Pheochromocytoma - Tabulated Notes

1. Overview

Feature	Detail
Definition	Neoplasm of chromaffin cells (adrenal medulla) that synthesizes and releases catecholamines
Cell of origin	Chromaffin cells (neural crest-derived)
Synonym	"Paraganglioma" when arising at extraadrenal sites
Incidence	2-8 cases/million/year; found in 0.2-0.6% of hypertensive patients
Significance	Surgically correctable cause of hypertension; can cause fatal hypertensive crises if missed

2. The "10% Rules"

Rule	Detail
10% extraadrenal	Organ of Zuckerkandl (aortic bifurcation/origin of IMA), carotid body, bladder, sympathetic ganglia
10% bilateral	Rises to ~50% in familial syndromes
10% malignant	Up to 20% malignancy in extraadrenal tumors
10% normotensive	Increasingly found on incidental imaging
10% in children	More common in hypertensive children (~1.7%)
>10% familial	Proportion has risen; genetic testing now standard
>10% metastatic at diagnosis	Also increasing in recent series

Note: The strict 10% rule is now considered outdated and applies best to familial/syndromic cases. - Robbins & Kumar Basic Pathology

3. Genetics & Associated Syndromes

Syndrome	Gene	Chromosome	Pheo Features	Other Features
MEN2A	RET (proto-oncogene)	10q11	~50%, often bilateral	Medullary thyroid carcinoma, parathyroid adenoma, cutaneous lichen amyloidosis
MEN2B	RET	10q11	Usually bilateral	Medullary thyroid carcinoma, mucosal/submucosal neuromas, marfanoid habitus, Hirschsprung disease
Von Hippel-Lindau (VHL) type 2	VHL (tumor suppressor)	3p25-26	~20% get pheo/paraganglioma	Retinal & cerebellar hemangioblastomas, clear cell renal carcinoma, pancreatic neuroendocrine tumors
Neurofibromatosis type 1 (NF1)	NF1 (tumor suppressor)	17q11.2	~2%, usually adrenal	Café au lait spots, neurofibromas, Lisch nodules, axillary freckling
SDHx mutations	SDHA/B/C/D	Various	Higher metastatic risk (SDHB)	Paraganglioma syndromes; SDHB associated with malignant disease
Sporadic	Multiple (RET, VHL, NF1, EPAS1, SDHx)	-	~40% carry somatic mutations	-

Pathogenic mechanisms:

RET, NF1 → enhanced growth factor receptor signaling
VHL, SDHx subunits, EPAS1 → increased hypoxia-inducible factor (HIF) activity

4. Clinical Presentation

Feature	Detail
Classic triad	Headache, sweating attacks, hypertension (present in ~95% in large series)
Hypertension pattern	Sustained in majority; paroxysmal in ~2/3
Paroxysmal episode contents	Abrupt BP rise + tachycardia, palpitations, headache, diaphoresis, tremor, apprehension, nausea/vomiting, abdominal/chest pain
Triggers of paroxysms	Palpation of tumor, physical exertion, drugs (e.g., tricyclics, dopamine antagonists), anesthesia induction, surgery
Acute complications	Congestive heart failure, pulmonary edema, MI, ventricular fibrillation, CVA
Chronic complications	Catecholamine cardiomyopathy, catecholamine-induced vasculitis
Other hormones secreted	ACTH, somatostatin (can cause Cushing's features)
Micturition syncope	Pathognomonic of bladder paraganglioma

Physical signs in syndromic patients:

Café au lait spots + neurofibromas → NF1
Retinal hemangiomas → VHL
Port wine stain → Sturge-Weber
Marfanoid habitus + mucosal neuromas → MEN2B
Subungual fibromas, ash leaf patches, adenoma sebaceum → tuberous sclerosis

5. Morphology & Histology

Feature	Detail
Gross appearance	Yellow-tan, well-circumscribed; large tumors are hemorrhagic, necrotic, cystic
Size	Small confined lesions to several-kilogram masses
Dichromate test	Turns dark brown with potassium dichromate (oxidizes catecholamines)
Microscopy	Polygonal-to-spindle chromaffin cells in "zellballen" (small nests) separated by rich vascular network
Cytoplasm	Finely granular (catecholamine-containing granules); highlighted by silver stains
Nuclei	Often pleomorphic even in benign tumors
EM finding	Variable membrane-bound, electron-dense secretory granules
Malignancy criterion	Only by the presence of metastases (not by histological features alone)
Metastatic sites	Regional lymph nodes, liver, lung, bone

Pheochromocytoma gross (A) and histology (B)

Fig A: Gross specimen - hemorrhagic tumor enclosed within attenuated cortex

Histology of pheochromocytoma showing nests of cells with abundant cytoplasm

Fig B: H&E - characteristic nests of chromaffin cells with abundant cytoplasm and a bizarre cell (center, even in benign tumors) - Robbins & Kumar Basic Pathology, Fig. 18.38

6. Biochemical Diagnosis

Test	Sensitivity	Specificity	Notes
Plasma-free metanephrines (metanephrine + normetanephrine)	96-100%	85-89% (drops to 77% in >60 yrs)	Best screening test; high sensitivity but many false positives
24-hr urine fractionated metanephrines + catecholamines	98%	98%	Best confirmatory test; two collections recommended
Urinary VMA (vanillylmandelic acid)	Lower (historical)	-	Less used now; replaced by fractionated metanephrines
Clonidine suppression test	-	-	0.3 mg oral clonidine → measure plasma normetanephrine; used for equivocal results

Cutoff principle: Values >2x upper limit of normal on urine testing = positive

Drugs/conditions causing false positives:

Tricyclics, levodopa, cocaine, amphetamines, ephedrine, pseudoephedrine, phencyclidine, LSD, isoproterenol
Clonidine/alcohol withdrawal
Subarachnoid hemorrhage, migraine, preeclampsia, acute illness

7. Localization & Imaging

Modality	Sensitivity	Specificity	Notes
CT (with/without contrast)	90-100%	~70%	First-line; HU >10, vigorous early enhancement, <60% washout; 5 mm slices
MRI	Slightly higher than CT	~70%	Preferred in pregnancy, children, lactation, CT contrast allergy; T2-weighted hyperintense ("light-bulb sign")
MIBG scintigraphy (¹²³I or ¹³¹I)	77-90%	Very high	Reserved for suspected multifocal/malignant disease; high specificity
⁶⁸Ga-DOTATATE PET/CT	97.6%	High	Best overall lesion detection; superior to FDG-PET (49%) and ¹⁸F-DOPA PET (75%)
¹⁸F-DOPA PET/CT	75%	High	Good for hereditary cases
¹⁸F-FDG PET/CT	49%	-	Useful for SDHB-related metastatic disease

Important rule: Always confirm biochemically before imaging.

8. Perioperative Management

Step	Detail
Alpha-blockade first	Start 7-14 days preoperatively (longer if cardiomyopathy/vasculitis)
Preferred alpha-blocker	Phenoxybenzamine (irreversible, non-selective) - initial 10 mg BD, titrate to 20-100 mg/day
Alternative alpha-blocker	Doxazosin (selective α1) - start 1 mg at night; increasingly preferred
BP targets (seated)	<120/80 mmHg seated; systolic >90 mmHg standing
Beta-blockade	ONLY after adequate alpha-blockade (risk of unopposed alpha stimulation = worse hypertension if given first)
Beta-blocker indication	HR >80 bpm after alpha-blockade; e.g., extended-release metoprolol 25 mg once daily
High-sodium diet	≥5000 mg/day (to reverse catecholamine-induced volume contraction and alpha-blockade-related orthostasis)
Additional agents	Metyrosine (α-methyl-p-tyrosine, 250 mg q6h) - inhibits catecholamine synthesis; amlodipine up to 20 mg/day
Intraoperative hypertensive crisis	IV sodium nitroprusside, phentolamine, or nicardipine (NOT beta-blockers)
Perioperative mortality	Historically 26-50%; now ~1% at specialty centers

9. Surgical Management

Feature	Detail
Treatment of choice	Complete surgical resection
Surgical survival rate	98-100%
Preferred approach	Laparoscopic adrenalectomy for most tumors
Open approach	Large (>6 cm), malignant, or locally invasive tumors
Pheo-specific consideration	Early ligation of adrenal vein to minimize catecholamine spillage
Post-excision BP	May drop significantly (have IV fluids and vasopressors ready)
Hypertension cure rate	~75% (rest may have persistent essential hypertension)
Postop monitoring	24-48 hr ICU; glucose monitoring (rebound hypoglycemia from insulin release)

10. Metastatic/Malignant Pheochromocytoma

Feature	Detail
Definition of malignancy	Presence of metastases only (no reliable histological criteria)
Incidence	>10% metastatic at diagnosis (rising)
Risk factors	Extraadrenal location, large size, SDHB mutation (highest risk)
Metastatic sites	Lymph nodes, bone, liver, lung
Treatment options	¹³¹I-MIBG therapy, CVD chemotherapy (cyclophosphamide + vincristine + dacarbazine), sunitinib, ⁶⁸Ga-DOTATATE-guided PRRT, metyrosine for symptom control
5-year survival	~50% for metastatic disease

11. Follow-Up

Parameter	Detail
Annual biochemical testing	Fractionated plasma/urine metanephrines for life (detects recurrence, delayed primaries, metastatic disease)
Imaging follow-up	Not needed unless biochemistry becomes elevated
Genetic testing	Recommended for all patients, especially young age (<40), bilateral, extraadrenal, malignant, or family history
Family screening	Offered to first-degree relatives if germline mutation identified

12. Differential Diagnosis

Condition	Distinguishing Feature
Essential hypertension	No paroxysms; normal catecholamines
Panic disorder	Normal catecholamines; normal BP between attacks
Hyperthyroidism	Thyroid function tests elevated; TFTs differentiate
Carcinoid syndrome	Flushing + diarrhea; elevated urine 5-HIAA
Autonomic epilepsy	EEG changes; no catecholamine elevation
Drug withdrawal (clonidine)	History; resolves with reinstatement
Renovascular hypertension	Renal artery imaging; normal catecholamines
Adrenal carcinoma	Non-functional or cortisol-secreting; different biochemistry

13. Key Points / Exam Mnemonics

Mnemonic	Meaning
5 Hs	Headache, Hypertension, Hyperhidrosis, Hyperglycemia, Heart palpitations
"10% tumor"	10% extraadrenal, bilateral, malignant, normotensive, familial, in children
Alpha before Beta	NEVER start beta-blockade before alpha-blockade
Zellballen	Pathognomonic nest-like histological pattern
"Light-bulb sign"	Bright T2 signal on MRI
PHEO = Paraganglioma/pheo Has Extra Origins	Neural crest → chromaffin cells → both adrenal and extraadrenal sites

Sources: Robbins & Kumar Basic Pathology; Sabiston Textbook of Surgery 21e; Goldman-Cecil Medicine; Brenner & Rector's The Kidney; Current Surgical Therapy 14e; Campbell Walsh Wein Urology

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