Surgery is the single most important procedure in the successful treatment of adrenocortical tumors (ACT). It is performed by a transabdominal approach. Sometimes, it is necessary to do an en bloc resection, which may include the kidney, portions of the pancreas or liver, or other adjacent structures. If there are clinically enlarged lymph nodes, they should be removed as well. Because of tumor friability, rupture of the capsule and tumor spillage is frequent (occurring in approximately 20% of cases during the initial procedure and in 43% after local recurrence). Therefore laparoscopic resection should be avoided in children. Infiltration of the vena cava may make radical surgery difficult in some cases, although successful complete resection of the tumor thrombus has been reported with cardiopulmonary bypass. Patients with a glucocorticoid-secreting tumor are assumed to have suppression of the contralateral adrenal gland; hence, steroid replacement therapy is given. Surgical resection of recurrent local and distant disease is also important. Multiple surgical resections may be necessary to render patients free of disease. This aggressive approach is associated with prolonged survival, particularly when combined with chemotherapy.
Combination chemotherapy has been commonly used for children with residual or metastatic disease. For children with completely resected tumors, its role has not been established. There have not been formal trials of conventional chemotherapy agents in pediatric ACT, but the available case reports and the experience of the IPACTR suggest that a subset of pediatric adrenocortical tumors is chemotherapy sensitive (Rodriguez-Galindo, Figueiredo et al. 2055). The adjuvant combination used most often in pediatrics consists of mitotane, cisplatin, and etoposide with or without doxorubicin. Mitotane, an insecticide derivative that produces adrenocortical necrosis, has been used extensively in adults with ACT, but its efficacy in children is not known (Terzolo, Angeli et al. 2007; Ribeiro, Pinto et al. 2010; Wangberg, Khorram-Manesh et al. 2010). Mitotane has been used to treat advanced metastatic ACT, given prior to surgery in cases of inoperable tumors or after surgery in patients at high risk of relapse (adjuvant chemotherapy), combined with other agents and used to control symptoms associated with increased production of adrenal hormones. Objective responses to mitotane are obtained in 15% to 60% of treated adult patients (Terzolo, Angeli et al. 2007). The wide variation in response rates may, in part, reflect the pharmacokinetics of mitotane. There has been evidence of greater tumor response when the plasma concentration of mitotane is above 14 mg/L. The most important common toxicities of mitotane are nausea, vomiting, diarrhea, and abdominal pain (Ribeiro, Pinto et al. 2010). Less-frequent reactions include somnolence, lethargy, ataxic gait, depression, and vertigo. Of interest, prepubertal patients can develop gynecomastia or thelarche. Another shortcoming of mitotane treatment is that it significantly alters steroid hormone metabolism such that blood and urine steroid measurements cannot be used as markers of tumor relapse. Mitotane should be considered an experimental agent in the treatment of children with ACT. Because of the lack of uniform treatment in pediatric ACT, Children’s Oncology Group investigators developed the ARAR0332 protocol (Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy), a collaboration between COG and Brazilian institutions. The ARAR0332 protocol opened in August 2006 in the North American institutions and in June 2008 in the 2 institutions in Southern Brazil. Sixty patients were enrolled as of July 2011. Importantly, more than one third of the patients enrolled are from Southern Brazil, where a cluster of ACT associated with a founder TP53 mutation has been found (Ribeiro, Sandrini et al. 2001; Pinto, Billerbeck et al. 2004). Hopefully, this study will allow gathering a significant amount of data to better document the clinical characteristics, treatment, and outcomes for children with ACT and to increase our knowledge of its biology and epidemiology.
The role of radiotherapy in treatment of ACT is controversial, but its use has been advocated by some investigators (Ribeiro, Pinto et al. 2010; Ferrarini, Auteri-Kaczmarek et al. 2011). Because children with ACT usually carry a germline TP53 mutation, the use of radiotherapy in these patients has to be carefully considered.
There are two main tumor registries aimed at capturing pediatric adrenocortical tumor information:
IPACTR, International Pediatric Adrenocortical Tumor Registry (St. Jude Children's Research Hospital)
Children's Oncology Group's rare tumor research registry
Treatment Protocol ARAR0332 – Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy
The aims are as follows:
- Efficacy of surgery alone for stage I tumors
- Role of retroperitoneal lymph node resection in reducing local recurrence of stage II tumors
- Impact of mitotane and cisplatin-based chemotherapy for unresectable and metastatic disease