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Pediatric pheochromocytoma

current status of diagnostic imaging and treatment procedures

Peard, Lesliea; Cost, Nicholas G.b; Saltzman, Amanda F.a

doi: 10.1097/MOU.0000000000000650
PAEDIATRIC URO-ONCOLOGY: Edited by Manuela P. Hiess
Free

Purpose of review To provide an overview of relevant data available and updated recommendations for management of pediatric patients with pheochromocytoma (PCC).

Recent findings Much of the available data surrounding pediatric PCC is in the form of case reports and case series. With the accumulation of data over time, pediatric PCC does in fact differ significantly from not only what is known in the adult population, but also from classic teaching. Pediatric patients are much more likely to have a hereditary predisposition as well as aggressive and malignant disease. Much of the recent literature focuses on defining these genetic syndromes in order to provide recommendations for screening and genetic counseling. Other recent advances center around developing treatments for metastatic disease. Timely diagnosis with plasma metanephrines and cross-sectional imaging, and appropriate preoperative medical optimization followed by surgical resection remain the center of treatment.

Summary Although rare and adult principles are applied to pediatric PCC, genetic testing plays a pivotal role in management of children, adolescents and young adults with PCC.

aDepartment of Urology, University of Kentucky, Lexington, Kentucky

bDivision of Urology, Department of Surgery, University of Colorado and Children's Hospital Colorado, Aurora, Colorado, USA

Correspondence to Nicholas G. Cost, MD, 1nue3123 E 16th Avenue, Box 463, Aurora, CO 80045, USA. Tel: +1 720 777 6167; fax: +1 720 777 7370; e-mail: nicholas.cost@childrenscolorado.org

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INTRODUCTION

Pheochromocytoma (PCC) is a rare catecholamine-secreting tumor arising from the chromaffin cells in adrenal medulla [1]. This same tumor arising in an extraadrenal location is called a paraganglioma. PCC has an annual incidence of three cases per 1 million individuals, and PCC in children accounts for 20% of all PCC diagnoses [1]. The average age of presentation in children is between 11 and 13 years old, but patients can present at any age [2,3]. Patients classically present with symptoms of catecholamine excess including hypertension, headache, perspiration, palpations, tremor and facial pallor [4]. These symptoms can be episodic, but in children, symptoms, including hypertension, are more likely to be sustained [4]. In fact, up to 1.7% of children with hypertension have catecholamine secreting tumors compared with 0.2–0.6% of adults [4].

Although the majority of PCCs are benign, the systemic effects of catecholamine excess can have significant morbidity and mortality [5]. Classically, the ‘rule of 10s’ (Table 1) suggests 10% of PCCs are malignant and 10% hereditary. However, children are more likely to have malignancy with aggressive features and reported rates of metastasis reaching up to 50% [1,2,6]. Approximately, 40% of pediatric PCC have a hereditary disposition. Pediatric cases are known to have high rates of associated germline mutations, inherited or sporadic, with rates as high as 70–80% [7,8]. Much of the recent literature focuses on defining these associations as well as developing appropriate screening and surveillance regimens [9▪▪,10].

Table 1

Table 1

There are limited data available concerning management of this rare tumor, particularly in children and adolescents specifically. Recommendations in this age group are often extrapolated from case reports, case series, and data from the adult population. Although the mainstay of treatment for pediatric PCC remains surgery, new treatments and methods for management of metastatic disease have emerged [11,12]. This review aims to provide a critical view of the current status of the literature concerning diagnosis, imaging, and management of pediatric PCC.

Box 1

Box 1

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DIAGNOSIS

Suggested methods of diagnosis are well established in adults, and recommendations for children have been extrapolated from adult studies. There continues to be some debate and emerging data on preference for imaging modalities, particularly considering the goal of minimizing radiation exposure in children.

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LABORATORY TESTING

If there is clinical suspicion for PCC/paraganglioma or for any newly discovered adrenal mass, initial laboratory testing is recommended to evaluate catecholamine excess. Plasma-free fractionated metanephrines or 24-h urine metanephrines are superior to measurement of plasma catecholamines (i.e. norepinephrine, epinephrine) or urine vanillylmandelic acid [13]. In 2002, Wiese et al.[14] worked to establish appropriate reference ranges in children, improving screening with use of this reference range in patients with von Hippel-Lindau (VHL) compared with if adult ranges were used. However, false-positive rates remain high. In general, if levels are less than three to four times normal, a false positive should be considered and testing should be repeated. Medications may lead to a false positive result, including selective serotonin reuptake inhibitors, tricyclic amines, monoamine oxidase inhibitors, and sympathomimetics including amphetamines, decongestants, caffeine or nicotine [15▪]. These medications should be stopped prior to lab testing. It is also recommended that samples be obtained from a fasting patient while supine for at least 30 min [4,16]. In a retrospective review of 113 patients with paraganglioma or PCC, Boot et al. evaluated results from seated patients, finding that noncompliance with appropriate testing conditions can lead to a five-fold to seven-fold increase in false positive results, highlighting the necessity to repeat testing under these conditions [17].

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IMAGING

Patients with laboratory confirmation of catecholamine excess should undergo further evaluation with cross-sectional imaging. Recommended initial imaging includes either Computed tomography (CT) or MRI of the abdomen, which is known to have from over 90% sensitivity for detecting adrenal PCC [3]. PCC has a classic appearance on MRI, often referred to as the lightbulb sign because of its bright appearance on T2-weighted imaging (Fig. 1). In general, MRI is preferred in the pediatric population in an effort to minimize radiation exposure. Functional imaging is indicated in patients with high index of suspicion for PCC but with inconclusive biochemical testing, and to assess for metastasis, multifocal disease, or regional extension. Options for functional imaging include 123I-metaiodobenzylguanidine or 131I-metaiodobenzylguanidine (MIBG) scintigraphy and PET.3123I-MIBG has higher sensitivity compared with 131 I-MIBG and is generally preferred (Fig. 2) [4]. Both PET and 123I-MIBG are sensitive tests for localizing tumor, but PET is preferred for identifying metastatic disease [18]. A recent retrospective review by Sait et al.[18] evaluated 11 pediatric patients with metastatic PCC or paraganglioma and showed that 123I-MIBG was inferior for detection of skeletal metastasis. However, 123I-MIBG has utility when evaluating eligibility of patients with metastatic disease for high-dose 131I-MIBG therapy [19].

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

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GENETIC TESTING AND SCREENING

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 [7]. 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 [8]. 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▪].

Table 2

Table 2

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], 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.

Approximately 10–20% of patients diagnosed with VHL will develop PCC or paraganglioma [1]. Multiple recent cases have been published describing children with VHL and atypical presentations of PCC, including weight loss with adrenal lesion seen on abdominal ultrasound [22], metastatic disease in an asymptomatic child found by elevated plasma metanephrines on screening [23], and bilateral PCC as the presenting symptom of VHL [24].

Although less common, patients with NF1 have a higher risk of developing PCC compared with the general population [25]. 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.[25] 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 [25].

Description of germline mutations of SDH complex genes and their association with PCC has been more recently described. Jha et al.[10] 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 [10]. Additionally, SDHB has been associated with higher prevalence of aggressive and metastatic disease [7]. Asymptomatic carriers are generally identified through genetic testing of family members with SDH-related disease [26]. 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 [26]. There are no defined screening recommendations in patients with SDHA, SDHC, or SDHD, but it is generally accepted that screening can be less frequent [26].

Carney triad syndrome is a rare nonhereditary syndrome associated with PCC/paraganglioma [27]. The syndrome is characterized by PCC/paraganglioma, gastrointestinal stromal tumors (GIST), and pulmonary chondromas, and patients are typically young women. About one half of patients will develop PCC/paraganglioma, with 20% having multiple lesions [1]. Similarly, Carney-Stratakis syndrome, or Carney dyad, is characterized by GIST and PCC/paraganglioma [27]. Tumors in patients with Carney triad syndrome have been shown to have decreased SDH enzymatic activity [27].

Recently, there have been more cases describing a relationship between cyanotic congenital heart disease and PCC/paraganglioma [28]. These cases describe patients who have been in a chronic hypoxic state, suggesting a link between hypoxia-induced cellular pathways and tumorigensis [29]. 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 [30].

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TREATMENT

Surgical resection is the gold standard treatment for PPC [3]. However, appropriate perioperative management is critical to preventing significant morbidity and mortality from hypertensive crisis. Given the high success rate with resection, recent literature and ongoing clinical trials focus on alternative options for management for metastatic disease.

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PERIOPERATIVE MANAGEMENT

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 [31]. Alpha blockade is recommended preoperatively along with a high-salt diet and hydration to increase intravascular volume [3]. Options for alpha-adrenergic blockade include phenoxybenzamine, doxazosin, prazosin, or terazosin [4]. 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 [32]. 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 [33] . 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.

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SURGICAL RESECTION

When feasible, minimally invasive surgical techniques are preferable for tumor resection in the appropriately selected patient [34]. 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 [35].

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 [36]. 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 [37].

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MANAGEMENT OF MALIGNANT DISEASE

Malignant PCC is defined as occurrence in nonchromaffin tissue, separate from the primary tumor site (i.e. distant spread) [38]. 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 [6]. Surgical resection remains the mainstay of treatment for malignant PCC as these tumors have relatively poor responses to alternative therapies. Mittal et al.[38] 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 [5]. It has been studied both as palliation as well as an adjunct to surgical debulking, but surgical resection remains the standard therapy [40,41].

High-dose 131I-MIBG administration can be therapeutic in patients with malignant disease and a positive MIBG scan [42]. The radioactive compound is selectively taken up by tumor cells by the norepinephrine transporter delivering radiation directly to the cancer cells. A 2014 meta-analysis of 17 studies analyzing the effect of 131I-MIBG on tumor volume in patients with PCC/paraganglioma of all ages concluded tumor volume remains stable with partial hormone response in 40–50% of patients (good response), and there was no further progression of disease. However, because of the relative paucity of data, especially in children, it is unclear if this is reflective of response to therapy or natural disease progression [42]. In addition, 131I-MIBG therapy carries a risk of secondary malignancy in children with neuroblastoma, so this risk must be considered here also [43]. There is a current ongoing clinical trial (NCT01163383) aimed to evaluate 131I-MIBG therapy for refractory neuroblastoma and metastatic paraganglioma or PCC in patients more than 1 year of age.

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 [12].

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 [11]. 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 [44]. Due to the rarity of this disease, there are limited data supporting its use.

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FOLLOW-UP RECOMMENDATIONS

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 [4].

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CONCLUSION

Pediatric PCC is rare with recommendations extrapolated from adult PCC and paraganglioma data. Accurate diagnosis, preoperative optimization and complete surgical resection are essential. Pediatric patients with PCC or paraganglioma often have an underlying genetic predisposition to these tumors, unlike adults. It is critical to recommend genetic counseling to these patients and their families.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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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 and paraganglioma. Front Oncol 2019; 9:53.
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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 and paraganglioma: 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.
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28. Zhao B, Zhou Y, Zhao Y, et al. Co-occurrence of pheochromocytoma-paraganglioma 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-paraganglioma in a 29-year-old woman with cyanotic congenital heart disease. Surgery 2019; 165:228–231.
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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.

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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.
Keywords:

adrenal mass; paraganglioma; pheochromocytoma

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