What is a Pheochromocytoma
A pheochromocytoma is a rare catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, with an annual incidence of 0.1 to 0.6 per 100,000 population. 1
Tumor Origin and Classification
Pheochromocytomas specifically arise from chromaffin cells within the adrenal medulla, distinguishing them from paragangliomas which develop from extra-adrenal chromaffin tissue along the sympathetic or parasympathetic nervous system 1
These tumors derive from pluripotent neural crest stem cells and are associated with neurons of the autonomic nervous system 1
The term "paraganglioma" refers to tumors arising anywhere along the paraganglial system from the skull base to the sacrum, while pheochromocytoma is reserved for intra-adrenal tumors 1
Clinical Presentation
Approximately 95% of patients present with hypertension, with equal distribution between sustained and paroxysmal patterns 2, 3
The classic triad of headache, palpitations, and episodic profuse sweating has 90% diagnostic specificity 2
Additional symptoms include pallor, apprehension, anxiety, and increased blood pressure variability which independently increases cardiovascular morbidity and mortality risk 1, 3
A critical diagnostic challenge is that the average time from initial symptoms to diagnosis is approximately 3 years, and many cases are completely missed, with 75% not suspected during life 3
Epidemiology and Prevalence
Pheochromocytomas account for approximately 4% of adrenal incidentalomas, with higher prevalence in autopsy series 1
The prevalence ranges from 0.01-0.2% in the general hypertensive population but increases to 4% in patients with resistant hypertension 2
Hereditary Nature
Approximately 35% of pheochromocytomas are hereditary, representing one of the highest rates of genetic predisposition among solid tumors 1, 2, 3
Associated genetic syndromes include multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), and succinate dehydrogenase (SDH) mutations 2
Ten susceptibility genes have been identified: SDHB, SDHC, SDHD, SDHAF2, SDHA, VHL, RET, NF1, TMEM127, and MAX 1
SDHB mutations carry particularly high malignancy risk, estimated between 31% to 71%, requiring lifelong monitoring 1, 2
Malignancy Potential
Most pheochromocytomas are benign and progress slowly, but metastasization rates range widely from less than 1% to more than 60% depending on tumor location, size, and genetic background 1
Malignancy is defined only by the presence of metastatic lesions at sites where chromaffin cells are normally absent 4
Risk factors for malignancy include tumor size ≥5 cm, extra-adrenal location (paraganglioma), SDHB germline mutation, and elevated plasma methoxytyramine (>3x upper limit) 4, 3
A PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score of ≥4 indicates higher risk requiring extended monitoring 1
Diagnostic Approach
Plasma free metanephrines have the highest sensitivity (96-100%) and specificity (89-98%) for diagnosis 2, 3
If plasma testing is equivocal, 24-hour urine collection for fractionated metanephrines and catecholamines should follow 4
Abdominal CT or MRI should be performed for tumor localization after biochemical confirmation, with MRI preferred over CT due to risk of hypertensive crisis with IV contrast 2
Functional imaging with 123I-MIBG scintigraphy helps detect multifocal disease 4
Critical Clinical Caveat
Biopsy carries high risk of hypertensive crisis and tachyarrhythmia and should only be performed after pheochromocytoma is biochemically ruled out 1
This is particularly important when evaluating retroperitoneal extraadrenal masses where differential diagnosis includes lymph node metastases and other tumors 1