What is pheochromocytoma, a tumor of the adrenal gland affecting adults, particularly those with a family history of genetic disorders such as multiple endocrine neoplasia type 2 (MEN2) or von Hippel-Lindau disease?

What is Pheochromocytoma

Pheochromocytoma is a rare catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla that causes hypertension and characteristic symptoms through excessive secretion of epinephrine and norepinephrine. 1

Tumor Origin and Classification

• Pheochromocytomas originate specifically from chromaffin cells within the adrenal medulla 1, 2
• When similar tumors arise from extra-adrenal chromaffin tissue (paraganglia), they are termed paragangliomas, leading to the combined designation of pheochromocytomas and paragangliomas (PPGLs) 1
• Extra-adrenal paragangliomas can occur anywhere along the sympathetic chain from the skull base to the pelvis, with sympathetic paragangliomas typically producing catecholamines while parasympathetic head and neck paragangliomas are usually non-functional 1

Epidemiology and Prevalence

• The incidence is extremely rare at 2-8 cases per million people per year in the general population 1
• Among hypertensive patients, prevalence ranges from 0.01-0.2%, but increases to approximately 4% in patients with resistant hypertension 3, 2
• These tumors can occur at any age with equal gender distribution, though hereditary cases typically present earlier than sporadic disease 4

Genetic and Hereditary Aspects

• Approximately 35% of all pheochromocytomas are hereditary, making genetic screening essential for all patients with confirmed disease 1, 2
• The major hereditary syndromes include multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and succinate dehydrogenase (SDH) gene mutations 1, 2, 4
• Ten susceptibility genes have been identified, including SDHB, SDHC, SDHD, SDHAF2, SDHA, VHL, RET, NF1, TMEM127, and MAX 1
• SDHB mutations carry the highest malignancy risk (31-71%) and require lifelong intensive surveillance 1
• Familial cases demonstrate autosomal dominant transmission and are more frequently bilateral and recurring compared to sporadic cases 5

Clinical Manifestations

• The classic triad of headache, palpitations, and sweating occurring episodically has 90% diagnostic specificity and 93.8% sensitivity 3, 2
• Approximately 95% of patients present with hypertension, which can be sustained (50% of cases) or paroxysmal (50% of cases) 2, 6
• Additional symptoms include pallor, anxiety, weight loss, and diabetes resulting from catecholamine excess 6, 5
• The presentation is highly variable and can mimic many other conditions including panic attacks, making diagnosis challenging 5
• Pheochromocytomas can cause life-threatening hypertensive crises requiring specific management before any surgical or diagnostic intervention 1

Pathophysiology and Hormone Production

• These tumors produce, store, and secrete excessive amounts of catecholamines including epinephrine, norepinephrine, and dopamine, along with their metabolites metanephrine, normetanephrine, and methoxytyramine 7
• The clinical effects result from stimulation of alpha- and beta-adrenergic receptors by these catecholamines 5
• Catecholamine excess impacts both short-term survival and quality of life, requiring specific treatments to block hormonal effects 1

Malignancy Potential

• Approximately 10% of pheochromocytomas are malignant, diagnosed by the presence of lymph node, visceral, or bone metastases 5
• Malignancy risk is higher with SDHB mutations, large tumors (≥5 cm), and extra-adrenal location 1, 5
• A PASS (Pheochromocytoma of the Adrenal gland Scaled Score) ≥4, large primary tumor size, and SDHB mutation should trigger extended lifelong monitoring 3

Diagnostic Approach

• All patients with suspected pheochromocytoma must undergo biochemical confirmation before any intervention, as unrecognized tumors can cause fatal hypertensive crises 3
• Plasma free metanephrines provide the highest sensitivity (96-100%) and specificity (89-98%) for diagnosis 3, 2
• 24-hour urinary fractionated metanephrines offer an acceptable alternative with sensitivity of 86-97% and specificity of 86-95% 3
• Fine needle biopsy of suspected pheochromocytoma is absolutely contraindicated due to risk of precipitating hypertensive crisis 3
• Following biochemical confirmation, anatomical localization uses CT or MRI, with MRI preferred to avoid hypertensive crisis from IV contrast 3, 2

Treatment Principles

• All patients require preoperative alpha-adrenergic blockade for at least 10-14 days before surgery to prevent intraoperative hypertensive crises 2, 8
• Complete surgical resection (R0 resection) is the only potentially curative treatment and should be performed only in specialized centers 2
• Laparoscopic adrenalectomy is the preferred surgical approach for benign disease 6, 7
• All patients with suspected or proven pheochromocytoma should be discussed in a multidisciplinary expert team meeting at initial diagnosis (ideally before surgery) and with progressive disease 1

Follow-up and Surveillance

• Biochemical testing should be performed 8-14 days post-operatively to confirm complete resection 2
• Patients require indefinite follow-up, especially those with familial disease, extra-adrenal tumors, or SDHB mutations 2, 5
• For hereditary pheochromocytoma/paraganglioma syndromes, surveillance should begin at age 6-8 years, while VHL syndrome surveillance starts at age 2 years 3