pheochromocytoma; paroxysmal hypertension; adrenal medullary paraganglioma; chromoffinoma
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Introduction
Rare tumors of chromaffin cells generally in the adrenal medulla, but also may occur in the sympathetic ganglia & bladder wall.
Etiology
unknown
Epidemiology
- uncommon
- generally sporadic, but may be familial
- most commonly present as adrenal incidentaloma[17]
- older patients more commonly present as adrenal incidentaloma[17]
- patients with adrenergic symptoms/uncontrolled hypertension generally younger
Pathology
- 80-90% of pheochromocytomas arise from chromaffin cells in the adrenal medulla
- 80% are unilateral
- secrete norepinephrine with or without epinephrine
- dopamine & neuropeptide Y are also secreted
- 10% develop in sympathetic ganglia (paraganglioma)
- pheochromocytomas may occur anywhere in the sympathetic chain
- tumors tend to be bilateral
- extra-adrenal tumors secrete only norepinephrine
- 10% are malignant
- dampened baroreceptor reflex (orthostatic hypotension)
Microscopic pathology
- nests of polygonal/spindle shaped cells
- rich vascular network
- finely granular basophilic or amphophilic cytoplasm
- intracytoplasmic hyaline globules
- may have marked pleomorphism
- rare/no mitotic figures
- capsular and vascular invasion common in benign behaving tumors
Immunophenotype
- chromogranin +
- synaptophysin +
- inhibin +
- S100 (sustentacular cells) +
- neuron specific enolase +
- melan A -
Genetics
- 10% of cases hereditary
- family history of pheochromocytoma or paraganglioma
- 5-10% are inherited in autosomal dominant mode
- may occur in association with
- loss of heterozygosity:
- 1p34-36 in 45%
- VHL gene (3p25) in 45%
- associated with defects in SDHB, SDHD
- susceptibility may be associated with germline mutations in tumor-suppressor genes VHL & NF1 & proto-oncogene RET
- other implicated genes INSM1
Clinical manifestations
- high systolic & diastolic blood pressure
- paroxysmal or sustained
- most frequent presentation
- may present as hypertension in response to a stimulus such as anesthesia or iodinated contrast agent[5]
- resistant hypertension at a young age
- paroxysms of palpitations
- tachycardia
- hypoxemia (case report)[16]
- diaphoresis
- pounding headache
- tremulousness
- nausea/vomiting
- abdominal pain
- anxiety
- syncope
- orthostatic hypotension
- chronic weight loss
- glucose intolerance
- idiopathic cardiomyopathy[5]
- micturition-associated symptoms of catecholamine excess (if pheochromocytoma is localized to the bladder wall)
Laboratory
- increased 24 hour urine metanephrines*
- increased 24 hour urine catecholamines
- plasma free metanephrines*
- apparently levels remain elevated after episode of hypertension has resolved[5]
- annual surveillance following surgical resection[5]
- between paroxysms, paroxysm may be induced by IV histamine
- during paroxysms, IV phentolamine (Regitine) lowers BP
- glucagon tolerance panel, for pheochromocytoma
- serum glucose may be elevated
- genetic screening (see Genetics: above)[16]
- pulse oximetry or blood gas
- see ARUP consult[6]
* urinary metanephrines with higher specificity
* plasma free metanenephrines with higher sensitivity
* do not use plasma catecholamines[13]
* medications to be discontinued 2 weeks prior to testing
- acetaminophen, prochlorperazine, phenoxybenzamine, antipsychotics, buspirone, MAO inhibitors, SNRIs, tricyclic antidepressants, amphetamines, methylphenidate, cocaine, caffeine, levodopa, pseudoephedrine, ephedrine, reserpine, clonidine, ethanol, illicit drugs
* metaephrine levels 5-fold higher in patients with adrenergic symptoms & uncontrolled hypertension[17]
Diagnostic procedures
- electrocardiogram (similar to Takotsubo cardiomyopathy)
- ST segment elevations may be present
- diffuse T-wave inversions in precordial leads
- echocardiogram
- cardiac apical dyskinesia with preserved function at cardiac base
- apical ballooning similar to Takotsubo cardiomyopathy
- cardiac apical dyskinesia with preserved function at cardiac base
Radiology
- imaging recommended only after diagnosis of pheochromocytoma is confirmed by laboratory testing[5]
- CT or MRI may reveal a mass near or in the adrenal gland
- contrast-enhanced computed tomography of abdomen & pelvis[5]
- prior alpha-blockade required
- phentolamine, prazosin, doxazosin, terazosin, or phenoxybenzamine
- administration of iodine contrast media to a patient without alpha-blockage may precipitate hypertensive crisis[5]
- variable-size with round clear margins
- heterogenous enhancement with cystic areas
- density > 10 HU
- contrast washout < 50% (10 minutes)
- prior alpha-blockade required
- magnetic resonance imaging (MRI)
- hyperintense on T2-weighted images
- contrast-enhanced computed tomography of abdomen & pelvis[5]
- I-131 meta-iodobenzylguanidine (MIBG) scan
- may be helpful when other imaging techiniques are negative
- extra-adrenal lesions suspected
- average size (diameter) of pheochromocytoma is 7 cm[14]
- largest 19 18 x 12 cm[15]
Management
- surgical excision of tumor
- pre-operatively administer alpha-blockers*
- phenoxybenzamine for 10-14 days prior to surgery[5]
- associated with hypotension[5][7]
- prazosin, doxazosin, terazosin or phentolamine with may be associated with less hypotension than phenoxybenzamine[5][7]
- phenoxybenzamine for 10-14 days prior to surgery[5]
- follow with beta-blocker after alpha blockade if needed for blood pressure & cardiac rhythm control
- beta-blockers contraindicated without prior alpha-blocker administration[5][7]
- medical therapy should precede surgery by at least 2 weeks to allow for adequate volume repletion
- perioperative IV normal saline to maintain intravascular volume
- laparoscopic adrenalectomy
- pre-operatively administer alpha-blockers*
- hypertensive crisis
- sodium nitroprusside
- alpha-blockers (phentolamine)
- beta-blockers may be used after alpha blockade if tachycardia is excessive
- metyrosine (may be combined with alpha-blockers)
- annual surveillance after surgical resection with plasma free metanenephrines
- > 90% 10 year survival for resected carcinoid [5]
* also administer alpha-blocker prior to contrast-enhanced CT scan[5]
More general terms
Additional terms
- alpha adrenergic receptor antagonist
- catecholamine
- catecholamine metabolism
- metanephrines in 24 hour urine
- metyrosine (Demser)
- multiple endocrine neoplasia type-2 (MEN-2)
- neurofibromatosis (von Recklinghausen's disease)
- von Hippel-Lindau disease
References
- ↑ DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 341
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 657-58
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 482-83
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 6.0 6.1 ARUP Consult: Pheochromocytoma - Paraganglioma The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/pheochromocytoma
Paraganglioma Pheochromocytoma Genetic Testing Algorithm https://arupconsult.com/algorithm/paraganglioma-pheochromocytoma-genetic-testing-algorithm
Pheochromocytoma Testing Algorithm https://arupconsult.com/algorithm/pheochromocytoma-testing-algorithm - ↑ 7.0 7.1 7.2 7.3 Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007 Nov;92(11):4069-79. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17989126
- ↑ Prejbisz A, Lenders JW, Eisenhofer G, Januszewicz A. Cardiovascular manifestations of phaeochromocytoma. J Hypertens. 2011 Nov;29(11):2049-60 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21826022
- ↑ Lenders JW, Duh QY, Eisenhofer G et al Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24893135
- ↑ Eisenhofer G, Goldstein DS, Walther MM et al Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003 Jun;88(6):2656-66. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1278887
- ↑ Fishbein L, Orlowski R, Cohen D. Pheochromocytoma/Paraganglioma: Review of perioperative management of blood pressure and update on genetic mutations associated with pheochromocytoma. J Clin Hypertens (Greenwich). 2013 Jun;15(6):428-34. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23730992 Free PMC Article
- ↑ van Berkel A, Lenders JW, Timmers HJ. Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma. Eur J Endocrinol. 2014 Feb 4;170(3):R109-19. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24347425
- ↑ 13.0 13.1 American Society for Clinical Pathology Thirty Things Physicians and Patients Should Question Released September 4, 2019 (26-30) http://www.choosingwisely.org/societies/american-society-for-clinical-pathology/
- ↑ 14.0 14.1 Uysal E et al Giant multicystic malignant pheochromocytoma. Turk J Surg. 2015 Jul 14;33(4):296-298 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29260138 PMCID: PMC5731569 Free PMC article
- ↑ 15.0 15.1 Ambati D, Jana K, Domes T. Largest pheochromocytoma reported in Canada: A case study and literature review. Can Urol Assoc J. 2014 May;8(5-6):E374-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24940470 PMCID: PMC4039607 Free PMC article
- ↑ 16.0 16.1 16.2 NEJM Knowledge+
Thomas RM, Ruel E, Shantavasinkul PC, Corsino L. Endocrine hypertension: An overview on the current etiopathogenesis and management options. World J Hypertens. 2015;5(2):14-27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26413481 PMCID: PMC4582789 Free PMC article.
Mulla CM, Marik PE. Pheochromocytoma presenting as acute decompensated heart failure reversed with medical therapy. BMJ Case Rep. 2012 Jul 19;2012:bcr2012006319. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22814979 PMCID: PMC4543352 Free PMC article.
Reisch N, Peczkowska M, Januszewicz A, Neumann HP. Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens. 2006 Dec;24(12):2331-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17082709 Review. - ↑ 17.0 17.1 17.2 17.3 Aggarwal S et al. Pheochromocytomas most commonly present as adrenal incidentalomas: A large tertiary center experience. J Clin Endocrinol Metab 2024 Jan; 109:e389. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37417693 PMCID: PMC10735286 Free PMC article. https://academic.oup.com/jcem/article/109/1/e389/7220962
- ↑ National Cancer Institute Pheochromocytoma and Paraganglioma Treatment (PDQ) - Health Professional version https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq
Patient information
pheochromocytoma patient information