Personalized Management of Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.

Keywords: diagnostics; follow-up; molecular cluster; paraganglioma; pheochromocytoma; treatment.

Graphical Abstract

Figure 1.

Gene mutations impairing either Krebs cycle (cluster 1A) or hypoxia-signaling (cluster 1B) are associated with the development of pseudohypoxic cluster 1 PPGLs. These molecular changes offer potential targets for personalized medicine. Loss of function mutations in SDHA[AF2]/B/C/D, FH, MDH2, IDH, GOT2, SLC25A11, and DLST affect the Krebs cycle, resulting in severe impairment of mitochondrial oxidative phosphorylation and an accumulation of oncometabolites such as succinate. Accumulation of these oncometabolites as well as mutations (PDH1/2, VHL) leading to a decreased degradation of HIF-α result in an enhanced expression and stabilization of HIF-α. Moreover, gain-of-function mutation in HIF2A underlines the importance of hypoxia signaling in cluster 1 PPGLs. Highlighted in red are potential drugs that could be used to negate the molecular changes in cluster 1 PPGLs, which are in preclinical and clinical evaluation. In addition, targeting the somatostatin receptor (possibly higher expression compared to cluster 2) or the norepinephrine transporter (possibly lower expression compared to cluster 2) can be used to treat these tumors. Further approaches address immune checkpoints such as PD-1 or DNA repair mechanisms.

Figure 2.

General diagnostic flow-chart.

Figure 3.

Cluster-specific diagnostic flow-chart.

Figure 4.

Flow-chart for systemic therapy of metastatic disease (1, 4, 22); black letters: potentially interesting therapy for cluster 1; gray letters: potentially interesting therapy for cluster 2. Abbreviations: SSA, somatostatin analogues; TKI, tyrosine kinase inhibitor.

Figure 5.

Gene mutations leading to an activation of kinase signaling pathways (cluster 2) and derived molecular targets for a personalized therapy. Mutations in RET, NF1, HRAS, TMEM127, MAX, FGFR1, Met, MERTK, BRAF and NGFR activate phosphatidylinositol-3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTORC1)/p70S6 kinase (p70S6K), and RAS/RAF/ERK signaling pathways. Highlighted in red are potential drugs that address the molecular changes in cluster 2 PPGLs and are in preclinical and clinical evaluation. Molecular-targeted signaling pathway inhibitors (alone and in combination) might be specifically effective in these tumors. Moreover, similar to cluster 1, cluster 2 PPGLs provide the somatostatin receptor (possibly lower expression compared to cluster 1) and the norepinephrine transporter (possibly higher expression compared to cluster 1) as potential targets for the treatment of these tumors. Immune checkpoint inhibitors and drugs addressing DNA repair and synthesis mechanisms are furthermore under evaluation.

Figure 6.

Gene mutations leading to an activation of Wnt signaling (cluster 3) and derived molecular targets for a personalized therapy. Mutations in MAML3 and CSDE1 activate Wnt/ß-catenin signaling. Highlighted in red are potential drugs that address the molecular changes in cluster 3 PPGLs and are in preclinical evaluation.