Paragangliomas and pheochromocytomas

Abstract

Paragangliomas, including the intra-adrenal forms known as pheochromocytomas, are nonepithelial neuroendocrine neoplasms that produce catecholamines as their principal hormonal product. Clinically and biochemically they are divided into two categories. Parasympathetic paragangliomas that make dopamine include head and neck paragangliomas such as carotid body tumors and jugulotympanic tumors, sympathetic paragangliomas that produce epinephrine and norepinephrine occur mainly in the abdomen, most commonly in the adrenal and the organ of Zuckerkandl. Paragangliomas also occur in unusual locations, including the sella turcica, paranasal sinuses, larynx, thyroid and parathyroid glands, mediastinum, heart and lungs, gallbladder, liver, gut, pancreas, and mesentery. These tumors have a characteristic morphology. They are composed of nests known as "Zellballen" and the tumor cells tend to be large polygonal neuroid cells with abundant granular basophilic cytoplasm; rarely they are eosinophilic, chromophobic, or amphophilic epithelioid cells or elongated and spindle-shaped cells. They stain for chromogranin and synaptophysin but are negative for keratins; they express the nuclear transcription factor GATA3 and the enzymes involved in catecholamine synthesis including tyrosine hydroxylase that is a valuable tool for confirmation of the diagnosis, and phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, and can be used to distinguish tumors that make epinephrine. S100 protein accentuates sustentacular stromal cells that also express SOX10. These tumors are familial in about 40% of cases, leading to multifocal tumors and in some, adrenal medullary hyperplasia. There is a long list of genes that are mutated in kindred with these tumors. Some familial tumors have specific morphologic features and molecular immunohistochemistry can be used to identify tumors associated with SDHx, VHL, and FH-related disease. Rarely these tumors can be the source of ectopic production of other peptide hormones. All paragangliomas have malignant potential; therefore, they are not classified as benign or malignant but rather only as primary and metastatic. Metastasis must be distinguished from multifocal primary disease. Prognosis is dependent on resectability.