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.

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. Paraganglioma and pheochromocytoma are exceedingly 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.

Genetic Factors and Syndromes Associated With Pheochromocytoma and Paraganglioma

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.[1-4]

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

1. von Hippel-Lindau (VHL) syndrome: Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL.
2. Multiple endocrine neoplasia (MEN) syndrome type 2: Codon-specific mutations of the RET gene are associated with a 50% risk of development of pheochromocytoma in MEN2A and MEN2B. Somatic RET mutations are also found in sporadic pheochromocytoma and paraganglioma.
3. Neurofibromatosis type 1 (NF1): Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1, and 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, associated with germline mutations of mitochondrial SDH complex genes (refer to Table 1). They are all inherited in an autosomal dominant manner but with varying penetrance.

   • PGL1: Associated with SDHD mutations, manifests more commonly with head and neck paragangliomas, and has a very high penetrance, with more than 80% of carriers developing disease by age 50 years.
   • PGL2: Associated with SDHAF2 mutations, is very rare, and generally manifests as parasympathetic paraganglioma.
   • PGL3: Associated with SDHC mutations, is very rare, and usually presents with parasympathetic paraganglioma, often unifocal, benign, and in the head and neck.
   • PGL4: Associated with SDHB mutations and usually manifests with intra-abdominal sympathetic paraganglioma. The neoplasms associated with this mutation have a much higher risk of malignant behavior, with more than 50% of patients developing metastatic disease. There is also an increased risk of renal cell carcinoma and gastrointestinal stromal tumor (GIST).
   (Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
5. Other syndromes:

   • Carney triad syndrome. Carney triad syndrome is a condition that includes three tumors: paraganglioma, 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 the patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately 20% of the cases. About 20% of the 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 the patients have germline variants in the SDHA, SDHB or SDHC genes.[5,6]
   • Carney-Stratakis syndrome. Carney-Stratakis syndrome (Carney dyad syndrome) is a condition that 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 mutations in the SDHB, SDHC, or SDHD genes.[6]
6. Other susceptibility genes recently discovered include KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX.[4]

These susceptibility genes can be divided into the following cluster groups on the basis of transcriptomic profiles:[7]

• Pseudohypoxia group, which can be further divided into two subgroups:

  -

  Tricarboxylic acid (TCA) cycle related, containing germline mutations in the four subunits of the SDH complex (SDHA, SDHB, SDHC, and SDHD), SDHAF2, and FH.

  -

  VHL/EPAS1 related, with somatic and germline mutations in those genes.

• WNT signaling group, which includes somatic mutations in CSDE1 and somatic gene fusions affecting MAML3.
• Kinase signaling group, which includes germline or somatic mutations in NF1, RET, TMEM127, HRAS, and MAX.

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.[7]

Molecular Features

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:

1. In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline mutation 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 mutation correlated with the site and extent of disease.

   • The germline mutation 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 mutations was very high (72%) and most presented with disease in the retroperitoneum; five died of their disease.
   • All patients with SDHD mutations had head and neck primary tumors.
2. In another study, the incidence of germline mutations 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 mutation.[2]
   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-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX (refer to Table 1).
3. In a retrospective review of 55 patients younger than 21 years referred to the National Cancer Institute, 80% of patients had a germline mutation.[3]

   • Most patients were found to have either the VHL (38%) or the SDHB (25%) mutation. 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 mutations (79%).
4. A retrospective analysis from the European-American-Pheochromocytoma-Paraganglioma-Registry identified 177 patients with paraganglial tumors who were diagnosed before age 18 years.[4][Level of evidence: 3iiA]

   • Eighty percent of registrants had germline mutations (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 mutations. Eight patients (5%) died, all of whom had a germline mutation. Mean life expectancy was 62 years for patients with hereditary disease.
5. A large retrospective review from tertiary medical centers identified 95 of 748 patients whose tumor first presented in childhood.[5]

   • 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 than did adults.
   • Tumors caused by cluster 1 mutations, which are associated with the absence of epinephrine production, were more prevalent among children than adults (76% vs. 39%; P < .0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs. 57.3%).

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.[6,7] 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.

Clinical Presentation

Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production:

• Hypertension.
• Headache.
• Perspiration.
• Palpitations.
• Tremor.
• Facial pallor.

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).[1]

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.[1] 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).[2]

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.[3] 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.[3-5] 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.[2]

Diagnostic Evaluation

The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging:

• Biochemical testing: Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when the diagnosis of a secreting paraganglioma or pheochromocytoma is suspected. A 24-hour urine collection for catecholamines (epinephrine, norepinephrine, and dopamine) and fractionated metanephrines can also be performed for confirmation.[1,2]
  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]
• Imaging: Imaging modalities available for the localization of paraganglioma and pheochromocytoma include the following:

  -

  Computed tomography (CT).

  -

  Magnetic resonance imaging.

  -

  Iodine I 123 or iodine I 131-labeled metaiodobenzylguanidine (123/131I-MIBG) scintigraphy.

  -

  Fluorine F 18-6-fluorodopamine (18F-6F-FDA) positron emission tomography (PET).

  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 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. Tyrosine kinase inhibitor therapy (sunitinib).

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.[1-3] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival (OS) is less clear.

Responses have also been obtained to high-dose 131I-MIBG and sunitinib.[4,5]

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, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  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.
• NCT02961491 (Expanded Access Program of Ultratrace Iobenguane I 131 for Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma): The purpose of this study is to provide expanded access to iobenguane I 131 for newly enrolled subjects with iobenguane-avid metastatic and/or recurrent pheochromocytoma/paraganglioma and to collect additional safety data.
• NCT01163383 (Iodine I 131-labeled metaiodobenzylguanidine [131I-MIBG] Therapy for Refractory Neuroblastoma and Metastatic Paraganglioma/Pheochromocytoma): MIBG is a substance that is taken up by neuroblastoma or pheochromocytoma/paraganglioma tumor cells. MIBG is combined with radioactive iodine (131I) in the laboratory to form a radioactive compound, 131I-MIBG. This radioactive compound delivers radiation specifically to the cancer cells, causing them to die. The purpose of this research protocol is to provide a mechanism to deliver MIBG therapy when clinically indicated, but also to provide a mechanism to continue to collect efficacy and toxicity data that will be provided.
• NCT03165721 (A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine [SGI-110], in Children and Adults With Wild-Type Gastrointestinal Stromal Tumor [GIST], Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and Hereditary Leiomyomatosis and Renal Cell Cancer [HLRCC]-associated Kidney Cancer): Most people with GIST are treated with imatinib; however, it may not work in many children with GIST. Researchers hypothesize that the drug SGI-110 may help treat people with GIST, pheochromocytoma and paraganglioma, or kidney cancer related to HLRCC. The objective of this trial is to determine whether SGI-110 shrinks tumors or slows tumor growth and to test how it acts in the body.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

(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.[2] 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%.[3] 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.[4] 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:

• The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP]) defines a pediatric rare tumor as one with an incidence of less than two cases per 1 million population per year and is not included in other clinical trials.[7]
• The Children's Oncology Group has opted to define rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
  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.

Changes to This Summary (12/23/2019)

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 is a new summary.

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.

About This PDQ Summary