Abstract: Pheochromocytoma and paraganglioma (PCC/PGL) are rare tumors that originate from adrenal or extra-adrenal chromaffin cells. A significant clinical manifestation of PCC/PGL is that the tumors release a large number of catecholamines continuously or intermittently, causing persistent or paroxysmal hypertension and multiple organ functions and metabolic disorders. Though majority of the tumors are non-metastatic, about 10% are metastatic tumors. Others even have estimated that the rate of metastasis may be as high as 26%. The disease is most common in individuals ranging from 20 to 50 years old and the age of onset strongly depends on the genetic background: patients with germline mutations in susceptible genes have an earlier presentation. Besides, there are no significant differences in the incidence between men and women. At present, traditional treatments, such as surgical treatment, radionuclide therapy, and chemotherapy are still prior choices. However, they all have several deficiencies so that the effects are not extremely significant. Contemporary studies have shown that hypoxia-associated signal pathway, associated with the cluster 1 genes of PCC/PGL, and increased kinase signal pathways, associated with the cluster 2 genes of PCC/PGL, are the two major pathways involving the molecular pathogenesis of PCC/PGL, indicating that PCC/PGL can be treated with targeted therapies in emerging trends. This article reviews the progress of molecular-targeted therapies for PCC/PGL.

Keywords: pheochromocytoma, paraganglioma, targeted therapies, signal pathways


Pheochromocytoma and paraganglioma (PCC/PGL) are neuroendocrine tumors arising from the chromaffin cells which are derived from the embryonic neural crest, including adrenal medulla PCC and extra-adrenal sympathetic and parasympathetic paraganglia (PGL). PCC/PGL often show an increase in catecholamines (adrenalin, norepinephrine, and/or dopamine), which affects the cardiovascular system and metabolic processes, thus causing high blood pressure.1 Though hypertension is the most critical clinical symptom of PCC/PGL, this disease may also be associated with orthostatic hypotension. Besides, other common symptoms include recurrent headaches, excessive sweating, tachycardia as well as weight loss. It is reported that the features of headache, sweating, and palpitations appeared in 30–40% of the cases and could be seen as the best clue to suspect PCC/PGL.2 There are also some clinical atypical presentations of PCC/PGL including sustained hypertension and incidental mass without associated symptoms. If PCC/PGL are not diagnosed in time, delaying in treatment can cause serious heart, brain, kidney vascular damages, and even death. In terms of catecholamines in PCC/PGL, different patients may have different levels. Recent researchers have found that catecholamine excretion varied according to gene mutations.3 For example, mutations in NF1 and RET genes are almost always associated with PCC/PGL that produce catecholamine.4,5 In opposite, some tumors due to mutations in VHL and SDHx genes lack significant excretion of catecholamine.5 Some PCC/PGL express high levels of tyrosine hydroxylase (TH) which is the rate-limiting enzyme for catecholamine biosynthesis. For instance, the level of endogenous VHL tumor suppressor protein (pVHL) in PC12 cells expressing VHL antisense RNA reduced by 5–10 folds while the levels of TH protein and mRNA increased by 2–3 folds. Therefore, loss of pVHL function may be responsible for PCC-related hyper-catecholemia.6

The prevalence of PCC/PGL is estimated to be 1:6500–1:2500. Autopsy results show that the prevalence is as high as approximately 1:2000, indicating that many PCC/PGL were not diagnosed. The annual incidence rate is reported to be 2–10:1,000,000.7 Most PCC/PGL are discovered at 30–50 years old, and the incidence rate of males and females is basically equal.

It has been reported that PCC/PGL have the highest heritability in human tumors.8 Furthermore, it is a kind of human tumor model that has inherited mutations in a metabolic enzyme gene, succinate dehydrogenase subunit D (SDHD). In addition to classic mutations in the genes encoding for the subunits of SDH, in the past five years more germline or somatic mutations have been found in genes encoding for other enzymes catalyzing pivotal steps of the tricarboxylic cycle acid (TCA), such as fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), glutamic-oxaloacetic transaminase 2 (GOT2), and dihydrolipoamide S-succinyltransferase (DLST), in PCC/PGL.9 In regard to the molecular pathogenetic mechanism of PCC/PGL, the hypoxia-related signal pathway (Figure 1) and the increased kinase signal pathways (Figure 2) are two main pathways involving the tumor.10 It has been proved that the mutations of subunits of succinate dehydrogenase (SDH) (including SDHA, SDHB, SDHC, SDHD, SDHAF2), FH, prolyl hydroxylase domain protein 2 (PHD2), von Hippel Lindau (VHL), and hypoxia-inducible factor 2A (HIF2A), which are the cluster 1 genes of PCC/PGL, influenced the hypoxia‑related signal pathway, while the mutations of rearranged during transfection proto-oncogene (RET), myc-associated factor X (MAX), transmembrane protein 127 (TMEM127), neurofibromin 1 (NF1), and kinesin family member1B β (KIF1Bβ), which are the cluster 2 genes of PCC/PGL, influenced the increased kinase signal pathways.10

Figure 1

Figure 2

If it were diagnosed and treated in a timely and early manner, PCC/PGL could be cured. Traditional therapies (surgical treatment, radionuclide therapy, and chemotherapy) are the most commonly used treatments for PCC/PGL nowadays, but they have shown suboptimal results in shrinking tumors and improving survival. Currently, effective molecular-targeted therapies aiming at permanent control of these highly complex neoplasms are the research hotspot and the aim of efforts and molecular characterization of PCC/PGL suggests the targeted therapies should be optional treatments (Table 1). The current progress in the treatments of PCC/PGL is summarized as follows.

Table 1

(To view a larger version of Table 1, click here.)

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