Pheochromocytoma

Description

Phaeochromocytoma is a rare, predominantly benign, neuroendocrine tumour arising from the chromaffin cells of the adrenal medulla, which synthesises and releases catecholamines. This can lead to hypertension and other cardiovascular complications.

Pathogenesis

The exact cause of sporadic phaeochromocytomas remains unclear. However, there is a known genetic component, as these tumours may occur as a feature of various familial syndromes, including Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis type 1 (NF1), Von Hippel-Lindau disease, and familial paraganglioma syndromes.

Epidemiology, Risk Factors & Associations

• Pheochromocytoma is a rare condition with an incidence of about 2-8 cases per million each year.
• Can occur at any age, with peak incidence in the fourth to fifth decades of life.
• A familial association exists, with 30-40% of cases being attributed to genetic causes.
• 25% of patients with sporadic pheochromocytomas are carriers of gene mutations.
• Associated with several syndromes including:
  • Multiple Endocrine Neoplasia type 2 (MEN2) – Includes medullary thyroid carcinoma and hyperparathyroidism. Most common of the associated syndromes.
  • Neurofibromatosis type 1 (NF1) (up to 6% of patients with NF1) – Characterised by changes in skin colouring and growth of tumours along nerves in the skin, brain, and other parts of the body
  • Von Hippel-Lindau disease (VHL)
  • Familial paraganglioma syndromes – Genetic conditions causing paragangliomas, similar tumours that originate in nerve tissue). SDHB mutation.
  • Sturge-Weber
  • Tuberous Sclerosis
  • Carney Triad

Classic teaching (Rule of 10’s):

• 10% extraadrenal (paraganglioma)
• 10% bilateral
• 10% silent
• 10% malignant
• 10% extra-abdominal
• 10% familial
• 10% paediatric
• 10% autosomal dominant transmission

Clinical Features

The classic triad of symptoms, due to the effects of secreted catecholamines, includes episodic headache, diaphoresis, and tachycardia. Other symptoms include hypertension, palpitations, and pallor.

Complications

Potential complications include hypertensive emergency, cardiomyopathy, arrhythmias, stroke, and acute pulmonary oedema.

Metastatic disease is seen in 10% of all pheochromocytomas:

• Lymph nodes (70%): The most common site of metastasis.
• Liver (50%)
• Bone (40%)
• Lung (30%)

Subtypes

There are no specific subtypes of phaeochromocytoma, but it’s worth noting that related paragangliomas can occur at extra-adrenal locations.

Pathological Features

Histopathology

• Typically composed of cells with abundant granular cytoplasm, arranged in nests (zellballen pattern) surrounded by a rich vascular network.
• Nuclei have salt and pepper chromatin

Biochemistry

The diagnosis of phaeochromocytoma is typically confirmed by demonstrating elevated levels of plasma or urinary metanephrines, which are metabolites of catecholamines.

• Plasma-free metanephrines: First-line test for the diagnosis. A normal level practically excludes the diagnosis of a phaeochromocytoma, while markedly elevated levels (>4 times upper limit of normal) provides strong evidence.
• 24-hour urine collection for metanephrines and catecholamines: Highly sensitive and specific, and may be used in conjunction with plasma testing.
• Plasma catecholamines: Plasma norepinephrine and epinephrine levels can be measured, but they are less sensitive than metanephrines.
• Chromogranin A: This protein can be elevated in patients with neuroendocrine tumours, including pheochromocytomas. However, it is less specific and sensitive than metanephrine measurements.

Genetics

• Genetic mutations in RET, NF1, VHL, and SDHx genes are known to be associated with familial phaeochromocytoma.

Radiological Features

General Features

• Location: Primarily adrenal medulla, but extra-adrenal paragangliomas can occur.
• Morphology: Typically a well-defined, round to oval mass.
• Usually solid but can be cystic or contain calcium, haemorrhage, and fat.

CT

Non-contrast

• Typically shows a well-defined, round to oval adrenal mass, often larger than 3 cm.
• Density usually low/soft tissue (usually HU > 40 but almost always > 10)
• The lesion may be heterogeneous due to necrosis, haemorrhage, or cystic degeneration.
• A fluid-fluid level may be seen within the cystic component
• Mural calcification is sometimes seen

Post-contrast

• Early arterial phase (approx. 30 secs): Intense enhancement of solid components due to high vascularity.
• Portal venous phase (approx. 70 secs): Begins to washout.
• Delayed phase (approx. 15 mins): Significant washout of contrast, with tumour appearing hypodense compared to liver.
• After intravenous contrast, avid enhancement of the solid components and slow washout.

MRI

• T1: Hypo- to isointense relative to liver, isointense to muscle. Heterogenous signal may indicate areas of haemorrhage or necrosis.
• T2: Hyperintense due to high water content (light bulb sign). Low T2 signal does not exclude phaeochromocytoma. Heterogenous salt-and-pepper appearance due to tumour vascularity where salt represents parenchyma and pepper represents flow void of vessels.
• Post-contrast: Shows intense enhancement in the early phase or heterogenous salt-and-pepper enhancement. Enhancement may be prolonged. Substantial washout in the delayed phase.
• DWI: Generally not useful for differentiating tumour
• In/out-of-phase: No signal loss on out-of-phase imaging as pheochromocytomas rarely contain a significant amount of intracellular lipid

PET

• MIBG scintigraphy: Metaiodobenzylguanidine (MIBG) is a compound similar to noradrenaline, which is taken up by adrenergic tissues such as pheochromocytomas. Radiolabelled MIBG, usually with iodine-123, has a sensitivity and specificity of over 90% for pheochromocytoma.
• PET: Positron Emission Tomography scanning with gallium-68 DOTA peptides (such as DOTATATE) or fluorine-18 FDG can be used for tumour localisation and staging. These tests are particularly useful for detecting metastatic or recurrent disease as neuroendocrine tumours express somatostatin receptors.
• Somatostatin receptor scintigraphy: Also known as Octreoscan, this is used less commonly but can detect tumours with somatostatin receptors. This may be useful in patients with metastatic disease, in whom other imaging modalities have been inconclusive.

Grading and Staging

There is no formal staging system for phaeochromocytoma. However, the presence of local invasion or metastasis usually indicates malignancy.

Diagnosis

Biopsy is contraindicated and may precipitate hypertensive crisis.

Differential Diagnosis

• Adrenal Adenoma: These are benign tumours that can produce hormones, though vast majority are non-functional. May not present with classic symptoms of catecholamine excess. Often shows lipid-rich characteristics (low HU on CT). May not enhance significantly after contrast administration.
• Adrenal Cortical Carcinoma: Malignant adrenal gland tumours. Often large size at presentation, and they may produce different hormones like corticosteroids. Frequently large and heterogeneous with necrosis and haemorrhage on imaging. Calcification is a common feature.
• Renal Cell Carcinoma: Originates from the kidneys but might be confused if the mass is at the upper pole of the kidney. It doesn’t produce catecholamines and typically presents with haematuria or flank pain. It tends to enhance earlier in the corticomedullary phase due to its vascular nature
• Adrenal Metastases: Adrenal glands are common sites for metastases from lung, breast, and melanoma primaries. They generally don’t produce catecholamines. History of a primary malignancy can guide diagnosis. Often bilateral and heterogeneous with irregular margins. Contrast enhancement pattern may depend on the primary tumour type.
• Paragangliomas: These are extra-adrenal pheochromocytomas. Located along the paravertebral axis from the base of the skull to the pelvis. Functioning tumours will still produce symptoms of catecholamine excess. Typically show intense and prolonged contrast enhancement on CT/MRI due to their hypervascularity.
• Adrenal Myelolipoma: Small benign lesion with no malignant potential containing marrow elements usually found incidentally and rarely extra-adrenal. Has predominant fat density and signal on CT and MRI (lose signal on fat-suppressed). Haemorrhage is uncommon. Calcification seen in one-third of lesions. May show a pseudocapsule.
• Neuroblastoma: This is a common adrenal gland tumour in children, and can secrete catecholamines but usually present with abdominal mass or discomfort. Presents as a large, irregular mass that can cross the midline. Calcifications are common.
• Ganglioneuroma/Ganglioneuroblastoma: These are rare, usually benign tumours of the sympathetic ganglia. They are typically asymptomatic and do not secrete catecholamines. Typically demonstrate homogeneous enhancement and may contain areas of calcification.

Management

• Management usually involves a multidisciplinary team including endocrinologists and surgeons.
• Initial management focuses on controlling symptoms and blood pressure with alpha-blockade, followed by surgical removal of the tumour.
• Genetic counselling may be appropriate for patients with familial syndromes.