Pheochromocytoma (intra-adrenal); Paraganglioma (extra-adrenal)
1. What every clinician should know
Clinical features and incidence
Pheochromocytomas and paragangliomas are rare catecholamine-producing neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. The term pheochromocytoma describes the intra-adrenal tumors that represent the majority of these catecholamine-producing tumors. Paragangliomas describe extra-adrenal tumors classified according to their derivation: sympathetic tumors are usually situated in the chest, abdomen or pelvis, whereas parasympathetic tumors are generally located in the head and neck.
Pheochromocytomas and paragangliomas secrete high levels of the catecholamines, specifically epinephrine and norepinephrine and, to some extent, dopamine. These tumors are rare but potentially lethal for both mother and fetus as the presence of these tumors is often misdiagnosed in pregnancy owing to its similarity in presentation to the much more common cause of hypertension in pregnancy, preeclampsia and to a lesser extent, hyperthyroidism.
Adrenal tumors may secrete both epinephrine and norepinephrine or may be epinephrine-secreting only. Extra-adrenal tumors produce primarily norepinephrine. Excessive release of catecholamines causes the typical symptoms of paroxysmal, labile or intermittent hypertension, tachycardia, palpitations, headache, anxiety, diaphoresis/sweating and orthostatic hypotension due to decreased circulating volume. The classic triad of headaches, palpitations and sweating in a patient with paroxysmal hypertension mandates an evaluation for pheochromocytoma.
Episodic symptoms are characteristic of the epinephrine-producing tumors, and patients may present with anxiety, palpitations, syncope and hyperglycemia. Continuous symptoms such as hypertension, sweating and headaches are more typical of norepinephrine-producing tumors. Secondary hypertension can be caused by activation of the sympathetic nervous system. Stimulation of the α and β receptors results in the vasoconstrictive or vasodilatory effects.
Clinical presentation may vary, and patients may attend with chest or abdominal pain, nausea, vomiting, tremor, seizures, hyperglycemia or “new-onset” diabetes mellitus, cardiomyopathy, congestive heart failure, myocardial infarction, abnormal electrocardiogram or tachyarrhythmias. Others may complain of unusual reactions to medications, and some may report symptoms during or after micturition (paraganglioma of the urinary bladder).
The reported incidence of pheochromocytoma is less than 0.2 per 10,000 pregnancies, although, this condition is likely underreported. Pheochromocytoma is the etiology in approximately 0.1% cases of hypertension in the general population.
Relevant considerations regarding pheochromocytoma can be remembered by the rule of 10’s: it occurs most commonly in the adrenal medulla but 10% are extra-adrenal; 10% are bilateral; 10% are malignant; 10% are symptomatic; originally it was thought that 10% were hereditary but this is no longer true with the detection of new mutations showing a genetic predisposition in 25-30% of cases (MEN 2A, MEN 2B, von Hippel Lindau, neurofibromatosis type 1, succinate dehydrogenase mutation).
2. Diagnosis and differential diagnosis
Establishing the diagnosis
Patients presenting with the classic triad of headache, sweating, and palpitations with labile hypertension should prompt the clinician to consider the possible diagnosis of a pheochromocytoma. Hypertension is generally present, but pheochromocytoma is a diagnostic challenge, particularly in pregnancy, as in some cases it can be present despite a normal blood pressure (with epinephrine-secreting only tumor). Patients may also present with new-onset diabetes and others may become symptomatic on standing due to the relative hypotension associated with pheochromocytoma due to their contracted blood volume. (See Algorithm, Figure 1)
The location and size of the pheochromocytoma (adrenal) or paraganglioma (extra-adrenal) dictate the type and amount of catecholamine secreted. The small pheochromocytomas secrete mainly epinephrine whereas large pheochromocytomas and paragangliomas secrete norepinephrine. A dopamine secreting tumor may suggest malignancy.
24-hour urine collection for catecholamines (pregnancy does not elevate urinary catecholamine levels into the range for pheochromocytoma) levels 2x upper limit of normal diagnostic.
metabolites – vanillylmandelic acid (VMA), metanephrine (98-99% sensitive & has largely replaced VMA), & normetanephrine
24-hour urine collection for total protein (differential diagnosis preeclampsia).
liver function tests.
electrolytes and glucose.
urine drug screen.
magnetic resonance imaging.
genetic testing in individuals with positive family history to evaluate for hereditary causes.
Problems with testing in pregnancy
catecholamines may be increased with stress or illness
sleep apnea syndrome
catecholamines may be increased with drug interactions
tricyclic antidepressant medications/drugs inhibiting catecholamine reuptake
drugs containing catecholamines (decongestants) & amphetamines
In pregnant women, as listed in the algorithm above, 24-hour urinary catecholamine collection is the initial step in screening for pheochromocytoma. This test is reliable in pregnancy and is 98% sensitive. Screening for pheochromocytoma using plasma metanephrines as an initial test is discouraged owing to the lack of specificity (85-89%) and false-positive rate of 11-15%.
After biochemical confirmation of diagnosis, MRI (without gadolinium) is the preferred diagnostic imaging modality in pregnancy. MRI can locate adrenal and extra-adrenal masses and is considered safe in pregnancy. Abdominal ultrasound has been utilized to locate these tumors, but visualization is limited by the expanding uterus. Functional imaging modalities utilizing 123I-meta-iodo-benzyl-guanidine (123I-MIBG) may be considered in the postpartum period to determine the nature of the tumor, confirm its site and exclude metastasis. Functional imaging is helpful for detecting multiple tumors.
Clues to the diagnosis of pheochromocytoma in pregnancy include labile or paroxysmal blood pressure in the setting of the classic triad of headache, sweating and palpitations/tachycardia, and orthostatic/postural hypotension. As the diagnosis of pheochromocytoma is elusive during pregnancy, consider screening for this entity in the woman with persistent hypertension when the usual maximal dose, multidrug therapy does not lower her blood pressure. It is of paramount importance to review relevant family history.
It is important to consider hereditary causes of pheochromocytoma. Genetic screening should be considered for at-risk patients or families. Family or personal history of pheochromocytoma or family history of multiple endocrine neoplasia type 2A and B (MEN 2A, MEN 2B), von Hippel-Lindau syndrome, neurofibromatosis type 1 and hereditary glomus tumors may uncover a diagnosis of pheochromocytoma (see below). Germline mutations in 6 genes (VHL, NF1, RET, SDHB, SDHD, SDHC) may account for as many as 25% of cases of pheochromocytoma and paraganglioma. Individuals with von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), and MEN 2 (RET) mutations primarily develop adrenal tumors.
Those with mutations in mitochondrial succinate dehydrogenase (SDH) are associated with paragangliomas 1 (SDHD), 3 (SDHC), and 4 (SDGC). With mutations in SDHB, patients mainly present with chest and abdomen paragangliomas of sympathetic origin. Mutations in SDHD and SDHC confer an increased likelihood of parasympathetic paragangliomas of the head and neck. Inheritance is largely autosomal dominant, but mutations in SDHD are maternally imprinted, meaning that mothers are capable of transmitting the mutation but only fathers can transmit the disease.
medullary thyroid carcinoma
unilateral or bilateral pheochromocytoma
hyperparathyroidism (less common)
medullary thyroid carcinoma
multiple mucosa neuromas (distal portion of tongue, lips, subconjuctival area, & GI tract)
von Hippel-Lindau syndrome
hemangioblastoma in cerebellum & spine
cysts & carcinoma in kidney
cysts & endocrine tumors in pancreas
6 or more cafe-au-lait spots
2 or more cutaneous neurofibromas
inguinal or axillary freckles
iris hamartomas (Lish nodules)
bone lesions (dysplasia of sphenoid bone or pseudarthrosis)
First on the differential of labile hypertension in pregnancy is preeclampsia, although with preeclampsia, the increased blood pressure is usually sustained and with pheochromocytoma increased blood pressure is paroxysmal.(See Table I)
|Signs & Symptoms|
|Time of presentation||>20 weeks gestation||Anytime during pregnancy|
|Bipedal edema||May be present||Absent|
|Thrombocytopenia||May be present||Normal|
Adapted from PMID: 20083723, Table 2, p. 603.
Additional diagnoses include an exacerbation of chronic hypertension, hyperthyroidism, ilicit drug use (cocaine), pulmonary embolism and lupus flare. Blood pressure records prior to and during pregnancy may establish a timeline for when hypertension began. Pregnant women that present prior to 20 weeks with severe hypertension and complain of headaches, palpitations or sweating may have an underlying pheochromocytoma. Others with labile hypertension not responding to usual antihypertensive therapy may have a pheochromocytoma.
Genetic causes should be suspected in women with in women with a family history as listed above. Labile hypertension with “new-onset” diabetes mellitus may indicate a pheochromocytoma. For women presenting with hypertension and cafe-au-lait spots and cutaneous neurofibromas, think pheochromocytoma. Women with a prior surgically removed pheochromocytoma and new-onset labile hypertension may have a pheochromocytoma, as these tumors recur.
Suspect catecholamine excess when faced with the gravida with severe hypertension and orthostatic hypotension suspected to have peripartum cardiomyopathy. Clinical clues of the underlying pheochromocytoma include a low ejection fraction and absence of ventricular dilatation.
Diagnosis and subsequent management of a patient with catecholamine excess from a pheochromocytoma often includes a multidisciplinary team. Possible consultants include maternal-fetal medicine, critical care, cardiology, anesthesia, endocrinology, surgery and neonatology.
Identification is critical, and the key to management is early recognition, which allows for medical treatment followed by definitive surgical therapy for tumor removal. The timing of surgical removal is predicated on when the tumor is diagnosed (before 24 weeks versus after 24 weeks or postpartum) and maternal response to medical therapy. Owing to the varied clinical features, pheochromocytoma has the pseudonym of the “great mimic” or “great imitator.”
An adrenergically mediated process is suggested by the combination of paroxysmal hypertension, orthostatic hypotension and tachyarrhythmias. Obstetric providers should consider pheochromocytoma in the differential of a patient with labile hypertension, headaches and failure to respond to conventional therapy. Symptoms may be apparent for the first time in pregnancy due to the increased vascularity of the tumor.
Paroxysmal hypertension, Palpitations
Evaluation for preeclampsia and MENS
Other – arrhythmia, sweating, anxiety
mechanical pressures stimulating catecholamine secretion
increased intraabdominal pressure
abdominal surgical interventions
increased vascularity of tumor in pregnancy
aggressive medical therapy begins as soon as diagnosis established with alpha blockade regardless of trimester is preferred initial choice to prevent hypertensive crisis.
phenozybenzamine (pregnancy class C) 10 to 20 mg once or twice daily increased by 0.5-1.0 mg/kg/daily until hypertension controlled or doxazosin x 10-14 days.
control of hypertension and expansion of contracted plasma volume.
goal of antihypertensive treatment is BP of less than or equal to 130/80 mm Hg while sitting and 100 mm Hg systolic while standing.
target heart rate of 60-70 bpm sitting and 70-80 bpm standing.
volume expansion with high salt diet or IV fluid.
add beta blocker to control tachycardia.
use cautiously and only if needed to control reflex tachycardia & arrhythmias after alpha blockade.
never prescribe before alpha blockade as beta blockade alone can cause a hypertensive crisis due to unopposed alpha-adrenergic effects by catecholamines.
calcium channel blockers.
amlodipine, nifedipine, nicardipine, verapamil.
supplement to alpha blockade if inadequate blood pressure control.
not recommended as may worsen symptoms.
many are receiving magnesium due to working diagnosis of preeclampsia.
inhibition of catecholamine release from adrenal medulla.
reduction in sensitivity of alpha-adrenergic receptors to catecholamines.
potent antiarrhythmic effect.
surgery is definitive treatment for pheochromocytoma.
timing of surgery controversial.
dependent of gestational age at diagnosis.
also dependent on clinical response to medical therapy.
tumor removal early in pregnancy after medical treatment for 10-14 days if less than 24 weeks gestation.
after 24 weeks, surgical removal after elective cesarean delivery (either simultaneous or subsequent).
vaginal delivery conveys higher mortality rate for mother.
recheck catecholamine levels 4-6 weeks after surgery.
Complications as a consequence of condition
Pheochromocytoma and paragangliomas are potentially lethal etiologies of secondary hypertension in pregnancy. Early recognition is critical, with improved outcomes when diagnosed antenatally. Unfortunately, the diagnosis is often overlooked or delayed as a result of its similar presentation to preeclampsia. Diagnosis of pheochromocytoma, especially in pregnancy, is elusive due to its variable presentation, justifying the nickname “the great imitator.”
Abrupt hemodynamic deterioration may occur in the peripartum period owing to anesthesia, labor and normal vaginal delivery in women with undiagnosed pheochromocytoma. Optimizing and stabilizing the maternal medical condition prior to definitive surgery with blood pressure control and careful hemodynamic monitoring is critical in decreasing maternal and perinatal morbidity and mortality.
Possible pregnancy complications
intrauterine growth restriction
intrauterine hypoxia (rebound episodes of hypotension)
Complications as a consequence of management
Patients are at risk for an acute hypertensive crisis before or during surgery requiring intravenous medical therapy with phentolamine, nitroprusside, nicardipine or nitroglycerine. Monitoring in an intensive care unit after surgery is recommended for careful monitoring of blood pressure, laboratory assessment and for volume status management. Hypotension is a consequence of continued action of the preoperative medical management and a down-regulation of chronic exposure to catecholamines. Intravenous fluids and pressors may be needed. Monitoring for hypoglycemia is also essential as this may occur postoperatively.
5. Prognosis and outcome
Maternal and fetal/neonatal outcomes
Pheochromocytoma in pregnancy is extremely rare but may have disastrous consequences for both mother and fetus if misdiagnosed. Improved maternal and fetal outcomes are ascribed to early recognition. Older literature reports a high probability of maternal and fetal morbidity and mortality, but in many cases this was due to untreated or undiagnosed pheochromocytoma cases. Prior to 1969, the maternal mortality rate was 26%, which fell to 17% in the 1970s. By the 1990s, the majority of cases were diagnosed antenatally.
Maternal and fetal morbidity and mortality continue to fall with heightened awareness and improved diagnostic modalities. With prompt antenatal diagnosis and medical treatment prior to surgery, maternal mortality has decreased to 1-2%. Fetal outcomes are accordingly improved with early detection and management of pheochromocytoma, with a fetal loss rate of 11-15%. Labile, severe hypertension in the untreated or undiagnosed gravida may lead to placental abruption and fetal death; fetal hypoxia may be the result of rebound hypotension.
Impact on long-term health
Long-term follow-up is essential in women diagnosed and treated for pheochromocytoma due to the possibility of incomplete tumor removal, recurrences or metastasis of a malignant tumor. Malignant pheochromocytomas are uncommon and may be present in 10% of cases. There is a higher risk of malignancy in individuals carrying the SDHB mutation of mitochondrial succinate dehydrogenase (paraganglioma 4). Differentiating between benign and malignant tumors is not straightforward and may become known by local invasion or presence of metastases. Patients with malignant pheochromocytoma have a bleak prognosis, with a 5-year survival rate of less than 50%.
6. What is the evidence for specific management and treatment recommendations
Oliva, R, Angelos, P, Kaplan, E, Bakris, G. “Pheochromocytoma in pregnancy: a case series and review”. Hypertension. vol. 55. 2010. pp. 600-6. (This review describes the contemporary evaluation and management of the catecholamine-secreting tumors, pheochromocytoma and paraganglioma. The historic background, epidemiology, and clinical presentation are reviewed and a thorough review of the biochemical evaluation and metabolism of catecholamines is included. This publication is not specific for pheochromocytoma in pregnancy but contains a diagnostic and therapeutic algorithm and techniques for tumor localization. Particularly helpful is the discussion of familial syndromes and specific germline mutations associated with pheochromocytoma and paraganglioma. Medical and definitive surgical therapy are outlined. Prognosis and follow-up recommendations are given.)
Donckier, JE, Michel, L. “Phaeochromocytoma: state-of-the-art”. Acta Chir Belg. vol. 110. 2010. pp. 140-8. (This case series and review of pheochromocytoma in pregnancy published by the American Heart Association describes 6 cases of pheochromocytoma managed at the University of Chicago Medical Center between 1984 and 2009. The authors present an excellent topic review, differentiating the features of pheochromocytoma and preeclampsia. An algorithm for the assessment and diagnosis of a symptomatic pregnant patient is included. Medical and surgical management, maternal and fetal outcomes, and genetic screening are reviewed.)
Lindsay, JR, Nieman, LK. “Adrenal disorders in pregnancy”. Endocrinol Metab Clin North Am. vol. 35. 2006. pp. 1-20, v. (The natural history, causes, diagnosis and treatment of a myriad of adrenal disorders in pregnancy are contained in this review, including a section on pheochromocytoma in pregnancy. Diagnosis in pregnancy, morbidity and mortality, genetic syndromes associated with this rare entity and a differential diagnosis are presented. Diagnostic techniques for identifying tumors and for tumor localization with functional imaging modalities in the postpartum period are suggested. Medical treatment recommendations, definitive surgical therapy and mode of delivery are presented.)
Grodski, S, Jung, C, Kertes, P, Davies, M, Banting, S. “Phaeochromocytoma in pregnancy”. Intern Med J. vol. 36. 2006. pp. 604-6. (The authors present a very succinct, contemporary report and discussion of pheochromocytoma in pregnancy. The classic presentation, familial and genetic links, diagnostic steps and method of tumor localization are highlighted. Early recognition allowing for medical and surgical treatment is illustrated in their case. Elective cesarean is recommended as the preferred mode of delivery in women with pheochromocytoma.)
Golshevsky, JR, Karel, K, Teale, G. “Phaeochromocytoma causing acute pulmonary oedema during emergency caesarean section”. Anaesth Intensive Care. vol. 35. 2007. pp. 423-7. (Described is an interesting case report of a multiparous woman at 36 weeks who presents with severe pulmonary edema following induction of general anesthesia. Her pregnancy was complicated by labile blood pressure. Etiology, genetic predisposition, diagnostic clues and traditional approach to management are reviewed. Triggers for the surge in catecholamine release related to pregnancies complicated by pheochromocytoma are included.)
Desai, AS, Chutkow, WA, Edelman, E, Economy, KE, Dec, GW. “Clinical problem-solving. A crisis in late pregnancy”. N Engl J Med. vol. 361. 2009. pp. 2271(In this article, the presentation and assessment of a patient at 37 weeks to an emergency department and the clinicians’ stepwise assessment and preliminary diagnosis are described as the case unfolds. The differential diagnosis and clinical clues to the initially missed diagnosis of pheochromocytoma are examined at each step. Laboratory findings, imaging modalities and patient presentation are discussed in reference to the working diagnosis. The pertinent positives and negatives in the considered diagnoses prior to making the final diagnosis of pheochromocytoma are spelled out.)
Hudsmith, JG, Thomas, CE, Browne, DA. “Undiagnosed phaeochromocytoma mimicking severe preeclampsia in a pregnant woman at term”. Int J Obstet Anesth. vol. 15. 2006. pp. 240-5. (The case of an undiagnosed pheochromocytoma in a 40-year-old multiparous woman at 38 weeks mimicking severe preeclampsia ultimately ending in both maternal and fetal death 36-hours postpartum due to cardiogenic shock is presented. The patient had symptoms of hypertension, visual disturbances and proteinuria suggestive of preeclampsia. Important clues to the diagnosis of pheochromocytoma that are uncommon in preeclampsia include glycosuria and pulmonary edema. Widening one’s differential diagnoses was suggested by the authors.)
Lata, I, Sahu, S. “Management of paroxysmal hypertension due to incidental pheochromocytoma in pregnancy”. J Emerg Trauma Shock. vol. 4. 2011. pp. 415-7. (A case presentation and review of the literature in the management of paroxysmal hypertension in pregnancy due to pheochromocytoma is highlighted. Clues to the diagnosis were severe, resistant hypertension and labile blood pressures despite usual medical therapy. Diagnostic signs and symptoms, evaluation, medical treatment, and definitive surgical treatment involving a multidisciplinary group are underscored. Authors suggest cesarean as the preferred mode of delivery when the tumor is still present. Of import, authors conclude that the only way to diagnose a pheochromocytoma is to first think of it.)
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- Pheochromocytoma (intra-adrenal); Paraganglioma (extra-adrenal)
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
- 4. Complications
- 5. Prognosis and outcome
- 6. What is the evidence for specific management and treatment recommendations