malignes Phäochromozytom

malignes Phäochromozytom

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 familial
• ~10% are not associated with hypertension
• ~10% contain calcification

Epidemiology

The estimated prevalence of pheochromocytomas 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.

Associations

The majority of cases are sporadic. In 5-10% of cases, a pheochromocytoma is a manifestation of an underlying condition including :

• multiple endocrine neoplasia type II (MEN II): both MEN IIa and MEN IIb
  • account for 3% of all pheochromocytomas
  • almost never extra-adrenal
  • almost always bilateral
• von Hippel-Lindau disease
• von Recklinghausen disease (neurofibromatosis type I)
• Sturge-Weber syndrome
• Carney triad: for extra-adrenal pheochromocytoma
• tuberous sclerosis
• familial pheochromocytoma

Clinical presentation

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

The first investigation in cases where pheochromocytoma is suspected is usually urinary catecholamines. When those results are positive, then imaging is performed to try and localize the tumor or tumors.

Pathology

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 likelihood of metastasis .

Location

Adrenal

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

Extra-adrenal locations

Approximately 10% of all pheochromocytomas are not located in the adrenal glands. Extra-adrenal tumors are more likely to be malignant and metastasize .

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.

Radiographic features

As a general rule, tumors in the adrenal region tend to be large at presentation, usually >3 cm, with an average size of approximately 5 cm. 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 .

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 .

Ultrasound

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

CT

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 .

• usually large, heterogeneous masses with areas of necrosis and cystic change
• they typically enhance avidly
  • may wash out similar to an adrenal adenoma, but they tend to have a greater enhancement in an arterial or portal venous contrast phase
  • tend to enhance more on the portal venous phase than the arterial phase
  • 110 HU of enhancement on the arterial phase is compatible with pheochromocytoma; hypervascular metastases could be considered in an appropriate setting
• up to 7% demonstrate areas of calcification

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 put pheochromocytomas as a contraindication .

MRI

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

• T1
  • slightly hypointense to the remainder of the adrenal
  • if necrotic and/or hemorrhagic then the signal will be more heterogeneous
• T2
  • markedly hyperintense (lightbulb sign): this is a helpful feature
    • ~ 1/3 do not have marked T2 hyperintensity
  • areas of necrosis/hemorrhage/calcification will alter the signal
• in-phase/out-of-phase: no signal loss on out-of-phase imaging (pheochromocytomas do not contain a large amount of intracellular lipid)
• T1 C+ (Gd)
  • heterogeneous enhancement
  • enhancement is prolonged, persisting for as long as 50 minutes

Nuclear medicine

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 .

Octreotide is usually labeled with either In-DTPA (Octreoscan) or (less commonly) I-Tyr3-DTPA .

I-123 MIBG (metaiodobenzylguanidine)

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

PET

18F-Dopa PET is thought to be highly sensitive according to initial results . Galium-68 DOTATATE PET/CT imaging has also been advocated due to their higher lesion to background tissue contrast and high specificity for pheochromocytoma .

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

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 intraoperative hypertensive crises and typically consists of the non-competitive alpha-adrenergic blockade (e.g. phenoxybenzamine). Later, but never before 7-10 days of alpha blockade, a beta-blocker may need to be added to control tachycardia or some arrhythmias .

Metastases from malignant pheochromocytomas are typical to the lung, bone and liver .

Differential diagnosis

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

• adrenal adenoma: also washes out, but <120 HU on an arterial or portal venous contrast phase
• adrenal carcinoma
• adrenal metastasis(es)

In large tumors, especially if malignant, differentiating them from renal cell carcinomas can be difficult, especially on CT images.

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 of arterial/portal venous phase: >110-120 HU