New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification

Abstract

A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient's outcome, including cures and, ultimately, disease prevention.

Figure 1.

Different PPGL molecular subgroups with corresponding driver mutations and a proportion of hereditary disease in the respective cluster. TCA cycle–related mutations include SDHA, SDHB, SDHC, SDHD, SDHAF2, and FH genes. MYC, c-MYC induced pathways; MAPK, mitogen-activated protein kinase cascade; mTOR, the mammalian target of rapamycin pathway. Anatomic figure was adopted and modified from Lips et al. (5).

Figure 2.

Approximate frequency of PPGL in different heritable contexts, according to localization and hormone profile. Upper left shows different differentiation stages indicated by color of sympathetic PPGL, including expressed enzymes and hormone production. Bar diagrams indicate frequency of parasympathetic and sympathetic PGLs at different anatomic locations as well as PCC and metastatic disease in different mutational contexts. +, enzyme expression, −, no enzyme expression; CgA, chromogranin A; DBH, dopamine β hydroxylase; EPI, epinephrine; NE, norepinephrine; PNMT, phenylethanolamine N-methyltransferase; TH, tyrosine hydroxylase.

Figure 3.

Current synthesis of the important clinical facts that contribute to the decision-making process in diagnosis, follow-up, and treatment of PPGL.

Figure 4.

Algorithm for personalized follow-up of pheochromocytoma and paraganglioma patients where risk from genetic subtype is added to disease characteristics (healthy carriers assigned zero risk) to estimate a PPGL risk score that incorporates risk of new PPGL events and frequency of metastatic disease. In addition, family history of metastatic PPGL and presentation at a young age may warrant increased surveillance of other members of that particular family, especially in patients with SDHx. Proposed definition of high-risk PCC: diameter >5 cm, 3–3.5 cm for SDHB carriers, young age at diagnosis, or moderately to poorly differentiated PPGL accordingly to GAPP classification system. Detailed description of surveillance, clinical; patient history and clinical investigation to cover symptoms of catecholamine secretion in addition to relevant information for the particular genetic syndrome. Metanephrines: selection of biochemical tests can be guided by mutation subtype as well as PPGL secretory profile of that particular patient. 3-methoxytyramine is recommended for SDHx patients only. Chromogranin A is optional. Imaging should include MRI or ultrasound of relevant anatomical sites; CT scan can be used too, based on MRI results, a radiologist’s advice, or a physician’s recommendation after detailed patient evaluation. R0, absence of residual PPGL after treatment. *, indicates high uncertainties in assumption of PPGL risk score.

Figure 5.

Schematic of a future precision medicine workflow. Top: Relevant factors for disease assessment. Middle: Recommendations presented on a precision medicine card based on whether the patient is disease free. Bottom: Future potential treatments for systemic disease. PARP, poly [ADP-ribose] polymerase; TKI; tyrosine kinase inhibitor.