Pheochromocytoma classification

Pheochromocytomas and paragangliomas (collectively referred to as PPGLs) are rare tumors that originate from chromaffin cells in the adrenal medulla (pheochromocytoma) or in the extra-adrenal neural ganglia (paraganglioma). These tumors can be either biochemically active (producing a catecholamine like epinephrine, nor-epinephrine and dopamine) or biochemically silent. PPGLs can be either sporadic or genetic, with association to several familial syndromes. PPGLs can also be classified according to their spread into local, regional, or metastatic. The defining characteristic of malignancy in PPGLs is the presence of metastasis.

Pheochromocytoma and paragangliomas may be classified into several subtypes based on:

• Type of cells
• Nature of tumor
• Location
• Biochemical secretory patterns
• Genetics
• Mutations and pathogenetic pathways

Pheochromocytomas and paragangliomas may be classified according to the cells they are derived from: ^[1]

• Sympathetic– adrenal medulla or sympathetic trunk
• Parasympathetic– carotid body, glomus tympanicum, glomus jugulare, glomus vagale.

• Benign
• Metastatic/ Malignant

Malignant and benign tumors share the same biochemical and histological characters. The only difference is the ability of the malignant tumor to metastasize to distant tissues and have high rates of recurrence.

• According to the WHO 2017 Classification of Tumors of Endocrine Organs, all parangangliomas have metastatic potential and hence the term “malignant” was replaced with “metastatic”. ^[2]
• Common sites of metastasis include:
  • Lung
  • Bone
  • Head
  • Thorax
  • Liver

• 95% of pheochromocytomas are found in the abdomen
• Intra-adrenal– 85-90%
• Extra-adrenal (paragangliomas)– 10-15% are prevertebral and paravertebral sympathetic ganglia of the chest, abdomen, and pelvis.
  • The tumors in the abdomen most commonly arise from the organ of Zuckerkandl which is a collection of chromaffin tissue around the origin of the inferior mesenteric artery or the bifurcation of aorta. ^{[3] [4]}

Pheochromocytoma and paragangliomas (PPGL) can be classified based on the biochemical secretory pattern: ^[2]

• Noradrenergic phenotype (predominant norepinephrine secreting)- associated with Von Hippel-Lindau syndrome
• Adrenergic phenotype (predominant epinephrine secreting)- associated with MEN2 or neurofibromatosis type 1 (NF1)
• Dopamine secreting- associated with SDHB, SDHD or SDHC mutations and potentially metastatic tumors.

• Familial pheochromocytoma is associated with several hereditary disorders such as:
  • Multiple Endocrine Neoplasia types 2A
  • 2B (MEN2) (caused by mutations of the RET gene)
  • Von Hippel-Lindau (VHL) disease (caused by mutations of the VHL gene)
  • Familial paraganglioma of the neck (cause by mutations of the gene for succinate dehydrogenase subunit D (SDHD))
  • Neurofibromatosis type 1 (NF1)

• Resulting from sporadic germ-line mutations, which have been documented in about 20% of cases.
• The majority of them are positive for KIT expression. A partial explanation was provided by the finding of activating mutations in another gene encoding an RTK, the platelet-derived growth factor receptor alpha (PDGFRA) gene in some KIT-negative GISTs

• Most catecholamine-secreting tumors are sporadic. Mutations have been identified in most of the sporadic cases.

• Sporadic tumors may be due to spontaneous mutation, decreased penetrance or maternal imprinting.^[5]
• 50% of patients had a pathogenic mutation in SDHB, SDHD, or VHL.^[6]

Pheochromocytoma and paragangliomas (PPGL) can be classified into the following clusters- ^{[7] [8] [9]}

• Cluster 1
  • Mutations involving in overexpression of vascular endothelial growth factor (VEGF) as a result of pseudohypoxia
  • Impaired DNA methylation leading to increased vascularization
• Cluster 2
  • Activating mutations of Wnt-signaling pathway including Wnt receptor signaling and Hedgehog signaling.
  • Mutations of CSDE1 (Cold shock domain containing E1) and MAML3 (Mastermind like transcriptional coactivator 3) genes7.
• Cluster 3
  • Abnormal activation of kinase signaling pathways like PI3Kinase/AKT, RAS/RAF/ERK, and mTOR pathways.