Table 1.
Pheochromocytomas and paragangliomas (PCC/PGL) characteristics depending on underlying germline/somatic mutations and their clinical presentation and evaluation.
| Genes | Cluster 1 (Pseudohypoxic Krebs Cycle-Related): SDHx (SDHA, B, C, D, F2), FH, MDH2 (10–15% of PCC/PGL) | Cluster 1 (Pseudohypoxia VHL/EPAS1-Related: VHL, EPAS1/2 (HIF2A), PHD1/2 (15–20% of PCC/PGL) | Cluster 2 (Kinase Signaling-Related): RET, NF1, MAX, TMEM127, HRAS (50–60% of PCC/PGL) | Cluster 3 (Wnt Signaling-Related): CSDE1, MAML3 5–10% of PCC/PGL) |
|---|---|---|---|---|
| Percentage of germline mutations [2] | Germline 100% | Germline 25% | Germline 20% | Germline 0% |
| Signaling pathways | Pseudohypoxia, Krebs cycle-related, HIF-2α stabilization and signaling | Pseudohypoxia, VHL/EPAS1-related signaling | Kinase signaling: PI3K/AKT, RAS/RAF/ERK, mTORC1/p70S6K | Wnt signaling |
| Biochemistry | Normetanephrine, 3-methoxytyramine | Normetanephrine | Normetanephrine and metanephrine or metanephrine alone | Normetanephrine, metanephrine |
| Imaging | [68Ga]Ga-DOTA-SSA PET/CT (possibly except for FH) | [18F]FDOPA PET/CT (possibly also for FH) | [18F]FDOPA PET/CT in most | Unknown |
| Tumor location | Mostly extra-adrenal | Adrenal, extra-adrenal | Adrenal | Unknown |
| Metastatic risk | High-Intermediate | Intermediate-Low | Low | Intermediate |
| Age of presentation | Early (under 20–30 year-old) | Early, some often during childhood | Late but some can present early | Unknown |