PHEOCHROMOCYTOMA AND PARAGANGLIOMA

Typical Duration of Spell

• Spell Duration: Commonly 15–20 minutes, but may be much shorter or last several hours.
• Important Note: Most patients with spells do not have a pheochromocytoma.

Additional Clinical Signs of Catecholamine-Secreting Tumors

1. Cardiovascular
   • Hypertensive retinopathy.
   • Orthostatic hypotension (possible paradoxical feature).
   • Angina.
2. Gastrointestinal
   • Nausea, constipation (megacolon can be a presenting symptom).
3. Metabolic
   • Hyperglycemia, diabetes mellitus (α-adrenergic inhibition of insulin release).
   • Hypercalcemia (often resolves post-tumor removal, may be MEN 2–related or due to PTHrP).
   • Raynaud phenomenon, livedo reticularis.
   • Erythrocytosis (secondary to increased catecholamine stimulation).
4. Mass Effects
   • Tumor size/location effects.
   • Bladder paragangliomas: Painless hematuria, paroxysmal spells triggered by micturition or defecation.
5. Cosecreted Hormones
   • ACTH → Cushing syndrome.
   • PTH-related peptide → hypercalcemia.
   • Vasopressin → SIADH.
   • VIP → watery diarrhea.
   • GHRH → acromegaly.
6. Cardiomyopathy and Heart Failure
   • Possibly unrecognized as pheochromocytoma cause.
   • May be dilated or hypertrophic, often reversible post-resection.
   • Myocarditis, myocardial infarction with normal coronaries also possible.

Physical Exam and Genetic Syndromes

• Possible findings from hereditary predispositions:
  • Retinal angiomas, marfanoid habitus, café-au-lait spots, axillary freckling, subcutaneous neurofibromas, mucosal neuromas (e.g., MEN 2B).
• Some patients may be asymptomatic despite high catecholamine levels (receptor desensitization from chronic stimulation).

The “Rule of 10” (Historically)

• 10% are extra-adrenal.
• 10% occur in children.
• 10% are multiple/bilateral.
• 10% recur post-surgery.
• 10% are malignant.
• 10% are familial.
• 10% of benign sporadic pheos found incidentally.

(Modern data suggests up to 20% familial, and about 50% discovered incidentally in some series.)

Increasing Incidental Detection

• Widespread use of CT imaging and familial testing → up to 50% discovered before symptoms.
• Tumors found incidentally may be small (<3 cm) but can be large (≥10 cm).

Diagnosis

1. Biochemical Confirmation
   • Fractionated catecholamines and metanephrines (plasma or 24-hour urine).
2. Imaging only after biochemical confirmation:
   • Pheochromocytomas: Typically adrenal; average ~4.5 cm.
   • Paragangliomas: Extra-adrenal chromaffin tissue (para-aortic, organ of Zuckerkandl, bladder wall, sympathetic chain in neck/mediastinum).
3. Head/Neck Paragangliomas:
   • Usually parasympathetic origin, nonsecretory.
4. Thoracic/Abdominal/Pelvic Paragangliomas:
   • Sympathetic origin, typically catecholamine-secreting.

ADRENAL MEDULLA AND CATECHOLAMINES

Anatomy and Cells

• Adrenal Medulla: Central 10% of the adrenal gland volume.
• Chromaffin Cells (Pheochromocytes): Stain brown with chromium salts (due to oxidation of epinephrine/norepinephrine).
• Sympathetic Input: Preganglionic fibers from T10–L1 splanchnic nerves.
• Stressful Stimuli: Trigger catecholamine release (MI, anesthesia, hypoglycemia).

Catecholamine Basics

• Catechol Nucleus: ortho-dihydroxybenzene ring + amino side chain.
  • Epinephrine: Principal adrenal medulla hormone (80% of normal output).
  • Norepinephrine: Also in adrenal medulla & peripheral sympathetic nerves.
  • Dopamine: Precursor, main CNS transmitter.

Physiologic Effects

1. Cardiovascular: ↑HR, BP, myocardial contractility, conduction velocity.
2. Receptor Subtypes
   • α1: Vascular smooth muscle contraction → ↑BP.
   • α2: Presynaptic inhibition of NE release; central anti-hypertensive effect.
   • β1: Cardiac inotropy, chronotropy; renin release, lipolysis.
   • β2: Bronchodilation, vasodilation in skeletal muscle, glycogenolysis.
   • β3: Lipolysis, energy expenditure.
   • DA1 (renal vasculature dilation), DA2 (presynaptic inhibition of NE release).

Pharmacologic Implications

• Selective α/β agonists/antagonists treat various conditions (e.g., β1-blockers for HTN, α2-agonists for HTN, β2-agonists for asthma).

CATECHOLAMINE SYNTHESIS, STORAGE, SECRETION, METABOLISM, INACTIVATION

Synthesis

1. Tyrosine → DOPA via tyrosine hydroxylase (rate-limiting).
   • Inhibited by cytoplasmic catecholamines; relieved by secretory depletion.
   • α-Methylparatyrosine (metyrosine) inhibits tyrosine hydroxylase.
2. DOPA → Dopamine via aromatic L-amino acid decarboxylase.
3. Dopamine → Norepinephrine via dopamine β-hydroxylase (DBH) in storage vesicles.
4. Norepinephrine → Epinephrine via phenylethanolamine N-methyltransferase (PNMT) in cytosol.
   • PNMT requires glucocorticoids and S-adenosylmethionine.

Storage and Secretion

• Vesicular Monoamine Transporters (VMAT): Pump catechols into secretory vesicles.
• Secretory Granules: Contain catecholamines, ATP, calcium, neuropeptides, chromogranins.
• Exocytosis Trigger: Acetylcholine (via nicotinic receptors) → depolarization → voltage-gated Ca²⁺ channels → vesicle fusion and release.
• Short Plasma Half-Life: 10–100 seconds. About half loosely bound to albumin.

Metabolism and Inactivation

• Reuptake: ~90% of synaptic NE taken up by presynaptic nerve (uptake-1); inhibited by cocaine, TCAs.
• Enzymatic: Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) degrade catechols.
  • Metanephrine/normetanephrine formed by COMT.
  • Final major metabolite: vanillylmandelic acid (VMA).
• Dopamine: Metabolized to homovanillic acid (HVA).