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Pheochromocytomas are an uncommon tumor of the adrenal gland, with characteristic clinical, and to a lesser degree, imaging features. The tumors are said to follow a 10% rule:
~10% are extra-adrenal
~10% are bilateral
~10% are malignant
~10% are found in children
~10% are not associated with hypertension
~10% contain calcification
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The estimated prevalence of pheochromocytomas in hypertensive adults is thought to range from 0.1-0.6%. The incidence in the general population is believed to be around 0.05% based on autopsy series 9.
The majority of cases are sporadic. In 25% of cases, a pheochromocytoma 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 pheochromocytomas
almost never extra-adrenal
almost always bilateral 4
Carney triad: for extra-adrenal pheochromocytoma
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 edema) or neurological events (severe headache, visual disturbance, hemorrhagic strokes) 5.
The first investigation in cases where pheochromocytoma is suspected is usually 24-hour urinary or plasma metanephrines, metabolites of norepinephrine and epinephrine 19,20. When results are positive, imaging is then performed to try and localize the tumor or tumors.
They most frequently arise from the chromaffin cells of the adrenal medulla.
Approximately 10% of all pheochromocytomas are not located in the adrenal glands. Extra-adrenal tumors are more likely to be malignant and metastasize 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 pheochromocytoma.
Pheochromocytomas are a type of paraganglioma. They are catecholamine-secreting tumors derived from chromaffin cells. They typically demonstrate a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor 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.
As a general rule, tumors in the adrenal region tend to be large at presentation, usually >3 cm, with an average size of ~5 cm 22. When confined to the adrenal glands, and especially if suspected clinically, the diagnosis is readily made. Small extra-adrenal tumors can, however, be a challenge to find. Overall 98% of tumors 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 pheochromocytomas merely on the direct appearance of the mass. Rather, the distinction is made on demonstrating evidence of direct tumor invasion into adjacent organs/structures or the presence of metastases 4.
Pheochromocytomas can have a variable appearance ranging from solid to mixed cystic and solid to cystic 9.
CT is the first imaging modality to be used, with an overall sensitivity of 89%. This is on account of 98% of tumors 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, 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 pheochromocytoma, but is not specific; hypervascular metastases could be considered in an appropriate setting
10% (range 7-12%) demonstrate areas of calcification 4,21
It should be noted that suspected cases of pheochromocytomas 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 pheochromocytomas as a contraindication to iodinated contrast administration 13,16,21.
MRI is the most sensitive modality for the identification of pheochromocytomas and is particularly useful in cases of extra-adrenal location. The overall sensitivity is said to be 98% 6.
slightly hypointense to the remainder of the adrenal
if necrotic and/or hemorrhagic then the signal will be more heterogeneous
some are markedly hyperintense (lightbulb sign)
~1/3 do not have marked T2 hyperintensity 18
areas of necrosis/hemorrhage/calcification will alter the signal
in/out-of-phase: no signal loss on out-of-phase imaging (pheochromocytomas rarely contain a significant amount of intracellular lipid) 12
T1 C+ (Gd)
enhancement is prolonged, persisting for as long as 50 minutes 4
Some agents can be used to attempt to image pheochromocytomas and are especially useful in trying to locate an extra-adrenal tumor (when CT of the abdomen is negative) or metastatic deposits. Unfortunately, these agents are not very specific for pheochromocytomas and have a limited spatial resolution, usually requiring the tumor to be >1 cm in diameter.
Octreotide (somatostatin) scans
Over 70% of tumors 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 labeled 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 pheochromocytoma. Overall sensitivity is ~80% 6. However, as many neuroendocrine tumors demonstrate uptake with MIBG, it is not as specific for pheochromocytoma outside of the adrenal.
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 pheochromocytoma 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 pheochromocytomas typically spread to the lung, bone, and liver 4.
When located in the adrenal gland, the differential is essentially that of an adrenal tumor 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
Differentiating large tumors, from renal cell carcinomas can be difficult, especially malignant ones and especially on CT.
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
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