Pheochromocytoma

Risk factors

• Family history of pheochromocytoma, paraganglioma, or syndromic disease
• MEN2A (RET) — bilateral pheochromocytoma + medullary thyroid + parathyroid hyperplasia
• MEN2B (RET) — pheo + medullary thyroid + mucosal neuromas + marfanoid
• Von Hippel-Lindau (VHL) — pheo + retinal/CNS hemangioblastoma + renal cell carcinoma
• Neurofibromatosis type 1 (NF1) — café-au-lait, neurofibromas, Lisch nodules
• Hereditary paraganglioma syndromes — SDHB (most malignant potential), SDHD, SDHC, SDHA
• Carney triad, Carney-Stratakis dyad

Pathophysiology

Chromaffin cells synthesize and store catecholamines (epinephrine, norepinephrine, dopamine). Tumors release catecholamines episodically or continuously, producing the clinical syndrome. Extra-adrenal paragangliomas usually secrete norepinephrine (lack PNMT for epi synthesis). SDHB-mutant tumors are more often metastatic.

Clinical presentation

Differential diagnosis

• Essential hypertension with anxiety — Sustained HTN without paroxysms; normal metanephrines
• Panic disorder — Episodic anxiety, palpitations, but normal BP and normal metanephrines
• Hyperthyroidism / thyroid storm — Heat intolerance, weight loss, goiter, abnormal TSH
• Carcinoid syndrome — Flushing, diarrhea, wheezing; elevated 5-HIAA
• Cocaine / sympathomimetic toxicity — Drug history, tox screen
• Pseudopheochromocytoma — Symptomatic with paroxysmal HTN but normal metanephrines; clonidine suppression testing may help
• MAOI + tyramine ('cheese reaction') — Drug/diet history; transient
• Renovascular hypertension — Renal artery stenosis; bruit; imaging

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Paroxysmal HTN, headache,<br/>palpitations, diaphoresis] --> B[Plasma free metanephrines<br/>OR 24-h urine metanephrines]
  B --> C{Metanephrine result?}
  C -->|Normal| D[PPGL effectively excluded]
  C -->|Mild rise| M["Mild rise, under 3× ULN:<br/>repeat supine sampling off interfering drugs<br/>± clonidine suppression test"]
  M -->|Normal on repeat| D
  M -->|Confirmed| E[Adrenal CT or MRI]
  C -->|Marked rise| N["Marked rise, 3× ULN or more:<br/>PPGL highly likely"]
  N --> E
  E --> F{Tumor identified?}
  F -->|No| G["MIBG or DOTATATE PET<br/>(extra-adrenal paraganglioma)"]
  F -->|Yes| H["Genetic testing<br/>(MEN2, VHL, NF1, SDH)"]
  H --> I[Pre-op alpha-blockade<br/>phenoxybenzamine 10-14 days<br/>+ salt and water loading]
  I --> J["Add beta-blocker AFTER alpha<br/>(days 3-5; never first)"]
  J --> K[Laparoscopic adrenalectomy]
  K --> L["Post-op surveillance:<br/>annual metanephrines"]

Complications

• Hypertensive crisis, stroke, MI, dissection, cardiomyopathy (catecholamine-induced)
• Multi-organ failure during induction of anesthesia or beta-blockade alone
• Hyperglycemia, hypercalcemia (usually coexisting MEN2A hyperparathyroidism; rarely tumor PTHrP)
• Recurrence or metachronous tumors (especially hereditary)
• Metastatic disease (SDHB-mutant most concerning)
• Postoperative hypotension and hypoglycemia

PANCE pearls

• ALPHA BEFORE BETA — beta-blockade alone can cause unopposed alpha vasoconstriction and lethal hypertensive crisis.
• Plasma free metanephrines (or 24-h urinary metanephrines) is the screening test of choice. Single best test.
• Acetaminophen, labetalol, TCAs, MAOIs, levodopa, and caffeine cause false-positive metanephrine results.
• Screen ALL patients with pheochromocytoma for hereditary syndromes (MEN2, VHL, NF1, SDH mutations).
• Always screen for and treat pheochromocytoma BEFORE thyroidectomy in MEN2 (medullary thyroid cancer).
• Liberal salt and water during alpha-blockade reverses volume contraction and prevents post-op hypotension.

References

• Endocrine Society 2014 — Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline (Lenders et al., J Clin Endocrinol Metab 2014)
• NANETS 2021 — The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma (Fishbein et al., Pancreas 2021;50:469-493)
• ESH 2020 — Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension (Lenders et al., J Hypertens 2020;38:1443-1456)