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Home > Living Well > Health Library > Childhood Adrenocortical Carcinoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior.
The incidence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers). Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[2,3] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[4,5,6]
In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million individuals. Internationally, however, the incidence of adrenocortical tumors appears to vary substantially. It is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[8,9,10,11]
Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1.0.[3,5,6]
Germline TP53 mutations are almost always the predisposing factor. The likelihood of a TP53 germline mutation is highest in the first years of life and diminishes with age. Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe and in 95% of the Brazilian cases.
Patients with Beckwith-Wiedemann and hemihyperplasia syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors. Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome. However, less than 1% of children with adrenocortical tumors have these syndromes.
The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.
Unlike adult adrenocortical tumors, histologic differentiation of pediatric adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[1,2] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.
Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[4,5,6]
Morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[8,9] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from tumor characteristics, such as tumor necrosis; mitotic rate; the presence of atypical mitoses; and venous, capsular, or adjacent organ invasion.[6,7,10,11]
A study performed on 71 pediatric adrenocortical tumors (37 in a discovery cohort and 34 in an independent cohort) provided a description of the genomic landscape of pediatric adrenocortical carcinoma.
Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[1,2]
Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.
Nonfunctional tumors are rare (<10%) and tend to occur in older children.
Overall, adverse prognostic factors for adrenocortical carcinoma include the following:
Stage I disease appears to be associated with a better prognosis.
The overall probability of 5-year survival for children with adrenocortical tumors depends on stage and ranges from greater than 80% for patients with resectable disease to less than 20% for patients with metastases.[1,2,3,6,7,10,11,12,13]
A portion of patients with adrenocortical carcinoma do not have a germline TP53 mutation. A retrospective review of children with adrenocortical carcinoma identified 60 patients without germline TP53 mutations. There was a strong female predominance (female to male ratio, 42:18) in this group of patients. The 3-year progression-free survival (PFS) rate was 71.4%, and the overall survival (OS) rate was 80.5%. Prognostic factors for this group were the same as the factors identified in previous analyses that did not segregate for TP53 germline status. Unfavorable prognostic features included older age, higher disease stage, heavier tumor weight, presence of somatic TP53 mutations, and higher Ki-67 labeling index. Ki-67 labeling index and age remained significantly associated with PFS after adjusting for stage and tumor weight.
At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.
Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used. Surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[2,3,4,5]; [Level of evidence: 3iiiA]
Treatment options for childhood adrenocortical tumors include the following:
The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. One study reported that three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcomas that arose within the radiation field.[5,14]
(Refer to the PDQ summary on Adrenocortical Carcinoma Treatment [Adult] for more information.)
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 is an example of a national and/or institutional clinical trial that is 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 Adrenocortical Carcinoma Treatment (Adult).
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.
Treatment of Childhood Adrenocortical Carcinoma
Added checkpoint inhibitors as a treatment option for childhood adrenocortical tumors. Also added text to state that in a phase I/II trial of pediatric patients with advanced or relapsed solid tumors who were treated with pembrolizumab, two of four patients with adrenocortical carcinoma achieved partial responses (cited Geoerger et al. as reference 13).
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 adrenocortical carcinoma. 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.
Reviewers and Updates
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).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Adrenocortical Carcinoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Adrenocortical Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/adrenocortical/hp/child-adrenocortical-treatment-pdq. Accessed <MM/DD/YYYY>.
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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2020-06-08
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