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.[1,2]
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:[1,2]
It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (refer to Table 1). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of subjects have disease by age 26 years.[1,2,3,4]
|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:
(Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
These susceptibility genes can be divided into the following cluster groups on the basis of transcriptomic profiles:
The pseudohypoxia cluster group tumors are characterized by the absence of epinephrine production (noradrenergic phenotype), whereas tumors in the other two cluster groups produce epinephrine (adrenergic phenotype). These differences reflect the absence, versus the presence, of the enzyme phenylethanolamine N-methyltransferase, responsible for conversion of norepinephrine to epinephrine.
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 (refer to Table 1).
Immunohistochemical SDHB staining may help triage genetic testing; tumors of patients with SDHB, SDHC, and SDHD mutations have absent or very weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[7,8] Therefore, immunohistochemical SDHB staining can help identify potential carriers of a SDH mutation early, obviating the need for extensive and costly testing of other genes. Early identification of young patients with SDHB mutations using radiographic, serologic, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB mutation.
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:
These symptoms are often 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. Epinephrine production is also associated with cluster genotype. Cluster 1 tumors are characterized by absence of epinephrine production (noradrenergic phenotype), whereas cluster 2 tumors produce epinephrine (adrenergic phenotype).
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 clinical behavior of paraganglioma and pheochromocytoma appears to be more aggressive in children and adolescents and metastatic rates of up to 50% have been reported.[3,4,5] As previously discussed, children and adolescents with pheochromocytoma and paraganglioma have a higher prevalence of hereditary, extra-adrenal, multifocal, metastatic, and recurrent pheochromocytomas and paragangliomas; they also have a higher prevalence of cluster 1 mutations, which is paralleled by a higher prevalence of noradrenergic tumors than in adults.
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.[3,4]
For tumor localization, 18F-6F-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 18F-6F-FDA PET than by 123/131I-MIBG.[5,6] Other functional imaging alternatives include indium In 111-octreotide scintigraphy and fluorine F 18-fludeoxyglucose PET, both of which can be coupled with CT imaging for improved anatomic detail.
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.
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.[1,2,3] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival (OS) is less clear.
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, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
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 and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years. The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons. Therefore, all pediatric cancers are considered rare.
The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and they are estimated to account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:
Most cancers within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer 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 incidence 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 the PDQ summary on adult Pheochromocytoma and Paraganglioma Treatment.
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.
Added text about a National Institutes of Health study that reported the clinical characteristics and outcomes of 64 pediatric patients who had pheochromocytoma and paraganglioma with SDHB germline mutations (cited Jochmanova et al. as reference 6).
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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 who care for cancer 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: 2021-03-12
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