Approximately 40% of pediatric PCCs have a hereditary disposition, despite the ‘classic’ teaching from the rule of 10s. Multiple endocrine neoplasia 2 (MEN2), VHL, and neurofibromaosis 1 (NF1), and germline mutations in Succinate Dehydrogenase (SDH) constitute the best-known genetic syndromes associated with PCC (Table 2) [1,5]. In addition, up to 70–80% of pediatric patients with PCC or paraganglioma have an associated germline mutation, which may or may not be hereditary in nature or associated with a genetic syndrome [2,7,8]. King et al. evaluated 49 patients less than 20 years old with PCC or paraganglioma and found that 79% of patients had a germline mutation involving SDH, VHL, or NF1 . Similarly, Neumann et al. found 70% of patients less than 10 years, 51% of patients between 10 and 20 years, and 16% of patients more than 20 years of age had an associated germline mutation when tested for RET, VHL, and SDH . Considering this strong association, genetic testing is recommended in all children, adolescents and young adults with PCC or paraganglioma [20▪▪]. Similarly, patients with either a family history or known genetic disposition including MEN2 and VHL should undergo regular screening, generally with biochemical testing yearly starting at age 5 years (Table 2) [15▪].
MEN2 is a rare autosomal dominant disorder characterized by an activating mutation in the RET oncogene that is associated with a more than 50% risk of developing PCC [1,3]. In a recent study by Makri et al., 21% of patients with MEN2B developed PCC, and all of these were associated with the classic M918T RET mutation. Five of these were diagnosed with screening, and only three patients presented with clinical symptoms, highlighting the importance of screening for early diagnosis.
Although less common, patients with NF1 have a higher risk of developing PCC compared with the general population . In general, PCC occurs in these patients at a later age and is not frequently seen in pediatric patients [15▪]. A retrospective study by Gruber et al. identified 41 patients with NF1 and PCC and analyzed patient and tumor characteristics at presentation and methods of diagnosis. With this data, they proposed biochemical screening in patients with NF1 should be completed every 3 years starting at age 10 years .
Description of germline mutations of SDH complex genes and their association with PCC has been more recently described. Jha et al. described 15 patients aged 11–57 years with PCC/paraganglioma and a mutation in SDHA. Ten of these patients had documented metastasis during the study period . Additionally, SDHB has been associated with higher prevalence of aggressive and metastatic disease . Asymptomatic carriers are generally identified through genetic testing of family members with SDH-related disease . Considering lesions associated with SDH mutations are generally biochemically silent, screening requires serial imaging. For patients with SDHB mutations, abdominal MRI is recommended every 18 months with MRI of the neck, thorax, abdomen and pelvis every 3 years . There are no defined screening recommendations in patients with SDHA, SDHC, or SDHD, but it is generally accepted that screening can be less frequent .
Recently, there have been more cases describing a relationship between cyanotic congenital heart disease and PCC/paraganglioma . These cases describe patients who have been in a chronic hypoxic state, suggesting a link between hypoxia-induced cellular pathways and tumorigensis . A recent case series by Song et al. describes seven patients diagnosed with PCC or paraganglioma following a Fontan operation, which separates the pulmonary and systemic circulation .
Perioperative management focuses on preventing morbidity from catecholamine release. A catecholamine storm with intraoperative tumor manipulation can result in hypertensive crisis with cardiac arrhythmias, myocardial ischemia, pulmonary edema, and stroke if not managed appropriately [15▪]. There is no randomized trial assessing various regimens of preoperative management, and management in pediatric patients is again largely extrapolated from the adult literature . Alpha blockade is recommended preoperatively along with a high-salt diet and hydration to increase intravascular volume . Options for alpha-adrenergic blockade include phenoxybenzamine, doxazosin, prazosin, or terazosin . Alternative regimens include a tyrosine hydroxylase inhibitors or calcium channel blockers. Calcium channel blockers have also been used as adjunctive therapy, or rarely monotherapy in mild cases . Following alpha blockade, patients generally require beta blockade to prevent reflex tachycardia. In many cases, patients are admitted preoperatively for medical optimization and fluid management  . Of critical importance is presurgical optimization, involving endocrinology and/or nephrology and anesthesiology. Postoperatively, most patients will require admission to an ICU to monitor for postoperative blood pressure and rebound hypoglycemia.
When feasible, minimally invasive surgical techniques are preferable for tumor resection in the appropriately selected patient . However, open resection may be a safer approach for large, locally invasive tumors because of risk of tumor spillage. Depending on surgical expertise, the approach may be transperitoneal or retroperitoneal, although the majority of cases reported are a transperitoneal approach owing to superior exposure [34,35]. Considering laparoscopic adrenalectomy remains a relatively new approach in children, there is very little literature available evaluating safety of the laparoscopic approach in pediatric patients with PCC. A study reported a series of 68 patients, 9 with PCC, who underwent minimally invasive adrenalectomy with overall favorable results and low intraoperative complication rates. Two of the patients with PCC, both with VHL, did have recurrence, one locally and one with para-aortic recurrence .
Cortical sparing surgery (partial adrenalectomy) is recommended for patients with known bilateral disease or patients at high risk of disease recurrence, such as patients with known hereditary syndromes. A residual remnant of about 15% of the adrenal is adequate to preserve function . On the basis of available data, patients are at a 10% risk of local disease recurrence following cortical sparing surgery, highlighting the need for continued follow-up in these patients .
Malignant PCC is defined as occurrence in nonchromaffin tissue, separate from the primary tumor site (i.e. distant spread) . Malignancy rates are significantly higher in the pediatric population and have been reported up to 50% [6,39▪▪]. Common sites of metastases include bone, lung, liver, and lymph nodes. Disease-specific survival is significantly lower in malignant PCC at 31% compared with 100% in benign disease . Surgical resection remains the mainstay of treatment for malignant PCC as these tumors have relatively poor responses to alternative therapies. Mittal et al. recently reported a case of a 14-year-old child with local recurrence of PCC and multiple para-aortic lymph node metastases 8 years following left adrenalectomy. The patient was successfully treated with retroperitoneal lymph node dissection. There are a variety of available therapies that aim to control malignant disease that is not amenable to surgical resection, but data in the pediatric population are sparse. The inherent differences between tumors in adults and children must be considered as well as the impact of toxic therapies in the pediatric population.
Ablative therapy has been shown to be effective in adults with metastatic disease . It has been studied both as palliation as well as an adjunct to surgical debulking, but surgical resection remains the standard therapy [40,41].
Radiotherapy can be also used for palliation. External beam radiation therapy has been used alone or in conjunction with 131I-MIBG therapy but with the goal of maintaining disease stability and less for regression of disease or cure .
Multiple chemotherapy regimens have been reported, including regimens of gemcitabine and docetaxel, vincristine, cyclophosphamide, doxorubicin, and dacarbazine. The combination of cyclophosphamide, vincristine, dacarbazine has been shown to increase progression-free and overall survival rates in patients without evidence of tumor progression in retrospective review of 23 patients with a mean age 41.7 . There is currently an active phase II clinical trial (NCT03165721) aimed to evaluate the efficacy of guadecitabine, a DNA methyl transferase inhibitor in children and adults with gastrointestinal stromal tumor, PCC, or paraganglioma associated with a germline SDH mutation. Tyrosine kinase inhibitor therapy with sunitinib has also been described for management of refractory malignant PCC . Due to the rarity of this disease, there are limited data supporting its use.
Follow-up including detailed history, blood pressure monitoring, and biochemical testing for patients with history of PCC is recommended at 6 weeks, 6 months, and 1 year postoperatively followed by annual screening with intermittent imaging. Lifetime follow-up is recommended particularly in patients with recurrent or metastatic disease .
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Unusual Cancers of Childhood Treatment (PDQ (R)): health professional version. In: Board PPTE, ed. PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute; 2019.
2. Bausch B, Wellner U, Bausch D, et al. Long-term prognosis of patients with pediatric pheochromocytoma
. Endocr Relat Cancer 2014; 21:17–25.
3. Bholah R, Bunchman TE. Review of pediatric pheochromocytoma
. Front Pediatr 2017; 5:155.
4. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma
: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99:1915–1942.
5. Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma
, and medullary thyroid cancer. Pancreas 2010; 39:775–783.
6. Pham TH, Moir C, Thompson GB, et al. Pheochromocytoma
in children: a review of medical and surgical management at a tertiary care center. Pediatrics 2006; 118:1109–1117.
7. King KS, Prodanov T, Kantorovich V, et al. Metastatic pheochromocytoma
related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 2011; 29:4137–4142.
8. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma
. N Engl J Med 2002; 346:1459–1466.
9▪▪. Babic B, Patel D, Aufforth R, et al. Pediatric patients with pheochromocytoma
should have routine preoperative genetic testing for common susceptibility genes in addition to imaging to detect extra-adrenal and metastatic tumors. Surgery 2017; 161:220–227.
This is a retrospective study including 55 patients aged less than 21 years with a diagnosis of PCC or paraganglioma. Patient characteristics including genetic testing were analyzed, finding 80% of patients had an associated germline mutation; 38% VHL, 25% SDHB. Sixty-seven percent of patients had pheochromocytoma and 51% of these patients had bilateral tumor. Of patients with bilateral tumor, 79% of patients with bilateral PCCs had VHL mutation. This study provides good demographic data in a fairly large group of pediatric patients, highlighting differences from an adult population and the importance of genetic analysis in considering disease prognosis and management.
10. Jha A, de Luna K, Balili CA, et al. Clinical, diagnostic, and treatment characteristics of SDHA-related metastatic pheochromocytoma
. Front Oncol 2019; 9:53.
11. Asai S, Katabami T, Tsuiki M, et al. Controlling tumor progression with cyclophosphamide, vincristine, and dacarbazine treatment improves survival in patients with metastatic and unresectable malignant pheochromocytomas/paragangliomas. Horm Cancer 2017; 8:108–118.
12. Fishbein L, Bonner L, Torigian DA, et al. External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma
and nonhead and -neck paraganglioma
: combination with 131I-MIBG. Horm Metab Res 2012; 44:405–410.
13. Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic Acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma
. J Clin Endocrinol Metab 2007; 92:4602–4608.
14. Weise M, Merke DP, Pacak K, et al. Utility of plasma free metanephrines for detecting childhood pheochromocytoma
. J Clin Endocrinol Metab 2002; 87:1955–1960.
15▪. Jain A, Baracco R, Kapur G. Pheochromocytoma
-an update on diagnosis, evaluation, and management. Pediatr Nephrol 2019; doi: 10.1007/s00467-018-4181-2. [Epub ahead of print].
This is the most recent review of available literature available, providing a comprehensive overview of the diagnosis and management of pediatric PCC.
16. Darr R, Pamporaki C, Peitzsch M, et al. Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions. Clin Endocrinol (Oxf) 2014; 80:478–486.
17. Boot C, Toole B, Johnson SJ, et al. Single-centre study of the diagnostic performance of plasma metanephrines with seated sampling for the diagnosis of phaeochromocytoma/paraganglioma
. Ann Clin Biochem 2017; 54:143–148.
18. Sait S, Pandit-Taskar N, Modak S. Failure of MIBG scan to detect metastases in SDHB-mutated pediatric metastatic pheochromocytoma
. Pediatr Blood Cancer 2017; 64: doi: 10.1002/pbc.26549. [Epub ahead of print].
19. Rufini V, Treglia G, Castaldi P, et al. Comparison of metaiodobenzylguanidine scintigraphy with positron emission tomography in the diagnostic work-up of pheochromocytoma
: a systematic review. Q J Nucl Med Mol Imaging 2013; 57:122–133.
20▪▪. Dias Pereira B, Nunes da Silva T, Bernardo AT, et al. A clinical roadmap to investigate the genetic basis of pediatric pheochromocytoma
: which genes should physicians think about? Int J Endocrinol 2018; 2018:8470642.
This is a a comprehensive review of the known genetic syndromes and gene mutations associated with PCC. The aim is to provide guidance for genetic testing based on phenotype of disease.
21. Makri A, Akshintala S, Derse-Anthony C, et al. Pheochromocytoma
in children and adolescents with multiple endocrine neoplasia type 2B. J Clin Endocrinol Metab 2019; 104:7–12.
22. Igaki J, Nishi A, Sato T, Hasegawa T. A pediatric case of pheochromocytoma
without apparent hypertension associated with von Hippel-Lindau disease. Clin Pediatr Endocrinol 2018; 27:87–93.
23. Colvin A, Saltzman AF, Walker J, et al. Metastatic pheochromocytoma
in an asymptomatic 12-year-old with von Hippel-Lindau disease. Urology 2018; 119:140–142.
24. Dagdeviren Cakir A, Turan H, Aykut A, et al. Two childhood pheochromocytoma
cases due to von hippel-lindau disease, one associated with pancreatic neuroendocrine tumor: a very rare manifestation. J Clin Res Pediatr Endocrinol 2018; 10:179–182.
25. Gruber LM, Erickson D, Babovic-Vuksanovic D, et al. Pheochromocytoma
in patients with neurofibromatosis type 1. Clin Endocrinol (Oxf) 2017; 86:141–149.
26. Tufton N, Sahdev A, Akker SA. Radiological surveillance screening in asymptomatic succinate dehydrogenase mutation carriers. J Endocr Soc 2017; 1:897–907.
27. Settas N, Faucz FR, Stratakis CA. Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. Mol Cell Endocrinol 2018; 469:107–111.
28. Zhao B, Zhou Y, Zhao Y, et al. Co-occurrence of pheochromocytoma
and cyanotic congenital heart disease: a case report and literature review. Front Endocrinol (Lausanne) 2018; 9:165.
29. Wcislak SM, King WS, Waller BR3rd, et al. Multifocal pheochromocytoma
in a 29-year-old woman with cyanotic congenital heart disease. Surgery 2019; 165:228–231.
30. Song MK, Kim GB, Bae EJ, et al. Pheochromocytoma
in Fontan patients: common more than expected. Congenit Heart Dis 2018; 13:608–616.
31. Fishbein L, Orlowski R, Cohen D. Pheochromocytoma
: review of perioperative management of blood pressure and update on genetic mutations associated with pheochromocytoma
. J Clin Hypertens (Greenwich) 2013; 15:428–434.
32. Lebuffe G, Dosseh ED, Tek G, et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia 2005; 60:439–444.
33. Romero M, Kapur G, Baracco R, et al. Treatment of hypertension in children with catecholamine-secreting tumors: a systematic approach. J Clin Hypertens (Greenwich) 2015; 17:720–725.
34. Dokumcu Z, Divarci E, Ertan Y, Celik A. Laparoscopic adrenalectomy in children: a 25-case series and review of the literature. J Pediatr Surg 2018; 53:1800–1805.
35. Fascetti-Leon F, Scotton G, Pio L, et al. Minimally invasive resection of adrenal masses in infants and children: results of a European multicenter survey. Surg Endosc 2017; 31:4505–4512.
36. Brauckhoff M, Stock K, Stock S, et al. Limitations of intraoperative adrenal remnant volume measurement in patients undergoing subtotal adrenalectomy. World J Surg 2008; 32:863–872.
37. Yip L, Lee JE, Shapiro SE, et al. Surgical management of hereditary pheochromocytoma
. J Am Coll Surg 2004; 198:525–534. discussion 534- 525.
38. Mittal J, Manikandan R, Dorairajan LN, Toi PC. Recurrent malignant pheochromocytoma
with lymph nodal metastasis in a child: a rare case. J Indian Assoc Pediatr Surg 2017; 22:242–244.
39▪▪. Pamporaki C, Hamplova B, Peitzsch M, et al. Characteristics of pediatric vs adult pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 2017; 102:1122–1132.
This large retrospective study includes 748 patients from seven different tertiary medical centers. Out of 748 patients, 95 presented in childhood. In this pediatric subset, 80.4% of patients had hereditary predisposition vs. 52.6% in adults, 66.3% had extra-adrenal disease vs. 35.1% of adults, 32.6% had multifocal vs. 13.5% of adults, 49.5% had metastatic disease vs. 29.1% of adults, and 29.5% had disease recurrence vs. 14.2% of adults. This is one of the largest data sets we have that notes the significant differences between the pediatric and adult population.
40. Kohlenberg J, Welch B, Hamidi O, et al. Efficacy and safety of ablative therapy in the treatment of patients with metastatic pheochromocytoma
. Cancers (Basel) 2019; 11: pii: E195.
41. de Paula Miranda E, Lopes RI, Padovani GP, et al. Malignant paraganglioma
in children treated with embolization prior to surgical excision. World J Surg Oncol 2016; 14:26.
42. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. (131)I-MIBG therapy for malignant paraganglioma
and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) 2014; 80:487–501.
43. Garaventa A, Gambini C, Villavecchia G, et al. Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine. Cancer 2003; 97:1332–1338.
44. Ayala-Ramirez M, Chougnet CN, Habra MA, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 2012; 97:4040–4050.