Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups

Abstract

In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT's antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high-specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.

Keywords: 131I-MIBG; 18F-FDG; 18F-FDOPA; 68Ga-DOTATATE; PPGL; SDHB; paraganglioma; peptide receptor radionuclide therapy; pheochromocytoma; somatostatin receptor; succinate dehydrogenase complex; theranostics.

Figure 1.. Multifocal SDHD-related vagal PGLs (VPGLs). A.

Craniocervical ¹⁸F-FDOPA PET image (maximum intensity projection: MIP) showing the 2 VPGLs (arrows). B. Craniocervical ⁶⁸Ga-DOTATATE image (MIP) showing 2 VPs (arrows) with higher tumor uptake compared to ¹⁸F-FDOPA PET. C-E: magnetic resonance (MR) images (C: T2 weighted image; D: T1-weighted dynamic contrast enhanced (DCE) image; E: T1-weighted DCE image/T2 weighted image fusion image) showing both VPGLs with arterial enhancement pattern on magnetic resonance angiogram images.

Figure 2.. Proposed clinical algorithm for nuclear imaging investigations of pheochromocytoma/paraganglioma patients according to genotype.

The algorithm has been proposed for patients with suspected or confirmed PPGL in order to help towards the appropriate use of PET radiopharmaceuticals across PPGL subtypes. It may suffer from potential limitation of reported small number of cases. The optimal follow-up algorithm for non-proband SDHx-associated PPGLs remains to be determined but mostly relies on annual biochemical screening and MRI at regular intervals. CT/MRI: anatomic imaging with computed tomography and/or magnetic resonance imaging; ¹⁸F-FDG: ¹⁸F-fluorodeoxyglucose; ¹⁸F-FDOPA: ¹⁸F-fluorodihydroxyphenylalanine; FH: fumarate hydratase gene, ⁶⁸Ga-DOTA-SSA: gallium-68 (⁶⁸Ga)-labeled somatostatin receptor analogs; HNPGL: head and neck paraganglioma; HIF2A: hypoxia-inducible factor 2 alpha, MAX: germline mutation of MYC-associated factor X gene; NF1: neurofibromatosis 1 gene; N.A.: not available; PHEO: pheochromocytoma; PPGL: pheochromocytoma/paraganglioma; PET/CT: positron emission tomography-computed tomography; PHD1/2: prolyl hydroxylase 1 and 2 gene; RET: rearranged during transfection gene; SDHB: germline mutation of succinate dehydrogenase subunit B gene; SSA: somatostatin analog; SDHx: germline mutation in one of the succinate dehydrogenase complex genes; symp-PPGL: sympathetic PPGL; PRRT: peptide receptor radionuclide therapy.

Figure 3.. First-choice PET radiopharmaceuticals across genotypes

Figure 4.. ¹⁷⁷Lu-DOTATATE in a SDHB-patient with metastatic jugular paraganglioma.

A-B: Post-therapy SPECT/CT following 1st administration of ¹⁷⁷Lu-DOTATATE. A: SPECT/CT fusion images centered over the jugular PGL (long arrow), B: Volume rendering (jugular PGL: long arrow, metastases: short arrows). C: Pre-therapeutic MRI. D: Post-therapeutic MRI (2-months following the 4th cycle of ¹⁷⁷Lu-DOTATATE) showing a tumor shrinkage (asterisk).

Figure 5.. Proportion of PPGL patients with partial response or stable disease after PRRT.

Plots of individual studies and pooled proportion (with 95% confidence interval) of inoperable/metastatic PPGL patients with response or stable disease after PRRT (random-effects model). The size of the squares indicates the weight of each study. Mild heterogeneity among studies was evident (I-square test = 37.6%, p=0.099).