal. The clini- degradation, resulting in upregulation of components involved in cell- cal presentation is variable, ranging from an adrenal incidentaloma cycle progression, glucose metabolism, and oxygen sensing. to a hypertensive crisis with associated cerebrovascular or cardiac In addition to germline mutations, somatic mutations have been complications. Given the wide range of clinical signs, diagnosis may observed in >20 genes, broadly grouped into three different clusters be delayed for years. of pathogenetically relevant genes: cluster 1, the pseudohypoxia group EPIDEMIOLOGY comprising mainly the genes SDHx (subunits of SDH), FH, VHL, and The incidence of PPGL ranges from 0.04 to 0.95 cases per 100,000 HIF2A; cluster 2, the kinase signaling group (RET, NF1, TMEM127, per year, with a gradual increase over time probably due to genetic MAX, HRAS, KIF1B β , PDH); and cluster 3, the Wnt signaling group familial screening, changes in imaging modalities, and more frequent (CSDE1, MAML3). Vagus n. Tympanic n. Jugular p. Jugular ganglion Jugular v. Intravagal p. Nodose ganglion Glossopharyngeal n. Sup. laryngeal a. Intercarotid p. Int. Sup. laryngeal p. laryngeal a. Inf. laryngeal p. Recurrent laryngeal n. Subclavian p. Aortico- pulmonary p. Pulmonary p. Coronary p. Descending aorta A Adrenal B Extra-adrenal C Head and neck paraganglioma pheochromocytoma pheochromocytoma FIGURE 399-1 The paraganglial system and topographic sites (in red) of pheochromocytomas and paragangliomas. (Parts A and B reproduced with permission from WM Manger, RW Gifford: Clinical and experimental pheochromocytoma. Cambridge: Blackwell Science; 1996.) [PAGE 3074] 3074 PART Endocrinology and Metabolism TABLE 399-1 Clinical Features Associated with Pheochromocytoma, TABLE 399-2 Biochemical and Imaging Methods Used for Diagnosis of Listed by Frequency of Occurrence Pheochromocytoma and Paraganglioma 1. Headaches 10. Weight loss DIAGNOSTIC METHOD SENSITIVITY SPECIFICITY 2. Profuse sweating 11. Paradoxical response to 24-h urinary tests 3. Palpitations and tachycardia antihypertensive drugs Catecholamines +++ +++ 4. Hypertension, sustained or 12. Polyuria and polydipsia Fractionated metanephrines ++++ ++ paroxysmal 13. Constipation Total metanephrines +++ ++++ 5. Anxiety and panic attacks 14. Orthostatic hypotension Plasma tests 6. Pallor 15. Dilated cardiomyopathy Catecholamines +++ ++ 7. Nausea 16. Erythrocytosis 8. Abdominal pain 17. Elevated blood sugar Free metanephrines ++++ +++ 9. Weakness 18. Hypercalcemia Imaging CT ++++ +++ MRI ++++ +++ CLINICAL FEATURES MIBG scintigraphy ++ ++++ Its clinical presentation is so variable that pheochromocytoma has been termed “the great masquerader” (Table 399-1). Among the presenting Somatostatin receptor scintigraphya ++ ++ manifestations, episodes of palpitation, headache, and profuse sweating 18Fluoro-DOPA PET/CT ++++ ++++ are typical, and these manifestations constitute a classic triad that is 68Gallium-DOTATOC or DOTATATE PET/CT ++++ ++++ seen in roughly a third of patients with pheochromocytoma. The pres- aValues are particularly high in head and neck paragangliomas. ence of all three manifestations in association with hypertension makes Abbreviations: CT, computed tomography; MIBG, metaiodobenzylguanidine; MRI, pheochromocytoma a likely diagnosis. However, a pheochromocytoma magnetic resonance imaging; PET/CT, positron emission tomography plus CT. For can be asymptomatic for years or can be identified through imaging the biochemical tests, the ratings correspond globally to sensitivity and specificity screening in a patient presenting with a hereditary syndrome. Some rates as follows: ++, <85%; +++, 85–95%; and ++++, >95%. tumors grow to a considerable size before patients note symptoms. The dominant sign is hypertension. Classically, patients have metanephrines are the most sensitive and are less susceptible to false- episodic hypertension, but sustained hypertension is also common. positive elevations from stress, including venipuncture. Although Catecholamine crises can lead to heart failure, pulmonary edema, the incidence of false-positive test results has been reduced by arrhythmias, and intracranial hemorrhage. During episodes of hor- the introduction of newer assays, physiologic stress responses and mone release