Table 11.
Individualized management plan depending on the cluster affiliation
| Cluster | Cluster 1A (Krebs cycle-related): SDHx (SDHA, B, C, D, F2), FH, MDH2 (10%-15% of PPGL) | Cluster 1B (VHL/EPAS1-related): VHL, EPAS1(HIF2A), (15%-20% of PPGL) | 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 | Almost 100% germline | 25% germline (0%EPAS1(HIF2A)) | 20% germline | 0% germline |
| Signaling pathways | Pseudohypoxia, Krebs cycle-related, HIF-2α stabilization | Pseudohypoxia, VHL/EPAS1-related, HIF-2α stabilization | Kinase signaling: PI3K/AKT, RAS/RAF/ERK, mTORC1/p70S6K | Wnt signaling |
| Biochemistry | Noradrenergic/dopaminergic (low catecholamine content, constant release) | Noradrenergic (low catecholamine content, constant release) | Adrenergic with additional elevation of normetanephrine (high catecholamine content, better secretory control, episodic secretion) | Unknown, highest CgA overexpression |
| Symptoms | More likely constant hypertension and tachycardia/-arrhythmia | More likely constant hypertension and tachycardia/-arrhythmia | More likely episodic “spells”, higher sign/symptom scores, more likely tremor, anxiety/panic, pallor | Unknown |
| Imaging | [68Ga]-DOTA-SSA PET/CT (except for FH) | [18F]FDOPA PET/CT (also for FH) | [18F]FDOPA PET/CT | Unknown |
| Tumor location | Mostly extra-adrenal | Adrenal, extra-adrenal | Adrenal | Adrenal |
| Metastatic risk | High-intermediate | Intermediate-low | Low | High-intermediate |
| Age of presentation | Early (20-30 years old, earliest 5 years old) | Early, some during childhood | Late (40-50 years old), some can present early (earliest 10 years old) | Unknown |
| Therapy | Surgery, systemic: CVD, temozolomide, SSTR2-based radionuclide therapy (PRRT), (HSA) [131I]-MIBG, TKIs | Surgery, systemic: CVD, temozolomide, SSTR2-based radionuclide therapy (PRRT), (HSA) [131I]-MIBG, TKIs | Surgery, systemic in rare cases: (HSA) [131I]-MIBG, TKIs, SSTR2-based radionuclide therapy (PRRT), CVD, temozolomide | Surgery, systemic: CVD, temozolomide, SSTR2-based radionuclide therapy (PRRT), (HSA) [131I]-MIBG, TKIs |
Black letters: potentially specifically interesting for cluster 1; gray letters: potentially specifically interesting for cluster 2
Abbreviations: CgA, chromogranin A; CVD, cyclophosphamide/vincristine/dacarbazine; HSA, high-specific activity; MIBG, meta-iodobenzylguanidine; PCC, pheochromocytoma; PET/CT, positron emission tomography/computed tomography; PGL, paraganglioma; PPGL, pheochromocytoma/paraganglioma; PRRT, peptide receptor radionuclide therapy; SDHA/x, succinate dehydrogenase subunit A/x; SSTR, somatostatin receptor; TKI, tyrosine kinase inhibitor; VHL, von Hippel–Lindau.