Pediatric cases of PPGL are exceptionally rare with an incidence of 0.45 cases per million in childhood/adolescence as opposed to 4.6 cases per million in adults which is a 10-fold greater incidence [2, 32, 33]. The most common cause of PPGLs in children and adolescents are pathogenic variants in cluster 1 genes: VHL (27–51%) and SDHD (8–10%). These PPGL variants are quite prevalent and on average present at the age of 9 (for VHL-associated tumors) and 10 (for SDHD-associated tumors), respectively [32–38]. In children, metastases may be synchronous (present at the time of diagnosis), but are more likely to develop over time, further emphasizing the need for lifetime surveillance so that providers can identify the signs and symptoms of progressive disease [32]. Recognition of these indicators allows for appropriate selection of treatment; the risk of metastasis in children (due to disease going undetected) is higher than in adults and may have catastrophic implications if stored catecholamines are suddenly released (by surgery, induction of anesthesia, and or interfering medications) [33]. Poor prognostic indicators include extra-adrenal tumor location (PGL compared to PCC), size (≥ 5 cm) at presentation, familial inheritance (in these cases often cluster 1A PPGLs), non-secretory status (as tumors are considered less differentiated), metastasis (especially metastases to the lung and liver), and metastatic interval (patients with a shorter metastatic interval are younger and more likely to have soft tissue metastases) [13, 16, 33, 38–40]. In contrast, favorable prognostic indicators include cluster 2 PPGLs (e.g., well-differentiated and often lower grade) and small tumors (preferably found in the adrenal gland) [13, 16, 32, 38–40].

Evaluation for PPGL in pediatric patients tends to be prompted by symptoms (hypertension: 64–93%, headache: 39–95%, diaphoresis: 90%, palpitations: 53%) in 90% of patients or by detection of an incidentally noted mass [2, 13]. Subsequent biochemical analysis may be performed—taking care to avoid interfering agents—with plasma metanephrines, which are the most sensitive, or urinary metanephrines which are less sensitive but avoid the difficulties of venipuncture in children [3, 29, 41, 42]. Beyond metanephrine and normetanephrine, plasma 3-methoxytyramine (3-MTY, the metabolite of dopamine) or chromogranin A may reveal clinically silent/non-secretory tumors [3, 41, 43–46].

Whole-body imaging (e.g., CT and/or MRI) should be obtained when PPGL(s) are suspected with CT providing superior diagnostic sensitivity in identifying metastatic pulmonary lesions [13, 47]. Alternatively, MRI avoids radiation exposure but often requires sedation and endotracheal intubation while gadolinium (if used) has been shown to accumulate in the CNS with unclear significance [35]. The imaging modality (CT vs MRI) with the best benefit and least risk should be chosen on a case-by-case basis.

In general, anatomic imaging usually precedes functional imaging; but is lacking in its ability to characterize small nodules or bony lesions [47]. Functional imaging in PPGLs utilizes radiopharmaceuticals that target functional receptors/proteins for precise localization of these tumors within the body [13, 23, 47–49]. Radiopharmaceuticals such as ⁶⁸Ga-DOTATATE, ¹⁸F-flurodopa (¹⁸F-FDOPA), ¹⁸F-fluorodopamine (¹⁸F-FDA), and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) are used for PPGL imaging. However, ⁶⁸Ga-DOTATATE, along with the non-specific radiopharmaceutical ¹⁸F-FDG are used most often to screen for PPGL [47, 49, 50]. Particularly, ⁶⁸Ga-DOTATATE PET/CT has excellent sensitivity in cluster 1A (e.g., SDHx) PPGLs including in pediatric patients, HNPGLs, and metastatic lesions [10, 17, 49–60]. In comparison, ¹⁸F-FDOPA PET/CT has excellent sensitivity for tumors in cluster 1B (VHL, EPAS1/HIF2A) and cluster 2 (RET, MAX, NF1, etc.) PPGLs and apparently sporadic PCC [61–67]. ¹²³I-mIBG scintigraphy is mainly performed along with ⁶⁸Ga-DOTATATE to establish whether treatment with ¹³¹I-mIBG or ¹⁷⁷Lu/²²⁵Ac-DOTATATE (respectively) would be suitable [23, 48–52, 68].

PET imaging is often used as a surrogate for invasive procedures in patients with metastatic or progressive disease. Where surgery or biopsy is avoided for fear of inducing the release of stored catecholamines resulting in catecholamine-induced hypertensive crisis, especially in children [24, 33]. Patients who can undergo resection or biopsy qualify for histopathological analysis to verify molecular pathogenesis active in tissues through IHC staining (with biochemical markers such as chromgogranin, synatophyosin, and Ki-67). A component of this analysis may include the Grading Systems for Adrenal PCC and PGL (GAPP) and/or the PCC of the Adrenal Gland Scales Score (PASS) validation systems which assist in the classification of metastatic PPGL. However, both systems have shown a lack of utility in the clinical environment displaying limited predictive ability [8].

Treatment consists of operative and non-operative interventions. Notably, adrenoceptor blockade is advisable in secretory tumors before any intervention (operative or non-operative) that may cause tumor disruption. α-Adrenoceptor blocking agents followed by β-adrenoceptor blocking agents should be administered to avoid unbalanced adrenoceptor blockade which may precipitate (or worsen) hypertension or tachyarrhythmias and lead to PPGL crisis [1].

In operable patients with PPGL, resection is the first line of treatment for solitary lesions and is sometimes indicated for lesions causing mass effect or to decrease catecholamine excess associated with various symptoms/signs. Therefore, surgery (in those that qualify) collectively increases overall survival by 24% [69].

In inoperable patients with PPGL (due to poor performance status or location, for example, HNPGLs abutting eloquent neurologic structures, thus precluding surgery) systemic and/or local radiotherapies are the treatments of choice [33, 34].

Rate-of-growth (fast versus slow growing) in progressive disease, guides subsequent management. In more rapidly progressive inoperable disease, patients are most often treated with CVD chemotherapy, followed by tyrosine kinase inhibitors (TKIs), and finally, in some selected patients, immunotherapy [22, 69]. Immunotherapy using pembrolizumab, a humanized anti-PD-1 receptor antibody, is being investigated in clinical trials evaluating patients with cluster 1 and 2 tumors with PD-L1 expression but must be further reviewed [69–71]. Chemotherapy can elicit a response (defined as decreased or normalized blood pressure/decreased number and dosage of antihypertensive medications and/or reduced tumor size) in a few weeks as opposed to radionuclide therapies that may require 6–12 months [69]. CVD chemotherapy is usually the first line of treatment and is especially effective in patients with cluster 1 tumors (complete response: 11%, partial response 44%) [6, 69]. Chemotherapy with temozolomide (TMZ) is a common second line of treatment, due to its efficacy as a short-term treatment, or in conjunction with capecitabine (CAPTEM), which has been shown to prolong survival in advanced neuroendocrine tumors, but requires further study in PPGLs [70, 71]. TKIs are also being studied in the treatment of PPGL and may be an alternative if CVD and/or CAPTEM are ineffective or implemented as a first-line therapy [72–74]. Current TKIs under ongoing investigation include: sunitinib, pazopanib, cabozantinib, axitinib, and anlotinib which have been shown to elicit very promising responses in various cohorts overall [73, 75, 76]. Notably, both CVD and systemic radiotherapy may lead to cell lysis, consequent catecholamine release, and associated complications; therefore, close monitoring upon initiation of treatment is advisable.

In more indolent inoperable disease, patients are treated with targeted peptide receptor radionuclide therapies (¹³¹I-mIBG: low-specific-activity or high-specific-activity) or ¹⁷⁷Lu-DOTATATE (Lutathera^©) if their corresponding functional imaging (¹²³I-mIBG or ⁶⁸Ga-DOTATATE) demonstrates radiotracer uptake within their tumors. Previously, some treatment options included either high-specific-activity ¹³¹I-mIBG or ¹⁷⁷Lu-DOTATATE (Lutathera^©). Patients with sufficient bone marrow reserve, high catecholamine burden, and avidity on ¹²³I-mIBG scintigraphy qualify for the FDA-approved high-specific-activity ¹³¹I-mIBG therapy (Azedra^©), however, its production has been discontinued [23, 68, 77]. So, in such cases, low-specific-activity ¹³¹I-mIBG therapy is a suitable alternative [23, 68]. Lutathera^© (¹⁷⁷Lu-DOTATATE) is best suited for patients who are avid on ⁶⁸Ga-DOTATATE or ⁶⁴Cu-DOTATATE [23, 58, 68]. It is often well-tolerated with a disease control rate of up to 90% and can be given to patients greater than 65 years of age or patients with compromised bone marrow reserve [23, 68]. Thus, in hypoxic patients with disease that is avid on both studies (¹²³I-mIBG and ⁶⁸Ga-DOTATATE), perhaps Lutathera^© may be preferable as it imposes less of a risk in suppressing erythropoiesis (an essential compensation in hypoxic patients), especially if high ¹³¹I-mIBG doses are considered for treatment [23]. However, endocrinopathies may be seen with Lutathera^© [78, 79]. Other options for inoperable patients with ⁶⁸Ga-DOTATATE avid disease include somatostatin analogs, such as lanreotide or octreotide, often in those with cluster 1 tumors, especially SDHx PPGLs [80–82]. Currently, a phase II trial evaluating lanreotide in inoperable/metastatic PPGL is ongoing (LAMPARA, NCT03946527) and its results would be pivotal in determining its efficacy in this cohort.

Therefore, in short, these imaging modalities have a two-fold benefit as they bind to and highlight somatostatin receptors upon tumors, allowing them to be imaged, while simultaneously demonstrating that therapy directed toward somatostatin receptors is effective [7, 82–84]. Alternatively, if patients progress on chemotherapy and radionuclide therapy, or cannot qualify for radionuclide therapy (because the disease is not avid on ¹²³I-mIBG scintigraphy or ⁶⁸Ga-DOTATATE PET), these patients may be treated with TKIs or chemotherapy with CVD or TMZ, as described above.

Avidity on various imaging modalities is a significant indicator of treatment viability and certain pathogenic variants have a higher incidence of positive response on certain therapies. CVD therapy has been shown to elicit continued tumor reduction in SDHB-mutated tumors. This positive response with CVD can also be extended to subsequent treatment with TMZ which has higher susceptibility due to increased methylation in the O⁶-methylguanine-DNA methyltransferase (MGMT) promoter region in SDHB-mutated tumors [6]. As such, a similar response is elicited in SDHx pathogenic variants due to similar pseudohypoxia-driven increases in succinate and DNA hypermethylation [6]. For those patients with fast-growing metastatic disease SDHx pathogenic variants that demonstrate sensitivity to ⁶⁸Ga-DOTATATE PET/CT usually have a positive response to somatostatin analogs [23]. A trial at the NIH evaluating patients that underwent treatment with Lutathera^© demonstrated a 6-month progression-free survival of 19.1 months (22.7 in sporadic cohorts, and 15.4 in SDHx cohorts) further demonstrating that differences in treatment efficacy can be observed with different pathogenic variants [23, 85]. If these, more therapeutic, treatment options do not suffice, experimental options (as discussed below) can be pursued.

Currently, promising therapies include antagonists of the hypoxia signaling pathway (such as belzutifan), which is overactive in cluster 1 pathogenic tumors, PRRT with somatostatin antagonist, and α-emitter based targeted radiotherapy [86–89]. Clinical trials assessing the utility of belzutifan (NCT04924075), a HIF-2α inhibitor currently approved for the treatment of tumors harboring a VHL pathogenic variant, are ongoing [86–88]. Belzutifan could be a promising treatment modality carefully selected for patients with lung metastases given its efficacy, tolerability, and mechanism as it opposes the overactive hypoxia signaling pathway. Nevertheless, caution must be exercised in patients with hypoxemia as belzutifan decreases erythropoietin production resulting in anemia and potentially worsening tissue hypoxia [87, 88, 90, 91]. Providers that encounter non-hypoxic pediatric patients with lung metastases from cluster 1 tumors and suitable bone marrow reserve should consider enrollment on a clinical trial if available. Alternatively, an initial pilot study with ²²⁵Ac-DOTATATE suggests that α-emitter therapy could control metastatic disease and improve the quality of life in PPGL patients [23, 89].

Pediatric patients with PPGL are predisposed to more aggressive disease presentations (multifocal/metastatic, extra-adrenal, and recurrent) over their lifespan compared to adult patients. If PPGLs metastasize to the lungs the risk of mortality may increase, especially when lesions are innumerable and secretory, as represented by patient 3 presented in this report. Despite these clinical challenges, by rationally considering the context of hypoxia, catecholamine excess, genetic background, and age, early intervention can minimalize morbidity and offer a favorable prognosis.