Abstract
Background
Pediatric pheochromocytomas and paragangliomas (PC/PGLs) are rare with limited data as to what the optimal management approach is. The aim of this study was to determine the role of genetic testing and imaging to detect extra-adrenal and/or metastatic tumors in pediatric PC/PGLs.
Methods
A retrospective study of 55 patients diagnosed at ≤ 21 years of age with PC/PGLs was performed with analysis of data on genetic testing and multimodal imaging.
Results
Eighty percent of patients (n=44/55) had a germline mutation. The majority were found to have either VHL (38%) or SDHB (25.4%) mutation. PC was present in 67% (n=37/55) of patients and was bilateral in 51.3% (n=19/37). The majority of patients with bilateral PC had VHL (79%). Abdominal PGL was present in 21.8% (n=12/55), head and neck PGL in 11% (n=6/55) and thoracic PGL in 3.6% (n=2/55) of patients. For PGL, SDHx accounted for 72% (n=13/18) of mutations. The rate of malignancy was 16.4% (n=9/55), 55.5% had SDHB mutations. In two-thirds of patients, functional imaging identified either extra-adrenal PGL and/or metastatic disease.
Conclusions
The majority of pediatric patients with PC/PGL have germline mutations. Therefore, all pediatric patients with PC/PGLs require genetic testing and imaging to detect extra-adrenal PGL and metastatic disease to guide treatment and follow up.
Keywords: pheochromocytoma, paraganglioma, pediatric, genetic testing, imaging
Introduction
Pheochromocytomas and paragangliomas (PC/PGL) are rare neoplasms in the pediatric population, arising from the neural crest derived chromaffin cells of the adrenal medulla and extra-adrenal ganglion. The incidence of PC/PGL in the pediatric population is 0.2–0.3 cases per million persons. PC and the majority of abdominal PGL of sympathetic ganglia origin are functionally active with hypersecretion of catecholamines and their metabolites. Signs and symptoms of catecholamine excess include hypertension, headaches and/or palpitations. PGLs of the head and neck are derived from parasympathetic ganglia and are commonly non-functioning1.
More than 14 germline and somatic mutations have been identified in association with PC/PGLs2. Common susceptibility genes for PC/PGLs include germline mutations in VHL, SDHx (SDHB and SDHD), RET, and NF1. Previous studies have identified that mutations in these genes may be present in up to 70% of individuals younger than 18 years who have PC/PGL3,4. In the pediatric population, about one-third of patients with PC/PGL present with bilateral adrenal PC and 18 to 22% have extra-adrenal PGL5,6. The rate of malignancy reported has varied depending on the study and ranges from 12–56%7. The rate of malignancy also varies depending on the presence of the specific germline mutation. For example, King and colleagues8 describing metastatic PC/PGL associated with SDHB germline mutations in 71.9% of patients. A recent Endocrine Society Practice Guideline recommended considering genetic testing in all patients with PC/PGLs, although the clinical utility may be limited in individuals with unilateral PC, no family history and no evidence of metastatic disease. In addition, computed tomography (CT) was recommended as first line imaging for a new diagnosis of PC/PGL and functional imaging to evaluate for metastatic disease9.
The aim of this study was to determine the role of genetic testing and imaging to detect extra-adrenal and/or metastatic tumors in pediatric PC/PGLs.
Methods and Materials
A retrospective analysis in pediatric patients (≤ 21 years of age at diagnosis) with PC/PGLs was conducted. All patients were enrolled in clinical protocols (NCT00004847, NCT00062166, and NCT01005654) at the National Institutes of Health Clinical Center after written informed consent was obtained from the patient or their guardians. The studies were approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Cancer Institutes (NCI) institutional review board.
Inclusion criteria for the current study included patients ≤ 21 years of age with biochemical, histologic and or imaging evidence of PC/PGLs. Demographic data, including age at diagnosis, clinical presentation, family history, biochemical data, imaging, and pathology results were obtained from the electronic medical and radiology records. Biochemical data included plasma free metanephrine and normetanephrine, 24-hour urine fractionated metanephrine and normetanephrine, total 24-hour urine metanephrine, and plasma and 24-hour urine dopamine. Imaging studies included contrast-enhanced anatomic imaging with CT and/or magnetic resonance imaging (MRI) and functional imaging; 18F-fluorodeoxyglucose (18F-FDG) PET/CT, 18F-L-dihydroxyphenylalanine (18F-FDOPA) PET/CT, 18F-Fluorodopamine (18F-FDA) PET/CT, I-123 metaiodobenzylguanidine (I-123 MIBG), and or 68Ga-DOTATATE PET/CT. Tumors were classified as solitary or multiple, PC laterality (unilateral or bilateral), bilateral at initial presentation (synchronous) or developing a contralateral PC after initial presentation (metachronous), recurrence, defined as tumor recurrence at previously resected site or developing new primary at different anatomic location that was not metastatic disease. Recurrent lesions were biochemically active and/or patients were symptomatic. Primary tumor location was defined as adrenal or extra-adrenal abdominal, head and neck or thoracic. Tumors were classified as benign or malignant, based on metastasis to lymph nodes or distant sites were chromaffin cells are not present.
Genetic testing in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory for PC/PGL susceptibility genes (VHL, RET, SDH A-D and MAX) was performed. Recurrence time was defined as presentation of new lesion(s) requiring operative intervention in months from the last operative intervention. CT and/or MRI and at least one functional imaging modality (18F-FDG PET/CT, I-123MIBG, 18F-FDOPA PET/CT, 68Ga-DOTATATE PET/CT, and/or 18F-FDA PET) results were analyzed for the detection of number of tumors and sites of extra-adrenal disease. This was compared to the number of tumors confirmed on pathology and the detection rate calculated. Skeletal metastasis was evaluated based on anatomic and functional imaging and not based on pathological confirmation.
Results
Genetic Findings and Rate of Extra-adrenal and Metastatic PC/PGLs
Fifty-five pediatric patients with PC/PGLs were included with a mean age at diagnosis of 13.6 ± 5.03 years. The clinical and genetic features of the study cohort are summarized in Table 1. In Figure 1, the frequency of distribution of PC/PGLs by age category and the germline mutation status is summarized. Genetic testing revealed that 80% of patients had a germline mutation in a known susceptibility gene; VHL 38%, SDHB 25.4%, SDHD 7.2%, RET 5.4%, SDHA 1.8%, NF1 1.8% and MAX 1.8%. In 20% (n=11/55) of patients, there was no known germline mutation identified. In the entire cohort, 40% (n=22/55) of patients had a family history and of those with a family history, all had a germline mutation. Of patients without a family history, 66.7% had a germline mutation (n=22/33), VHL (n=5/22), RET (n=3/22), SDHB (n=9/22), SDHD (n=3/22), SDHA (n=1/22), and NF1 (n=1/22).
Table 1.
Demographics, clinical and genetic features
| Variable | Mean ± SD, Number (%) |
|---|---|
| Age at presentation | 13.9 ± 5.03 years |
| Gender, n (%) | |
| Male | 30 (54.5) |
| Female | 25 (45.5) |
| Germline Mutations, n (%) | 44 (80) |
| VHL | 21 (38.2) |
| SDHB | 13 (23.6) |
| SDHD | 4 (7.3) |
| SDHA | 1 (1.8) |
| RET | 3 (5.5) |
| NF1 | 1 (1.8) |
| MAX | 1 (1.8) |
| No known germline mutation | 11 (20) |
| Tumor Location, n (%) | |
| Adrenal | 37 (67) |
| Extra-adrenal abdominal | 12 (21) |
| Extra-adrenal head and neck | 6 (10.9) |
| Extra-adrenal thoracic † | 2 (3) |
| Number of tumors, n (%) | |
| Solitary | 41 (74.5) |
| Multiple | 14 (25.5) |
| Malignancy, n (%) | |
| Benign | 47 (85.6) |
| Malignant | 9 (16.4) |
| Recurrence, n (%) | |
| Recurrence in remnant adrenal gland ‡ | 6 (10.9) |
| Recurrence in contralateral adrenal gland | 11 (20) |
| Recurrence at different anatomic site (not metastatic) § | 16 (29) |
| Initial Presentation, n (%) | |
| Signs and symptoms | |
| Screening because of family history | 22 (40) |
| Hypertension | 17 (30.9) |
| Headaches | 2 (3.6) |
| Neck mass | 3 (5.5) |
| Thyroid nodule | 2 (3.6) |
| Clinical manifestations (café-au lait spots) | 1 (1.8) |
| Other (dysphagia, abdominal pain, polycythemia, anemia) | 4 (7.3) |
| Unknown | 4 (7.3) |
| Biochemical Evaluation, n(%) ‖ | |
| Plasma fractionated metanephrines (ref 12–61 mcg/24 hr), n=53 | |
| Normal | 45 (85) |
| Elevated | 8 (15) |
| Plasma fractionated normetanephrines (ref 18–112 pg/mL), n=53 | |
| Normal | 16 (30.2) |
| Elevated | 37 (69.8) |
| 24 hr urine metanephrines (ref 69–221 mcg/24 hr), n=43 | |
| Normal | 40 (93) |
| Elevated | 3 (7) |
| 24 hr urine normetanephrines (ref 29–145 mcg/24 hrs), n=43 | |
| Normal | 28 (65.1) |
| Elevated | 15 (34.9) |
| Total 24 hr urine metanephrines (ref 57–210 mcg/24 hr), n=49 | |
| Normal | 31 (63.3) |
| Elevated | 18 (36.7) |
| Plasma dopamine (ref 3–46 pg/mL), n=45 | |
| Normal | 28 (62.2) |
| Elevated | 17 (37.7) |
| 24 hr urine dopamine (ref 65–400 mcg/24 hrs), n=44 | |
| Normal | 38 (86.4) |
| Elevated | 6 (13.6) |
Two patients with previous PC/PGL resections presented with thoracic PGLs on follow-up
One patient with positive margins
Patients had more than one recurrence
Records not available for all patients
Figure 1.
Frequency of distribution by age category of pheochromocytoma (PC) and paraganglioma (PGL).
At initial presentation, PC was present in 67% (n=37/55) of patients and 21.6% (n=8/37) presented with bilateral synchronous PCs. Six of these patients with bilateral synchronous PC were found to have a VHL germline mutation. The remaining two patients had a germline SDHD and no known germline mutation. Eight percent (n=3/37) of patients with PC presented with metastatic disease. Solitary PC with no family history or evidence of metastatic disease was present in 35.1% (n=13/37) of patients. Of these patients, 61.5% (n=8/13) had a germline mutation. VHL and RET were the most common mutation in patients with a solitary PC and no family history, each with 37.5% (n=3/8). Thirty percent (n=11/37) of patients with PCs developed metachronous, contralateral PCs over a span of 1.3 to 10 years (mean 2.7 ± 1.1 years). Ultimately, 51.3% (n=19/37) of pediatric patients had either bilateral synchronous or metachronous PCs. The majority of these patients (15/19) were found to have a VHL germline mutation (Table 2). Six patients with VHL and PC had recurrences. Four recurrences were a new primary at an extra-adrenal location (three abdominal and one thoracic PGL) and two in the remnant adrenal gland after partial adrenalectomy. Recurrence occurred over a span of 6 months to 16 years (mean 8.1 ± 6.2 years). The patient who recurred within 6 months had positive margins at the initial operation.
Table 2.
Summary of mutations by anatomic tumor location
| Tumor type | Number | VHL | SDHB | SDHD/A | RET | MAX | NF1 | No known germline mutation |
|---|---|---|---|---|---|---|---|---|
| PC | 37 | 20 | 3 | 2 | 3 | 1 | 1 | 7 |
| Solitary | 18 | 5 | 3 | 1 | 2 | 1 | 1 | 5 |
| Bilateral | 19 | 15 | - | 1 | 1 | - | - | 2 |
| PGL | 18 | 1 | 10 | 3 | - | - | - | 4 |
| A-PGL | 12 | 1 | 8 | - | - | - | - | 3 |
| HN-PGL | 6 | - | 2 | 3 | - | - | - | 1 |
| T-PGL | 2* | 1* | 1* | - | - | - | - | - |
| Total | 55 | 21 | 13 | 5 | 3 | 1 | 1 | 11 |
PC=pheochromocytoma; PGL=paraganglioma; A-PGL=abdominal; HN-PGL=head and neck; T-PGL=thoracic pgl
Two patients with previous PC/PGL resections presented with thoracic PGLs during follow-up
Eighteen patients at initial presentation had a PGLs. Extra-adrenal abdominal PGL were present in 21.8% (n=12/55). Six patients presented with head and neck PGL. Two patients with previous PC/PGL resections presented with thoracic PGLs during follow-up. SDHx germline mutations were identified in 72% (n=13/18) of patients with PGLs (SDHB 55.5%, n=10/18; SDHD 16.6%, n=3/18). In the remaining five patients, one had a VHL mutation, and four patients had no germline mutation identified. Seventy-two percent (n=13/18) of patients presenting with extra-adrenal and extra-abdominal PGLs had no family history.
The rate of malignancy was 16.4% (n=9/55). Five patients had SDHB germline mutations, one patient had a SDHA germline mutation, and three patients had no known germline mutation. Three of the nine patients initially presented with a PC, four with extra-adrenal abdominal PGLs and two with head and neck PGLs. Five of nine patients had skeletal metastasis; three patients had SDHB mutations. Of the remaining two patients one had SDHA mutation and one with no known mutation. The other four patients had evidence of metastasis based on pathology (two had germline SDHB mutations).
Imaging Study Results
Imaging studies included anatomic imaging with contrast-enhanced CT and/or MRI, and functional imaging with one or more of the following modalities: 18F-FDG, 18F-FDOPA, 18F-FDA PET/CT, I-123MIBG, and 68Ga-DOTATATE PET/CT. Preoperative imaging studies were analyzed in the detection of PC/PGL based on histologically confirmed PC/PGLs of patients who had an operative intervention at our institution (Tables 3 and 4). CT identified all PC and extra-abdominal PGLs, but had a 68.2% detection rate for abdominal PGLs. MRI had a detection rate of 92.6% for PC, 74% for abdominal PGLs and 100% for extra-abdominal PGLs. 18F-FDG PET/CT identified all extra-abdominal disease and had a higher detection rate for extra-adrenal PGLs compared to all other imaging modalities (Table 4).
Table 3.
Number of tumors detected by preoperative imaging studies in patients with PC/PGL
| Anatomic Location (n1) | ||||
|---|---|---|---|---|
| Imaging | Total | Adrenal | Abdominal PGL |
Head & neck/ Thoracic PGL |
| 71 | 36 | 28 | 7 | |
| CT (n=45) | 57 | 35 | 15 | 7 |
| MRI (n=37) | 48 | 25 | 17 | 6 |
| 18F-FDG PET/CT (n=30) | 45 | 19 | 20 | 6 |
| I-123MIBG (n=26) | 26 | 20 | 6 | * |
| 18F-FDOPA PET/CT (n=10) | 21 | 6 | 13 | 2 |
| 18F-FDA PET/CT (n=6) | 14 | 3 | 11 | * |
| 68Ga-DOTATATE PET/CT (n=4) | 6 | 4 | 2 | * |
Imaging was not performed in patient(s)
n = number of radiological studies performed
n1 = number of histologically confirmed lesions
Table 4.
Detection rate of preoperative imaging studies in patients with PC/PGL
| Abdominal PC and PGL |
PC | Abdominal PGL |
Head & neck/ Thoracic PGL |
Skeletal Metastasis |
|
|---|---|---|---|---|---|
| Imaging Modality | Detection Rate % | ||||
| CT | 87.8 | 100 | 68.2 | 100 | 100 |
| MRI | 84 | 92.6 | 74 | 100 | 100 |
| 18F-FDG PET/CT | 90.7 | 86.4 | 95.2 | 100 | 100 |
| I-123MIBG | 81.2 | 90.9 | 60 | * | 33.3 |
| 18F-FDOPA PET/CT | 86.4 | 100 | 81.3 | 100 | 100 |
| 18F-FDA PET/CT | 93.3 | 100 | 91.6 | * | 100 |
| 68Ga-DOTATATE PET/CT | 60 | 100 | 33.3 | * | * |
Imaging was not performed
18F-FDG PET/CT detected more skeletal metastasis when compared to I-123MIBG. Five of nine (55%) patients with malignant PC/PGL were found to have skeletal metastases by imaging. 18F-FDG PET/CT identified skeletal metastases in all five patients. Two of the five patients with increased focal skeletal avidity on 18F-FDG PET/CT did not have increased uptake on I-123MIBG. I-123MIBG failed to identify skeletal metastasis in two patients with SDHB mutation. Two of five patients with skeletal metastasis had additional functional imaging in addition to 18F-FDG PET/CT: one 18F-FDOPA and one 18F-FDA PET/CT. Both had the same findings as 18F-FDG PET/CT. The number of studies performed for the other functional imaging modalities (18F-FDOPA, 18F-FDA PET/CT, 68Ga-DOTATATE PET/CT) was less in comparison to 18F-FDG PET/CT and I-123MIBG, however all modalities did identify a subset of known PC and PGL lesions.
Discussion
PC/PGL in the pediatric population is rare. In this study, 80% of pediatric patients with PC/PGL were found to have a germline mutation in a known susceptibility gene. Of patients who had no family history, 66% had a germline mutation. Solitary PC with no family history or evidence of metastatic disease was present in 35.1% (n=13/37) of patients with pheochromocytoma. Of those patients, 61.5% (n=8/13) had a germline mutation, with VHL and RET mutations in three patients each and SDHx in the remaining two. 18F-FDG PET/CT detected more extra-adrenal tumors as compared to all other imaging modalities. 18F-FDG PET/CT had comparable number of scans performed to I-123MIBG and was superior when compared to I-123MIBG for detecting extra-adrenal PGL and skeletal metastasis. A small number of other functional studies were performed (18F-FDOPA, 18F-FDA PET/CT), which also detected skeletal metastasis.
A recent Endocrine Society Practice Guideline recommended considering genetic testing in patients with PC/PGL, but there were no specific recommendations for the pediatric population. In addition, the guideline also stated it may not be a necessity to perform genetic testing in individuals with solitary PC or in those who do not have a family history or evidence of metastatic disease9. Our data supports that in the pediatric population, which is defined as individuals younger than 21 in this study, all patients presenting with a PC/PGL should undergo genetic testing, including patients who present with a solitary PC and no family history or evidence of metastasis. This is because approximately two-thirds of patients with a solitary PC with no family history or evidence of metastatic disease had a germline mutation. This finding underscores the importance of genetic testing in the pediatric population regardless of findings of a solitary PC or the lack of family history.
A comprehensive family history for PC/PGL and clinical manifestations (MEN 2 and NF1) are indispensable when evaluating for which genetic test to perform. For patients without a family history, sequential genetic testing based on biochemical profile of catecholamine excess, age at presentation, tumor site, and tumor multiplicity and laterality have been previously proposed9,10. We believe our data supports testing for all known susceptibility genes given the high carrier rate identified in the pediatric population. Of the many susceptibility genes, VHL germline mutations have been described as the most common in pediatric PC/PGL, with patients as young as five years of age developing PC11. SDHB is the most common genetic mutation in PGL3 and should be investigated in individuals presenting with abdominal PGL and metastatic disease. Head and neck PGLs are frequently associated with SDHD mutations12. Head and neck PGL have a low rate of metastatic disease, although this depends on the tumor location (e.g. the rate of metastatic disease is 1.4% for carotid body PGL as compared to 10% for vagal PGL)13. In our cohort, one-third of patients with head and neck PGLs had metastatic disease, which was diagnosed on functional imaging alone. Patients with multiple endocrine neoplasia type 2 (MEN2), caused by a mutation in the RET proto-oncogene, present or develop PC in in 50% of cases14. Rarely, patients with neurofibromatosis type 1 (NF1) present with a PC (1–5.7% of patients). This syndrome is caused by a mutation in the NF1 tumor suppressor gene15 and is commonly diagnosed based on clinical criteria, which includes the presence of six or more caféau-lait spots, two or more neurofibromas and the presence of axillary or inguinal freckles16,17. MAX, myc-associated factor X, mutation was recently characterized18. The gene encodes proteins that are part of a family of transcription factors. A recent analysis of a large cohort of patients with PC/PGL evaluated for MAX mutations and only 1.12% were positive for the mutation19.
Our study results showing a high rate of germline mutations in PC/PGL susceptibility genes in pediatric patients with PC/PGL are consistent with most studies. Hammond and colleagues20 identified germline mutations in 100% of seven patients with PC/PGL. Other investigators have also found a high rate of germline mutations, up to 70 %, in patients under the age of 18 years3,4,21. Our data suggest that all pediatric patients presenting under age 21 with a PC/PGL should have genetic testing performed for common susceptibility genes. This is also supported by the fact that 60% of the pediatric patients did not have a family history. One important factor previously used to support for sequential susceptibility gene testing for PC/PGL was the cost of genetic testing. However, with advances in next generation sequencing allowing for simultaneous testing for mutations/deletions in multiple susceptibility genes such an approach could be cost-effective in pediatric patients with PC/PGL.
Contrast enhanced CT is recommended as the first-line imaging modality for evaluation of PC/PGL with a reported sensitivity of 88–100%, while MRI has been recommended for detection of head and neck PGL, and 18F-FDG PET/CT for metastatic disease9,22. Our results support previously described findings that found 18F-FDG PET/CT had higher sensitivity in comparison to I-123MIBG for detecting metastatic lesions, specifically skeletal metastasis22 as well as recurrent disease23. Functional imaging identified additional sites of disease not identified on anatomical imaging, specifically skeletal metastasis. It is necessary to have both anatomic and functional imaging when evaluating all pediatric patients who present with PC/PGL.
One of the main limitations of the current study is that we are a referral center and thus our study has a selection bias. However, individuals with no family history, solitary tumors, or only symptoms and/or biochemical evidence of a PC/PGL without localization are also evaluated at our institution. This is evident in that 60% of the study cohort had no family history and 74.5% had a solitary tumor at presentation, suggesting our findings would be applicable to the pediatric population with PC/PGL. Furthermore, the number of patients in the cohort is small but pediatric PC/PGL is rare. A limited number of functional imaging studies were performed, excluding 18F-FDG PET/CT and I-123MIBG, to draw definitive conclusions about the specific functional imaging study that is best for detecting extra-adrenal or metastatic disease.
In summary, we found that pediatric patients with PC/PGL have a high rate of germline mutations despite a lack of family history. Given these findings, pediatric patients with PC/PGL would benefit from genetic screening for all known susceptibility genes. Furthermore, these patients require multimodal imaging including anatomical and functional imaging to detect all disease sites for appropriate treatment selection.
Acknowledgments
Grant Support: This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
Footnotes
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AAES Society Paper: American Association of Endocrine Surgeons 37th Annual Meeting (April 10–12, 2016 Baltimore, MD).
Disclosure of Potential Conflicts of Interest: The authors have no potential conflicts of interest to disclose.
References
- 1.Waguespack SG, Rich T, Grubbs E, et al. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010;95:2023–2037. doi: 10.1210/jc.2009-2830. [DOI] [PubMed] [Google Scholar]
- 2.Curras-Freixes M, Inglada-Perez L, Mancikova V, et al. Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet. 2015;52:647–656. doi: 10.1136/jmedgenet-2015-103218. [DOI] [PubMed] [Google Scholar]
- 3.Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466. doi: 10.1056/NEJMoa020152. [DOI] [PubMed] [Google Scholar]
- 4.Cascon A, Inglada-Perez L, Comino-Mendez I, et al. Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients. Endocr Relat Cancer. 2013;20:L1–L6. doi: 10.1530/ERC-12-0339. [DOI] [PubMed] [Google Scholar]
- 5.Barontini M, Levin G, Sanso G. Characteristics of pheochromocytoma in a 4- to 20-year-old population. Ann N Y Acad Sci. 2006;1073:30–37. doi: 10.1196/annals.1353.003. [DOI] [PubMed] [Google Scholar]
- 6.Beltsevich DG, Kuznetsov NS, Kazaryan AM, et al. Pheochromocytoma surgery: epidemiologic peculiarities in children. World J Surg. 2004;28:592–596. doi: 10.1007/s00268-004-7134-9. [DOI] [PubMed] [Google Scholar]
- 7.Armstrong R, Sridhar M, Greenhalgh KL, et al. Phaeochromocytoma in children. Arch Dis Child. 2008;93:899–904. doi: 10.1136/adc.2008.139121. [DOI] [PubMed] [Google Scholar]
- 8.King KS, Prodanov T, Kantorovich V, et al. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011;29:4137–4142. doi: 10.1200/JCO.2011.34.6353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–1942. doi: 10.1210/jc.2014-1498. [DOI] [PubMed] [Google Scholar]
- 10.Erlic Z, Rybicki L, Peczkowska M, et al. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009;15:6378–6385. doi: 10.1158/1078-0432.CCR-09-1237. [DOI] [PubMed] [Google Scholar]
- 11.Aufforth RD, Ramakant P, Sadowski SM, et al. Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome. J Clin Endocrinol Metab. 2015;100:4498–4504. doi: 10.1210/jc.2015-3045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hermsen MA, Sevilla MA, Llorente JL, et al. Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. Cell Oncol. 2010;32:275–283. doi: 10.3233/CLO-2009-0498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rinaldo A, Myssiorek D, Devaney KO, et al. Which paragangliomas of the head and neck have a higher rate of malignancy? Oral Oncol. 2004;40:458–460. doi: 10.1016/j.oraloncology.2003.08.018. [DOI] [PubMed] [Google Scholar]
- 14.Tsang VH, Tacon LJ, Learoyd DL, et al. Pheochromocytomas in Multiple Endocrine Neoplasia Type 2. Recent Results Cancer Res. 2015;204:157–178. doi: 10.1007/978-3-319-22542-5_7. [DOI] [PubMed] [Google Scholar]
- 15.Fishbein L. Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment. Hematol Oncol Clin North Am. 2016;30:135–150. doi: 10.1016/j.hoc.2015.09.006. [DOI] [PubMed] [Google Scholar]
- 16.Zografos GN, Vasiliadis GK, Zagouri F, et al. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends. World J Surg Oncol. 2010;8:14. doi: 10.1186/1477-7819-8-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bausch B, Borozdin W, Neumann HP. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354:2729–2731. doi: 10.1056/NEJMc066006. [DOI] [PubMed] [Google Scholar]
- 18.Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667. doi: 10.1038/ng.861. [DOI] [PubMed] [Google Scholar]
- 19.Burnichon N, Cascon A, Schiavi F, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012;18:2828–2837. doi: 10.1158/1078-0432.CCR-12-0160. [DOI] [PubMed] [Google Scholar]
- 20.Hammond PJ, Murphy D, Carachi R, et al. Childhood phaeochromocytoma and paraganglioma: 100% incidence of genetic mutations and 100% survival. J Pediatr Surg. 2010;45:383–386. doi: 10.1016/j.jpedsurg.2009.10.082. [DOI] [PubMed] [Google Scholar]
- 21.Mazzaglia PJ. Hereditary pheochromocytoma and paraganglioma. J Surg Oncol. 2012;106:580–585. doi: 10.1002/jso.23157. [DOI] [PubMed] [Google Scholar]
- 22.Timmers HJ, Chen CC, Carrasquillo JA, et al. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2009;94:4757–4767. doi: 10.1210/jc.2009-1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Fikri AS, Kroiss A, Ahmad AZ, et al. Localization and prediction of malignant potential in recurrent pheochromocytoma/paraganglioma (PCC/PGL) using 18F-FDG PET/CT. Acta Radiol. 2014;55:631–640. doi: 10.1177/0284185113504330. [DOI] [PubMed] [Google Scholar]