Endocrinology · PANCE / PANRE

Pheochromocytoma

Catecholamine-secreting tumor of adrenal medullary chromaffin cells; classic triad of paroxysmal headache, palpitations, and diaphoresis.

Also known as: pheochromocytoma, paraganglioma, PPGL, chromaffin cell tumor, 10% tumor

Overview

Catecholamine-secreting tumor arising from chromaffin cells. Adrenal medullary tumors are pheochromocytomas; extra-adrenal sympathetic ganglia tumors are paragangliomas (PGL); collectively PPGLs. Up to 40% are now recognized as hereditary.

Epidemiology

Annual incidence ~0.8 per 100,000. Account for ~0.1-0.5% of hypertension cases. Peak age 30-50 (younger if hereditary). The 'rule of 10s' (10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial) has been revised — up to 40% are hereditary with modern testing.

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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

Symptoms

  • Classic triad (only ~50%): paroxysmal headache, palpitations, diaphoresis
  • Episodic or sustained hypertension (~90%)
  • Anxiety, sense of doom, pallor (vasoconstriction)
  • Weight loss, heat intolerance, hyperglycemia (β-adrenergic effects)
  • Orthostatic hypotension (volume contraction)
  • Symptoms triggered by anesthesia, intubation, surgery, contrast, beta-blocker alone, certain foods

Signs / physical exam

  • Hypertension (paroxysmal in 50%, sustained in 50%) often labile and severe
  • Tachycardia, pallor during paroxysm
  • Postural hypotension
  • Diaphoresis, tremor
  • Café-au-lait or neurofibromas (NF1), mucosal neuromas (MEN2B)

Classic findings

Paroxysmal severe HTN + headache + diaphoresis + palpitations in a young adult, especially with family history.

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 criteria

Elevated plasma free metanephrines or 24-h urinary metanephrines >2× upper limit + tumor on cross-sectional imaging.

Labs

  • Plasma free metanephrines (preferred for high pretest probability) OR 24-hour urinary metanephrines and catecholamines (preferred for low pretest probability)
  • Plasma metanephrines: high sensitivity (>95%) but lower specificity; many false positives from stress, TCAs, levodopa, MAOIs
  • Sampling conditions: supine for 30 min, fasting, avoid acetaminophen and labetalol (assay interference)
  • Chromogranin A — adjunct (elevated in many neuroendocrine tumors)
  • Genetic testing recommended for ALL pheochromocytomas (high hereditary yield)

Imaging

  • Adrenal CT or MRI after biochemical confirmation
  • MIBG (iobenguane I-123) or Ga-68 DOTATATE PET/CT if metastatic disease or paraganglioma suspected
  • Whole-body imaging for SDHB-mutant tumors (high metastatic risk)

Diagnostic algorithm

flowchart TD
  A[Paroxysmal HTN, headache,<br/>palpitations, diaphoresis] --> B[Plasma free metanephrines<br/>OR 24-h urine metanephrines]
  B --> C{Elevated >2× ULN?}
  C -->|No| D[Pheo unlikely]
  C -->|Yes| E[Adrenal CT or MRI]
  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]
Pheochromocytoma — diagnostic workup and preoperative preparation (alpha before beta).

Complications

  • Hypertensive crisis, stroke, MI, dissection, cardiomyopathy (catecholamine-induced)
  • Multi-organ failure during induction of anesthesia or beta-blockade alone
  • Hyperglycemia, hypocalcemia (rare)
  • 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 — North American Neuroendocrine Tumor Society Consensus Guidelines for Pheochromocytoma and Paraganglioma (Fishbein et al., Pancreas 2021)
  • ENS@T 2020 — European Network for the Study of Adrenal Tumors guidance on PPGL management

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