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.

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

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).[1] 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.[4-6]

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.[7] Internationally, however, the incidence of adrenocortical tumors appears to vary substantially. In southern Brazil, it is approximately 10 to 15 times higher than that observed in the United States.[8-11]

Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1.0.[3,5,6]

Risk Factors

Germline TP53 mutations are almost always the predisposing factor for adrenocortical tumors. 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.[1]

• In the non-Brazilian cases, relatives of children with adrenocortical tumors often, although not invariably, have a high incidence of nonadrenal cancers (Li-Fraumeni syndrome). Germline mutations usually occur within the region coding for the TP53 DNA-binding domain (exons 5 to 8, primarily at highly conserved amino acid residues).[1,2]
• In the Brazilian cases, the patients’ families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed.[3,4] In a Brazilian study, neonatal screening for the TP53 R337H mutation, which is prevalent in the region, identified 461 (0.27%) carriers among 171,649 newborns who were screened.[5] Carriers and relatives younger than 15 years were offered clinical screening. Adrenocortical tumors identified in the screening participants were smaller and more curable than the tumors found in carriers who did not elect to participate in screening.

Patients with Beckwith-Wiedemann and hemihyperplasia syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors.[6] 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.[7] However, less than 1% of children with adrenocortical tumors have these syndromes.[8]

The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.[9]

Histology

Unlike in 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.[3]

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 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 distinguish the two types of neoplasm.[4-6]

Morphological 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.[7] IGF2 expression also appears to discriminate between carcinomas and adenomas in adults but not in children.[8,9] Other histopathological 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]

Molecular Features

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.[1]

• IGF2 overexpression. The most common genomic alteration, present in approximately 90% of cases, was copy number loss of heterozygosity for 11p15 with retention of the paternal allele resulting in IGF2 overexpression.
• TP53 mutations. TP53 mutations were commonly observed. Twelve of 71 cases had the Brazilian founder R337H TP53 germline mutation. Excluding the Brazilian founder mutation cases, TP53 germline mutations were observed in approximately one-third of cases, with somatic TP53 mutations observed in approximately 10% of the remaining cases, such that approximately 40% of non-Brazilian cases had TP53 mutations. Among cases with TP53 mutations, chromosome 17 loss of heterozygosity with selection against wild-type TP53 was present in virtually all cases.
• ATRX mutations. ATRX genomic alterations (primarily structural variants) were present in approximately 20% of cases. All ATRX alterations occurred in the presence of TP53 alterations. The co-occurrence of TP53 and ATRX mutations correlated with advanced stage, large tumor size, increased telomere length, and poor prognosis.
• CTNNB1 mutations. Activating CTNNB1 mutations were found in approximately 20% of cases and were mutually exclusive with TP53 germline alterations.

Clinical Presentation

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]

• Virilization. Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) caused by an excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients.[3,4]
• Hyperestrogenism. Hyperestrogenism can also occur.[5]
• Cushing syndrome. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[1-3,6,7]

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.[3]

Nonfunctional tumors are rare (<10%) and tend to occur in older children.[1]

Prognostic Factors

Overall, adverse prognostic factors for adrenocortical carcinoma include the following:

• Large tumor size. Tumor weight higher than 200 g and tumor volume greater than 200 cm³ have been associated with a worse outcome.[1,2] Patients with small tumors have an excellent outcome when treated with surgery alone, regardless of histological features.[3-5]
• Metastatic disease. [1 ,2 ,4 - 6]
• Age. Age older than 4 or 5 years.[1,2,4,5,7]
• Microscopic tumor necrosis. [5]
• Para-aortic lymph node involvement. [5]
• Incomplete resection or spillage during surgery. [1 ,2 ,4]
• Low HLA class II antigen expression. A low expression of the HLA class II antigens HLA-DRA, HLA-DPA1, and HLA-DPB1 has been associated with older age, larger tumor size, presence of metastatic disease, and worse outcome.[8] In pediatric patients, increased expression of MHC class II genes, especially HLA-DPA1, is associated with a better prognosis.[9]

Stage I disease appears to be associated with a better prognosis.[5]

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.[1,2,6,7,10-12]

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.[13] 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 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.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence 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.)

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[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 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. 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 side effects of cancer therapy 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 people. 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.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• The Italian Tumori Rari in Eta Pediatrica group 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 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 the PDQ summary on Adrenocortical Carcinoma Treatment (Adult).

Treatment of Childhood Adrenocortical Carcinoma

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.[1]

The European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project (Paediatric Rare Tumours Network - European Registry) has published consensus guidelines for the diagnosis and treatment of childhood adrenocortical tumors.[2] 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.[3-6]; [7][Level of evidence: 3iiiA]

Treatment options for childhood adrenocortical tumors include the following:

1. Surgery: An aggressive surgical approach toward the primary tumor and all metastatic sites is recommended when feasible.[8,9] Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (approximately 20% of initial resections and 43% of resections after recurrence).[1] When the diagnosis of adrenocortical tumor is suspected, laparotomy and a curative procedure are recommended rather than fine-needle aspiration to avoid the risk of tumor rupture.[9,10] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[11]
2. Mitotane and cisplatin-based regimens: In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[4] Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[4,12]

   • A retrospective analysis in Italy and Germany identified 177 adult patients with completely resected adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 to 5 g per day.[13] (Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)
   • In a review of 11 children with advanced adrenocortical tumors treated with mitotane and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was approximately 4 g/m², and therapeutic levels were achieved after 4 to 6 months of therapy.[4]
   • In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival.[6,7]

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 them 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.[6,14]

(Refer to the PDQ summary on Adrenocortical Carcinoma Treatment [Adult] for more information.)

Treatment of Relapsed Childhood Adrenocortical Carcinoma

Treatment options for relapsed childhood adrenocortical tumors include the following:

1. Checkpoint inhibitors: 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.[1]

Treatment Options Under Clinical Evaluation for Childhood Adrenocortical Carcinoma

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:

• 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.

Changes to This Summary (09/17/2021)

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.

Special Considerations for the Treatment of Children With Cancer

Added American Academy of Pediatrics as reference 2.

Treatment of Childhood Adrenocortical Carcinoma

Added text to state that the European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project has published consensus guidelines for the diagnosis and treatment of childhood adrenocortical tumors (cited Virgone et al. as reference 2).

Treatment of Relapsed Childhood Adrenocortical Carcinoma

Added this new section.

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