Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. Paraganglioma and pheochromocytoma are exceedingly rare in the pediatric and adolescent population, accounting for approximately 20% of all cases.[
Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into the following subtypes:[
Comprehensive molecular profiling of 173 cases of pheochromocytomas and paragangliomas (mean age at diagnosis, 47 years) identified three well-defined molecular subgroups: pseudohypoxia-related clusters 1A and 1B, kinase signaling–related cluster 2, and Wnt signaling–related cluster 3.[
|Subgroup||Associated Genetic Mutations||Germline or Somatic Mutations|
|Cluster 1A||SDHA,SDHB,SDHC,SDHD,FH,MDH2,IDH1,IDH2,GOT2,SLC25A11, andDLST||Most are germline|
|Cluster 1B||EGLN2,EGLN1,VHL,EPAS1, andACO1||25% are germline|
|Cluster 2||RET,NF1,HRAS,TMEM127,MAX, andFGFR1||20% are germline|
|Cluster 3||CSDE1andMAML3||All are somatic|
It is estimated that up to 30% of all pheochromocytomas and paragangliomas are familial, and several susceptibility genes have been described (see Table 2). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of patients have the disease by age 26 years.[
|Germline Mutation||Syndrome||Proportion of all PGL/PCC (%)||Mean Age at Presentation (y)||Penetrance of PGL/PCC (%)|
|MEN1 = multiple endocrine neoplasia type 1; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; VHL = von Hippel-Lindau.|
| a Adapted from Welander et al.[
|SDHB, C, D||Carney-Stratakis||<1||33||Unknown|
|No mutation||Sporadic disease||70||48.3||-|
Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:
Tumors from patients with SDHB and SDHC mutations mainly arise in extra-adrenal locations, whereas tumors from patients with SDHD mutations are mainly found in the head and neck area. SDHA mutations are linked to sympathetic and parasympathetic paragangliomas. For more information, see Table 2.
For more information, see the Familial Pheochromocytoma and Paraganglioma Syndrome section in Genetics of Endocrine and Neuroendocrine Neoplasias.
Studies of germline mutations in young patients with pheochromocytoma or paraganglioma have shown that these patients have a higher prevalence (70%–80%) of germline mutations and have further characterized this group of neoplasms, as follows:
It is important to note that these two studies did not include systematic screening for other genes that have been recently described in paraganglioma and pheochromocytoma syndromes, such as KIF1B, EGLN1, TMEM127, SDHA, and MAX (see Table 2).
Immunohistochemical SDHB staining may help triage genetic testing. Tumors of patients with SDHB, SDHC, and SDHD mutations have absent or weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[
Given the higher prevalence of germline alterations in children and adolescents with pheochromocytoma and paraganglioma, genetic counseling and testing should be considered in this younger population.
Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production:
In one study, 2,291 adult patients were evaluated for the diagnosis of pheochromocytoma and paraganglioma. Patients were tested because of initial signs or symptoms, detection of an incidental mass on imaging or during routine surveillance because of a previous history of pheochromocytoma or paraganglioma, or a hereditary risk associated with a mutation of a tumor susceptibility gene. The study used a 7-point clinical scoring system that included pallor, hyperhidrosis, palpitations, tremor, nausea, body mass index of less than 25 kg/m2, and heart rate of 85 beats per minute or higher to identify patients at risk of having pheochromocytoma or paraganglioma. A score of 3 or higher was associated with a 5.8-fold higher likelihood of being diagnosed with a paraganglioma or a pheochromocytoma, compared with patients who had a lower score.[
Symptoms of pheochromocytoma and paraganglioma can be paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half of patients. These symptoms can also be induced by exertion, trauma, induction of anesthesia, resection of the tumor, consumption of foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder).[
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression, but also may be asymptomatic and diagnosed incidentally.[
The pediatric and adolescent patient appears to present with symptoms similar to those of the adult patient, although with a more frequent occurrence of sustained hypertension.[
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging:
Catecholamine metabolic and secretory profiles are impacted by hereditary background; both hereditary and sporadic paraganglioma and pheochromocytoma differ markedly in tumor contents of catecholamines and corresponding plasma and urinary hormonal profiles. About 50% of secreting tumors produce and contain a mixture of norepinephrine and epinephrine, while most of the rest produce norepinephrine almost exclusively, with occasional rare tumors producing mainly dopamine. Patients with epinephrine-producing tumors are diagnosed later (median age, 50 years) than those with tumors lacking appreciable epinephrine production (median age, 40 years). Patients with multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1) syndromes, all with epinephrine-producing tumors, are typically diagnosed at a later age (median age, 40 years) than are patients with tumors that lack appreciable epinephrine production secondary to mutations of VHL and SDH (median age, 30 years). These variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of paraganglioma and pheochromocytoma for different progenitor cells with variable susceptibility to disease-causing mutations.[
For tumor localization, 18F-6-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 18F-6-FDA PET than by 123/131I-MIBG.[
A single-institution retrospective evaluation of consecutive pediatric patients with pheochromocytoma and paraganglioma (aged, ≤20 years) compared functional imaging with 131I-MIBG, 18F-FDG PET-CT, and 68Ga-DOTATATE PET-CT.[
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[
The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[
Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.
These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.
Information about these tumors may also be found in sources relevant to adults with cancer, such as Pheochromocytoma and Paraganglioma Treatment.
Treatment options for childhood paraganglioma and pheochromocytoma include the following:
Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha- and beta-adrenergic blockade must be optimized before surgery. A single-institutional study reviewed the experience of laparoscopic partial adrenalectomy for bilateral pheochromocytoma in patients with von Hippel-Lindau disease.[
For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or different combinations of vincristine, cyclophosphamide, doxorubicin, and dacarbazine.[
Responses have also been obtained to high-dose 131I-MIBG and sunitinib.[
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Molecular Characterization of Pheochromocytoma and Paraganglioma
Added this new section.
Genetic Factors and Syndromes Associated With Pheochromocytoma and Paraganglioma
Added text to state that one patient with Pacak-Zhuang syndrome was treated with belzutifan, a potent and selective small-molecule inhibitor of the HIF-2 alpha protein. This treatment led to a rapid and sustained tumor response, along with a resolution of hypertension, headaches, and long-standing polycythemia (cited Kamihara et al. as reference 8).
Added text about the results of a single-institution retrospective evaluation of consecutive pediatric patients with pheochromocytoma and paraganglioma that compared functional imaging with iodine I 131-labeled metaiodobenzylguanidine, fluorine F 18-fludeoxyglucose positron emission tomography-computed tomography (PET-CT), and gallium Ga 68-DOTATATE PET-CT (cited Jaiswal et al. as reference 10).
Treatment of Childhood Pheochromocytoma and Paraganglioma
Added text about the results of a single-institutional study that reviewed the experience of laparoscopic partial adrenalectomy for bilateral pheochromocytoma in patients with von Hippel-Lindau disease (cited Rubalcava et al. as reference 2).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Pheochromocytoma and Paraganglioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/pheochromocytoma/hp/child-pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2022-06-08
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