Childhood Adrenocortical Carcinoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Incidence

Adrenocortical tumors encompass a spectrum of diseases with an often seamless transition from benign (adenoma) to malignant (carcinoma) characteristics.

The incidence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers).[1] In children, 25 new cases generally occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million individuals.[2,3] 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.[4,5,6]

Incidence rates of adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[7] 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.[3,8,9,10]

Female sex is consistently predominant in most studies, with a female-to-male ratio of 1.6:1.0.[7,9,10]

References:

1. Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004.
2. Berstein L, Gurney JG: Carcinomas and other malignant epithelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 11, pp 139-148. Also available online. Last accessed August 23, 2022.
3. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
4. Figueiredo BC, Sandrini R, Zambetti GP, et al.: Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43 (1): 91-6, 2006.
5. Pianovski MA, Maluf EM, de Carvalho DS, et al.: Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 47 (1): 56-60, 2006.
6. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al.: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 (3): 265-73, 2005.
7. Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004.
8. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003.
9. Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012.
10. Gulack BC, Rialon KL, Englum BR, et al.: Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 51 (1): 172-7, 2016.

Risk Factors

Predisposing genetic factors have been implicated in more than 50% of adrenocortical carcinoma cases in North America and Europe and in 95% of cases in Brazil.[1] Germline TP53 pathogenic variants are almost always the predisposing factor for adrenocortical tumors. The likelihood of a TP53 germline pathogenic variant is highest in the first years of life and diminishes with age.

• 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 pathogenic variants 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 exhibit a lower incidence of cancer than in the classic Li-Fraumeni syndrome, and a single, unique variant 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 variant, 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 hemihypertrophy 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]

References:

1. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al.: Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. J Clin Oncol 33 (6): 602-9, 2015.
2. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al.: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 (3): 265-73, 2005.
3. Ribeiro RC, Sandrini F, Figueiredo B, et al.: An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98 (16): 9330-5, 2001.
4. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Springer-Verlag, 2012, pp 436-44.
5. Custódio G, Parise GA, Kiesel Filho N, et al.: Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31 (20): 2619-26, 2013.
6. Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998.
7. Wijnen M, Alders M, Zwaan CM, et al.: KCNQ1OT1 hypomethylation: a novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors? Pediatr Blood Cancer 59 (3): 565-6, 2012.
8. Steenman M, Westerveld A, Mannens M: Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28 (1): 1-13, 2000.
9. El Wakil A, Doghman M, Latre De Late P, et al.: Genetics and genomics of childhood adrenocortical tumors. Mol Cell Endocrinol 336 (1-2): 169-73, 2011.

Clinical Presentation

Pediatric adrenocortical tumors are almost universally functional. As a result, 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.[1,2,3,6,7]

Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor. This profile may help evaluate response to treatment and monitor for tumor recurrence.[3]

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

References:

1. Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004.
2. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003.
3. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Springer-Verlag, 2012, pp 436-44.
4. Gönç EN, Özön ZA, Cakır MD, et al.: Need for comprehensive hormonal workup in the management of adrenocortical tumors in children. J Clin Res Pediatr Endocrinol 6 (2): 68-73, 2014.
5. Ghazi AA, Mofid D, Salehian MT, et al.: Functioning adrenocortical tumors in children-secretory behavior. J Clin Res Pediatr Endocrinol 5 (1): 27-32, 2013.
6. Hanna AM, Pham TH, Askegard-Giesmann JR, et al.: Outcome of adrenocortical tumors in children. J Pediatr Surg 43 (5): 843-9, 2008.
7. Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012.

Histology

Unlike adult adrenocortical tumors, histological differentiation of pediatric adenomas and malignant carcinomas is difficult.[1,2] In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.[3]

It appears that approximately 10% to 20% of pediatric cases are adenomas.[1,2] 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 adenomas. 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 histological criteria that may help distinguish the two types of neoplasms.[4,5,6]

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. Risk groups may be identified based on 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]

References:

1. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993.
2. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003.
3. Figueiredo BC, Stratakis CA, Sandrini R, et al.: Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84 (3): 1116-21, 1999.
4. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8 (3): 163-9, 1984.
5. van Slooten H, Schaberg A, Smeenk D, et al.: Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55 (4): 766-73, 1985.
6. Das S, Sengupta M, Islam N, et al.: Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation? J Pediatr Surg 51 (11): 1795-1800, 2016.
7. Stojadinovic A, Ghossein RA, Hoos A, et al.: Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20 (4): 941-50, 2002.
8. Almeida MQ, Fragoso MC, Lotfi CF, et al.: Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93 (9): 3524-31, 2008.
9. West AN, Neale GA, Pounds S, et al.: Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67 (2): 600-8, 2007.
10. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Springer-Verlag, 2012, pp 436-44.
11. Gupta N, Rivera M, Novotny P, et al.: Adrenocortical Carcinoma in Children: A Clinicopathological Analysis of 41 Patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr 90 (1): 8-18, 2018.

Genomic Alterations

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 this disease.[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 variants. TP53 variants were commonly observed. Twelve of 71 cases had the Brazilian founder R337H TP53 germline pathogenic variant. Excluding the Brazilian founder variant cases, TP53 germline pathogenic variants were observed in approximately one-third of cases and somatic TP53 variants were observed in approximately 10% of the remaining cases. Approximately 40% of non-Brazilian cases had TP53 variants. Among cases with TP53 variants, chromosome 17 loss of heterozygosity with selection against wild-type TP53 was present in virtually all cases.
• ATRX variants. 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 variants correlated with advanced stage, large tumor size, increased telomere length, and poor prognosis.
• CTNNB1 variants. Activating CTNNB1 variants were found in approximately 20% of cases and were mutually exclusive with TP53 germline alterations.

Paternal 11p15 uniparental disomy (UPD). A retrospective analysis of patients with adrenocortical tumors at the St. Jude Children's Research Hospital identified six children with wild-type TP53 and germline paternal 11p15 UPD.[2] The median age of the five girls and one boy was 3.2 years (range, 0.5–11 years). Two patients met the criteria for Beckwith-Wiedemann syndrome before diagnosis of their adrenocortical tumors. However, adrenocortical tumor was the first and only manifestation of paternal 11p15 UPD in four of the children. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients were alive 8 to 21 years after their cancer diagnosis.

References:

1. Pinto EM, Chen X, Easton J, et al.: Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6: 6302, 2015.
2. Pinto EM, Rodriguez-Galindo C, Lam CG, et al.: Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment. Front Endocrinol (Lausanne) 12: 756523, 2021.

Prognostic Factors

The overall probability of 5-year survival for children with adrenocortical tumors depends on stage. Survival rates range from greater than 80% for patients with resectable disease to less than 20% for patients with metastases.[1,2,3,4,5,6,7]

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

• Presence of somatic TP53 variants.[8]
• Larger tumor size. Tumor weights heavier than 200 g and tumor volumes greater than 200 mL have been associated with worse outcomes.[5,6] Patients with small tumors have an excellent outcome when treated with surgery alone, regardless of histological features.[9,10,11]
• Disease Stage. Stage I disease is associated with a better prognosis,[11] and metastatic disease is associated with worse outcomes.[5,6,7,10,11]
• Age. Age older than 4 or 5 years.[1,5,6,10,11]
• Microscopic tumor necrosis.[11]
• Para-aortic lymph node involvement.[11]
• Incomplete resection or spillage during surgery.[5,6,10]
• 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.[12] In pediatric patients, increased expression of MHC class II genes, especially HLA-DPA1, is associated with a better prognosis.[13]
• Higher Ki-67 labeling index. A retrospective analysis of patients with adrenocortical carcinoma reported that higher Ki-67 labeling index correlated with worse overall survival (OS) and disease-free survival.[14]

A portion of patients with adrenocortical carcinoma do not have a germline TP53 pathogenic variant. A retrospective review of children with adrenocortical carcinoma identified 60 patients without germline TP53 pathogenic variants.[8] 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 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 pathogenic variant status. Unfavorable prognostic features included older age, higher disease stage, heavier tumor weight, presence of somatic TP53 variants, and higher Ki-67 labeling index. Ki-67 labeling index and age remained significantly associated with PFS after adjusting for stage and tumor weight.

References:

1. Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004.
2. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003.
3. Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 82 (7): 2027-31, 1997.
4. Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012.
5. McAteer JP, Huaco JA, Gow KW: Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 48 (5): 1025-31, 2013.
6. Cecchetto G, Ganarin A, Bien E, et al.: Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Pediatr Blood Cancer 64 (6): , 2017.
7. Gupta N, Rivera M, Novotny P, et al.: Adrenocortical Carcinoma in Children: A Clinicopathological Analysis of 41 Patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr 90 (1): 8-18, 2018.
8. Pinto EM, Rodriguez-Galindo C, Pounds SB, et al.: Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study. J Clin Oncol 35 (35): 3956-3963, 2017.
9. Klein JD, Turner CG, Gray FL, et al.: Adrenal cortical tumors in children: factors associated with poor outcome. J Pediatr Surg 46 (6): 1201-7, 2011.
10. Gulack BC, Rialon KL, Englum BR, et al.: Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 51 (1): 172-7, 2016.
11. Bulzico D, de Faria PA, de Paula MP, et al.: Recurrence and mortality prognostic factors in childhood adrenocortical tumors: Analysis from the Brazilian National Institute of Cancer experience. Pediatr Hematol Oncol 33 (4): 248-58, 2016.
12. Leite FA, Lira RC, Fedatto PF, et al.: Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT). Pediatr Blood Cancer 61 (11): 1940-8, 2014.
13. Pinto EM, Rodriguez-Galindo C, Choi JK, et al.: Prognostic Significance of Major Histocompatibility Complex Class II Expression in Pediatric Adrenocortical Tumors: A St. Jude and Children's Oncology Group Study. Clin Cancer Res 22 (24): 6247-6255, 2016.
14. Martins-Filho SN, Almeida MQ, Soares I, et al.: Clinical Impact of Pathological Features Including the Ki-67 Labeling Index on Diagnosis and Prognosis of Adult and Pediatric Adrenocortical Tumors. Endocr Pathol 32 (2): 288-300, 2021.

Staging

Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC). For more information, see the Stage Information for Adrenocortical Carcinoma section in Adrenocortical Carcinoma Treatment.

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%.[3,4,5] 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 Adrenocortical Carcinoma Treatment.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Treatment of Childhood Adrenocortical Carcinoma

At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors that 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 using the data from 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.[3,4,5,6]; [7][Level of evidence C1]

Treatment options for childhood adrenocortical tumors include the following:

1. Surgery with or without adjuvant chemotherapy.

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. Therefore, open adrenalectomy remains the standard of care.[11]

Evidence (surgery):

1. The Children's Oncology Group conducted a prospective, single-arm, risk-stratified, interventional study between 2006 and 2013 (ARAR0332 [NCT00304070]).[12][Level of evidence B4] Patients with stage I disease had small tumors limited to the adrenal gland and were treated with adrenalectomy alone. Patients with stage II disease had tumors larger than 200 mL or heavier than 100 g and were treated with adrenalectomy and retroperitoneal lymph node dissection (RPLND). Patients with stage III disease had incompletely resected primary tumors. Patients with stage IV disease had distant metastatic disease. Patients with stage III and stage IV disease were treated with surgery of the primary tumor, RPLND, cisplatin, etoposide, doxorubicin, and mitotane.
   • The 5-year event-free survival rate estimates were 86.2% for patients with stage I disease (n = 24), 53.3% for patients with stage II disease (n = 15), 81% for patients with stage III disease (n = 24), and 7.1% for patients with stage IV disease (n = 14).
   • On multivariable analysis, only stage and age were significantly associated with outcome.
   • The authors reported that the combination of mitotane and chemotherapy resulted in significant toxicity. One-third of patients with advanced disease could not complete the scheduled treatment.

   The stated goal of the study was to determine if RPLND would improve outcomes for patients with stage II disease. The operative notes to assess the adequacy of the RPLND were available for 11 of 15 patients. The median number of lymph nodes resected was 4 (range, 1–30). In a multivariable analysis performed in a cohort of 283 adult patients with adrenocortical carcinoma, patients who underwent RPLND (defined as >5 nodes resected) had a significantly reduced recurrence risk and disease-related death rate than patients who did not undergo nodal dissection.[13] The authors speculate that the RPLNDs performed in this study may not have been as thorough as the procedures carried out in the adult series, which could confound conclusions about the potential value of RPLND.

Chemotherapy

Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[4,14] In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[4]

Evidence (surgery and chemotherapy):

1. One review included 11 children with advanced adrenocortical tumors who were treated with a mitotane and cisplatin-based chemotherapeutic regimen.[4]
   • 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.
2. In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival in children.[6,7]
3. A retrospective analysis identified 177 Italian and German adult patients with completely resected adrenocortical carcinoma.[15]
   • Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane.
   • The benefit was present with 1 to 3 g per day of mitotane, and this dose was associated with fewer toxic side effects than doses of 3 to 5 g per day.

   For more information, see Adrenocortical Carcinoma Treatment.

Adrenocortical tumors are generally considered to be radioresistant. The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Furthermore, because many children with adrenocortical tumors carry germline TP53 pathogenic variants 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.[6,16]

For more information, see Adrenocortical Carcinoma Treatment.

References:

1. Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004.
2. Virgone C, Roganovic J, Vorwerk P, et al.: Adrenocortical tumours in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations. Pediatr Blood Cancer 68 (Suppl 4): e29025, 2021.
3. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al.: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 (3): 265-73, 2005.
4. Zancanella P, Pianovski MA, Oliveira BH, et al.: Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28 (8): 513-24, 2006.
5. Hovi L, Wikström S, Vettenranta K, et al.: Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report. Med Pediatr Oncol 40 (5): 324-6, 2003.
6. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Springer-Verlag, 2012, pp 436-44.
7. Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012.
8. Stewart JN, Flageole H, Kavan P: A surgical approach to adrenocortical tumors in children: the mainstay of treatment. J Pediatr Surg 39 (5): 759-63, 2004.
9. Hubertus J, Boxberger N, Redlich A, et al.: Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klin Padiatr 224 (3): 143-7, 2012.
10. Kardar AH: Rupture of adrenal carcinoma after biopsy. J Urol 166 (3): 984, 2001.
11. Gonzalez RJ, Shapiro S, Sarlis N, et al.: Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 138 (6): 1078-85; discussion 1085-6, 2005.
12. Rodriguez-Galindo C, Krailo MD, Pinto EM, et al.: Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol. J Clin Oncol 39 (22): 2463-2473, 2021.
13. Reibetanz J, Jurowich C, Erdogan I, et al.: Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg 255 (2): 363-9, 2012.
14. Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004.
15. Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007.
16. Driver CP, Birch J, Gough DC, et al.: Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15 (6): 527-32, 1998 Nov-Dec.

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 carcinomas achieved partial responses.[1]
2. Tyrosine kinase inhibitors. A single-arm phase II trial included patients aged 18 years and older who had adrenocortical carcinoma and were not candidates for surgery with curative intent. The administration of cabozantinib was associated with stable disease in 12 of 16 patients, for a median duration of 3.7 months, and confirmed partial responses in 2 patients.[2]

References:

1. Geoerger B, Kang HJ, Yalon-Oren M, et al.: Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol 21 (1): 121-133, 2020.
2. Campbell MT, Balderrama-Brondani V, Jimenez C, et al.: Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial. Lancet Oncol 25 (5): 649-657, 2024.

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, see the ClinicalTrials.gov website.

Latest Updates to This Summary (09 / 05 / 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

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 in the care of their 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:

• be discussed at a meeting,
• be cited with text, or
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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:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• William H. Meyer, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• D. Williams Parsons, MD, PhD (Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

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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>. [PMID: 31661213]

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Last Revised: 2024-09-05