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Childhood Adrenocortical Carcinoma Treatment (PDQ®)–Health Professional Version

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. It is particularly high in southern Brazil, where it is approximately 10 to 15 times 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]

References
  1. Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004. [PUBMED Abstract]
  2. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993. [PUBMED Abstract]
  3. 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. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. 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. [PUBMED Abstract]
  6. 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. [PUBMED Abstract]
  7. 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. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 11, pp 139-148. Also available online. Last accessed June 04, 2019.
  8. 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. [PUBMED Abstract]
  9. 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. [PUBMED Abstract]
  10. 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. [PUBMED Abstract]
  11. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: Springer-Verlag, 2012, pp 436-44.

Risk Factors

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.[1]

  • In the non-Brazilian cases, relatives of children with adrenocortical tumors often, although not invariably, have a high incidence of other 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 of the 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]

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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  4. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: 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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]

Histology

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.[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 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.[4-6]

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.[7] 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]

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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  4. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8 (3): 163-9, 1984. [PUBMED Abstract]
  5. van Slooten H, Schaberg A, Smeenk D, et al.: Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55 (4): 766-73, 1985. [PUBMED Abstract]
  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. [PUBMED Abstract]
  7. Stojadinovic A, Ghossein RA, Hoos A, et al.: Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20 (4): 941-50, 2002. [PUBMED Abstract]
  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. [PUBMED Abstract]
  9. West AN, Neale GA, Pounds S, et al.: Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67 (2): 600-8, 2007. [PUBMED Abstract]
  10. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: 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. [PUBMED Abstract]

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.
References
  1. Pinto EM, Chen X, Easton J, et al.: Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6: 6302, 2015. [PUBMED Abstract]

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]

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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  3. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: 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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  6. Hanna AM, Pham TH, Askegard-Giesmann JR, et al.: Outcome of adrenocortical tumors in children. J Pediatr Surg 43 (5): 843-9, 2008. [PUBMED Abstract]
  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. [PUBMED Abstract]

Prognostic Factors

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

  • Large tumor size. Tumor weight higher than 200 g or 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 histologic 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.[1-3,6,7,10-13]

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.[14] 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.

References
  1. 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. [PUBMED Abstract]
  2. 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. [PUBMED Abstract]
  3. 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. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. 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. [PUBMED Abstract]
  6. 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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  8. 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. [PUBMED Abstract]
  9. 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. [PUBMED Abstract]
  10. 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. [PUBMED Abstract]
  11. Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 82 (7): 2027-31, 1997. [PUBMED Abstract]
  12. Hanna AM, Pham TH, Askegard-Giesmann JR, et al.: Outcome of adrenocortical tumors in children. J Pediatr Surg 43 (5): 843-9, 2008. [PUBMED Abstract]
  13. 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. [PUBMED Abstract]
  14. 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. [PUBMED Abstract]

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]

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.[2-5]; [6][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.[7,8] 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.[8,9] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[10]
  2. Mitotane and cisplatin-based regimens: In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[3] Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[3,11]
    • 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 g to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 g to 5 g per day.[12] (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.[3]
    • In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival.[5,6]

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.[5,13]

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

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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  3. 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. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: Springer-Verlag, 2012, pp 436-44.
  6. 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. [PUBMED Abstract]
  7. 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. [PUBMED Abstract]
  8. 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. [PUBMED Abstract]
  9. Kardar AH: Rupture of adrenal carcinoma after biopsy. J Urol 166 (3): 984, 2001. [PUBMED Abstract]
  10. 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. [PUBMED Abstract]
  11. Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004. [PUBMED Abstract]
  12. Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007. [PUBMED Abstract]
  13. Driver CP, Birch J, Gough DC, et al.: Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15 (6): 527-32, 1998 Nov-Dec. [PUBMED Abstract]

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.

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 Adrenocortical Carcinoma Treatment (Adult).

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. [PUBMED Abstract]
  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. 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. [PUBMED Abstract]
  6. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PUBMED Abstract]
  7. Ferrari A, Bisogno G, De Salvo GL, et al.: The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer 43 (4): 654-9, 2007. [PUBMED Abstract]
  8. 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. [PUBMED Abstract]
  9. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed June 04, 2019.

Changes to This Summary (10/25/2019)

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

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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)
  • 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)
  • 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)

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>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

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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