Are you sure the patient has a pheochromocytoma or paraganglioma?
Pheochromocytomas and paragangliomas are neoplastic lesions originating from ganglia cells of the autonomic nervous system. Pheochromocytomas are localized in the adrenal medulla. Sympathetic paragangliomas are mainly found in the abdomen. Parasympathetic paragangliomas are found in the head and neck area.
Classical symptoms are spell-like and caused by catecholamine surges, which cause episodic palpitations, headache, pallor, perspiration and anxiety. Signs are tachycardia, hypertension. These episodes last minutes (not seconds) to hours, and sometimes symptoms are constant. Most pheochromocytomas will cause some degree of symptoms and signs. However, head and neck paragangliomas are usually clinically silent and mainly cause problems from local growth. They are therefore present with compressive symptoms (e.g., tinnitus, nerve palsy). Pheochromocytomas on occasion can also present as incidental findings on cross-sectional imaging.
Currently, the main screening test for patients with suspicious clinical symptoms or signs are urine or plasma metanephrine and normetanephrine levels.
What else could the patient have?
In the setting of typical spell-like symptoms and elevated metanephrine and/or normetanephrine levels, a typical tumor observed on imaging makes the diagnosis straightforward. However, each of these findings (symptoms, elevated hormones and adrenal mass) has a unique differential diagnosis.
Neuroendocrine tumors: Spells are usually dry, and flushing is more prominent then pallor. Neuroendocrine tumors and carcinoid tumors often cause diarrhea, which is unusual with pheochromocytoma.
Menopause: Menopausal flushing is much shorter (seconds) than in pheochromocytoma.
Anxiety: Anxiety and pheochromocytoma symptoms are difficult to differentiate. A detailed psychiatric history may be helpful. In addition, anxiety is rarely the predominant symptom patients will complain about; it’s secondary. Patients will rather complain of palpitations, pounding heartbeat, etc.
The differential diagnosis of adrenal tumors is broad. Functional cortical tumors can be differentiated by clinical syndromes due to cortisol, androgen or mineralocorticoid excess. Other tumors of the adrenal glands include neuroblastomas, ganglioneuromas, metastasis, myelolipoma, lymphoma and sarcoma. Pheochromocytomas almost invariably show attenuation on unenhanced CT scans of > 20 HU and are very bright on T2-weighted MRI imaging.
Elevated Metanephrine and Normetanephrine levels
In most pheochromocytoma patients, metanephrine and normetanephrine levels are elevated > 4-fold the normal range. Normetanephrine and metanephrine levels are often mildly elevated in patients with essential hypertension. Normetanephrine levels are significantly elevated in patients treated with tricyclic antidepressive drugs or serotonin noradrenaline uptake inhibitors. Obstructive sleep apnea causes regular surges of catecholamines and elevated metanephrines, and normetanephrines are present in 24-hour urine collections.
Key laboratory and imaging tests
Traditionally, catecholamines (epinephrine and norepinephrine, as well as their breakdown products homovanillic acid (HVA) and vanillylmandelic acid (VMA) in blood and urine) have been used in the evaluation of pheochromocytomas. However, measurement of these hormones has become obsolete with the advent of metanephrine and normetanephrine measurements. Secretions of these catechol-O-methyltransferase (COMT)-derived substances from a tumor is rather constant and not episodic in nature; therefore, plasma levels fluctuate less.
While the sensitivity and specificity of urine versus plasma metanephrines varies minimally, most centers prefer plasma-free metanephrines as a screening tool, followed by confirmation in 24-hour urine. Interpretation is dependent on the pre-test probability, which differs significantly depending on patient ascertainment. For patients with hypertension (low level of suspicion), levels should be elevated 2-4 fold. However, any elevation over the normal range (especially metanephrine) is concerning in a patient with an adrenal tumor with imaging characteristics of a pheochromocytoma or a familial syndrome predisposing to pheochromocytoma development (high level of suspicion).
Normetanephrine levels are significantly elevated in patients treated with tricyclic antidepressant drugs or serotonin noradrenaline uptake inhibitors. These substances may need to be held for repeat testing. Obstructive sleep apnea causes regular surges of catecholamines and elevated metanephrines, and normetanephrines are present in 24-hour urine colections.
Chromogranin A can be helpful in further substantiating the diagnosis of a pheochromocytoma.
Unspecific laboratory changes may include hyperglycemia.
Only after biochemical confirmation of a pheochromcytoma is imaging performed. The main initial imaging is cross-sectional imaging by either CT or MRI. On CT scan, most pheochromocytomas have an attenuation of > 20 HU (unenhanced) and show delayed washout (<60% absolute and <40% relative). Most pheochromocytomas will appear inhomogeneous, may have cystic parts as well as areas of necrosis and hemorrhage as well as calcifications. On MRI, pheochromocytomas typically appear bright on T2-weighted images.
Functional imaging with metaiodobenzylguanidine (MIBG), octreotide or fluorodeoxyglucose-positron emission tomography (FDG-PET) may be considered in cases where a metastatic or extra-adrenal pheochromocytoma needs to be evaluated or followed. The main use of these imaging modalities lies in evaluating the full extent of disease after the initial diagnosis of a pheochromocytoma or paraganglioma has been made. These modalities are of no use in finding an “occult” pheochromocytoma.
Other tests that may prove helpful diagnostically
Every patient with a pheochromocytoma or paraganglioma will need to have a full evaluation for possible hereditary predisposition. Family history, personal medical history, tumor localization, biochemical profile and multifocality are helpful in determining the most likely underlying syndrome. For genetic evaluation, the patient should be referred to a genetic counselor and clinical geneticist or endocrinologist experienced in endocrine genetics.
The main syndromes to take into consideration are:
Hereditary paraganglioma syndrome: caused by mutations in genes of the succinate dehydrogenase complex subunits.
SDHB (succinate dehydrogenase complex subunit B): Patients mainly present with abdominal paragangliomas, which are often norepinephrine-secreting. A higher percentage of SDHB-related paraganglioma and pheochromocytomas have been found to be malignant. Patients with SDHB mutations are at risk for developing other tumors.
SDHD (succinate dehydrogenase complex subunit D): These mutations predispose rather for head and neck paragangliomas, which often are non-functional.
SDHC (succinate dehydrogenase complex subunit C): Most of these tumors occur in the head and neck area, and often are non-functional.
Other mutations (SDHA, SDHAF2) are much rarer and their phenotype is not well assessed yet.
von Hippel-Lindau disease (VHL)
VHL caused by mutations in the VHL gene predisposes to hemangioblastoma of the CNS, spine and retina, renal cell carcinoma, neuroendocrine and cystic pancreatic tumors and endolymphatic sac tumors. Occasionally VHL may present with bilateral pheochromocytoma in the absence of any other disease expression. These tumors are almost invariably localized in the adrenal gland and produce norepinephrine.
Multiple endocrine neoplasia type 2 (MEN2)
MEN2 presents less often with pheochromocytoma, but more commonly with medullary thyroid cancer. Pheochromocytomas occur in ~50% of MEN2 patients and are always localized in the adrenal gland and produce epinephrine.
Neurofibromatosis type 1 (NF1)
The clinical diagnosis of NF1 is usually present or can be made at the time of diagnosis of a pheochromocytoma. NF1 is rarely confirmed genetically as sequencing of the NF1 gene is cumbersome.
Other (TMEM127, MAX mutations)
The phenotype of these gene mutations is not well described yet, but both seem to predispose rather to pheochromocytoma than to paraganglioma.
Management and yreatment of the disease
Hypertension with pheochromocytoma
Usually hypertensive urgency is defined as blood pressure >220mmHg/>120mmHg. When concomitant end-organ damage (e.g., visual disturbances, confusion, hematuria) is present, it is called a hypertensive emergency. If hypertensive urgency or emergency is caused by catecholamine surges from a pheochromocytoma, the preferred treatment is oral (or occasionally IV) α-blockade, using the reversible phentolamine (1–5mg repeated every 15min as required) or irreversible phenoxybenzamine (1mg/kg infused over at least 2h). It is never appropriate to initiate β-blockade first or alone because of the resultant unopposed α-effects and potential for a hypertensive crisis.
Every patient with a pheochromocytoma or paraganglioma should be initiated on antihypertensive treatment until definitive surgery is possible, regardless of the presence of hypertension. Traditionally, phenoxybenzamine loading has been used, starting at nighttime with 10 mg and then increasing by 10 mg every day or every other day until hypertension is controlled and the patient develops nasal congestion and edema. Salt and fluid intake should be liberal during this period. Alternatively titration of doxazosin or other reversible α-blocker can be used. Another alternative is the use of calcium antagonists.
After 1-2 weeks of α-blockade, it is usually safe to add a β-blocker, such as metoprolol, targeting a heart rate of ~60/min.The initiation of sufficient α- & β-blockade controls the patient’s blood pressure and prevents the effects of catecholamine surges (e.g., stroke) during anesthesia and surgery.
Surgery for pheochromocytoma
Surgery is the only curative therapy for pheochromocytoma. Presurgical blood pressure control is a necessary prerequisite. Small pheochromocytomas may be removed laparoscopically. For larger tumors, concurrent lymphadenectomy to assess for loco-regional extension is recommended.
The only definite sign of malignancy of pheochromocytomas and paragangliomas is the presence of metastasis. Therapy for metastasized tumors is largely experimental and should ideally take place in the context of a clinical trial. Most metastatic pheochromocytomas are slow-growing and can often observed and treated only symptomatically (α- & β-blockade) without definitive cancer therapy. Definitive cancer therapy may be initiated when either biochemical progression (e.g., urine metanephrine, normetanephrine, serum chromogranin A), tumor growth or new metastases are observed.
Traditionally, combination cytotoxic chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) has been used with a biochemical response of up to 70%. Recently therapy with I-131-MIBG (meta-iodobenzylguanidine) has emerged as a true alternative, which may be specifically beneficial in some of the hereditary variants. Current studies are evaluating targeted therapy with tyrosine kinase inhibitors and other cytotoxic regimens.
What’s the evidence?/references
Welander, J, Söderkvist, P, Gimm, O. “Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas”. Endocr Relat Cancer. vol. 18. 2011. pp. R253-76. (Review)
Eisenhofer, G. “Screening for pheochromocytomas and paragangliomas”. Curr Hypertens Rep. vol. 14. 2012. pp. 130-7. (Review)
Eisenhofer, G. “Catecholamine metabolism: A contemporary view with implications for physiology and medicine”. Pharmacol Rev. vol. 56. 2004. pp. 331-49.
Parmer, RJ. “Catecholaminergic pathways, chromaffin cells, and human disease”. Ann N Y Acad Sci . vol. 71. 2002. pp. 497-505.
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- Are you sure the patient has a pheochromocytoma or paraganglioma?
- What else could the patient have?
- Key laboratory and imaging tests
- Other tests that may prove helpful diagnostically
- Management and yreatment of the disease
- What’s the evidence?/references