The solution will be displayed at the end of the clinical pearl. In the next section, we will explore why these biochemical signatures emerge, how they relate to tumor origin, and what they can reveal about potential genetic alterations.

Catecholamine Synthesis and Metabolism

Catecholamine synthesis is a multi-step process that requires several specific enzymes. It begins with tyrosine, which is converted to DOPA by tyrosine hydroxylase. DOPA is then decarboxylated to form dopamine via DOPA decarboxylase. Dopamine can subsequently be hydroxylated to norepinephrine through the action of dopamine β-hydroxylase. The final step, the conversion of norepinephrine to epinephrine, depends on phenylethanolamine N-methyltransferase (PNMT), which catalyzes the transfer of a methyl group to norepinephrine.

The characteristic catecholamine profiles observed in different tumor types reflect the pattern of enzyme expression within the tumor. This pattern, in turn, is determined by the tissue of origin and the genetic drivers underlying the tumor.

Epinephrine, norepinephrine, and dopamine are primarily metabolized by the enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). COMT catalyzes the O-methylation of the catechol ring, converting dopamine into 3-methoxytyramine, norepinephrine into normetanephrine, and epinephrine into metanephrine. These metabolites are subsequently further processed to form vanillylmandelic acid (VMA) and homovanillic acid (HVA), which represent the major urinary end products of catecholamine metabolism.

Illustration of catecholamine synthesis and metabolization

This Illustration was created from Endo-Cases in https://BioRender.com based on a submitted template by Purves et al. (2018) Neuroscience. 6th Ed. Oxford University Press

Tissue Origin

Pheochromocytomas, originating from the adrenal medulla, typically have intact enzyme expression and therefore produce both norepinephrine and epinephrine, which is reflected by elevated levels of normetanephrine and metanephrine. In contrast, sympathetic paragangliomas, arising from extra-adrenal sites, primarily secrete norepinephrine, resulting in a predominance of normetanephrine. These tumors rarely generate significant amounts of epinephrine, due to low or absent expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme required for its synthesis.

Illustration of typical catecholamine synthesis and patterns of Pheochromocytomas and sympathetic Paragangliomas

This Illustration was created from Endo-Cases in https://BioRender.com based on a submitted template by Purves et al. (2018) Neuroscience. 6th Ed. Oxford University Press

Head and neck paragangliomas typically arise from parasympathetic paraganglia, which normally do not synthesize substantial amounts of norepinephrine or epinephrine. This feature is reflected in their biochemical profile, as they rarely secrete catecholamines. When catecholamine production occurs, dopamine is more commonly released. The production of dopamine is supported by expression of the early enzymes in the catecholamine biosynthetic pathway, including tyrosine hydroxylase and aromatic L-amino acid decarboxylase, whereas dopamine β-hydroxylase, required for conversion of dopamine to norepinephrine, is typically absent or expressed at low levels, resulting in elevated dopamine and it’s metabolite methoxytyramine and normal/low normetanephrine and metanephrine.

Illustration of typical catecholamine synthesis and patterns of Pheochromocytomas, sympathetic and head and neck Paragangliomas

This Illustration was created from Endo-Cases in https://BioRender.com based on a submitted template by Purves et al. (2018) Neuroscience. 6th Ed. Oxford University Press

At low concentrations, dopamine mainly engages D1- and D2-like receptors, resulting in vasodilation and increased sodium excretion, especially in the renal and splanchnic vascular beds. When present at moderate to high levels, dopamine also stimulates β1-adrenergic receptors, which increases heart rate and cardiac contractility. At very high concentrations, it activates α1-adrenergic receptors, causing vasoconstriction and a rise in blood pressure.

Head and neck paragangliomas that secrete dopamine are generally clinically silent, because dopamine has much lower activity at adrenergic receptors compared with norepinephrine and epinephrine. Furthermore, dopamine is rapidly metabolized, preventing it from reaching systemic levels sufficient to produce the classic symptoms of catecholamine excess. For more information about clinical manifestation of catecholamine excess see this Clinical Pearl.

Illustration of Catecholamine, their affinity to dopamine and adrenergic receptors and resulting effects

It should be emphasized that, although biochemical profiles can provide hints regarding tumor localization, their clinical utility is limited, as catecholamine patterns alone cannot consistently distinguish between different tumor types.

Genetic Alterations

Pheochromocytomas and paragangliomas exhibit the highest heritability among all tumor types. Together, germline and somatic mutations in over 20 known PPGL driver genes are found in approximately 70% of Caucasian patients. These genetic alterations are classified into three main molecular clusters: pseudohypoxia cluster 1 (subdivided into 1A and 1B), kinase-signaling cluster 2, and Wnt signaling cluster 3.

Advances in genetic profiling have facilitated the identification of distinct clinical, biochemical, and imaging phenotypes, enabling more personalized approaches to PPGL diagnosis, treatment, and long-term follow-up. In this section, we will focus on how these molecular clusters correlate with the biochemical patterns of catecholamine secretion.

Cluster 1 tumors (pseudohypoxia pathway), which include those associated with Krebs cycle–related genes, VHL, EPAS1, and succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD and SDHAF) are predominantly extra-adrenal (exept VHL-associated tumors) and typically exhibit a noradrenergic biochemical phenotype. This pattern arises from low or absent expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme responsible for converting norepinephrine to epinephrine. PNMT expression is suppressed by pseudohypoxic signaling driven by these mutations. Patients with cluster 1 tumors require close surveillance due to an increased risk of recurrence and metastasis.

In contrast, cluster 2 tumors (kinase-signaling pathway) are most often adrenal in location and display an adrenergic phenotype associated with episodic symptoms. Affected genes include the RET proto-oncogene as well as genes encoding for neurofibromin 1 (NF1), HRAS and transmembrane protein 127 (TMEM127). These tumors generally follow a less aggressive course and maintain high expression of the catecholamine biosynthetic enzymes, particularly PNMT and dopamine β-hydroxylase (DBH). This intact enzymatic machinery enables efficient conversion of norepinephrine to epinephrine, leading to substantial secretion of both catecholamines.

The clinical characteristics of cluster 3 tumors (Wnt signaling pathway) are less well defined, although aggressive behavior appears likely. Biochemically, these tumors exhibit variable or mixed catecholamine secretion patterns, without a consistent predominance of norepinephrine or epinephrine. Expression of catecholamine biosynthetic enzymes, including PNMT and DBH, is generally preserved but not markedly elevated or suppressed.

Illustration cluster dependent features: Note: The illustration depicts the general or typical predominant features; individual variation and differences within each group may occur. Some characteristics, such as the metastatic potential associated with specific genetic alterations, are based on limited data due to the rarity of these tumors.

This Illustration was created from Endo-Cases in https://BioRender.com based on a submitted template by Purves et al. (2018) Neuroscience. 6th Ed. Oxford University Press

Not all pheochromocytomas and paragangliomas can be fully classified within the established molecular cluster system. This may result from the absence of known driver mutations, the presence of rare or novel genetic alterations, or incomplete molecular characterization. Some tumors display mixed or atypical molecular features, and ongoing advances in molecular profiling continue to identify new subtypes.

While the molecular cluster of a pheochromocytoma or paraganglioma can often be inferred from clinical characteristics (tumor location, catecholamine secretion pattern, and metastatic behavior) a definitive classification and optimal management require molecular profiling. Such profiling informs the selection of appropriate biochemical assays, imaging strategies, genetic counseling, and surveillance protocols. Consequently, genetic testing is recommended for all patients with pheochromocytoma or paraganglioma.

Based on the biochemical profiles presented at the beginning of this clinical pearl, the most likely corresponding diagnoses are as follows:

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All Illustrations were created in https://BioRender.com

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