Case Series: ATRX Variants in Four Patients with Metastatic Pheochromocytoma.

Few reports have highlighted the rare presence of somatic ATRX variants in clinically aggressive, metastatic pheochromocytoma/paraganglioma (PCC/PGL); however, none have addressed detailed clinical presentation (including biochemistry and imaging) and management of these patients. Here, we address these clinical features and management based on four PCC patients with somatic ATRX variants from our National Institutes of Health PCC/PGL cohort. A total of 192 patients underwent exome sequencing (germline, somatic, or both), and four males were found to have somatic ATRX variants (with additional somatic VHL and FH oncogenic variants in patients 2 and 4, respectively). Per-lesion and per-patient comparisons were performed among functional imaging scans performed at the NIH. Biochemical phenotype and response to systemic treatment were evaluated. This mini-series supports prior studies showing aggressive/metastatic PCC in patients with somatic ATRX variants, as all developed widespread metastatic disease. All four PCC patients presented with noradrenergic biochemical phenotype, and some with significant elevation in 3-methoxytyramine. 18F-FDOPA PET/CT was found to be the superior functional imaging modality, with 100% lesion detection rate when compared to that of 68Ga-DOTATATE, 18F-FDG, 18F-FDA, and 123I-MIBG scans. While patients did not respond to chemotherapy or tyrosine kinase inhibitors, they responded to targeted radiotherapy using high-specific-activity 131I-MIBG (Azedra®) or 177Lu-DOTATATE (Lutathera®).

Diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body diagnostic CT and MRI in the detection of spinal bone metastases associated with pheochromocytoma and paraganglioma.

OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. • [68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.

Paediatric phaeochromocytoma and paraganglioma: A clinical update.

Paediatric phaeochromocytomas and paragangliomas (PPGLs), though rare tumours, are associated with significant disability and death in the most vulnerable of patients early in their lives. However, unlike cryptogenic and insidious disease states, the clinical presentation of paediatric patients with PPGLs can be rather overt, allowing early diagnosis, granted that salient findings are recognized. Additionally, with prompt and effective intervention, prognosis is favourable if timely intervention is implemented. For this reason, this review focuses on four exemplary paediatric cases, succinctly emphasizing the now state-of-the-art concepts in paediatric PPGL management.

Performances of Functional and Anatomic Imaging Modalities in Succinate Dehydrogenase A-Related Metastatic Pheochromocytoma and Paraganglioma.

The study identifies the importance of positron emission tomographic (PET) and anatomic imaging modalities and their individual performances in detecting succinate dehydrogenase A (SDHA)-related metastatic pheochromocytoma and paraganglioma (PPGL). The detection rates of PET modalities-68Ga-DOTATATE, 18F-FDG, and 18F-FDOPA-along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI) are compared in a cohort of 11 patients with metastatic PPGL in the setting of a germline SDHA mutation. The imaging detection performances were evaluated at three levels: overall lesions, anatomic regions, and a patient-by-patient basis. 68Ga-DOTATATE PET demonstrated a lesion-based detection rate of 88.6% [95% confidence interval (CI), 84.3-92.5%], while 18F-FDG, 18F-FDOPA, and CT/MRI showed detection rates of 82.9% (CI, 78.0-87.1%), 39.8% (CI, 30.2-50.2%), and 58.2% (CI, 52.0-64.1%), respectively. The study found that 68Ga-DOTATATE best detects lesions in a subset of patients with SDHA-related metastatic PPGL. However, 18F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both PET modalities in evaluating SDHA-related PPGL.

Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches.

Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient's tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.