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.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Incidence

Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. These tumors are also rare in the pediatric and adolescent population, accounting for approximately 20% of all cases.[1,2]

Anatomy

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]

• Sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines.
• Parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.

Molecular Characterization of Pheochromocytoma and Paraganglioma

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.[1] About 70% of patients with pheochromocytoma and paraganglioma can be assigned to one of these clusters. Each cluster has unique clinical, biochemical, and imaging characteristics that may help guide the treatment and follow-up of patients.[2,3]

• Cluster 1: These tumors account for about 25% to 35% of paragangliomas and pheochromocytomas, are usually extra-adrenal, and tend to have a noradrenergic biochemical phenotype because these tumors lack the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine.[3,4] Variants in this cluster stabilize HIF-2 alpha and promote angiogenesis and tumor progression. Patients with tumors in this cluster present at a younger age, especially those with SDHB variants (<20 years). Clinically, these patients have sustained hypertension. Patients with cluster 1 tumors develop multiple and recurrent tumors that have the potential for metastatic spread, particularly for patients with SDHA and SDHB variants. With a median follow-up of 5 years, 3 of 30 asymptomatic children (10%) who were carriers of an SDHB variant developed abdominal paragangliomas identified on surveillance imaging. This cluster can be further subdivided into clusters 1A and 1B, as described below.[5]

  • Cluster 1A tumors have variants in the Krebs cycle–associated genes SDHA (AF2), SDHB, SDHC, SDHD, FH, MDH2, IDH1, IDH2, GOT2, SLC25A11, and DLST. Most of these are germline pathogenic variants and have a higher metastatic risk.[5]
  • Cluster 1B tumors have variants in VHL- and EPAS1-related genes such as EGLN2, EGLN1, VHL, EPAS1, and ACO1. About 25% of these are germline pathogenic variants.[5]
• Cluster 2: These tumors usually arise in the adrenal gland and have an adrenergic biochemical phenotype. Cluster 2 tumors affect older patients, with a peak age of 40 years for clinical manifestations. Clinically, they present with an intermittent catecholamine secretion pattern. This cluster includes variants in tyrosine kinases, including RET, NF1, HRAS, TMEM127, MAX, and FGFR1.[5]
• Cluster 3: These tumors have somatic variants of the WNT signaling pathway, which includes variants in the CSDE1 gene and MAML3 gene fusions. These variants are associated with an aggressive clinical course. Cluster 3 tumors are located mainly in the adrenal gland and account for 5% to 10% of all pheochromocytomas and paragangliomas. They have an intermediate metastatic risk and can secrete normetanephrine and metanephrines. Genomic alterations in this cluster are somatic.[5]

Genetic Factors and Syndromes Associated With Pheochromocytoma and Paraganglioma

Up to 30% of all pheochromocytomas and paragangliomas are estimated to be 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.[1-4]

Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:

1. von Hippel-Lindau (VHL) disease: Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL. For more information, see Von Hippel-Lindau Disease.
2. Multiple endocrine neoplasia (MEN) syndrome type 2: Codon-specific variants of the RET gene are associated with a 50% risk of development of pheochromocytoma in individuals with MEN2A and MEN2B. Somatic RET variants are also found in those with sporadic pheochromocytoma and paraganglioma.
3. Neurofibromatosis type 1 (NF1): Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1. They typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.
4. Familial pheochromocytoma/paraganglioma syndromes: These syndromes are commonly caused by pathogenic variants in SDHA, SDHB, SDHC, and SDHD and are inherited in an autosomal dominant manner. Pathogenic SDHB variants are the most common, followed by SDHD, SDHC, and SDHA. Other genes implicated in this syndrome include SDHAF2, TMEM127, FH, and MAX.
   Tumors from patients with SDHB and SDHC variants mainly arise in extra-adrenal locations, whereas tumors from patients with SDHD variants are mainly found in the head and neck area. SDHA variants 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.
5. Other syndromes:

   • Carney triad syndrome: This condition includes three tumors: paraganglioma, gastrointestinal stromal tumor (GIST), and pulmonary chondromas. Pheochromocytomas and other lesions, such as esophageal leiomyomas and adrenocortical adenomas, have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately 20% of the cases. About 20% of patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn’t appear to run in families. However, approximately 10% of patients have germline pathogenic variants in the SDHA, SDHB, or SDHC genes.[5,6]
   • Carney-Stratakis syndrome: Also called Carney dyad syndrome, this condition includes paraganglioma and GIST but not pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. Most patients with this syndrome have been found to carry germline pathogenic variants in the SDHB, SDHC, or SDHD genes.[6] For more information, see Genetics of Endocrine and Neuroendocrine Neoplasias.
   • Pacak-Zhuang syndrome: This syndrome results from somatic gain-of-function variants in the hypoxia-inducible factor 2 alpha (HIF-2 alpha) protein, which is encoded by the EPAS1 gene. This syndrome is characterized by congenital polycythemia, multiple paragangliomas, and duodenal somatostatinomas.[7] 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.[8]

Correlation Between Clinical and Molecular Features

Studies of germline variants in young patients with pheochromocytoma or paraganglioma have shown that these patients have a high prevalence (70%–80%) of germline pathogenic variants and have further characterized this group of neoplasms, as follows:

1. In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline pathogenic variant that involved the SDHB (n = 27; 55%), SDHD (n = 4; 8%), VHL (n = 6; 12%), or NF1 (n = 2; 4%) gene.[1] The incidence and type of variant correlated with the site and extent of disease.

   • The germline pathogenic variant rates for patients with nonmetastatic disease were lower than those observed in patients who had evidence of metastases (64% vs. 87.5%).
   • Among patients with metastatic disease, the incidence of SDHB variants was high (72%), and most presented with disease in the retroperitoneum. Five patients died of their disease.
   • All patients with SDHD variants had head and neck primary tumors.
2. In another study, the incidence of germline pathogenic variants involving RET, VHL, SDHD, and SDHB in patients with nonsyndromic paraganglioma was 70% for patients younger than 10 years and 51% among those aged 10 to 20 years.[2] In contrast, only 16% of patients older than 20 years had an identifiable variant.
   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).
3. In a retrospective review of 55 patients younger than 21 years referred to the National Cancer Institute, 80% of patients had a germline pathogenic variant.[3]

   • Most patients were found to have either the VHL (38%) or the SDHB (25%) variant. Pheochromocytoma was present in 67% of the patients (37 of 55) and was bilateral in 51% of patients (19 of 37).
   • Most patients with bilateral pheochromocytomas had VHL variants (79%).
4. Similarly, in a study of 88 children with pheochromocytoma and paraganglioma identified in the German Pediatric Oncology Hematology–Malignant Endocrine Tumor registry, the following was observed:[4]

   • Pathogenic variant screening from 66 patients revealed that 96% of the variants were confined to the pseudohypoxia cluster (66% affecting the VHL and EPAS1 genes and 33% affecting the SDHB and SDHD genes).
   • In this analysis, extent of resection was a significant prognostic factor for disease-free survival.
5. A retrospective analysis from the European-American-Asian-Pheochromocytoma-Paraganglioma-Registry identified 177 patients with paraganglial tumors who were diagnosed before age 18 years.[5][Level of evidence C1]

   • Eighty percent of registrants had germline pathogenic variants (49% with VHL, 15% with SDHB, 10% with SDHD, 4% with NF1, and one patient each with RET, SDHA, and SDHC).
   • A second primary paraganglial tumor developed in 38% of patients, with increasing frequency over time, reaching 50% at 30 years from initial presentation.
   • Prevalence of second tumors was higher in patients with hereditary disease. Sixteen patients (9%) with hereditary disease had malignant tumors, ten at initial presentation and another six during follow-up. Malignancy was associated with SDHB variants. Eight patients (5%) died, all of whom had a germline pathogenic variant. Mean life expectancy was 62 years for patients with hereditary disease.
6. A large retrospective review from tertiary medical centers identified 95 of 748 patients whose tumors first presented in childhood.[6]

   • Compared with adults, children showed higher prevalence of hereditary (80.4% vs. 52.6%), extra-adrenal (66.3% vs. 35.1%), multifocal (32.6% vs. 13.5%), metastatic (49.5% vs. 29.1%), and recurrent (29.5% vs. 14.2%) pheochromocytoma or paraganglioma.
   • Tumors caused by cluster 1 variants, which are associated with the absence of epinephrine production, were more prevalent among children than adults (76% vs. 39%; P < .0001). This difference paralleled a higher prevalence of noradrenergic tumors in children, characterized by a relative lack of increased plasma metanephrine (93.2% vs. 57.3%).
7. The U.S. National Institutes of Health reported the clinical characteristics and outcomes of 64 pediatric patients who had pheochromocytoma or paraganglioma with SDHB germline pathogenic variants. There were 38 males and 26 females diagnosed at a median age of 13 years.[7]

   • Most patients displayed norepinephrine hypersecretion, and 73% of patients initially presented with a solitary tumor.
   • Metastasis developed in 70% of patients at a median age of 16 years. Most patients were diagnosed with metastasis in the first 2 years after the initial diagnosis and in years 12 to 18 postdiagnosis.
   • The presence of metastasis at the time of diagnosis had a strong negative impact on survival in males but not in females.
   • The estimated 5-year survival rate was 100%; the 10-year survival rate was 97.14%; the 20-year survival rate was 77.71%.
   • These tumors are relatively slow growing, which explains the late deaths and the need for prolonged follow-up.
   • The authors recommended that the initial diagnostic evaluation of SDHB variant carriers should begin at age 5 to 6 years, with initial work-up focusing on the abdominal region. Thorough monitoring of patients is crucial in the first 2 years after diagnosis, and more frequent follow-up evaluations are needed in years 10 to 20 postdiagnosis because of the increased risk of metastasis.

Immunohistochemical SDHB staining may help triage genetic testing. Tumors of patients with SDHB, SDHC, and SDHD variants have absent or weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[8,9] Therefore, immunohistochemical SDHB staining can help identify potential carriers of SDH variants early, obviating the need for extensive and costly testing of other genes. Early identification of young patients with SDHB variants using radiographic, serological, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB pathogenic variant.

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.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

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 children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate 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 current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies 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 2020, childhood cancer mortality decreased by more than 50%.[3-5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

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.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]
  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number 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 of Childhood Pheochromocytoma and Paraganglioma

Treatment options for childhood paraganglioma and pheochromocytoma include the following:

1. Surgery.
2. Chemotherapy for patients with metastatic disease.
3. High-dose iodine I 131-labeled metaiodobenzylguanidine (131I-MIBG).
4. Lutetium Lu 177-DOTATATE and Yttrium Y 90-DOTATOC.[1]
5. Tyrosine kinase inhibitor therapy (sunitinib and cabozantinib).[1]
6. mTOR inhibitors.[1]
7. Immunotherapy.[1]

Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha- and beta-adrenergic blockade must be optimized before surgery. A single-institution study reviewed the experience of laparoscopic partial adrenalectomy for bilateral pheochromocytoma in patients with von Hippel-Lindau disease.[2] In eight patients, all 16 adrenalectomies were performed laparoscopically. Fourteen of the procedures were partial adrenalectomies, and two patients required a contralateral total adrenalectomy because of tumor size and diffuse multinodularity. Two patients had new ipsilateral tumors identified after a median follow-up of 5 years (range, 4–6 years), with one patient who underwent repeat partial adrenalectomy. There were no deaths during the study period.

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.[3-5] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival is less clear.

Responses have also been obtained with high-dose 131I-MIBG and sunitinib.[6,7]

Specific consensus guidelines for the diagnosis and management of pheochromocytoma and paraganglioma in patients with germline SDHB and SDHD pathogenic variants have been published.[8,9]

Treatment Options Under Clinical Evaluation for Childhood Pheochromocytoma and Paraganglioma

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:

• NCT04924075 (Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma and Paraganglioma or Pancreatic Neuroendocrine Tumor): This study will evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced pheochromocytoma or paraganglioma or pancreatic neuroendocrine tumor. The primary goal is to evaluate the objective response rate of belzutifan per Response Evaluation Criteria in Solid Tumors Version 1.1 by blinded independent central review.
• NCT04394858 (Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy [Temozolomide] for Advanced Neuroendocrine Cancer): This phase II trial will study the effectiveness of the addition of olaparib to temozolomide (the usual treatment) in treating patients aged 18 years and older with metastatic or unresectable pheochromocytomas or paragangliomas.

Latest Updates to This Summary (09/09/2024)

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.

This summary was comprehensively reviewed.

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® Cancer Information for Health Professionals pages.

About This PDQ Summary