History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors include multiple endocrine neoplasia syndrome, Von Hippel-Lindau syndrome, gemline mutations in the succinate dehydrogenase [SDH] subunit B, C, and D genes, and neurofibromatosis type 1.

headache

Variable in intensity and duration; occurring in up to 90% of symptomatic patients.[49]

palpitations

Typically episodic and may be associated with tachycardia. Occurs in 60% of cases.

diaphoresis

Generalised, and occurs in up to 60% to 70% of patients.[49]

hypertension

Sustained or paroxysmal hypertension is the most common sign seen in up to 95% of cases.[47]

Paroxysmal hypertension occurs in about 45% of cases and can be on a background of sustained hypertension.[47] Paroxysms can be induced by multiple factors including exercise, anxiety, certain foods, medications, intravenous contrast, and surgery; however, the majority of attacks are unpredictable.[47]

Phaeochromocytomas may present with life-threatening acute hypertensive emergencies (e.g., encephalopathy), as well as clinical consequences of long-lasting hypertension (e.g., retinopathy, proteinuria).[47]

hypertensive retinopathy

Related to uncontrolled hypertension.

pallor

Can be attributed to intense alpha-mediated vasoconstriction of the dermal vasculature and is usually episodic.

impaired glucose tolerance/diabetes mellitus

Not uncommon, as hypercatecholaminaemia causes increased glycogenolysis and inhibits insulin secretion.[8] Glucose intolerance and diabetes may resolve after removal of the tumour.[9]

uncommon

family history of endocrine disorders

Important to elicit any family history of phaeochromocytomas, medullary thyroid cancer, hypertensive crises, hypercalcaemic disorders, or endocrine tumour development.

history of prior phaeochromocytoma

Would mandate regular follow-up, as the risk of recurrence can be high, especially with hereditary disorders.

tachyarrhythmias and myocardial infarction

Related to catecholamine stimulation of beta-adrenergic receptors.

panic attacks or a 'sense of doom'

Patients may present with episodic panic attack-like symptoms. These are commonly seen in adrenaline-producing phaeochromocytomas.[13]

Other diagnostic factors

common

orthostatic hypotension

This is thought to be due to volume contraction secondary to alpha-adrenergic stimulation.

uncommon

hypercalcaemia

Patients with phaeochromocytomas related to multiple endocrine neoplasia 2 syndrome may also have primary hyperparathyroidism, which can lead to hypercalcaemia.

Cushing syndrome

May develop secondary to ectopic adrenocorticotropic hormone (ACTH) or corticotrophin-releasing hormone production from the phaeochromocytoma.[50][51]

diarrhoea

A secretory diarrhoea may develop secondary to ectopic production of vasoactive intestinal peptide in patients with phaeochromocytomas.[52]

fever

Patients may present with fever of unknown origin.[53]

papilloedema

Secondary to severe and prolonged hypertension.

abdominal masses

Phaeochromocytomas and non-functional intra-abdominal paragangliomas are typically large when diagnosed.

tremors

Related to sympathetic overactivity from high catecholamine production by these tumours.

Risk factors

strong

Multiple endocrine neoplasia type 2 (MEN2)

Phaeochromocytoma risk is 50% in both MEN2A and MEN2B, the two subtypes of MEN2.[28]

MEN2A tumours are frequently bilateral. Approximately 50% of MEN2A patients are asymptomatic at diagnosis; only one third present with hypertension.[29]

MEN2, a hereditary cancer syndrome, arises from several RET proto-oncogene mutations. Both subtypes are associated with very high risk for medullary thyroid cancer (>95%); individuals with MEN2A are at increased risk for parathyroid hyperplasia or adenoma.[30]

Von Hippel-Lindau (VHL) disease

In those with VHL disease, lifetime risk is 10% to 20%.[31][32]

Other manifestations include renal cell carcinoma and haemangioblastoma, in the retina or CNS as well as renal and pancreatic cysts.[33]​ VHL disease results from a germline mutation in the VHL suppressor gene.[34]

succinate dehydrogenase (SDH) subunit B, C, and D gene mutations

Germline mutations in succinate dehydrogenase genes (SDHB, SDHC, SDHD) are reported in approximately 20% of patients with a diagnosis of phaeochromocytoma or paraganglioma (PPGL).[35][36]​​

Carriers of the SDH-B or -D gene mutations are more likely to have malignant disease.[37]​ SDH mutations are common in head and neck paraganglioma.[38]

weak

neurofibromatosis type 1 (NF1)

Phaeochromocytoma has been reported in 0.1% to 14.6% of patients with NF1.[39][40][41]​​​​​ 

Retrospective analyses suggest that patients with NF1 may have significantly smaller phaeochromocytoma, and less hypertension, than other patients treated for phaeochromocytoma.[42]

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