Pheochromocytoma

Phaeochromocytomas are an uncommon tumour of the adrenal gland, with characteristic clinical, and to a lesser degree, imaging features. The tumours are said to follow a 10% rule:

• ~10% are extra-adrenal

• ~10% are bilateral

• ~10% are malignant

• ~10% are found in children

• ~10% are notassociated with hypertension

• ~10% contain calcification

Epidemiology

The estimated prevalence of phaeochromocytomas in hypertensive adults is thought to range from 0.1 to 0.6%. The incidence in the general population is believed to be around 0.05% based on autopsy series ⁹.

Associations

The majority of cases are sporadic. In 25% of cases, a phaeochromocytoma is a manifestation of an underlying condition, often familial, including ^1-4,6:

• multiple endocrine neoplasia type II (MEN2): both MEN IIa and MEN IIb

  • account for 3% of all phaeochromocytomas

  • almost never extra-adrenal

  • almost always bilateral ⁴

• von Hippel-Lindau disease

• neurofibromatosis type 1

• Sturge-Weber syndrome

• Carney triad: for extra-adrenal phaeochromocytoma

• tuberous sclerosis

• familial phaeochromocytoma

Clinical presentation

It is a rare but classical cause of uncontrolled secondary hypertension, with a minority having superimposed paroxysmal hypertensive crises ¹¹. Patients may also present with cardiac dysfunction (myocardial infarction, pulmonary oedema) or neurological events (severe headache, visual disturbance, haemorrhagic strokes) ⁵.

The first investigation in cases where phaeochromocytoma is suspected is usually 24-hour urinary or plasma metanephrines, metabolites of noradrenaline and adrenaline ^19,20. When results are positive, imaging is then performed to try and localise the tumour or tumours.

Pathology

Microscopic appearance

Phaeochromocytomas are a type of paraganglioma. They are catecholamine-secreting tumours derived from chromaffin cells. They typically demonstrate a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumour cells containing eosinophilic cytoplasm separated by a fibrovascular stroma. Various pathological scoring systems are in use (PASS, GAPP) to predict differentiation and the likelihood of metastasis ¹⁵.

Location

They most frequently arise from the chromaffin cells of the adrenal medulla.

Approximately 10% of all phaeochromocytomas are not located in the adrenal glands. Extra-adrenal tumours are more likely to be malignant and metastasise ⁴.

They can be found along the sympathetic chain as well as in the urinary bladder and organ of Zuckerkandl. Thoracic paragangliomas are rare and only account for 1-2% of all cases of phaeochromocytoma.

Radiographic features

As a general rule, tumours in the adrenal region tend to be large at presentation, usually >3 cm, with an average size of approximately 5~5 cm²². When confined to the adrenal glands, and especially if suspected clinically, the diagnosis is readily made. Small extra-adrenal tumours can, however, be a challenge to find. Overall 98% of tumours are in the abdomen, and 90% are confined to the adrenal glands ⁶.

It is also important to note that it is not possible to distinguish malignant from benign phaeochromocytomas merely on the direct appearance of the mass. Rather, the distinction is made on demonstrating evidence of direct tumour invasion into adjacent organs/structures or the presence of metastases ⁴.

Ultrasound

Phaeochromocytomas can have a variable appearance ranging from solid to mixed cystic and solid to cystic ⁹.

CT

CT is the first imaging modality to be used, with an overall sensitivity of 89%. This is on account of 98% of tumours being located within the abdomen and 90% limited to the adrenal glands ⁶.

• usually large (4-6 cm), heterogeneous masses with areas of necrosis and cystic change^21,22

• density always >10 HU ²²

• they typically enhance avidly ⁸

  • one-third may wash out similar to an adrenal adenoma, but they tend to have a greater enhancement in an arterial or portal venous contrast phase. There is, however, overlap with some hyperenhancing adenomas

  • tend to enhance more on the portal venous phase than the arterial phase

  • 110-120 HU of enhancement on the arterial phase suggests phaeochromocytoma, but is not specific; hypervascular metastases could be considered in an appropriate setting

• up to10% (range 7-12%) demonstrate areas of calcification ^4,21

It should be noted that suspected cases of phaeochromocytomas have been historically managed as a contraindication for iodinated contrast administration, as it could theoretically precipitate a hypertensive crisis. However, studies have shown no evidence to support this theory and nowadays most radiology non-ionic iodinated contrast media guidelines do not place phaeochromocytomas as a contraindication to iodinated contrast administration ^13,16,21.

MRI

MRI is the most sensitive modality for the identification of phaeochromocytomas and is particularly useful in cases of extra-adrenal location. The overall sensitivity is said to be 98% ⁶.

• T1

  • slightly hypointense to the remainder of the adrenal

  • if necrotic and/or haemorrhagic then the signal will be more heterogeneous

• T2

  • some are markedly hyperintense (lightbulb sign)

  • ~1/3 do not have marked T2 hyperintensity ¹⁸

  • areas of necrosis/haemorrhage/calcification will alter the signal

• in/out-of-phase: no signal loss on out-of-phase imaging (phaeochromocytomas rarely contain a significant amount of intracellular lipid) ¹²

• T1 C+ (Gd)

  • heterogeneous enhancement

  • enhancement is prolonged, persisting for as long as 50 minutes ⁴

Nuclear medicine

Some agents can be used to attempt to image phaeochromocytomas and are especially useful in trying to locate an extra-adrenal tumour (when CT of the abdomen is negative) or metastatic deposits. Unfortunately, these agents are not very specific for phaeochromocytomas and have a limited spatial resolution, usually requiring the tumour to be >1 cm in diameter.

Octreotide (somatostatin) scans

Over 70% of tumours express somatostatin receptors. Imaging is obtained 4 hours (+/- 24/48 hours) after an intravenous infusion. Unfortunately, the kidney also has somatostatin receptors, as do areas of inflammation, mammary glands, liver, spleen, bowel, gallbladder, thyroid gland, and salivary glands. As such, interpretation can be difficult ⁵.

Octreotide is usually labelled with either ¹¹¹In-DTPA (Octreoscan) or (less commonly) ¹²³I-Tyr3-DTPA ⁵.

I-123 MIBG (metaiodobenzylguanidine)

I-123 MIBG uptake in an adrenal nodule is strong supporting evidence for a phaeochromocytoma. Overall sensitivity is ~80% ⁶. However, as many neuroendocrine tumours demonstrate uptake with MIBG, it is not as specific for phaeochromocytoma outside of the adrenal.

PET

18F-DOPA PET is thought to be highly sensitive according to initial results ³. Gallium-68 DOTATATE PET-CT imaging has also been advocated due to their higher lesion to background tissue contrast and high specificity for phaeochromocytoma ¹⁴. 

18F-FDOPA (6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine)-based PET-CT imaging can also be a useful tool in diagnosis ¹⁷.

Treatment and prognosis

Definitive treatment is surgical, and if complete resection is achieved, without metastases, then surgery is curative and hypertension usually resolves.

Preoperative medical management is essential in reducing the risk of an intraoperative hypertensive crisis and typically consists of non-competitive alpha-adrenergic blockade (e.g. phenoxybenzamine). Later, but never before completing 7-10 days of alpha blockade, a beta-blocker may need to be added to control tachycardia or some arrhythmias ^5,6.

Metastases from malignant phaeochromocytomas typically spread to the lung, bone, and liver ⁴.

Differential diagnosis

When located in the adrenal gland, the differential is essentially that of an adrenal tumour and includes:

• lipid poor adrenal adenoma: also washes out, but often <120 HU on an arterial or portal venous contrast phase

  • biochemical testing is useful to help differentiate

• adrenal cortical carcinoma

• adrenal metastasis

Differentiating large tumours, from renal cell carcinomas can be difficult, especially malignant ones and especially on CT.

Practical points

• clinical suspicion is almost always present before imaging: secondary hypertension and positive urinary catecholamines

• usually large and heterogeneous adrenal masses, with cystic and necrotic components 

• vivid enhancement in arterial/portal venous phase is suggestive: >110-120 HU