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Table of Contents   
ORIGINAL ARTICLE
Year : 2022  |  Volume : 27  |  Issue : 2  |  Page : 157-162
 

Adrenocortical neoplasms in children: Treatment and outcomes


1 Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
4 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
5 Department of Pediatrics, Division of Pediatric Endocrinology, All India Institute of Medical Sciences, New Delhi, India
6 Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission21-Oct-2020
Date of Decision17-Mar-2021
Date of Acceptance11-May-2021
Date of Web Publication01-Mar-2022

Correspondence Address:
Dr. Sandeep Agarwala
Department of Pediatric Surgery, 4th Floor, Teaching Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 016
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaps.JIAPS_351_20

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   Abstract 


Background: Adrenocortical tumors are rare tumors in children with a paucity of outcome data, especially in a resource-challenged setting. Materials and Methods: A retrospective study was conducted to evaluate the presentation, management, and outcomes of children with adrenocortical tumors who presented to our institute from January 1992 to December 2019. Results: During the study period, 28 children were included. Adenoma was present in nine children and the remaining 19 children had adrenocortical carcinoma. The median age of presentation was 48 months. Nearly half of the children with carcinomas presented with a mass compared to only 10% adenomas (P = 0.049). Virilization was present in 60% of the patients and in most cases was associated with Cushingoid features. Three children (15.7%) had metastasis at presentation. All children underwent surgical excision with a spill in 6 and gross residue in two patients. Recurrence was observed in five patients after a mean duration of 11.8 months. The 4-year overall survival and event-free survival were 100% in patients with adenomas compared to 75% and 44%, respectively, in carcinoma. Children who underwent complete surgical excision without any spill had a relatively favorable outcome. Conclusion: Adrenocortical tumors are uncommon tumors in children. Adenomas have a favorable outcome. There was no disease-free survival in incompletely resected or metastatic tumors. Tumor spill may also have an adverse outcome in completely resected tumors.


Keywords: Adenoma, adrenalectomy, adrenocortical, adrenocortical carcinoma, Cushing syndrome


How to cite this article:
Jain V, Sehgal M, Dhua A, Bakhshi S, Kandasamy D, Mani K, Sharma R, Jain V, Tandon N, Agarwala S. Adrenocortical neoplasms in children: Treatment and outcomes. J Indian Assoc Pediatr Surg 2022;27:157-62

How to cite this URL:
Jain V, Sehgal M, Dhua A, Bakhshi S, Kandasamy D, Mani K, Sharma R, Jain V, Tandon N, Agarwala S. Adrenocortical neoplasms in children: Treatment and outcomes. J Indian Assoc Pediatr Surg [serial online] 2022 [cited 2023 Mar 28];27:157-62. Available from: https://www.jiaps.com/text.asp?2022/27/2/157/338814





   Introduction Top


Adrenocortical tumors are rare tumors in children with a reported incidence of 0.2–0.3 per million children per year.[1],[2] It accounts for only 0.2% of all pediatric malignancies and 1.3% of all carcinomas in this age group.[1],[2] Most of these tumors are functional in children and present with virilization with or without Cushing syndrome in up to 80% of children.[2],[3],[4] Nonfunctional adrenocortical tumors are uncommon in children compared to adults.[5]

Surgical excision offers a definite treatment with drugs such as mitotane and antineoplastic drugs reserved for extensive or unresectable disease.[6],[7] Another perplexity of this tumor is in the diagnosis of malignancy on histopathological examination. Weiss criterion was used in the past to diagnose adrenocortical carcinoma (ACC) in both adults and in children.[8] Wienke in 2003 introduced new criteria to diagnose malignancy in children.[9] The outcome of the benign adrenocortical tumor, i.e., adenoma is excellent, but the survival of ACC is modest at approximately 60%.[1],[10],[11]

The data regarding these tumors are limited, especially from a resource challenged setting where access to mitotane is infrequent. Only two studies have been published from India that reported a dismal outcome with no disease-free survival.[5],[12] We planned this study to evaluate the presentation, management, and outcomes of children with adrenocortical tumors who presented during the past 25 years.


   Materials and Methods Top


A retrospective study was conducted, and children with adrenocortical tumor registered in pediatric surgery tumor clinic of a tertiary care hospital from January 1992 to December 2019 were included. Children who were lost to follow up before any definitive intervention or had incomplete records were excluded. Ethical clearance was obtained from the Institute Ethics Committee (IEC-145/6.3.2020).

The records of the patients were studied, and demographic data, presentation, hormonal profile, and imaging findings were recorded. The surgical findings, histopathology findings, and the need for any adjuvant therapy were also recorded. The data from clinical records, histopathology, and discharge summary were recorded in the proforma.

The diagnosis of ACC was based on Weiss criteria in the earlier part of the study and by Weinke criteria in the latter part. Patients with definite metastasis were considered carcinoma irrespective of histopathology.

The qualitative variables were analyzed using homogeneity tests based on the χ2 distribution when the expected values made this possible and using Fisher's exact tests, otherwise. A statistically significant difference was defined as P < 0.05. Kaplan–Meier survival analysis was performed to calculate the 4-year overall and event-free survival (EFS). Overall survival (OS) was the period from the date of diagnosis to the date of death due to any reason. EFS was measured from the date of complete response to the date of either local or distant relapse or death.


   Results Top


During the study period, forty children with adrenocortical tumors presented to us. Four children did not follow-up after the first visit. Three children had extensive disease with metastases at presentation, and the parents did not continue treatment. Proper records were not available for five patients. After these 12 children were excluded, the study group comprised 28 patients. Adenoma was present in 9 children, and the remaining 19 children had ACC. The median age of presentation was 48 months (3–156 months). The male-to-female ratio was 1:1. The age of presentation in children with adenoma and carcinoma is shown in [Table 1].
Table 1: Comparison of patient characteristics of children with adrenocortical adenoma and carcinoma

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Presentation

Patients presented with features of Cushing syndrome, virilization, both, or had other symptoms such as pain, mass, or hypertension [Figure 1]. The frequency of the symptoms at presentation is shown in [Table 1] and [Table 2]. The median duration of symptoms was 8 months (2–48 months). Children with adrenocortical adenoma had significantly (P = 0.04) longer duration of symptoms at presentation than children with ACC [Table 1]. The difference in the patient population of the children adenoma and carcinoma is presented in [Table 1].
Figure 1: (a) Presence of only virilizing features in a 4-year-old boy. (b) Presence of cushingoid features in a 3-year-old girl with adrenocortical carcinoma

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Table 2: Presenting symptoms and hormonal profile of the children with adrenocortical tumors

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Hormonal evaluation

Serum cortisol evaluation had been performed in all patients. Serum testosterone and dehydroepiandrosterone levels were performed in 14 and 20 patients, respectively. The elevated levels of hormones have been correlated with the symptoms at presentation in [Table 2]. Hormonal levels were elevated in all patients who presented with features of Cushing syndrome or virilization. The hormones were not elevated in children who presented with other symptoms.

Imaging findings

The right adrenal was more commonly affected in children with carcinoma than in children with adenomas who had near equal involvement of either side, although the difference was not statistically significant. Children with carcinoma had a significantly larger mass (P = 0.008) than children with adenoma [Table 1]. Three (15.7%) children had metastases. Two patients had hepatic metastases, and one had metastasis to the lung. Imaging also detected inferior vena cava (IVC) thrombus in two children.

Management

All patients had been stabilized before surgery, and the blood pressure, if elevated, was controlled by antihypertensives. All the children underwent surgical excision of the mass. Of the 19 patients with ACC, 3 (16%) had Stage IV disease, one patient (5%) had residual disease after surgery (Stage III), and the remaining 15 patients (79%) underwent complete excision of the mass (Stage I and II). Tumor spill occurred in six patients (32%). After surgery, gross residue was present in two patients (11%; one child each with Stage III and IV disease). Concomitant nephrectomy was performed in one patient. Five patients received adjuvant therapy. Of these two patients had an intraoperative spill, one patient had a residual disease, one patient had vascular and capsular invasion on histopathology. The first patient in this series received local radiotherapy, whereas the remaining four patients received six courses of etoposide and carboplatin.

Outcome

All nine children with adrenocortical adenoma remained asymptomatic at a median follow-up of 25 months (6–240 months).

  • Children with ACC had a median follow-up of 14 months (1–149 months). The children with ACC had a less favorable outcome:
  • Children with metastasis (3 children): Both the children with liver metastases (one had an IVC thrombus with an intraoperative spill and the other had a gross residual disease in the liver) expired after 1 month of surgery due to progressive disease before any adjuvant therapy was started. The child with pulmonary metastases, who also had an intraoperative spill, was advised adjuvant chemotherapy, but the parents refused further treatment. This patient developed liver secondaries and ascites after 2 months of surgery and did not follow-up any further
  • Children with a spill and no metastasis (4 children): Three patients did not receive any adjuvant therapy initially and developed local recurrence after 6, 12, and 24 months of surgery, respectively. Two of them refused further treatment, while one was given three courses of chemotherapy and was explored with the intention of complete excision. The child had multiple hepatic surface and peritoneal deposits. The surgery was abandoned, and the child was started on metronomic therapy. The child was alive at the last follow-up of 18 months from the initial surgery. The fourth child with spill received adjuvant chemotherapy and was alive and disease-free at last follow-up of 84 months
  • Children without spill or metastases (12 children): One child had tumor thrombus in the inferior vena cava and had gross residual disease. This child received adjuvant chemotherapy but had progressive disease and died. Two children had recurrence without any definite risk factors such as a spill or residual disease. One child had a recurrence in the liver, lungs, and the local site after 11 months and did not continue treatment. The other child had a developed a 1 cm nodule at the local site after 6 months, but the hormone levels were normal. The child was kept on close follow-up. The mass increased in size to 5 cm. The mass was excised. This child was alive and disease free at last follow-up after 23 months. All other children had no recurrence or residual disease. One patient, who had received adjuvant radiotherapy, developed pheochromocytoma after 10 years in the contralateral adrenal and was operated elsewhere.


Survival

The 4-year overall and EFS in children with adenoma was 100%. Three of 19 children with ACC died, giving a 4-year OS of 75% with 95% CI (40%, 99%). The mean OS was 103 months with 95% CI (66 months and 140 months) as shown in [Figure 2]. The 4-year EFS was 44% with 95% CI (18%, 70%) as shown in [Figure 2]. The mean OS was 68 months with 95% CI (32 months, 104 months). On comparing the effect of spill on Stage I and II tumors, only one of the four patients (25%) with a spill was disease free. Of the remaining 11 patients with Stage I and II tumors, 9 (81%) had disease-free survival. However, this difference was not statistically significant (P = 0.07). No patient with Stage III or IV was disease free.
Figure 2: Kaplan–Meier survival curve of overall survival and event-free survival of patients with adrenocortical carcinoma

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   Discussion Top


Adrenocortical tumors are rare but aggressive malignancies of childhood.[1],[2] Most childhood ACT present in the first 5 years of life with another small peak of occurrence during adolescence. The median age of presentation of adrenocortical tumors in our study 48 months, which is within the range of 3–5 years reported in other studies.[1],[12],[13],[14],[15],[16] Similar to these studies, 60% of our patients were <4 years of age. Some studies have reported a significantly higher age of presentation in ACC compared to adenoma.[12],[14] We did not find any significant difference in the age of presentation of adenoma and carcinoma in the index study.

The median duration of symptoms in carcinoma was 4 months, which were similar to other studies;[16],[17] however, children with adenomas presented late with a median duration of 12 months. The predilection for the right side for carcinomas has been supported by other studies as well.[14]

Most studies have reported isolated virilization as the most common presentation. In the index study, virilization was present in 60% of the patients, but in most cases, it was associated with Cushingoid features. American and European studies have quoted virilization to be present in up to 80% of the cases.[1],[15] Studies from Asia, like Chatterjee et al.[12] and Wang et al.,[14] have reported findings similar to ours, with 60% of children presenting with virilization. The study by Chatterjee et al.[12] did not provide further details of children who presented with only virilization and those who presented with both, virilization and cushingoid features. Wang et al. reported that only 20% of patients presented with symptoms of virilization only, whereas approximately 40% of children presented with mixed symptoms of virilization and Cushing syndrome. The reason for this difference in the presentation in studies from different regions is difficult to explain. Hypertension was the most common clinical feature at presentation, followed by an abdominal mass and pain abdomen in carcinoma patients. The incidence of hypertension is higher than those reported in other studies, which have shown only up to 33%–43% of patients with hypertension.[1],[10] Wang et al. reported hypertension in approximately 80% of their patients.[14] We propose that similar clinical presentations, i.e., a higher number of children with Cushing's syndrome in our study, and by Wang et al. can be the reason for this finding.

Pain is the presenting complaint in 13%–50% of children with ACT.[10],[13] The pain was the presenting complaint in 28% of our patients and was noted only in children with carcinoma, while none of the patients with adenoma presented with pain. It has been reported that a third of patients with ACC present with abdominal or flank pain due to tumor infiltration.[18] It has been well documented that adrenocortical adenoma is smaller, both in size and volume, compared with ACC.[9],[10],[14] We also documented that the size and weight of the adrenocortical adenomas were significantly larger than carcinomas. Taking note of these differences, it is easy to infer that pain is more common in carcinomas compared to adenomas.

Overall, 21% of children had no clinical evidence of endocrine dysfunction at presentation, which is much higher than 10%–12% reported in other studies on adrenocortical tumors.[4],[15] In the study by Wang et al.,[14] 25% of children did not have signs of endocrine dysfunction at the presentation, which is very similar to our study. However, five of them had hypertension and were proven to have hyperaldosteronism and hence were considered functional. Two patients in our study also had hypertension without any clinical endocrine dysfunction. Aldosterone levels had not been assessed in them. Probably, with more extensive hormonal workup, more tumors can be classified as functional. It has been reported that nonfunctional tumors present in the older age group. Michalkiewicz et al. reported that children with nonfunctional tumors presented at a mean age of 5.7 years, which was statistically significant.[1] Children with nonfunctional tumors in our study also presented to us at a median age of 5.5 years, but the difference was not statistically significant.

Imaging helps in staging, preoperative planning, and prognostication. In the index study, 78% of patients had Stage I or Stage II disease, and 15% of children had metastases, which is similar to that reported by the International Pediatric Adrenocortical tumor registry. It has been shown that patients with metastases have a poor prognosis.[19] Imaging also shows thrombus in the inferior vena cava, which is present in 6% of patients.[1] We noted metastases in three children (10%) and IVC thrombus in 2 children (7%). Although imaging does not reliably contribute to the differentiation of malignancy,[3] in our study, we found with statistically significant difference, a larger size of carcinomas than adenomas.

Complete primary resection is the cornerstone of the treatment. All our patients underwent open adrenalectomy. Adrenocortical tumors are friable due to extensive necrosis, hemorrhage, and fibrosis – leading to intraoperative spills, which alter the outcome significantly.[1],[20] In our study, tumor spill occurred in seven patients. Only one of the patients with intraoperative spills was alive and healthy at last follow-up compared to eight patients without a spill, which was not statistically significant.

Adjuvant therapy is being increasingly used to improve the outcomes in adrenocortical tumors.[7],[21],[22] Mitotane inhibits the biosynthesis of steroids and destroys the adrenal cortical cells. The utility of this drug is limited by its gastrointestinal and neurological toxicity and the need of close monitoring for dose adjustment.[13] The cost of this drug also limits its utility in our resource-challenged environment. The reliance was more on available and affordable chemotherapy. The use of cisplatin/carboplatin and etoposide is relatively recent, and hence its indications are still unclear due to a lack of lucid evidence. Hovi et al. in 2003 reported the use of etoposide and platinum-based chemotherapy for children with ACC irrespective of staging.[22] International Pediatric Adrenocortical tumor registry reported the use of combination chemotherapy in patients with Stage III and IV tumors, whereas only 2% of patients with Stage I or II received combination chemotherapy.[1] A report from the German GPOH-MET 97 trial also emphasized the role of neoadjuvant chemotherapy and utility in patients with spill.[6] Recently, a publication from Children's Oncology Group reported no additional benefit of retroperitoneal lymph node dissection in Stage II disease and proposed that these patients benefit from systemic therapy.[23] Adjuvant radiotherapy has a role in preventing local recurrence as described in a study by Glenn et al.[24] As the evidence of utility of chemotherapy in patients with intraoperative spill is recent, such patients in the initial part of the study did not receive chemotherapy.

The recurrence rate has been reported as high as 70% after a median recurrence-free interval of 11 months.[24] We observed recurrence only in 5 of 19 patients (26%) with ACC after a median duration of 10 months. The local site was the most common site of recurrence. We could excise only one recurrence successfully, and this patient did not have any re-recurrence. In one of the five recurrences, exploration revealed an unresectable tumor while the other three patients refused any further treatment.

The 4-year OS and EFS in patients with adenoma were 100%. While the 4-year OS and EFS in children with ACC in this study was 75% and 53%, which is similar to other studies.[1],[4],[6],[10]

One of the major limitations of this retrospective study is the loss to follow-up of patients. Another limitation of any retrospective study spread over 27 years is the continuous change in the standard of care. This is due to changing evidence, better assess to imaging, and improvement in general medical care. Over the past decade, disease-free survival was achieved in 6 of 9 (66%) children with ACC as compared to 5 of 10 children (50%) before that. Due to cost constraints, the utility of mitotane in the pediatric population could not be evaluated.


   Conclusion Top


Adrenocortical tumors are rare tumors. Adenomas have an excellent outcome with surgical resection. Patients with adenoma had an excellent outcome (100% OS and EFS), while those with ACC had a moderate outcome (75% OS; 53% EFS). Tumor spill occurred in 19% (4 patients) of the patients with ACC and leads to a higher incidence of recurrence. Adjuvant chemotherapy with etoposide and platinum-based regimes seems useful for patients with ACC Stage III or IV disease, and those with an intraoperative spill, especially in a resource-challenged setting where access to mitotane is limited.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG, et al. Clinical and outcome characteristics of children with adrenocortical tumors: A report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 2004;22:838-45.  Back to cited text no. 1
    
2.
Ribeiro RC, Pinto EM, Zambetti GP, Rodriguez-Galindo C. The international pediatric adrenocortical tumor registry initiative: Contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors. Mol Cell Endocrinol 2012;351:37-43.  Back to cited text no. 2
    
3.
Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer 2004;40:1117-26.6.  Back to cited text no. 3
    
4.
Pinto EM, Rodriguez-Galindo C, Pounds SB, Wang L, Clay MR, Neale G, 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 2017;35:3956-63.–63.  Back to cited text no. 4
    
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Sabaretnam M, Mishra A, Agarwal G, Agarwal A, Verma AK, Mishra SK. Adrenocortical carcinoma in children and adults: Two decades experience in a single institution. Indian J Cancer 2016;53:317-21.7.  Back to cited text no. 5
    
6.
Redlich A, Boxberger N, Strugala D, Frühwald MC, Leuschner I, Kropf S, et al. Systemic treatment of adrenocortical carcinoma in children: Data from the German GPOH-MET 97 trial. Klin Padiatr 2012;224:366-71.1.  Back to cited text no. 6
    
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Calabrese A, Basile V, Puglisi S, Perotti P, Pia A, Saba L, et al. Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 2019;180:387-96.  Back to cited text no. 7
    
8.
Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.  Back to cited text no. 8
    
9.
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 2003;27:867-81.  Back to cited text no. 9
    
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Hanna AM, Pham TH, Askegard-Giesmann JR, Grams JM, Iqbal CW, Stavlo P, et al. Outcome of adrenocortical tumors in children. J Pediatr Surg 2008;43:843-9.  Back to cited text no. 10
    
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Vassilopoulou-Sellin R, Schultz PN. Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 2001;92:1113-21.  Back to cited text no. 11
    
12.
Chatterjee G, DasGupta S, Mukherjee G, Sengupta M, Roy P, Arun I, et al. Usefulness of Wieneke criteria in assessing morphologic characteristics of adrenocortical tumors in children. Pediatr Surg Int 2015;31:563-71.  Back to cited text no. 12
    
13.
Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, Ribeiro RC. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 2005;45:265-73.  Back to cited text no. 13
    
14.
Wang Z, Liu G, Sun H, Li K, Dong K, Ma Y, et al. Clinical characteristics and prognosis of adrenocortical tumors in children. Pediatr Surg Int 2019;35:365-71.  Back to cited text no. 14
    
15.
Picard C, Orbach D, Carton M, Brugieres L, Renaudin K, Aubert S, et al. Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: Results from a national cohort study with pathological review. Mod Pathol 2019;32:546-59.  Back to cited text no. 15
    
16.
Michalkiewicz EL, Sandrini R, Bugg MF, Cristofani L, Caran E, Cardoso AM, et al. Clinical characteristics of small functioning adrenocortical tumors in children. Med Pediatr Oncol 1997;28:175-8.  Back to cited text no. 16
    
17.
Gupta N, Rivera M, Novotny P, Rodriguez V, Bancos I, Lteif A. Adrenocortical carcinoma in children: A clinicopathological analysis of 41 patients at the mayo clinic from 1950 to 2017. Horm Res Paediatr 2018;90:8-18.  Back to cited text no. 17
    
18.
Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev 2014;35:282-326.  Back to cited text no. 18
    
19.
Gulack BC, Rialon KL, Englum BR, Kim J, Talbot LJ, Adibe OO, et al. Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 2016;51:172-7.  Back to cited text no. 19
    
20.
Hubertus J, Günther B, Becker K, Graf N, Furtwängler R, Ferrari R, et al. Surgical aspects in the treatment of adrenocortical carcinomas in children: Data of the GPOH-MET 97 trial. Klin Padiatr 2012;224:143-7.  Back to cited text no. 20
    
21.
Zancanella P, Pianovski MA, Oliveira BH, Ferman S, Piovezan GC, Lichtvan LL, et al. Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: Mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 2006;28:513-24.  Back to cited text no. 21
    
22.
Hovi L, Wikström S, Vettenranta K, Heikkilä P, Saarinen-Pihkala UM. Adrenocortical carcinoma in children: A role for etoposide and cisplatin adjuvant therapy? Preliminary report. Med Pediatr Oncol 2003;40:324-6.  Back to cited text no. 22
    
23.
Rodriguez-Galindo C, Krailo MD, Pinto EM, Pashankar F, Weldon CB, Huang L, 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 2021;JCO2002871.  Back to cited text no. 23
    
24.
Glenn JA, Else T, Hughes DT, Cohen MS, Jolly S, Giordano TJ, et al. Longitudinal patterns of recurrence in patients with adrenocortical carcinoma. Surgery 2019;165:186-95.  Back to cited text no. 24
    


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