Phaeochromocytoma

Phaeochromocytoma is a catecholamine secreting tumor arising from chromaffin cells of the adrenal medulla.

When an analogous tumor arises from extra-adrenal sympathetic paraganglia rather than the adrenal medulla itself, it is termed a paraganglioma, and the two are often considered together given their shared biology and clinical presentation.

A meaningful proportion of cases, more than historically appreciated, arise in the context of an underlying hereditary syndrome, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and hereditary paraganglioma syndromes from succinate dehydrogenase gene mutations, which is why genetic counseling and testing is now recommended for essentially all patients diagnosed with a phaeochromocytoma or paraganglioma, regardless of whether an obvious family history is present.

The classic presentation is paroxysmal, with episodic symptoms from a surge of catecholamine release, though a substantial proportion of patients have persistent, sustained hypertension rather than a purely episodic pattern, and a smaller proportion are entirely asymptomatic, with the tumor identified incidentally on imaging performed for another reason.

The classic paroxysmal triad consists of episodic headache, sweating, and palpitations, often accompanied by a sense of anxiety or impending doom, pallor, and a significant surge in blood pressure during the episode. Episodes may be triggered by specific factors, including certain medications, abdominal palpation, or, notably, induction of anesthesia, which is part of why the diagnosis should be actively considered and excluded before any planned surgery on a patient with an incidentally discovered adrenal mass.

Hypertension, whether paroxysmal or sustained, is a near universal feature and is often resistant to standard antihypertensive therapy, which should prompt consideration of a secondary cause, including phaeochromocytoma, particularly in a younger patient or one with other suggestive features.

Biochemical testing is the first step and should precede any imaging, since imaging findings, particularly incidentally discovered adrenal masses, are common in the general population and non-specific without biochemical confirmation of catecholamine excess.

Plasma free metanephrines or 24 hour urinary fractionatedmetanephrines are the preferred initial tests, offering high sensitivity for catecholamine excess, since metanephrines are continuously produced within the tumor regardless of the episodic nature of catecholamine release itself, making them more reliable than measuring catecholamines directly, which can be normal between paroxysmal episodes.

Certain medications and circumstances can cause false positive results, and a careful review of medications (including certain antidepressants and other agents affecting catecholamine metabolism or measurement) and consideration of the testing conditions (ideally with the patient supine and rested, avoiding caffeine and strenuous exercise beforehand) is important when interpreting borderline results.

Once biochemical confirmation is obtained, CT or MRI of the abdomen localizes the tumor, with MRI often preferred, particularly in younger patients given the avoidance of radiation, and given its good sensitivity for adrenal and extra-adrenal disease. MIBG scintigraphy or, increasingly, PET imaging with specific tracers, provides functional confirmation and is particularly useful for localizing extra-adrenal paragangliomas or identifying metastatic disease, which occurs in a meaningful minority of cases and cannot be reliably predicted from histology alone.

Genetic testing, as noted above, is recommended for essentially all confirmed cases, given the substantial proportion of hereditary disease and the implications for the patient's own surveillance for other syndrome associated tumors as well as for family screening.

Differentials include other causes of paroxysmal hypertension and episodic symptoms, including panic disorder (see that entry), hyperthyroidism, and, importantly, other causes of an incidentally discovered adrenal mass without catecholamine excess (adrenal adenoma, adrenal cortical carcinoma, metastasis), which is why biochemical exclusion of a phaeochromocytoma is a standard part of the workup for any incidentally discovered adrenal mass.

Surgical resection is the definitive treatment and offers the potential for cure in localized disease, but must never be undertaken without adequate preoperative alpha blockade, given the risk of a catastrophic hypertensive crisis if the tumor is manipulated during surgery before adrenergic blockade is established.

Alpha blockade, typically with phenoxybenzamine or a selective alpha-1 blocker such as doxazosin, is started at least one to two weeks before planned surgery and titrated to achieve adequate blood pressure control, alongside a liberalized salt and fluid intake to counteract the volume contraction that chronic catecholamine excess causes, given the risk of significant hypotension once the tumor is removed and the catecholamine surge ceases.

Beta blockade is added only after adequate alpha blockade has been established, never before, since beta blockade in the presence of unopposed alpha adrenergic stimulation can precipitate a severe hypertensive crisis from unopposed vasoconstriction, an important and specific sequencing principle in the preoperative preparation of these patients.

Intraoperative and immediate postoperative management requires close hemodynamic monitoring, given the potential for significant blood pressure swings both during tumor manipulation and immediately after its removal.

Metastatic or unresectable disease is managed with a combination of continued alpha and beta blockade for symptom and blood pressure control, alongside systemic therapy directed at the tumor itself, which may include MIBG targeted radionuclide therapy for MIBG avid disease, or chemotherapy, guided by specialist endocrine oncology input.

Lifelong follow up, including periodic biochemical testing, is recommended after resection given the risk of recurrence or metachronous disease, particularly in patients with an identified hereditary syndrome.

Referral: endocrinology for diagnosis and perioperative medical management; endocrine surgery for resection; genetic counseling for all confirmed cases given the substantial hereditary component.