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Pheochromocytoma         

PHEOCHROMOCYTOMA        SX |  DX  |  RX  | Diff-Dx     

- Hypertensive patient with the triad of headache, sweating, & palpitations.                                                    REF:  ACP PIER 2006  

Pheochromocytoma is a adrenal medullary chromaffin cell tumor that typically causes symptoms and signs of episodic catecholamine release, including paroxysmal hypertension. The tumor is an unusual cause of hypertension and accounts for at most 0.1 to 0.2% of cases of high blood pressure.  About 90% of pheochromocytomas exist as solitary, unilateral, encapsulated adrenal medullary tumors. About 10% are bilateral, more commonly seen in several members of a family, 40 to 70% of whose members may have bilateral tumors.
The "rule of 10s"
is useful to recall approximate frequencies of pheochromocytoma that vary from the usual: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial, 10% pediatric, and 10% without blood pressure elevation.  Other sites include the paravertebral sympathetic ganglia, the urinary bladder, other autonomic ganglia (celiac, superior, or inferior mesenteric), the thorax (including the posterior mediastinum, the heart, and paracardiac regions), and the neck (in sympathetic ganglia, the carotid body, cranial nerves, or the glomus jugulare). Bilateral and extra-adrenal tumors are more common in children. Histologically, oval groups of cells, in clusters or "nests," stain for chromogranin A.  
Distant metastatic sites include bone, lung, lymph nodes, and liver. Bilateral adrenal medullary hyperplasia has been reported in gene carriers from kindreds with multiple endocrine neoplasia (MEN) type 2. This hyperplasia may be a precursor of pheochromocytoma.
The diagnosis of pheochromocytoma is typically made in young to middle-aged adults, most commonly in the fourth or fifth decade of life; about 10% of diagnoses are made in children (usually male). Autopsy series indicate that the incidence of pheochromocytoma increases progressively with age. In adults, no gender difference is seen in the incidence of pheochromocytoma.

Although rare (0.1% of hypertensive patients), pheochromocytoma is a life-threatening but potentially curable condition.
Over 90% of patients with pheochromocytoma have hypertension, and over half have sustained elevations of blood pressure.    

Clinical Clues to suspect & to evaluate for Pheochromocytoma

  1. Refractory hypertension
  2. Hypertension, accompanied by hyperadrenergic spells with:
    • Nonexertional palpitations
    • Diaphoresis
    • Headache
    • Tremor
    • Pallor
    • Family history of familial pheochromocytoma
  3. A genetic syndrome that increases the risk of pheochromocytoma, such as:
    • Multiple endocrine neoplasia type 2
    • von Hippel-Lindau disease
    • Neurofibromatosis type 1
  4. History of gastric stromal tumor or pulmonary chondromas (Carney triad)
  5. An incidentally discovered adrenal mass


History & Physical Elements for Pheochromocytoma:

History
Headache - Typically a “pounding” type headache that occurs with the paroxysm
Palpitation -  Patients may describe this as more of a “forceful heartbeat” rather than tachycardia; may occur in isolation or as part of the paroxysm
Diaphoresis - May be a drenching sweat; usually part of stereotypic spell  
Epigastric and chest pain -  Usually part of stereotypic spell
Pallor  -  Patients may feel “flushed”, but are actually pale; usually part of stereotypic spell
Nausea -  Usually part of stereotypic spell
Dyspnea -  Usually part of stereotypic spell
Anxiety -  Usually part of stereotypic spell
Tremor -  “Fine tremor”—similar to that seen with hyperthyroidism; usually part of stereotypic spell

Physical exam
Blood pressure: hypertension, sustained or paroxysmal; orthostatic Patients may have sustained hypertension or intermittent hypertension. Orthostatic drop in blood pressure is frequently present
Skin exam: café au lait spots, axillary freckling in Neurofibromatosis
Ophthalmic exam: hypertensive retinopathy, retinal angiomas.  Retinal angiomas indicative of von Hippel-Lindau disease
Ear, nose, and throat exam: mucosal neuromas on eyelids and tongue in Multiple endocrine neoplasia type 2B
Thyroid exam: thyroid mass in Multiple endocrine neoplasia type 2A and 2B
Marfanoid body habitus  in Multiple endocrine neoplasia type 2B  
Subcutaneous neurofibromas  in Neurofibromatosis

   

Lab. Evaluation for Pheochromocytoma

Consider measurement of metanephrines and catecholamines in a 24-hour urine collection and metanephrines in blood for patients with suspected pheochromocytoma.

If clinical suspicion for pheochromocytoma is low, measure 24-hour urinary metanephrine excretion ;
for example, in the asymptomatic patient with:

  • New onset, stage 1 hypertension
  • An incidentally discovered adrenal mass with findings on CT that are consistent with a benign cortical adenoma

If clinical suspicion for pheochromocytoma is high, measure 24-hour urinary excretion of metanephrines & catecholamines and plasma metanephrines ;
for example, in the patient with:

  • Resistant hypertension (poor blood pressure control on 3 or more antihypertensive agents that include a diuretic, a vasodilator, and a ß-adrenergic inhibitor)
  • Spells, with or without hypertension
  • Family history of pheochromocytoma
  • Past history of resected pheochromocytoma and now with recurrent hypertension or spells
  • No symptoms, but with an incidentally discovered adrenal mass that has CT findings consistent with pheochromocytoma
    (such as: Enhancement with intravenous contrast medium on CT; High signal intensity on T2-weighted MRI cystic and hemorrhagic changes; Typically >4 cm in diameter; Bilateral tumor)

* For a patient with episodic hypertension, start the 24-hour urine collection with the onset of a spell, if possible.
* If an accurate 24-hour urine collection is not possible (e.g., pediatric patient), then measure plasma metanephrines.

Be aware of the medications and clinical circumstances that may cause false-positive test results for pheochromocytoma.  
Ask about medications and activities that may increase measured levels of catecholamines and metabolites, including:

  • Tricyclic antidepressants , Labetalol, Levodopa, Drugs containing catecholamines (e.g., decongestants), Amphetamines, Buspirone (and most psychoactive agents), Sotalol, Withdrawal from clonidine hydrochloride and other drugs, Ethanol, Acetaminophen and phenoxybenzamine (fractionated plasma metanephrines), Physical stress (e.g., stroke, obstructive sleep apnea)

   

Diagnostic Laboratory to confirm the diagnosis of  Pheochromocytoma

* 24-hour urinary total metanephrines    - best test
Sensitivity 76-95%, Specificity 94-99%
24-hour urinary total metanephrines >1.3 mg
is consistent with pheochromocytoma (in a patient not taking an interfering medication and not physically stressed).

24-hour urinary catecholamines
Sensitivity 77-95%, Specificity 79-99%  
24-hour urinary total norepinephrine and epinephrine levels more than 2-fold increased above the ULN for the assay is consistent with pheochromocytoma.
(in a patient not taking an interfering medication and not physically stressed) .  (ULN = upper limits of normal)

Plasma metanephrines
Sensitivity 99-100%, Specificity 85-89%
Plasma normetanephrine and metanephrine levels >50% increased above the ULN for the assay in a patient not taking an interfering medication and not physically stressed is consistent with pheochromocytoma.
[Plasma concentrations of normetanephrine greater than 2.5 pmol/mL or metanephrine levels greater than 1.4 pmol/mL (more than 4- and 2.5-fold above the upper reference limits) indicate a pheochromocytoma with 100% specificity.
  Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.  JAMA  March 20, 2002;287:1427 - Jazques Lenders, etc. ]

Plasma catecholamines
Sensitivity 85% , Specificity 80%  
Plasma catecholamines (norepinephrine + epinephrine) drawn in a supine rested patient with an indwelling canula increased to values >2,000 pg/mL are consistent with pheochromocytoma.

* Urinary VMA is readily available but the least reliable due to the high incidence of false-negatives and false-positives. Many drugs and food products are known to interfere with this assay.


Obtain computer-assisted imaging (MRI or CT) of the adrenal glands and abdomen as the first localization test.

CT scan
Sensitivity 93-100%, Specificity 50%  
Sensitivity is excellent for adrenal pheochromocytoma and less for extra-adrenal catecholamine-secreting tumors. Specificity is poor due to the high prevalence of adrenal cortical adenomas.  

MRI scan
Sensitivity 93-100%, Specificity 75%  
Sensitivity is excellent for adrenal pheochromocytoma and less for extra-adrenal catecholamine-secreting tumors. Specificity is improved over CT due to the high signal intensity of pheochromocytomas on T-2 weighted imaging.

123I-MIBG scintigraphy
Sensitivity 80%, Specificity 99%
MIBG scintigraphy is very specific; however, the sensitivity is less than computerized imaging.
Iodine-131-MIBG, a radiolabeled analogue of guanethidine, is transported into chromaffin cells by the reuptake cell membrane catecholamine carrier. Because it accumulates in chromaffin cells, an MIBG abnormality is extraordinarily specific (about 98%) for pheochromocytoma, although somewhat less sensitive (85 to 90%) than CT or MRI.  MIBG imaging is especially useful for metastatic, recurrent, or extra-adrenal tumors.

   

MANAGEMENT OF PHEOCHROMOCYTOMA       
  1. Surgical resection of the adrenal tumor & Pre-op management
  2. Management of hypertensive crisis
  3. Management of hypertension control
  4. Management of malignant or unresectable pheochromocytoma

Hospitalize patients with pheochromocytoma for the management of hypertensive crisis with intravenously administered agents.

Be aware that acute hypertensive crises may occur before or during surgery, and should be treated with intravenous nitroprusside, nicardipine, or phentolamine.

  • Sodium nitroprusside (Direcxt Vasodilator):
    - IV infusion, 0.5 to 5.0 µg/kg·min; maximum dose should not exceed 800 µg/min
    - Side effects: Nausea, vomiting. apprehension, headache, dizziness, restlessness, perspiration palpitations, retrosternal discomfort, abdominal pain, muscle twitching
     (effects may be reduced by slowing the infusion rate). Also, sodium nitroprusside is metabolized rapidly to cyanide then thiocyanate. High plasma concentrations of thiocyanate may occur if treatment is continued for several days and may cause mental confusion, tinnitus, blurred vision, nausea, fatigue, ataxia, and unconsciousness.

  • Nicardipine (a calcium channel blocker):
    - To treat acute hypertensive crises: starting dose is 2.5 µg/kg·min IV infusion and titrated for blood pressure control
    - Usual dosage 20-90 mg/d ; Available as 30-, 45-, and 60-mg sustained-release capsules.  
      Initial dose: 30 mg (sustained-release capsule) once daily, titrated prn for blood pressure control
    - Benefit: Normotension and resolution of paroxysms
    - Side effects: Edema, dizziness, headache, flushing, nausea, dyspepsia

  • Phentolamine (a short-acting, nonselective, a-adrenergic blocker):
    - To treat acute hypertensive crises
    - Initial test dose of 1 mg, and if necessary, then 2-5 mg IV boluses prn, or continuous infusion (100 mg in 500 mL 5% dextrose and water)
    - Response is maximal 2 to 3 minutes after a bolus injection, and lasts 10 to 15 minutes
    - A solution of 100 mg of phentolamine in 500 mL of 5% dextrose and water can be infused at a rate titrated for blood pressure control
    - Postural hypotension, tachycardia, miosis, nasal congestion, diarrhea, inhibition of ejaculation, and fatigue
    - The response to phentolamine is 2-3 minutes maximum after a bolus injection and lasts 10-15 minutes

     


Hospitalize patients with known pheochromocytoma for resection of the tumor (laparoscopic adrenalectomy) .

Refer patients to an experienced surgeon/anesthesiologist team.

  1. Initiate drug therapy to control blood pressure and expand extra-cellular fluid volume before operating.
  2. Aim for total excision of the pheochromocytomas.
  3. Consider laparoscopic adrenalectomy for benign, sporadic, intra-adrenal catecholamine-secreting tumors that are <8 cm in diameter.
  4. Note that surgery most often normalizes blood pressure by the time the patient is discharged from the hospital; however, some patients remain hypertensive for up to 4 to 8 weeks postoperatively.
  5. Recognize that persistent hypertension may be related to: Accidental ligation of a polar renal artery, Resetting of baroreceptors, Established hemodynamic changes, Structural changes in blood vessels , Altered sensitivity of blood vessels to pressor substances, Functional or structural changes in the kidney, Coincident essential hypertension
  6. Monitor patient closely to determine if drug intervention is needed for hypertension.
  7. Treat intraoperative hypertensive crises with either nitroprusside or phentolamine.
  8. If a bilateral adrenalectomy is planned preoperatively (e.g., multiple endocrine neoplasia type 2), ensure that the patient receives glucocorticoid stress coverage while awaiting transfer to the operating room.
  9. Ensure that glucocorticoid coverage is initiated in the operating room if unexpected bilateral adrenalectomy is necessary.
  10. To avoid lifelong glucocorticoid dependence, consider cortical-sparing surgery in patients with bilateral adrenal pheochromocytomas.
  11. Be aware that premedication includes minor tranquilizers and barbiturates.
    • Do not use fentanyl or morphine because of the potential for stimulating catecholamine release from the pheochromocytoma.
    • Avoid parasympathetic nervous system blockade with atropine because of associated tachycardia.
    • Recognize that induction usually is accomplished with thiopental, and that general anesthesia is maintained with a halogenated ether,such as enflurane or isoflurane.

In patients with malignant or unresectable disease, consider treatment with tumor-directed non-drug therapy
in addition to the previously outlined drug therapy with a-adrenergic blocker, ß-adrenergic blocker, and/or a calcium channel blocker. .

  • Be aware that the only cure for malignant pheochromocytoma is complete resection; resect metastatic lesions if possible.
  • Treat painful skeletal metastatic lesions with external radiation therapy or radiofrequency ablation.
  • Note that radiofrequency ablation of hepatic and bone metastases may be very effective in selected patients.
  • If the tumor is considered to be aggressive and the quality of life is affected, consider a combination chemotherapy program consisting of cyclophosphamide, vincristine, and dacarbazine, given cyclically every 21 to 28 days.
  • Control hypertension and spells with combined a-adrenergic and ß-adrenergic blockade.

   


Pre-operative Management for Pheochromocytoma Resection

Hospitalize patients with known pheochromocytoma for resection of the tumor.

  • In most elective cases, admit patients to the hospital on the morning of surgery following thorough pharmacologic preparation.
  • Give the last doses of oral antihypertensive agents with a small sip of water on the morning of surgery.
  • Follow blood pressure and blood glucose closely after surgery.

Administer both a-adrenergic and ß-adrenergic blockers preoperatively.

  1. Aim for target blood pressures of <120/80 mm Hg (seated), with systolic blood pressure >90 mm Hg (standing),
    but modify them on the basis of age and comorbid disease.
  2. Maintain a liberal salt diet during the preoperative period.
  3. a-adrenergic and ß-adrenergic blockers:
    - Begin treatment with a long-acting, irreversible, nonselective, a-adrenergic receptor blocker (phenoxybenzamine) 7-10 days preoperatively to allow for expansion of the contracted blood volume.
    - Understand that relatively short-acting, selective a1-adrenergic receptor blockers (e.g., prazosin, terazosin, doxazosin) may be inadequate for preoperative drug preparation (although they are acceptable for chronic treatment in patients with malignant pheochromocytoma).
    - Only after adequate a-adrenergic blockade is achieved, initiate ß-adrenergic blockade (~3 days before surgery) with propranolol or cardioselective ß-adrenergic blockers (e.g., atenolol and metoprolol).  
  4. ß-adrenergic blockers:
    When initiating ß-adrenergic blockade, begin at a low dose (e.g., propranolol, 10 mg q 6 h) and increase as necessary to control tachycardia.
    - Note that not all patients require a ß -adrenergic blocker;
      if blood pressure and spells are controlled with a-adrenergic blockade and the patient is not tachycardic, a ß-adrenergic blocker is not required.
  5. Consider using the calcium channel blocker nicardipine in preoperative and intraoperative management
    if a-adrenergic and ß-adrenergic blocking agents are ineffective or poorly tolerated. or
    Alternatively, consider metyrosine (a-methyl-para-tyrosine), which is a tyrosine hydroxylase inhibitor, at an oral dose of 0.25 to 1.0 g qid PO.
    In addition, when excessive tumor manipulation or destruction is anticipated (e.g., radiofrequency ablation), consider using metyrosine in conjunction with a- and ß-adrenergic blocking agents.
  6. Treat intraoperative hypertensive crises with either nitroprusside or phentolamine.
  7. Be aware that premedication includes minor tranquilizers and barbiturates.
    • Do not use fentanyl and/or morphine because of the potential for stimulating catecholamine release from the pheochromocytoma.
    • Avoid parasympathetic nervous system blockade with atropine because of associated tachycardia.
  8. Anesthesia:
    Note that induction is usually accomplished with thiopental, and that general anesthesia is maintained with a halogenated ether, such as enflurane or isoflurane (see Drug Therapy).

DRUGS:

Phenoxybenzamine -  PBZ (Dizenzyline)  (a-adrenergic blocking agent)    Use as Pre-op drug therapy for pheochromocytoma resection.
- irreversible and long-acting 20-100 mg/d
- Available in 10-mg capsules
- Initial dosage: 10 mg po bid, increased by 10-20 mg every 2-3 days prn to control blood pressure and spells
- Benefits:  Normotension and resolution of paroxysms
- Side effects: Postural hypotension, tachycardia, miosis, nasal congestion, diarrhea, inhibition of ejaculation, and fatigue
- Note:  Given in twice daily dosing, starting with 10 mg bid and titrated for normal blood pressure and resolution of paroxysms
  The effects of daily administration are cumulative for nearly a week; ~25% of oral dose is absorbed

a-methyl-para-L-tyrosine (metyrosine)    (Catecholamine synthesis inhibitor)
- Dosage: 1,000-4,000 mg/d   (Max 4000mg/d) ; Available in 250-mg capsules
  Initial dosage: 250 mg qid, increase by 250-500 mg/day as needed and titrated for normal blood pressure and resolution of paroxysms
Benefits: Normotension and resolution of paroxysms
Side effects: Sedation, depression, diarrhea, anxiety, nightmares, crystalluria and urolithiasis, galactorrhea, and extrapyramidal manifestations
Note:  Use this agent with caution and only after other agents have been shown to be ineffective.
Especially useful for patients who, for cardiopulmonary reasons, cannot be treated with combined a- and ß-adrenergic blockade.
The extrapyramidal effects of phenothiazine or haloperidol may be potentiated, and their concomitant use with metyrosine should be avoided.
Ensure high fluid intake to avoid crystalluria for any patient taking >2 g/d

* Steroid "replacement" therapy after bilateral adrenalectomy often does not suffice for normalizing quality of life. Between 25% and 33% of patients undergoing bilateral adrenalectomy develop Addisonian crisis at some point, and attendant mortality rates are high. Moreover, 30% of patients develop clinically significant fatigue, and 48% consider themselves handicapped.  In patients with pheochromocytoma, partial adrenalectomy can preserve adrenocortical function and avoid the morbidity of medical adrenal replacement.

     

Differential Diagnosis of Pheochromocytoma       

Thyrotoxicosis
Signs and symptoms of hyperthyroidism (unintended weight loss, increased heart rate, tremor) and suppressed serum TSH concentration are present
Suppressed serum TSH and increased serum thyroxine are diagnostic, and symptoms resolve with thyroid-directed treatment  

Conditions where Normal levels of catecholamines and catecholamine metabolites exclude pheochromocytoma as the cause:

  1. Hyperadrenergic" spells
    This is a diagnosis of exclusion, and the signs and symptoms may be clinically indistinguishable from patients with pheochromocytoma
    except that all catecholamines and catecholamine metabolite levels are normal
  2. Unexplained flushing spells
    This is a diagnosis of exclusion and the signs and symptoms may be clinically indistinguishable from patients with pheochromocytoma except that all catecholamines and catecholamine metabolite levels are normal
  3. Anxiety, panic attacks, and hyperventilation
    Panic disorder symptoms are frequently confused with the presentation of pheochromocytoma
  4. Paroxysmal cardiac arrhythmia (especially in a hypertension patient)
    Palpitations are common in patients with pheochromocytoma
  5. Renovascular hypertension
    Paroxysmal hypertension and symptoms can occur in patients with renovascular disease
  6. Postural orthostatic tachycardia syndrome (POTS)
    Patients have posture-induced symptoms of lightheadedness and increased heart rate
  7. Mastocytosis (systemic or activation disorder)
    Typically presents with flushing and hypotension. Evaluation with urinary methylhistamine and serum tryptase is diagnostic
  8. Carcinoid syndrome
    Typically presents with flushing, diarrhea, and cardiac-related symptoms. 24-hour urinary excretion of 5-hydroxyindole acetic acid is diagnostic
  9. Recurrent idiopathic anaphylaxis
    Patients present with sudden onset of multiple symptoms that may include: hypotension, dyspnea, urticaria, palpitation, pallor, and syncope

Conditions where Catecholamines and catecholamine metabolites levels may be temporarily increased:

  1. Withdrawal of adrenergic-inhibiting medications (e.g., clonidine)
    Clinical setting is usually diagnostic
  2. Monoamine oxidase inhibitor treatment and concomitant ingestion of tyramine or a decongestant
    Clinical setting is usually diagnostic
  3. Sympathomimetic ingestion
    Clinical setting is usually diagnostic
  4. Illicit drug ingestion (e.g., cocaine, phencyclidine, lysergic acid)
    Clinical setting is usually diagnostic

* Disease states causing or simulating catecholamine excess and hypertension include thyrotoxicosis; acute intracranial disturbances such as subarachnoid hemorrhage or posterior fossa masses; hypertensive crisis of paraplegia, which can be initiated by visceral manipulation or bladder distention; and hypoglycemia, especially in the presence of Beta-blockade.

Differential Diagnosis of Elevated plasma catecholamine & urin. metanephrine levels:

  • Acute clonidine withdrawal
  • Acute alcohol withdrawal
  • Vasodilator Rx with hydralazine or minoxidil
  • Acute myocardial ischemia or infarction
  • Acute cerebrovascular accident (stroke)
  • Cocaine abuse
  • Severe CHF
  • IV dopamine, dopaminergic drugs, and acute hypoglycemia
  • Phenylpropanolamine abuse   

   

                    


REF:
ACP - PIER 2006
Goldman: Cecil Textbook of Medicine, 22nd ed., 2004

         

2006