Society for Endocrinology
Evaluation of prognostic factors in advanced pediatric ACC
Maria Riedmeier 1,2, Shipra Agarwal3, Sonir R R Antonini D4, Saniye Ekinci5, Martin Fassnacht6,7, Bonald Cavalcante Figueiredo8, Christoph Härtel1, Jagdish Prasad Meena9, Stephen D Marks10,11, Jessica Munarin12,13, Soraya Puglisi14, Gerdi Tuli12,13, Bilgehan Yalcin15, Paul G Schlegel1,2,5, Armin Wiegering6,16,17 and Verena Wiegering ®1,2,5,18
1University Hospital Würzburg, Department of Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, Germany
2KIONET, The Phase I/II Pediatric Oncology Network Bavaria, Würzburg, Erlangen, Regensburg, Augsburg, München, Germany
3Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
4Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
5Pediatric Surgery, Department of Pediatric Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
6Comprehensive Cancer Centre Mainfranken, University of Wuerzburg Medical Centre, Wuerzburg, Germany
7Department of Medicine, Division of Endocrinology and Diabetes, University of Wuerzbrug Medical Centre, Wuerzburg, Germany 8Pelé Pequeno Príncipe Research Institute and Pequeno Príncipe Faculty, Curitiba, Brazil 9Division of Pediatric Oncology, Department of Pediatrics, Mother & Child Block, All India Institute of Medical Sciences, New Delhi, India
10Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
11NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
12Department of Pediatric Endocrinology, Regina Margherita Children’s Hospital, Turin, Italy
13Department of Pediatrics, University of Turin, Turin, Italy
14Internal Medicine, Department of Clinical and Biological Sciences, S Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
15Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
16Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, Würzburg University Hospital, Würzburg, Germany
17Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany
18Mildred Scheel Early Career Center, University Hospital Wuerzburg, Wuerzburg, Germany
Correspondence should be addressed to V Wiegering: Wiegering_v@ukw.de
Abstract
Therapeutic options of advanced pediatric adrenocortical carcinoma (pACC) are limited, and achieving valuable risk stratification remains challenging. We refined the value of prognostic factors with an emphasis on resection status. Retrospective international data from 106 patients with advanced pACC from various collaborating centers of the international pACC working groups ENSAT-PACT, IC-PACT and/or from individual international collaboration diagnosed were collected. One hundred six patients aged 0.1-18.1 (median 7.6) years were diagnosed with pACC, with 42 tumor stage III and 64 stage IV, respectively. Eighty percent (85/106) of the tumors were hormone-producing, with a mean Ki67 index for both stage groups of 29%. Patient survival was 45% (48/106) with a mean follow-up of 17.7 months. Higher age, tumor stage IV and increased Ki67 index worsened the prognosis on overall survival. Resection status had an essential impact on survival, as the patients with R0 resection (n = 32) had a better overall survival (71% for stage III patients; 80% for stage IV patients) than patients with R1 (n = 24) (45% for stage III; 69% for stage IV), R2 (n = 33) (17% for stage III; 15% for stage IV) and Rx (n = 7) (0% for stage III; 17% for stage IV). Of the ten patients with tumor spillage, only a few (57% of stage III; 0% of stage IV patients) survived. The resection status has a significant impact on overall survival in pACC. Therefore, tumor surgery should only be undertaken by experienced surgeons proficient in adrenalectomy and oncology, ideally within specialized pediatric oncological centers with a multidisciplinary team setting.
Keywords: pediatric adrenocortical carcinoma; pACC; advanced adrenocortical carcinoma; pediatric adrenocortical tumor; prognostic factors; resection status; outcome
Introduction
Pediatric adrenocortical carcinoma (pACC) is an exceedingly rare malignancy, with an estimated incidence of only 0.2-0.3 per 1 million per year among ACC patients who are under 20 years of age (McAteer et al. 2013, Siegel et al. 2014). Pediatric ACC is closely linked to TP53-related tumor syndromes such as Li-Fraumeni syndrome, particularly in Southern Brazil, attributable to the inherited germline mutation TP53p.R337H (Wasserman et al. 2015). This genetic predisposition results in a remarkably higher incidence rate of the tumor entity in this geographical region (Ribeiro et al. 2001, Pinto et al. 2004, Bougeard et al. 2015).
Pediatric ACC, particularly those affecting infants, exhibit differences in pathogenesis, biological behavior and clinical symptoms compared to their adult counterparts, although there may be overlapping characteristics (Mendonca et al. 1995, Dehner & Hill 2009, Kerkhofs et al. 2014, Martins-Filho et al. 2021, Riedmeier et al. 2021, Bachega et al. 2022). As more than 90% of these pediatric tumors produce hormones, most children present with clinical signs of virilization, Cushing syndrome or both (Michalkiewicz et al. 2004, Riedmeier et al. 2021). The essential curative therapeutic pillars of advanced pACC include surgical resection of the tumor (Rodriguez-Galindo et al. 2021, Uttinger et al. 2022), chemotherapy, and medical treatment with mitotane (Veytsman et al. 2009, Redlich et al. 2012). In general, therapeutic options in advanced tumor stages are limited, and achieving valuable risk stratification remains challenging. Based on current knowledge, age below 4 years, virilization alone, small tumor size and stage, low pathological parameters such as the Ki67 index, and complete resection are the most recognized prognostic factors associated with better survival (Zambaiti et al. 2021, Riedmeier et al. 2022).
To refine the definition of prognostic factors with an emphasis on resection status, we present findings from international data involving patients diagnosed with advanced pACC. To ensure a homogeneous cohort and minimize potential bias, all included patients received systemic platinum-based chemotherapy.
Patients and methods
Retrospective international data from 106 patients were collected, sourced from various collaborating centers of the international pediatric ACC working groups of ENSAT (ENSAT-PACT) and/or the International Consortium on Pediatric Adrenocortical Tumors (ICPACT), and/or from
individual international collaborations. Patients from five different countries (Brazil, Germany, India, Italy and Turkey) were included if they met the following criteria: diagnosis of an advanced stage of adrenocortical tumor (tumor stage III and IV according to the (modified) TNM classification or the COG classification, in addition to the Wieneke index), treatment with platinum-based chemotherapy, age between 0 and 18 years, clinical key data and the presence of follow-up data.
All patients were diagnosed and checked by reference pathologists. Due to their national standards, there was no central review due to the retrospective character of the study. However, pathological reports were checked centrally by the authors.
Ethical approval for gathering anonymized data for the ongoing project was secured in Würzburg, Germany (reference number: 2022102002).
Results
General patient characteristics
In our study, we included data from 106 pediatric patients with advanced adrenocortical carcinoma from five countries. Among them, 42 patients were diagnosed with tumor stage III and 64 patients with tumor stage IV.
The median age was 7.6 years (ranging from 0.1 to 18.1 years), with 62 (58%) female patients. Most of the tumors (85/96; 80%) were hormone-producing. Specifically, most stage III tumors showed androgen production alone, whereas the majority of stage IV tumors had both androgen and glucocorticoid production. For stage IV patients, the percentage of non-hormone-producing tumors increased. The mean Ki67 index for both stage groups was 29%.
Patient survival was 45% (48/106) with a mean follow-up of 17.7 months. Of the patients who were alive, 36/51 (71%) were in complete remission, whereas 12/51 (24%) were living with tumor disease. Two of 51 patients were lost to follow-up. One patient suffered from a second tumor (see Table 1 for details).
Prognostic role of clinical and surgical factors on survival
In general, the survival rate was worse for stage IV patients (26/64; 41%) than for stage III patients
| Stage III (all) | Stage III (alive) | Stage IV (all) | Stage IV (alive) | Total | |
|---|---|---|---|---|---|
| Number of patients (n) | 42 | 22 (52%) | 64 | 26 (41%) | 106 |
| Age (mean and range, years) | 6.3 (0.1-18.1) | 4.7 (0.1-17.1) | 8.4 (0.2-17.8) | 7.4 (0.2-16.9) | 7.6 (0.1-18.1) |
| Sex (n patients) | |||||
| Male | 18 | 11 (61%) | 26 | 8 (31%) | 44 (42%) |
| Female | 24 | 11 (46%) | 38 | 18 (47%) | 62 (58%) |
| Hormone production (n patients) | |||||
| None | 3 | 0 (0%) | 18 | 6 (33%) | 21 (20%) |
| Androgen | 23 | 11 (48%) | 18 | 9 (50%) | 41 (39%) |
| Glucocorticoid | 8 | 4 (50%) | 4 | 3 (75%) | 12 (11%) |
| Mixed | 8 | 7 (88%) | 24 | 8 (33%) | 32 (30%) |
| Ki67 (mean in %) | 30 | 23 | 29 | 26 | 29 (27%) |
| Follow up (mean, months) | 29.1 | 50.1 | 10.2 | 19.3 | 17.7 |
| Outcome (n patients) | |||||
| CR1 | 18 | 13 (100%) | 18 | 18 (100%) | 36 (34%) |
| Alive with disease | 4 | 4 (100%) | 6 | 6 (100%) | 12 (11%) |
| DOD | 19 | 0 (0%) | 38 | 0 (0%) | 57 (54%) |
| Lost to follow up | 0 | 0 (0%) | 2 | 2 (100%) | 2 (2%) |
| Second cancer | 1 | 0 (0%) | 0 | 0 (0%) | 1 (1%) |
| Resection (n patients) | |||||
| R0 | 17 | 12 (71%) | 15 | 12 (80%) | 32 (30%) |
| R1 | 11 | 5 (45%) | 13 | 9 (69%) | 24 (23%) |
| R2 | 6 | 1 (17%) | 27 | 4 (15%) | 33 (31%) |
| RX | 1 | 0 (0%) | 6 | 1 (17%) | 7 (7%) |
| Tumor spillage | 7 | 4 (57%) | 3 | 0 (0%) | 10 (9%) |
| Surgical lymph node resection (n patients) | |||||
| Yes | 7 | 4 (57%) | 11 | 6 (55%) | 18 (26%) |
| No | 26 | 13 (50%) | 26 | 5 (19%) | 52 (74%) |
| Data not available | 9 | 27 | 36 | ||
| Macroscopic tumor-free (n patients) | |||||
| Yes | 16 | 11 (69%) | 9 | 6 (67%) | 25 (36%) |
| No | 18 | 6 (33%) | 27 | 4 (15%) | 45 (64%) |
| Data not available | 8 | 28 | 36 | ||
| Postoperative radiation of the tumor bed (n patients) | 4 (out of 34) | 2 (50%) | 3 (out of 36) | 2 (67%) | 7 |
| Data not available | 8 | 28 | 36 | ||
| Metastasis (n patients/n metastases) | 5/10 (secondary) | 2 (40%) | 36/53* | 10 (28%) | 41/63* |
| Lymph node (n metastases) | 4 | 2 (50%) | 7 | 3 (43%) | 11 (17%) |
| Lung (n metastases) | 3 | 0 (0%) | 21 | 2 (10%) | 24 (38%) |
| Liver (n metastases) | 2 | 0 (0%) | 9 | 2 (23%) | 11 (17%) |
| Bone (n metastases) | 1 | 0 (0%) | 5 | 1 (20%) | 6 (10%) |
| Brain (n metastases) | 0 | 0 (0%) | 2 | 1 (50%) | 2 (3%) |
| Peritoneum (n metastases) | 0 | 0 (0%) | 10 | 1 (10%) | 10 (16%) |
| Data not available | 27 | 27 | |||
| Remission after therapy (n) | |||||
| Yes | 10 | 7 (70%) | 9 | 6 (66%) | 20 (35%) |
| No | 9 | 5 (56%) | 31 | 5 (16%) | 37 (65%) |
| Data not available | 23 | 24 | 49 |
Showing clinical and surgical data of 106 patients sourced from international collaborating centers with advanced pACC (stage III and IV) and their corresponding survival rates.
*With known location of metastasis.
(22/42; 52%). Patients who survived were younger (5.9 vs 8.9 years, P-value <0.01) and had lower Ki67 indices (25 vs 32%, P-value 0.05). Ki67 indices did not differ significantly between stage III and IV patients. No prognostic relevance of hormone production on overall survival was observed.
In both tumor stage groups, the resection status had an essential impact on survival, as the patients who received
complete resection (R0) had better overall survival (12/17 (71%) for stage III patients and 12/15 (80%) for stage IV patients) than patients with incomplete resection: R1 (indicates the removal of all macroscopic disease, but microscopic margins are positive for the tumor) 5/11 (45%) for stage III and 9/13 (69%) for stage IV; R2 (indicates macroscopic residual disease (either locally or due to remaining metastases)) 1/6 (17%) for stage III and 4/27 (15%) for stage IV; Rx (uncertain resection status
Stage III R0
Stage III R1
Stage III R2
Stage III RX
Stage III spillage
Stage IV R0
Stage IV R1
Stage IV R2
Stage IV RX
Stage IV spillage
alive
dead
or not resected tumors) 0/1 (0%) for stage III and 1/6 (17%) for stage IV. Tumor spillage also worsened the prognosis, with only 4/7 (57%) of stage III patients and none (0/3) of the stage IV patients with tumor spillage surviving (see Table 1 and Fig. 1 for details). Among the surviving patients with tumor spillage, the resection status was not clearly defined; however, one patient was noted as being macroscopically tumor-free. Resection status was clearly associated with survival probability, independent of age, presence of metastasis and stage (Table 2).
Further surgery details were available for 73 patients, 34 patients with tumor stage III and 39 with tumor stage IV. In addition to the general resection status, surgical lymph node resection and achieving macroscopic tumor-free status also increased the overall survival of the patients. Only seven patients (four with stage III and three with stage IV tumors) - all with incomplete surgical tumor resection - received postoperative radiation of the tumor bed. Fifty-seven percent of them survived, but none of them achieved complete remission. Metastases significantly worsened the prognosis, as 40% (2/5) of the patients with stage III who developed secondary metastases and only 28% (10/36) of the stage IV patients (all by definition with metastases) survived. The most common metastatic sites were the lungs, followed by the peritoneum, liver and lymph nodes (see Table 1 for details).
Discussion
Our data align with previous studies regarding clinical prognostic factors in pACC, wherein factors such as higher age, elevated Ki67 index and the presence of
metastases significantly impact overall survival in patients with (advanced) pACC (Zambaiti et al. 2021, Riedmeier et al. 2022).
The aim of our study was to specifically investigate prognostic factors, with an emphasis on resection status and its impact on patient outcomes. Achieving complete tumor resection (R0) and resection of affected lymph nodes is paramount for ensuring a cure in the treatment of pACC, even in advanced stages (Hubertus et al. 2012, Fassnacht et al. 2018, Rodriguez-Galindo et al. 2021). European guidelines for adults advocate for an open ‘en bloc’ resection encompassing all suspected tissues, including peritumoral fat tissue (Fassnacht et al. 2018). Incomplete resection or tumor spillage significantly elevates the risk of recurrence and markedly worsens overall survival, consistent with our findings (Hubertus et al. 2012, Fassnacht et al. 2018, Uttinger et al. 2022).
Tumor biopsy, as evidenced by several studies (Hubertus et al. 2012, Fassnacht et al. 2018), is associated with a reduction in overall survival rates and should thus generally be avoided in both pediatric and adult populations. However, European guidelines make an exception for patients in incurable stage IV and/or those with inoperable primary tumors, permitting biopsy for histopathological confirmation (Fassnacht et al. 2018).
Our data show that surgical lymph node resection increased the overall survival rate of the patients. In pediatric patients, the utility of retroperitoneal lymph node dissection (RPLND) remains a subject of debate, particularly in light of the findings from the previous study conducted by the Children’s Oncology Group (ARAR0332 protocol), which failed to demonstrate any
| Patient distribution by age (in years) | <3 | 3-12 | >12 |
|---|---|---|---|
| Total number of patients | 27 | 54 | 25 |
| Alive/dead of disease | 20/7 | 19/35 | 9/16 |
| OS in % | 74% | 38% | 36% |
| Stage III/IV | 17/10 | 16/38 | 9/16 |
| Patients with metastasis | 13 | 39 | 17 |
| R0/>R0 resection | 10/17 | 18/36 | 4/21 |
| % of patient alive with R0 resection | 90% | 72% | 50% |
| Ki67 (mean in %) | 23.1 | 35.3 | 22.6 |
| Systemic treatment/RT | 27/0 | 54/1 | 25/6 |
| Follow up (months) | 32 (1-265) | 17 (1-187) | 5 (1-23) |
| Patient distribution by resection status | All | Alive | Dead |
| R0 | 32 | 24 (75%) | 8 (25%) |
| R1 | 24 | 14 (58%) | 10 (42%) |
| R2 | 33 | 5 (15%) | 28 (85%) |
| Rx | 7 | 1 (14%) | 6 (86%) |
| Tumor spillage | 10 | 4 (40%) | 6 (60%) |
| Patient distribution by metastasis | Metastasis | No metastasis | |
| Total number | 69 | 37 | |
| Alive/dead of disease | 28/41 | 20/17 | |
| OS in % | 41% | 54% | |
| Median age (in years) | 8.3 | 6.2 | |
| R0/>R0 resection | 18/51 | 14/23 | |
| % of patient alive with R0 resection | 78 | 71 | |
| Ki67 (mean in %) | 29.0 | 29.3 | |
| Systemic treatment/Radiotherapy | 69/1 | 37/3 | |
| Follow-up (months) | 13 (2-187) | 26 (2-265) |
Clinical and surgical data of 106 patients are presented, stratified by age groups (<3, 3-12 and >12 years), resection status (RO, R1, R2, Rx or tumor spillage) and the presence of metastasis at diagnosis and/or during follow-up.
improvement in overall survival (Rodriguez-Galindo et al. 2021). However, in contrast, adult patients who underwent RPLND exhibited an enhanced recurrence- free survival, as shown by Reibetanz et al. (2012).
Multiple studies involving adult patients have consistently demonstrated that tumor resections performed by surgeons being highly experienced in adrenalectomy correlate with improved overall survival rates (Park et al. 2009, Palazzo et al. 2016, Lindeman et al. 2018). European guidelines for adult patients recommend that specialized surgeons perform over 20 adrenalectomies annually, although a minimum of six adrenalectomies per year appears to provide sufficient experience (Fassnacht et al. 2018). However, similar studies and guidelines specific to the pediatric sector are currently lacking. Evidence regarding the optimal surgical approach (open, laparoscopic, RPLND) is lacking and remains an unsolved question. Nevertheless, our data underscore the prognostic significance of surgical outcomes in pediatric cases. Consequently, we strongly advocate for pediatric patients to undergo surgical treatment exclusively at specialized pediatric oncologic centers staffed by highly experienced surgeons.
In conclusion, resection status has an important impact on long-term event-free and overall survival in pACC.
Surgical procedures for suspected or confirmed ACC should only be undertaken by experienced surgeons proficient in adrenalectomy and oncology, ideally within specialized pediatric oncologic centers with an interdisciplinary setting (Hubertus et al. 2012, Fassnacht et al. 2018, Uttinger et al. 2022).
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work was supported by a research grant from Interdisziplinäres Zentrum für klinische Forschung (IZKF) training grant awarded to MR (project number: Z-02CSP/23), the Mildred Scheel program awarded to VW (project 70113303-6) and by the Deutsche Forschungsgemeinschaft (DFG) German Research Foundation (project 314061271-TRR 205) to MF. This work was also supported by a research grant from the Tour of Hope Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Acknowledgements
We would like to thank the Parents Initiative Group for Children with Leukemia and Solid Tumors Würzburg e.V. for their continuous support. Authors VW and MR are supported by COST Action CA20122 Harmonization.
References
Bachega FS, Suartz CV, Almeida MQ, et al. 2022 Retrospective analysis of prognostic factors in pediatric patients with adrenocortical tumor from unique tertiary center with long-term follow-up. J Clin Med 11 6641. (https://doi.org/10.3390/jcm11226641)
Bougeard G, Renaux-Petel M, Flaman J-M, et al. 2015 Revisiting Li-fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 33 2345-2352. (https://doi.org/10.1200/jco.2014.59.5728)
Dehner LP & Hill DA 2009 Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors? Pediatr Dev Patho/ 12 284-291. (https://doi.org/10.2350/08-06-0489.1)
Fassnacht M, Dekkers OM, Else T, et al. 2018 European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 179 G1-G46. (https://doi.org/10.1530/eje-18-0608)
Hubertus J, Boxberger N, Redlich A, et al. 2012 Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klin Padiatr 224 143-147. (https://doi.org/10.1055/s-0032-1304627)
Kerkhofs TM, Ettaieb MH, Verhoeven RH, et al. 2014 Adrenocortical carcinoma in children: first population-based clinicopathological study with long-term follow-up. Oncol Rep 32 2836-2844. (https://doi.org/10.3892/or.2014.3506)
Lindeman B, Hashimoto DA, Bababekov YJ, et al. 2018 Fifteen years of adrenalectomies: impact of specialty training and operative volume. Surgery 163 150-156. (https://doi.org/10.1016/j.surg.2017.05.024)
Martins-Filho SN, Almeida MQ, Soares I, et al. 2021 Clinical impact of pathological features including the Ki-67 labeling index on diagnosis and prognosis of adult and pediatric adrenocortical tumors. Endocr Pathol 32 288-300. (https://doi.org/10.1007/s12022-020-09654-x)
Mcateer JP, Huaco JA & Gow KW 2013 Predictors of survival in pediatric adrenocortical carcinoma: a surveillance, epidemiology, and end results (SEER) program study. J Pediatr Surg 48 1025-1031. (https://doi.org/10.1016/j.jpedsurg.2013.02.017)
Mendonca BB, Lucon AM, Menezes CA, et al. 1995 Clinical, hormonal and pathological findings in a comparative study of adrenocortical neoplasms in childhood and adulthood. J Uro/ 154 2004-2009. (https://doi.org/10.1097/00005392-199512000-00006)
Michalkiewicz E, Sandrini R, Figueiredo B, et al. 2004 Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Onco/ 22 838-845. (https://doi.org/10.1200/jco.2004.08.085)
Palazzo F, Dickinson A, Phillips B, et al. 2016 Adrenal surgery in England: better outcomes in high-volume practices. Clin Endocrinol 85 17-20. (https://doi.org/10.1111/cen.13021)
Park HS, Roman SA & Sosa JA 2009 Outcomes from 3144 adrenalectomies in the United States: which matters more, surgeon volume or specialty? Arch Surg 144 1060-1067. (https://doi.org/10.1001/archsurg.2009.191)
Pinto EM, Billerbeck AE, Villares MC, et al. 2004 Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors. Arq Bras Endocrinol Metabol 48 647-650. (https://doi.org/10.1590/s0004-27302004000500009)
Redlich A, Boxberger N, Strugala D, et al. 2012 Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 366-371. (https://doi.org/10.1055/s-0032-1327579)
Reibetanz J, Jurowich C, Erdogan I, et al. 2012 Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg 255 363-369. (https://doi.org/10.1097/sla.0b013e3182367ac3)
Ribeiro RC, Sandrini F, Figueiredo B, et al. 2001 An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98 9330-9335. (https://doi.org/10.1073/pnas.161479898)
Riedmeier M, Decarolis B, Haubitz I, et al. 2021 Adrenocortical carcinoma in childhood: a systematic review. Cancers 13 5266. (https://doi.org/10.3390/cancers13215266)
Riedmeier M, Decarolis B, Haubitz I, et al. 2022 Assessment of prognostic factors in pediatric adrenocortical tumors: a systematic review and evaluation of a modified S-GRAS score. Eur J Endocrino/ 187 751-763. (https://doi.org/10.1530/eje-22-0173)
Rodriguez-Galindo C, Krailo MD, Pinto EM, et al. 2021 Treatment of pediatric adrenocortical carcinoma with surgery, retroperitoneal lymph node dissection, and chemotherapy: the children’s oncology group ARAR0332 protocol. J Clin Oncol 39 2463-2473. (https://doi.org/10.1200/jco.20.02871)
Siegel DA, King J, Tai E, et al. 2014 Cancer incidence rates and trends among children and adolescents in the United States, 2001-2009. Pediatrics 134 e945-e955. (https://doi.org/10.1542/peds.2013-3926)
Uttinger KL, Riedmeier M, Reibetanz J, et al. 2022 Adrenalectomies in children and adolescents in Germany - a diagnose related groups based analysis from 2009-2017. Front Endocrinol 13 914449. (https://doi.org/10.3389/fendo.2022.914449)
Veytsman I, Nieman L & Fojo T 2009 Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol 27 4619-4629. (https://doi.org/10.1200/jco.2008.17.2775)
Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. 2015 Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children’s oncology group study. J Clin Oncol 33 602-609. (https://doi.org/10.1200/jco.2013.52.6863)
Zambaiti E, Duci M, De Corti F, et al. 2021 Clinical prognostic factors in pediatric adrenocortical tumors: a meta-analysis. Pediatr Blood Cancer 68 e28836. (https://doi.org/10.1002/pbc.28836)