High‐risk abdominal pediatric paraganglioma

To the Editor: Paragangliomas are extra-adrenal benign (90%) and neoplastic (10%) neuroendocrine tumors affecting neural crest derivatives,1,2 extremely rare in pediatric practice, with only 113 children in France from 2000 to 20163 and a worldwide incidence of less than 0.1% of pediatric cancers.4 Given its rarity, no standard protocol is validated andmost therapeutics are discussed in nationalmultidisciplinarymeetings. As in adults, complete excision is the gold standard,while adjuvant chemotherapy has limited indications.1 External beam radiotherapy (EBR) is mainly palliative for metastatic paragangliomas, based on retrospective studies with few patients and even fewer pediatric ones.5 In small localized tumors, local treatment with stereotactic body radiation therapy (SBRT) at a mean dose of 31.8 Gy delivered with 3.3 Gy fractions or stereotactic radiosurgery of 21.9 Gy delivered in 13.6 Gy fractions5 allows 86% of local control at 22months of follow-up. We report the case of a 14-year-old girl, with no personal or familial medical history, who presented in 2019 intense nausea, significant hypertension requiring antihypertensive bi-therapy. and faltering in height and weight gain. An abdominal ultrasound revealed a 39 × 24 mm retroperitoneal inter-aortico-caval mass. The workup for extension was completed with a thoraco-abdomino-pelvic computed tomography (TAP-CT) confirming the localization and size of the mass, and a 18F-fluorodeoxyglucose-positron emission tomography/CT (18F-FDG-PET/CT) that revealed highly suspicious multifocal bone lesions. A 123I-meta-metaiodobenzylguanide (MIBG) scintigraphy (exploring cells deriving from neural crests, such as paragangliomas and neuroendocrine tumors6) showed no uptake in any lesions. A vertebral biopsy was not contributive. Plasma metanephrine and both urinary noradrenaline and dopamine were increased, contrasting with nonpathologic urinarymetanephrine. Excision was only partial due to labile blood pressure and major infiltration of vascular vessels with high hemorrhagic risk. Pathological analysis confirmed the diagnosis of a FOLX2-negative, chromogranin-, synaptophysin-, PS100-positive paraganglioma with vascular embolisms and Ki67: 15%. Among paragangliomas and pheochromocytomas, 40% have a genetic origin, justifying the search for mutations in the SDHA, SDHB, SDHC, SDHD, VHL, RET, MAX, TMEM127, NF1, and FH genes.7 Genetic analysis revealed a pathogenic heterozygote variant c.137G>A on exon 2 of the SDHB gene, causing loss of expression of the SDHB protein. This case is consistent with other SDHB-mutated paragangliomas, which are more aggressive andmetastatic than SDHD-mutated paragangliomas.8,9 The patient underwent PET/CT with 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTATOC) to evaluate the tumoral residue, as it is superior for the diagnosis and follow-up of metastatic paragangliomas to MIBG scintigraphy10 or 18F-dihydroxyphenylalanine-PET-CT.11 68GaDOTATOC PET/CT showed intense uptake in the residual abdominal mass and the secondary bone lesions (Figure 1A). We presented the case to COMETE, the national expert multidisciplinary network specialized in adrenal tumors, which proposed to perform salvage surgery or palliative irradiation. As surgery was deemed unfeasible by local and national surgery panel, irradiation was performed without chemotherapy. The target volume (defined by planning CT, MRI, and 68GaDOTATOC PET/CT) was the macroscopic tumor and adjacent metastatic vertebrae T12 and L3–L4. Given the proximity with the kidneys and to protect the surrounding vertebrae, a comparative dosimetry was performed with a proton therapy center. The proton treatment plan included two posterior incidences to avoid the use of anterior beams, which carries uncertainty due to bowel movements that may vary from one to three the dose delivered,12 and pencil beam scanning treatment with a single-field uniform dose (SFUD). Their proton dosimetry was compared with our own dosimetry calculated with dynamic intensity-modulated radiotherapy with helical tomotherapy. Although proton dosimetry provides a lower dose to most organs at risk, the median dose delivered to the right kidney was above the dose constraints. Comparative dosimetric images are displayed in (Figure 1B,C) and comparison of dose to organs at risk in Table S1. Consequently, we decided to use helical intensity-modulated tomotherapy with 54 Gy in 30 fractions of 1.8 Gy each. This underlines that proton therapy is not systematically superior in terms of the sparing of organs at risk and tumor coverage to state-of-the-art photon plans. Considering the poor differentiation, SHDB mutation, and secondary hepatic localization, we performed an alternate follow-up with sequential 18F-FDG-PET and 68Ga-DOTATOC-PET/CT.13–15 The 18F-FDG-PET/CT performed at 3 months showed mild regression of tumoral uptake with no new uptake but asymptomatic bone progression (irradiated vertebrae and two untreated metastatic sites distant from the field). Clinically, the patient has performance status one with controlled hypertension, has no pain, and attends school daily. Given radiotherapy inefficacy, our patient could benefit from the ongoing European phase II clinical trial, NETTER-P, evaluating safety and dosimetry of radioligand therapy (RLT) with 177lutetium-dotatate in adolescent patients with somatostatin receptor-positive GEP-NET tumors, pheochromocytomas, and paragangliomas (NCT04711135).16 A prerequisite, present in our patient, is the tumoral expression of somatostatin receptors confirmed by the initial 68GaDOTATOC PET/CT. A meta-analysis of this treatment for advanced