Pheochromocytoma pathophysiology On the Web
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Pheochromocytoma arises from chromaffin cells of the adrenal medulla. On gross pathology, pheochromocytoma has a multinodular and a multicentric pattern of growth. On microscopic histopathological analysis, nesting (Zellballen) pattern composed of well-defined clusters of tumor cells separated by fibrovascular stroma may be seen. It may be benign, malignant, familial (multiple endocrine neoplasia 1 and type 2B) or sporadic. All of these forms have genetic origin depending on a large number of genes, for example, VHL, SDH, NF1, RET genes.
- Pheochromocytoma is a tumor which arises from the chromaffin cells of the adrenal medulla and sympathetic ganglia.
- Malignant and benign pheochromocytomas share the same biochemical and histological features.
- Pheochromocytoma leads to excessive secretion of catecholamines and subsequent stimulation of adrenergic receptors.
- Commonly secreted catecholamines include norepinephrine (predominant) and epinephrine. Some tumors may also secrete dopamine.
- Excessive secretion of catecholamines may be either continuous or intermittent.
- The exact mechanism responsible for surge in catecholamine secretion remains unclear but it has been postulated that certain medications (such as opiates, metoclopramide or beta blockers) and changes in tumor blood flow and pressure could be responsible factors.
Effects of adrenergic stimulation by pheochromocytoma
- Epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors.
- Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3:
- Binding to α1 receptors causes vasoconstriction. α1-adrenergic receptors are present in the blood vessels of skin, the sphincters of the gastrointestinal system, kidney (renal artery) and brain. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs.
- Binding to α2 receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. It suppresses the release of norepinephrine by negative feedback.
- Binding to β2 receptors causes smooth muscle relaxation in the uterus, GI tract, detrusor urinae muscle of bladder wall, and bronchi. It also causes dilatation of smaller coronary arteries, hepatic artery, arteries to skeletal muscle.
- Binding to β1 receptors causes renin release from juxtaglomerular cells and lipolysis in adipose tissue. It Increases cardiac output by:
- Pheochromocytomas can be familial and occur in patients with multiple endocrine neoplasia (MEN1 and MEN 2B).
- Patients with Von Hippel Lindau disease (VHL) may also develop pheochromocytoma.
- It has autosomal dominant inheritance and has two pathways of tumor pathogenesis. Cluster 1 tumors are noradrenergic. Cluster 2 tumors are adrenergic.
|Cluster 1 (Noradrenergic)||Cluster 2 (Adrenergic)|
- Von Hippel-Lindau (VHL) disease
- PCCs arise in about 10–20% of patients with VHL disease.
- VHL tumor suppressor protein is the main cause for VHL disease.
- The VHL tumor suppressor protein targets especially hypoxia-inducible factor-1 (HIF-1), MMP inhibitors, and atypical protein kinase C.
- HIF-1 is involved in erythropoiesis through its ability to induce transcription of mRNA coding for erythropoietin. It regulates several growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-beta, and transforming growth factor (TGF-alpha).
- Deletions in VHL from nonsense and frameshift mutations appear to be more common in type 1 disease, while missense mutations may be more common in type 2 disease.
- Missense mutations at codon 167 are associated with a particularly high risk of PCC.
- Multiple endocrine neoplasia type 2A
- The RET protein is a transmembrane receptor of the tyrosine kinase family.
- RET protein is derived from the neural crest and has a key role in regulating cell proliferation and survival during embryogenesis.
- The RET receptor can be activated through various factors such as glial-cell-line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin.
- Mutations of the RET proto-oncogene cause constitutive activation of the RET receptor and of intracellular signaling pathways, ultimately resulting in the cellular transformation.
- Mutations causing loss of function of the RET protein were found to be associated with Hirschsprung's disease, a disorder characterized by the absence of enteric ganglia in the intestinal tract.
- Neurofibromatosis type 1 (NF1)
- Mutations in the NF1 gene result in loss of functional protein causing the wide spectrum of clinical findings.
- The NF1 gene has been localized on chromosome 17qll.2 and encodes neurofibromin. In the absence or at decreased levels of neurofibromin, signaling is increased through various pathways resulting in the cell proliferation and inhibited apoptosis.
- Knudson's two-hit tumor suppressor model could be applied, resulting in a loss of heterozygosity at tumor level. The mutations include translocations, splicing, deletions, insertions, and point mutations.
- The Ras-GTPase-activating protein-related domain has the important role of stimulating the intrinsic GTPase of p21-Ras-GTP to hydrolyze GTP to GDP and inactivating p21-Ras. P21-Ras is a key component of many growth factors signaling pathways, and neurofibromin acts as a tumor suppressor protein.
- The cysteine-serine-rich domain (CSR) of neurofibromin plays an important role in the pathogenesis of NF1.
- Pheochromocytoma can be part of other syndromes named multiple endocrine neoplasia (MEN1 and MEN2B), which are autosomal dominant syndromes controlled by RET gene. Pheochromocytoma occurs in 50% of patients with MEN2 as follows:
|MEN 1||MEN 2|
- On gross pathology, pheochromocytoma varies from small to large and usually associated with hemorrhage and necrosis.
- Pheochromocytoma is usually lobulated and small tumors have compressed adrenal gland.
- Familial tumors are bilateral.
- It may be associated with hyperplasia in the adjacent medulla.
- Chromaffin reaction: fresh tumor cut section turns dark brown if add potassium dichromate at pH 5-6.
Bilateral pheochromocytoma in MEN2. Gross image. Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Bilateral_pheo_MEN2.jpg
On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
Micrograph of pheochromocytoma. Source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
Histopathology of adrenal pheochromocytoma. Adrenectomy specimen. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535945
Micrograph of pheochromocytoma. Source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535944
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