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Surgical Management and Outcomes in Pediatric Adrenocortical Carcinoma: A Pediatric Surgical Oncology Research Collaborative Study
Shachi Srivatsa, MD, MPH1, Jennifer H. Aldrink, MD2, Md Rejuan Haque, PhD3, Andrew Murphy, MD4, Daniel Gehle, MD4, Huma Halepota, MD4, Erika A. Newman, MD5, Keyonna Williams, MD5, Peter Mattei, MD6, William R. Johnston, MD6, Rosa Hwang, BS6, Timothy B. Lautz, MD7, Samantha A. Ayala, BS7, Nelson Piché, MD8, Caroline P. Lemoine, MD8, Julia Debertin, MPH9, Stephanie F. Polites, MD9, David H. Rothstein, MD, MS10, Kimberly J. Riehle, MD10, Nzuekoh Nchinda, MD10, Marcus M. Malek, MD11, Hannah N. Rinehardt, MD11, Catherine Gestrich, DO12, Shannon L. Castle, MD13, Adriana Lopez, BS14, Matthew S. Mayes, BS14, Emily K. Myers, MD15, Jonathan P. Roach, MD15, Brian T. Craig, MD16, Dave R. Lal, MD, MPH16, Jennifer Schuh, MD16, Barrett P. Cromeens, DO, PhD17, Sindhu V. Mannava, MD, MS17, Mary T. Austin, MD, MPH18, Lauren K. Mayon, PA18, Zachary J. Kastenberg, MD19, Marshall Wallace, MD19, Abigail Alexander, MD19, Michael A. Stellon, MD20, Hau D. Le, MD20, Devashish S. Joshi, MD20, Charbel Chidiac, MD21, Daniel S. Rhee, MD21, Danielle Cameron, MD, MPH22, Alyssa Stetson, MD22, Barrie S. Rich, MD23, Richard D. Glick, MD23, Elizabeth A. Fialkowski, MD24, Kathryn Fowler, MD24, Rukaya Fareh, BSN24, Erin G. Brown, MD25, Kathleen Doyle, MD26, Paige Abril, BA26, Christa Grant, MD27, Roshni Dasgupta, MD, MPH28, Chloé Boehmer, MA28, and Sara A. Mansfield, MD, MS2
1Center for Surgical Outcomes and Research, Abigail Wexner Research Institute, Division of Pediatric Surgery, Department of Surgery, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH; 2Division of Pediatric Surgery, Department of Surgery, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH; 3Department of Biomedical Informatics, The Ohio State University, Columbus, OH; 4Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN; 5C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI; ‘General, Thoracic and Fetal Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA; 7Department of Surgery, Division of Pediatric Surgery, Lurie Children’s Hospital, Northwestern School of Medicine, Chicago, IL; 8Division of Pediatric Surgery, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, Montréal, Canada; 9Department of Surgery, Mayo Clinic, Rochester, MN; 10Seattle Children’s Hospital, University of Washington, Seattle, WA; 11Division of Pediatric General and Thoracic Surgery, University of Pittsburgh Medical Center (UPMC) Children’s Hospital of Pittsburgh, Pittsburgh, PA; 12Division of Pathology, University of Pittsburgh Medical Center (UPMC) Children’s Hospital of Pittsburgh, Pittsburgh, PA; 13Division of Pediatric Surgery, Valley Children’s Hospital, Madera, CA; 14Valley Children’s Hospital, Madera, CA; 15Division of Pediatric Surgery, Department of Surgery, University of Colorado School of Medicine, Children’s Hospital of Colorado, Aurora, CO; 16Division of Pediatric Surgery, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, WI; 17Division of Pediatric Surgery, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN; 18MD Anderson Cancer Center, University of Texas, Houston, TX; 19Department of Surgery, Division of Pediatric Surgery, University of Utah, Primary Children’s Hospital, Salt Lake City, UT; 20Division of Pediatric Surgery, American Family Children’s Hospital, School of Medicine
@ Society of Surgical Oncology 2025
and Public Health, University of Wisconsin, Madison, WI; 21Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD; 22Massachusetts General Hospital, Boston, MA; 23Feinstein/ Northwell, Cohen Children’s Medical Center, Queens, NY; 24Department of Surgery, Oregon Health & Science University, Portland, OR; 25Division of Pediatric Surgery, Department of Surgery, University of California Davis Children’s Hospital, Sacramento, CA; 26Department of Surgery, University of California Davis, Sacramento, CA; 27New York Medical College, Valhalla, NY; 28Division of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
ABSTRACT
Background. Pediatric adrenocortical carcinoma (ACC) is a rare and aggressive cancer. The appropriateness of mini- mally invasive surgery (MIS), role of nodal dissection, and aggressiveness of surgery in patients with metastatic disease remain poorly understood.
Patients and Methods. We performed a retrospective review of patients < 18 years with ACC treated from 2012 to 2022 at 22 institutions participating in the Pediatric Surgical Oncology Research Collaborative. Data collected included demographics, clinical presentation, genetic predisposition, tumor characteristics, surgical approach, adjuvant treatment, and survival outcome. Survival probabilities were estimated with Kaplan-Meier methods.
Results. In all, 69 patients were included (median age: 8.4 years; 58% female), and 28% had Li-Fraumeni syndrome. At diagnosis, 36% had Stage IV disease and 28% had Stage I disease. A total of 55 (83%) patients underwent open adre- nalectomy, and 11 (17%) underwent MIS. MIS approaches were employed for significantly smaller tumors (median: 4.4 cm, 38 g) compared with open cases (median: 9.6 cm, 246 g; p < 0.001), and none had tumor spillage (versus 22% in open cases; p = 0.087). Lymph node sampling was per- formed in 44% of open cases (mean yield: 2.96); no lymph nodes were sampled in MIS cases (p = 0.008). The 5 year overall survival (OS) for the entire cohort was 65.9%, and 5-year event-free survival (EFS) was 54.1%. Patients without metastases had significantly better survival than those with more than five metastatic lesions (5 year OS: 84.5% versus 11.9%; p < 0.001).
Conclusions. Complete surgical resection remains para- mount for cure in children with ACC. Despite aggressive attempts at tumor clearance, outcomes in children with metastatic disease remain poor. Nodal dissection remains infrequently and incompletely performed, limiting conclu- sions on impact.
Keywords Adrenocortical carcinoma · Pediatric . Adrenal tumor · Minimally invasive surgery · Outcomes · Li-Fraumeni syndrome
Adrenocortical carcinoma (ACC) is an uncommon malig- nancy of the adrenal cortex with an overall poor prognosis. In children, ACC is exceedingly rare, with an incidence of only about 0.2-0.3 per million in individuals under 20 years
old, accounting for < 0.2% of pediatric cancers.1 Pediatric ACC is frequently associated with cancer predisposition syn- dromes. In particular, germline TP53 mutations (Li-Frau- meni syndrome), present in up to 50-80% of pediatric adren- ocortical carcinoma (ACC) cases, and IGF2 overexpression (often due to Beckwith-Wiedemann syndrome) are strongly linked to ACC in children.1
Complete surgical resection is the cornerstone of treat- ment for ACC at any age and offers the only potential for cure. A report from the International Pediatric Adrenocor- tical Tumor Registry (IPACTR) found an overall 5-year event-free survival (EFS) of 54% that was most significantly impacted by stage.3 However, the role and limitation of extensive surgery in patients with metastatic ACC remains poorly understood. Additionally, the role of templated ipsi- lateral retroperitoneal lymph node dissection (RPLND) in ACC is even more uncertain. RPLND was incorporated into the Children’s Oncology Group ARAR0332 protocol for pediatric patients with Stage II ACC, on the basis of the hypothesis that residual nodal disease may contribute to relapse, as suggested by adult data.4 However, the study found that RPLND, as documented, did not significantly improve event-free survival, calling into question the effi- cacy of RPLND in this setting, though limited nodal sam- pling and inconsistent surgical adherence may have clouded these data.
The optimal surgical approach for pediatric ACC is also still debated. In adults, due to the aggressive nature and fri- ability of ACC, open adrenalectomy has traditionally been recommended even for smaller tumors, to ensure en bloc resection and avoid tumor spillage.5 Retrospective analyses in adult ACC have yielded mixed findings regarding the role of minimally invasive surgery (MIS). In the pediatric popu- lation, data guiding the choice of open versus laparoscopic adrenalectomy for ACC are extremely limited. Pediatric surgeons have increasingly adopted MIS for other adrenal tumors (such as neuroblastic tumors and benign lesions) and report favorable experiences.6 However, for confirmed or suspected ACC in children, pediatric surgeons usually undertake an open approach due to extrapolation of adult ACC guidelines and fear of tumor spillage in a malignancy with high recurrence risk.7,8 Prior to this study, no series had specifically compared outcomes of open versus minimally invasive resection for pediatric ACC.
To address these gaps, we conducted a multi-institutional retrospective study of pediatric ACC through the Pediatric
Surgical Oncology Research Collaborative (PSORC). The objectives were (1) to investigate the impact of surgery on oncologic outcomes in patients with metastatic disease, (2) to evaluate the outcomes and appropriateness of minimally invasive approaches to pediatric ACC, and (3) to define the incidence of compliance with templated ipsilateral retrop- eritoneal lymph node dissection and its impact on oncologic outcomes. We hypothesized that surgical management influ- ences oncologic outcomes in children with metastatic ACC, that minimally invasive surgery in carefully selected patients yields survival outcomes comparable to open surgery, and that compliance with retroperitoneal lymph node dissection impacts oncologic outcomes. We aimed to inform surgical decision-making and overall management strategies for this rare pediatric malignancy.
PATIENTS AND METHODS
Study Design and Setting
A multi-center retrospective cohort study was performed through PSORC. After obtaining institutional review board approval at each participating site, a limited dataset were collected for children less than 18 years of age with ACC treated between January 2012 and December 2022. A total of 22 institutions contributed to this cohort.
Patient Selection
Inclusion criteria were patients aged < 18 years at diag- nosis with pathologically confirmed ACC. Patients who had initial surgery at a referring hospital but received additional treatment at a participating center were included if adequate surgical records were available. We used Weineke/Armed Forces Institute of Pathology (AFIP) or Weiss scoring of 3 or higher to designate ACC in cases where the histologic diagnosis was unclear.9,10 Exclusion criteria included adre- nal cortical tumors of uncertain malignant behavior (e.g., adenomas or tumors of unknown malignant potential) and patients without definitive ACC histopathology.
Data Collection
A standardized form (Supplemental Table 1) was used to abstract data from medical records at each site. Collected variables included patient demographics, clinical presenta- tion features, and presence of underlying tumor predispo- sition syndromes. Tumor characteristics on imaging and pathology were recorded, including tumor dimensions on preoperative imaging, evidence of vascular or local organ invasion, and presence of metastatic disease at diagnosis. The clinical stage was determined using a pediatric ACC staging system analogous to European Network for the Study
| Stage | Definition |
|---|---|
| I | Tumor confined to adrenal gland, ≤ 5 cm |
| II | Tumor > 5 cm or gross local extension without nodal or distant spread |
| III | Positive regional lymph nodes or unre- sectable local extension |
| IV | Distant metastases |
of Adrenal Tumors (ENSAT) staging (Table 1): Stage I (tumor confined to adrenal, ≤ 5 cm), Stage II (tumor > 5 cm or showing gross local extension but no nodal or distant spread), Stage III (positive regional lymph nodes or unre- sectable local extension), and Stage IV (distant metastases). Oligometastatic disease was defined as those with 5 or fewer metastases and extensive metastatic disease was defined as those with greater than 5 metastases.11
Operative details were abstracted from operative and pathology report. The surgical approach was categorized as open versus MIS. Open surgery included transabdominal laparotomy or thoracoabdominal incisions, whereas MIS included laparoscopic or robotic adrenalectomy. Perfor- mance of lymph node dissection or sampling was recorded, specifically, whether a formal, templated ipsilateral RPLND was attempted, or whether any regional lymph nodes were sampled for pathology. To aid with this determination, description of template RPLND was included in REDCap for reference.
Use of adjuvant treatments was noted, including chemo- therapy and radiation therapy. The date of last follow-up and vital status were documented for each patient. For those who developed recurrence, details of relapse including date and site of relapse, and any salvage therapies were collected.
Statistical Analysis
Patients were stratified by age group (< 5 years versus ≥ 5 years) on the basis of an observed bimodal age distribution in the cohort and by clinical rationale from prior reports.3 They were also stratified by surgical approach (open versus MIS). Descriptive statistics were used to summarize patient and tumor characteristics in these subgroups. Continuous variables were compared using the Wilcoxon rank-sum test, and categorical variables using Pearson’s chi-squared or Fisher’s exact test, as appropriate. Survival analyses were performed using the Kaplan-Meier method. Overall survival (OS) was defined as the time from diagnosis to death from any cause, or last follow-up if alive. Event-free survival was defined as time from diagnosis to the first event (relapse or death) or last follow-up. Patients without an event were censored at last contact. Survival distributions between
groups were compared with the log-rank test. Cox propor- tional hazards regression was used to evaluate associations between covariates (e.g., age, stage, surgical approach, and pathologic features) and OS/EFS, reporting hazard ratios (HR) with 95% confidence intervals. A p-value < 0.05 was considered statistically significant. Statistical analyses were conducted using R software (R Foundation for Statistical Computing, Vienna, Austria). 12
RESULTS
Patient Demographics and Clinical Presentation
A total of 69 children with ACC met inclusion crite- ria (Table 2). The median age at diagnosis was 8.4 years [interquartile range (IQR): 2.2-13.2]. In all, 40 were female (58%), and 29 were male (42%). A total of 41 (59%) patients had an identified cancer predisposition syndrome. The most common was Li-Fraumeni syndrome, present in 19 (28% of the entire cohort) patients, followed by Beckwith-Wiede- mann syndrome in 3 (4.3%) patients.
Clinical signs of hormonal excess were present in the majority of patients (n = 61, 88.4%), with most patients having multiple endocrine signs. Virilization was the most frequent presenting feature, observed in 41 (59%) patients. Cushing’s syndrome was noted in 18 (26%) patients, often in combination with virilizing features. In all, 19 (28%) patients had hypertension, and 2 (2.9%) were diagnosed with hyperaldosteronism.
Tumor Characteristics
On preoperative imaging, the median overall tumor size, in the largest single dimension, was 9.6 cm (IQR: 6.0, 12.5). Imaging evidence of vascular invasion was present in 16 (23.1%) patients. At diagnosis, distant metastases were present in 25 (36.2%) patients. Oligometastatic dis- ease (defined as five or fewer metastases) was present in 7 (10.1%) patients. Metastases were isolated to the lungs in 3 patients, to the liver in 15 patients, and were present in multiple sites in 7 patients. Overall, stage distribution was Stage I in 19 (28%) patients, Stage II in 11 (16%), Stage III in 14 (20%), and Stage IV in 25 (36%).
Age-Based Differences
There were 27 (39.1%) patients less than 5 years of age and 42 (60.9%) patients 5 years or older (Table 3). Li-Frau- meni syndrome was more prevalent in those children < 5 years when compared with those ≥ 5 years (44% versus 17%, p = 0.025). Virilization was the most common pres- entation and not different between children < 5 (17, 63%) and older children (24, 57%, p = 0.82). Tumors in younger
| Characteristic | N = 69 N (%) or median (IQR) |
|---|---|
| Sex | |
| Male | 29 (42%) |
| Female | 40 (58%) |
| Race | |
| White | 55 (80%) |
| Hispanic or Latino/Latina or Latinx | 3 (4.3%) |
| Multiracial-Hispanic | 3 (4.3%) |
| American Indian or Alaska Native | 1 (1.4%) |
| Black or African American | 2 (2.9%) |
| Multiracial :- non-Hispanic | 1 (1.4%) |
| Unknown or not listed | 4 (5.8%) |
| Age at diagnosis (years) | 106 (25, 158) |
| Syndrome | |
| None | 41 (59%) |
| Li-Fraumeni | 19 (28%) |
| Beckwith-Wiedemann | 3 (4.3%) |
| Multiple endocrine neoplasia | 0 (0%) |
| Carney's complex | 0 (0%) |
| Other | 4 (5.8%) |
| Symptoms at presentation | |
| No symptoms | 5 (7.2%) |
| Virilization | 41 (59%) |
| Cushing | 18 (26%) |
| Hyperaldosteronism (Conn's) | 2 (2.9%) |
| Hypertension | 19 (28%) |
| Incidental/nonfunctional | 12 (17%) |
| Tumor characteristics | |
| Tumor size (cm) | 8.6 (6.0, 12.5) |
| Tumor weight (g) | 220 (66, 515) |
| Presence of vascular extension | 16 (23%) |
| Presence of metastatic disease | 25 (36%) |
| Surgical details | |
| Age at resection (months) | 111 (25, 158) |
| Open | 55 (83%) |
| Minimally invasive | 11 (17%) |
| Preoperative biopsy | 18 (26%) |
| Retroperitoneal lymph node dissection performed | 12 (19%) |
| Lymph node sampling performed | 16 (26%) |
| Preoperative rupture | 5 (7.4%) |
| Intraoperative spill | 13 (19%) |
| Resection of adjacent organs | 10 (15%) |
| Additional resection performed | 14 (21%) |
| Tumor necrosis present | 49 (74%) |
| Positive margins | 17 (27%) |
| Negative margins | 47 (73%) |
| Invasion of adjacent organs | 15 (22%) |
| Nuclear grade | |
| 1 | 1 (1.8%) |
| Characteristic | N = 69 N (%) or median (IQR) |
|---|---|
| 3 | 2 (3.6%) |
| 4 | 3 (5.4%) |
| 5 | 50 (89%) |
| Capsular invasion present | 28 (44%) |
| Stage | |
| 1 | 18 (27%) |
| 2 | 11 (17%) |
| 3 | 12 (18%) |
| 4 | 25 (38%) |
| Presence of mutations | |
| Absent | 35 (51%) |
| TP53 | 20 (29%) |
| CTNNB1 | 2 (2.9%) |
| ATRX | 0 (0%) |
| Other | 8 (12%) |
| Adjuvant therapies | |
| Neoadjuvant chemotherapy received | 15 (22%) |
| Adjuvant chemotherapy received | 37 (55%) |
| Radiation therapy received | 10 (16%) |
| Surgery for metastatic disease | 15 (22%) |
| Outcomes | |
| Reached no evidence of disease | 40 (61%) |
| Sustained relapse | 16 (25%) |
| Status at last follow-up | |
| Alive with no evidence of disease | 40 (58%) |
| Alive with disease | 8 (12%) |
| Deceased | 21 (30%) |
| Deceased due to disease | 19 (90%) |
children were also significantly smaller (median: 6.7 cm versus 10.0 cm, p = 0.006) and demonstrated fewer inva- sive features, such as vascular invasion (7%, n = 7) com- pared with older children (33%, n = 21; p = 0.028). Younger children (< 5 years, n = 27) demonstrated more favorable clinical presentation, as defined by stage and presence of metastatic disease at presentation, than older children (≥ 5 years, n = 42). Stage I disease was more frequently observed in younger patients (44% versus 17%, p < 0.001), while advanced-stage disease (Stage III/IV) was more common among older children (50% versus 26%). Among younger children, 5/27 (18.5%) had metastatic disease evident on imaging at presentation, compared with 20/42 (47.6%) of those ≥ 5 years (p = 0.021).
Despite differences in clinical presentation, survival outcomes between age groups did not reach statistical sig- nificance. The 5-year OS for patients < 5 years was 79.6% (95% CI: 63.5-95.7%) compared with 56.3% (95% CI:
38.9-73.8%) in older children (p = 0.08). Similarly, the 5-year EFS was 68.3% (95% CI: 49.9-86.7%) in younger children and 45.1% (95% CI: 28.5-61.7%) in the older group (p = 0.08). Notably, younger children were signif- icantly more likely to achieve a result of no evidence of disease (NED) state, with 21 of 27 (77.8%) patients reach- ing NED, compared with only 19 of 42 (45.2%, p = 0.012) older patients. At last follow-up, relapse had occurred in 5 (18.5%) younger patients and 12 (28.6%) older patients, while 5 (18.5%) and 16 (38.1%) had died, respectively.
Surgical Approach
All 69 patients underwent surgical resection of the primary tumor as part of initial therapy, with operative approach data available for 66 cases (Table 4). The major- ity of patients (55, 83%) underwent open adrenalectomy, while 11 (17%) patients underwent minimally invasive sur- gery. Among those treated with open surgery, 49 underwent a standard laparotomy and 6 required a thoracoabdominal approach. All MIS procedures were completed laparoscopi- cally without conversion to open surgery.
There were no intraoperative spills among the MIS cases, compared with 22% (n = 12) in the open group (p = 0.087). All MIS resections were performed in patients with tumors clinically presumed to be Stage I or II. The median tumor size in the MIS group was 4.4 cm. Among the open surgery group, 10 patients required resection of adjacent organs, most commonly en bloc nephrectomy (n = 7). Addition- ally, three open surgery patients required cardiopulmonary bypass during the initial operation. None of the MIS patients required adjacent organ resection or bypass support.
The 5-year OS was 87.2% (95% CI: 63.8-100.0%) for patients who underwent MIS compared with 66.7% (95% CI: 52.9-80.5%) for those who underwent open surgery (p = 0.29). The 5-year EFS was 64.3% (95% CI: 31.8-96.8%) in the MIS group and 56.0% (95% CI: 41.8-70.2%) in the open group (p = 0.66). In a subset analysis limited to Stage I patients (n = 19; 13 open, 6 MIS), the 5-year EFS was 82.7% (95% CI: 60.3-100.0%) for open resection and 58.4% (95% CI: 12.5-100.0%) for MIS, with no statistically significant difference between groups (HR: 2.83, 95% CI: 0.40-20.26, p = 0.3004).
Pathology
The median tumor weight across the cohort was 220 g (IQR: 66-515 g), with a marked difference between sur- gical approaches. Tumors resected via MIS had a signifi- cantly lower median weight compared with those removed by open surgery (38 g versus 246 g; p < 0.001). Capsular invasion was observed in 28 (44%) tumors, the vast major- ity of which were resected through an open approach (n =
| Characteristic | < 5 years N= 27 N (%) or Median (IQR) | ≥ 5 years N = 42 N (%) or Median (IQR) | p-Value |
|---|---|---|---|
| Sex | |||
| Male | 14 (52%) | 15 (36%) | 0.28 |
| Female | 13 (48%) | 27 (64%) | |
| Race | |||
| White | 18 (67%) | 37 (88%) | 0.15 |
| Hispanic or Latino/Latina or Latinx | 1 (3.7%) | 2 (4.8%) | |
| Multiracial-Hispanic | 1 (3.7%) | 2 (4.8%) | |
| American Indian or Alaska Native | 1 (3.7%) | 0 (0%) | |
| Black or African American | 2 (7.4%) | 0 (0%) | |
| Multiracial-non-Hispanic | 1 (3.7%) | 0 (0%) | |
| Unknown or not listed | 3 (11%) | 1 (2.4%) | |
| Age at diagnosis (years) | 1.6 (0.8, 2.4) | 12.6 (10.1, 16.0) | < 0.01 |
| Syndrome | |||
| None | 13 (48%) | 28 (67%) | 0.20 |
| Li-Fraumeni | 12 (44%) | 7 (17%) | 0.03 |
| Beckwith-Wiedemann | 2 (7.4%) | 1 (2.4%) | 0.69 |
| Other | 1 (3.7%) | 3 (7.1%) | 0.95 |
| Symptoms at presentation | |||
| No symptoms | 2 (7.4%) | 3 (7.1%) | > 0.99 |
| Virilization | 17 (63%) | 24 (57%) | 0.82 |
| Cushing | 5 (19%) | 13 (31%) | 0.39 |
| Hyperaldosteronism (Conn's) | 1 (3.7%) | 1 (2.4%) | > 0.99 |
| Hypertension | 5 (19%) | 14 (33%) | 0.29 |
| Incidental/nonfunctional | 6 (22%) | 6 (14%) | 0.60 |
| Tumor characteristics | |||
| Tumor size (cm) | 6.7 (5.5, 9.8) | 10.0 (7.6, 13.0) | 0.01 |
| Tumor weight (g) | 97 (60, 264) | 255 (156, 649.2) | 0.01 |
| Presence of vascular extension | 2 (7.4%) | 14 (33%) | 0.03 |
| Presence of metastatic disease | 5 (19%) | 20 (58%) | 0.03 |
| Surgical details | |||
| Age at resection (months) | 18 (10, 30) | 154 (125, 193) | < 0.01 |
| Open | 20 (80%) | 35 (85%) | 0.82 |
| Minimally invasive | 5 (20%) | 6 (15%) | |
| Preoperative biopsy | 7 (26%) | 11 (27%) | > 0.99 |
| Retroperitoneal lymph node dissection performed | 4 (16%) | 7 (18%) | > 0.99 |
| Lymph node sampling performed | 7 (29%) | 10 (26%) | 0.99 |
| Preoperative rupture | 2 (7.4%) | 3 (7.3%) | > 0.99 |
| Intraoperative spill | 3 (12%) | 9 (22%) | 0.45 |
| Resection of adjacent organs | 2 (7.7%) | 8 (20%) | 0.33 |
| Additional resection performed | 4 (15%) | 10 (24%) | 0.52 |
| Tumor necrosis present | 20 (77%) | 29 (73%) | 0.91 |
| Positive margins | 2 (8.0%) | 15 (38%) | 0.02 |
| Negative margins | 23 (92%) | 24 (62%) | |
| Invasion of adjacent organs | 5 (19%) | 10 (24%) | 0.79 |
26), with only 2 occurring in the MIS group. Microscopic margin status was negative in 47 (73%) patients and positive in 17 (27%) patients, with data unavailable for 5 patients.
Tumor necrosis was present in 49 (74%) cases. The Ki-67 proliferation index was reported in 24 tumors, with a median value of 20% (IQR: 15-31%). Nuclear grading was available
| Characteristic | < 5 years N = 27 N (%) or Median (IQR) | ≥ 5 years N = 42 N (%) or Median (IQR) | p-Value |
|---|---|---|---|
| Nuclear grade | |||
| 1 | 1 (4.2%) | 0 (0%) | 0.15 |
| 3 | 0 (0%) | 2 (6.3%) | |
| 4 | 0 (0%) | 3 (9.4%) | |
| 5 | 23 (96%) | 27 (84%) | |
| Capsular invasion present | 7 (29%) | 21 (53%) | 0.12 |
| Stage | |||
| 1 | 12 (44%) | 7 (17%) | < 0.01 |
| 2 | 8 (30%) | 3 (7.1%) | |
| 3 | 2 (7.4%) | 12 (29%) | |
| 4 | 5 (19%) | 20 (48%) | |
| Presence of mutations | |||
| Absent | 9 (33%) | 26 (62%) | 0.04 |
| TP53 | 12 (44%) | 8 (19%) | 0.05 |
| CTNNB1 | 1 (3.7%) | 1 (2.4%) | > 0.99 |
| Other | 3 (11%) | 5 (12%) | > 0.99 |
| Adjuvant therapies | |||
| Neoadjuvant chemotherapy received | 3 (11%) | 12 (29%) | 0.16 |
| Adjuvant chemotherapy received | 8 (30%) | 29 (73%) | 0.01 |
| Radiation therapy received | 1 (3.8%) | 9 (24%) | 0.07 |
| Surgery for metastatic disease | 4 (15%) | 11 (28%) | 0.36 |
| Outcomes | |||
| Reached no evidence of disease | 21 (81%) | 19 (46%) | 0.01 |
| Sustained relapse | 5 (19%) | 12 (31%) | 0.41 |
| Status at last follow-up | |||
| Alive with no evidence of disease | 22 (81%) | 18 (43%) | < 0.01 |
| Alive with disease | 0 (0%) | 8 (19%) | |
| Deceased | 5 (19%) | 16 (38%) | |
| Deceased due to disease | 4 (80%) | 15 (94%) | 0.97 |
| 5-year OS1 | 79.6% (63.5-95.7%) | 56.3% (38.9-73.8%) | 0.08 |
| 5-year EFS1 | 68.3% (49.9-86.7%) | 45.1% (28.5-61.7%) | 0.08 |
in 56 cases and was predominantly high-grade: 50 (89%) tumors were grade 5. Lower grades were rare, with only one tumor graded as 1 (1.8%), two as grade 3 (3.6%), and three as grade 4 (5.4%). Molecular testing confirmed alterations in 30 patients. TP53 mutations were the most common, present in 20 (29%) patients, followed by CTNNB1 mutations in 2 (2.9%) patients, and other mutations in 8 (12%) patients.
Lymph Node Sampling
RPLND was documented in 11 (15.9%) patients, all concurrent with primary tumor resection. An additional 17 (24.6%) patients underwent lymph node sampling tar- geting periadrenal and para-aortic/caval regions. None of the patients in the MIS cohort had an RPLND, though one had an attempted lymph node sampling. The overall
median lymph node yield was 0.0 (range: 0.0, 26.0). Among patients who underwent open surgery, the median yield was 1.0 (range: 0.0, 26.0), and nodal metastases were identified in three patients, compared with 0.0 (range: 0.0, 0.0) in the MIS group (p = 0.008). The mean number of lymph nodes sampled was significantly higher in the open group com- pared with the MIS group (2.96 versus 0.00, p = 0.008).
The median lymph node yield in patients who underwent RPLND was 6.0 nodes (IQR: 3.5, 9.0). The median lymph node yield in patients who underwent lymph node sampling was 3.5 nodes (IQR: 1, 5). Among patients with Stage II or higher disease, those who underwent RPLND had an EFS of 52.3% (95% CI: 37.0-73.8%), which was not significantly different from the EFS of 35.7% (95% CI: 12.1-99.0%) observed in patients with similar stage who did not undergo RPLND (p=0.53).
| Characteristic | Open (N = 55) | Minimally invasive (N= 11) | p-Value |
|---|---|---|---|
| Age at diagnosisª | 0.10 | ||
| < 5 years | 20 (36%) | 5 (45%) | |
| 5-15 years | 27 (49%) | 2 (18%) | |
| ≥ 15 years | 8 (15%) | 4 (36%) | |
| Tumor size, cmb | 9.6 (7.0, 12.6) | 4.4 (2.8, 7.1) | < 0.01 |
| Tumor weight, gb | 246 (106, 548.2) | 38 (24, 60) | < 0.01 |
| Capsular invasionª | 0.26 | ||
| No | 27 (51%) | 7 (78%) | |
| Yes | 26 (49%) | 2 (22%) | |
| Lymph node sampling | 16 (29%) | 1 (9%) | 0.26 |
| Lymph node yield℃ | 2.96 (0.00, 26.00) | 0.00 (0.00, 0.00) | 0.01 |
| Intraoperativeª spill | 0.58 | ||
| No | 43 (78%) | 11 (100%) | |
| Yes | 12 (22%) | 0 (0%) | |
| Outcomesd | |||
| 5-year OS | 66.7% (52.9-80.5%) | 87.2% (63.8-100.0%) | 0.29 |
| 5-year EFS | 56.0% (41.8-70.2%) | 64.3% (31.8-96.8%) | 0.66 |
ªN, % Median, IQR “Mean, range d%, 95% CI
Metastatic Disease (Table 5)
For patients with oligometastatic disease (n = 7) (Fig. 1), three (42.9%) underwent resection of an adjacent organ during their initial surgical resection (two kidney and one liver), and three (42.9%) underwent metastatectomies dur- ing their initial surgical resection (two lung and one liver). Three (42.9%) patients in the oligometastatic group under- went neoadjuvant chemotherapy. All seven patients received adjuvant chemotherapy. Only one (14.3%) patient underwent radiation therapy (flank). Four (57.1%) patients received additional surgical intervention for metastatic disease (three lung resections and one liver resection). One (14.3%) patient suffered a relapse of disease. At last follow-up, two (28.6%) patients were alive with no evidence of disease, three patients (42.9%) were alive with disease, and two (28.6%) patients were deceased.
For patients with extensive metastatic disease (n = 18) (Fig. 1), four (22.2%) underwent resection of an adjacent organ during their initial surgical resection (three kidney and one liver), and five (27.8%) underwent metastatecto- mies during their initial surgical resection (four liver and one lung). In total, 10 (55.6%) patients in this cohort underwent neoadjuvant chemotherapy, and 14 (77.8%) patients received adjuvant chemotherapy. Four (22.2%) patients received radiation therapy (sites included lung, liver, pelvis, and spine). Five (27.8%) patients received additional surgical
intervention for metastatic disease (four liver resections and one lumbar spine resection). Four (22.2%) patients suffered a relapse of disease. At last follow-up, 2 (11.1%) patients were alive with no evidence of disease, 3 (16.7%) patients were alive with disease, and 13 (72.2%) patients were deceased.
Adjuvant Therapy
Of patients with Stage II disease or higher, 15 (15/50, 30%) patients received neoadjuvant chemotherapy, with 12 of them receiving mitotane as part of their regimen. Of the patients who received neoadjuvant therapy, 12 had documented metastatic disease. Adjuvant chemotherapy was administered to 37 patients, 31 of whom also received mito- tane. Among patients with metastatic disease, 21 received mitotane either as part of their neoadjuvant or adjuvant treat- ment. Additionally, ten (14.5%) patients underwent adjuvant radiation therapy, targeting the flank (n = 4), liver (n = 1), lung (n = 3), or bony regions (n = 5).
Survival and Oncologic Outcomes (Fig. 2)
The median follow-up for the cohort was 2.6 years (IQR: 1.1-12.1). At last follow-up, 40 (58.0%) patients were alive with no evidence of disease (NED), 8 (11.6%) patients were alive with disease, and 21 (30.4%) patients had died, with 19 deaths attributed to disease progression. The 5-year OS
| Characteristic | No metastatic disease N=7 N (%) or median (IQR) | Oligometastatic disease N=7 N (%) or median (IQR) | Extensive metastatic disease N= 18 N (%) or median (IQR) | p-Value |
|---|---|---|---|---|
| Sex | ||||
| Male | 22 (50%) | 2 (29%) | 5 (28%) | 0.21 |
| Female | 22 (50%) | 5 (71%) | 13 (72%) | |
| Race | ||||
| White | 35 (80%) | 5 (71%) | 15 (83%) | 0.38 |
| Hispanic or Latino/Latina or Latinx | 2 (4.5%) | 0 (0%) | 1 (5.6%) | |
| Multiracial-Hispanic | 1 (2.3%) | 0 (0%) | 2 (11%) | |
| American Indian or Alaska Native | 1 (2.3%) | 0 (0%) | 0 (0%) | |
| Black or African American | 2 (4.5%) | 0 (0%) | 0 (0%) | |
| Multiracial-non-Hispanic | 1 (2.3%) | 0 (0%) | 0 (0%) | |
| Unknown or not listed | 2 (4.5%) | 2 (29%) | 0 (0%) | |
| Age at diagnosis (months) | 57 (17, 154) | 177 (104, 195) | 132 (103, 159) | |
| Syndrome | ||||
| None | 27 (61%) | 5 (71%) | 9 (50%) | 0.56 |
| Li-Fraumeni | 13 (30%) | 1 (14%) | 5 (28%) | 0.70 |
| Beckwith-Wiedemann | 3 (6.8%) | 0 (0%) | 0 (0%) | 0.41 |
| Other | 2 (4.5%) | 0 (0%) | 2 (11%) | 0.48 |
| Symptoms at presentation | ||||
| No symptoms | 4 (9.1%) | 0 (0%) | 1 (5.6%) | 0.66 |
| Virilization | 28 (64%) | 4 (57%) | 9 (50%) | 0.61 |
| Cushing | 11 (25%) | 1 (14%) | 6 (33%) | 0.60 |
| Hyperaldosteronism (Conn's) | 1 (2.3%) | 1 (14%) | 0 (0%) | 0.15 |
| Hypertension | 6 (14%) | 5 (71%) | 8 (44%) | 0.01 |
| Incidental/nonfunctional | 8 (18%) | 2 (29%) | 2 (11%) | 0.57 |
| Tumor characteristics | ||||
| Tumor size (cm) | 7.0 (5.2, 8.8) | 16.4 (12.0, 17.6) | 12.9 (10.2, 14.2) | |
| Tumor weight (g) | ||||
| Presence of vascular extension | 4 (9.1%) | 3 (43%) | 9 (50%) | 0.001 |
| Surgical details | ||||
| Age at resection (months) | 59 (17, 154) | 177 (104, 202) | 134 (116, 156) | |
| Open | 34 (77%) | 7 (100%) | 14 (93%) | 0.16 |
| Minimally invasive | 10 (23%) | 0 (0%) | 1 (6.7%) | |
| Preoperative biopsy | 5 (11%) | 4 (57%) | 9 (53%) | < 0.01 |
| Retroperitoneal lymph node dissection performed | 9 (21%) | 1 (17%) | 2 (14%) | 0.85 |
| Lymph node sampling performed | 9 (22%) | 4 (57%) | 3 (21%) | 0.13 |
| Preoperative rupture | 3 (6.8%) | 1 (14%) | 1 (5.9%) | 0.75 |
| Intraoperative spill | 9 (20%) | 1 (14%) | 3 (19%) | 0.93 |
| Resection of adjacent organs | 3 (6.8%) | 3 (43%) | 4 (25%) | 0.02 |
| Additional resection performed | 6 (14%) | 3 (43%) | 5 (29%) | 0.12 |
| Tumor necrosis present | 30 (70%) | 5 (71%) | 14 (88%) | 0.38 |
| Positive margins | 10 (24%) | 2 (29%) | 5 (33%) | 0.77 |
| Negative margins | 32 (76%) | 5 (71%) | 10 (67%) | |
| Invasion of adjacent organs | 6 (14%) | 3 (43%) | 6 (35%) | 0.07 |
rate for the entire cohort was 65.9% (95% CI: 54.3-80.0%), and the 5-year EFS rate was 54.1% (95% CI: 42.5-68.9%).
Outcomes varied significantly on the basis of dis- ease stage. Among patients with Stage I disease, 18 of 19 remained alive and disease-free. In contrast, those with
| Characteristic | No metastatic disease N=7 N (%) or median (IQR) | Oligometastatic disease N=7 | Extensive metastatic disease N = 18 N (%) or median (IQR) | p-Value |
|---|---|---|---|---|
| N (%) or median (IQR) | ||||
| Nuclear grade | ||||
| 1 | 1 (2.8%) | 0 (0%) | 0 (0%) | 0.46 |
| 3 | 0 (0%) | 1 (17%) | 1 (7.1%) | |
| 4 | 2 (5.6%) | 0 (0%) | 1 (7.1%) | |
| 5 | 33 (92%) | 5 (83%) | 12 (86%) | |
| Capsular invasion present | 15 (36%) | 6 (86%) | 7 (47%) | 0.05 |
| Stage | ||||
| 1 | 18 (43%) | 0 (0%) | 0 (0%) | < 0.01 |
| 2 | 11 (26%) | 0 (0%) | 0 (0%) | |
| 3 | 10 (24%) | 1 (14%) | 1 (5.9%) | |
| 4 | 3 (7.1%) | 6 (86%) | 16 (94%) | |
| Presence of mutations | ||||
| Absent | 24 (55%) | 3 (43%) | 8 (44%) | 0.70 |
| TP53 | 14 (32%) | 3 (43%) | 3 (17%) | 0.34 |
| CTNNB1 | 1 (2.3%) | 0 (0%) | 1 (5.6%) | 0.70 |
| Other | 2 (4.5%) | 3 (43%) | 3 (17%) | 0.01 |
| Adjuvant therapies | ||||
| Neoadjuvant chemotherapy received | 2 (4.5%) | 3 (43%) | 10 (56%) | < 0.01 |
| Adjuvant chemotherapy received | 16 (36%) | 7 (100%) | 14 (88%) | < 0.01 |
| Radiation therapy received | 5 (12%) | 1 (17%) | 4 (27%) | 0.38 |
| Surgery for metastatic disease | 6 (14%) | 4 (57%) | 5 (31%) | 0.02 |
| Outcomes | ||||
| Reached no evidence of disease | 38 (88%) | 1 (14%) | 1 (6.3%) | < 0.01 |
| Sustained relapse | 12 (28%) | 1 (14%) | 3 (20%) | 0.66 |
| Status at last follow-up | ||||
| Alive with no evidence of disease | 36 (82%) | 2 (29%) | 2 (11%) | < 0.01 |
| Alive with disease | 2 (4.5%) | 3 (43%) | 3 (17%) | |
| Deceased | 6 (14%) | 2 (29%) | 13 (72%) | |
| Deceased due to disease | 6 (100%) | 1 (50%) | 12 (92%) | 0.11 |
A
Metastatic Burden at Diagnosis
B
Sites of Distant Metastases
Lung only
Extensive (>5 lesions)
Multiple sites
12.0%
26.1%
28.0%
63.8%
10.1%
No Metastases
Oligometastatic (≤5 lesions)
60.0%
Liver only
A 1.00-
1.00
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75
0.75-
0.50-
0.50
0.25-
0.25-
0.00-
0.00-
0
Time From Enrollment (months)
50
100
150
0
Time From Enrollment (months)
50
100
150
Number at risk
Number at risk
68
24
5
0
68
20
4
0
0
Time From Enrollment (months)
50
100
150
0
Time From Enrollment (months)
50
100
150
B
+
Stage 1 + Stage 2 + Stage 3 + Stage 4
+
Stage 1 + Stage 2 + Stage 3 + Stage 4
1.00-
1.00-
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75-
0.75-
0.50-
0.50-
0.25-
0.25-
p
< 0.0001
p
< 0.0001
0.00-
0.00-
0
Time From Enrollment (months)
50
100
150
0
Time From Enrollment (months)
50
100
150
Number at risk
Number at risk
Stage 1
18
9
1
7
0
Stage 1
18
8
1
0
Stage 2
11
7
3
1
0
Stage 2 -11
12
1
Stage 3
2
0
Stage 4
23
4
0
2
2
0
1
0
Stage 3 -12
Stage 4
23
3
0
0
0
Time From Enrollment (months)
50
100
150
0
Time From Enrollment (months)
50
100
150
C
Metastasis +
- 0 + Less than 5 + More than 5
Metastasis + 0 + Less than 5 + More than 5
1.00-
1.00-
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75
0.75-
0.50-
0.50-
0.25-
0.25-
p
< 0.0001
p <0.0001
0.00-
0.00-
0
50
100
Time From Enrollment (months)
150
0
50
Time From Enrollment (months)
100
150
Number at risk
Number at risk
Metastasis
0
44
22
5
0
Metastasis
0
44
19
4
0
Less than 5
7
1
0
0
Less than 5
7
1
0
0
More than 5
17
1
0
0
More than 5
17
0
0
0
0
50
100
150
Time From Enrollment (months)
0
50
100
150
Time From Enrollment (months)
D
+ Age < 5 Years +Age>=5 Years
+ Age < 5 Years + Age>= 5 Years
1.00-
1.00-
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75-
0.75-
0.50-
0.50-
0.25-
p =0.066
0.25-
p =0.071
0.00-
0.00-
0
50
100
150
0
Time From Enrollment (months)
Time From Enrollment (months)
50
100
150
Number at risk
Number at risk
Age < 5 Years
27
13
2
0
Age < 5 Years -27
13
2
0
Age >= 5 Years -41
11
3
0
Age >= 5 Years -41
8
2
0
0
Time From Enrollment (months)
50
100
150
0
Time From Enrollment (months)
50
100
150
E
Approach + Open + Laproscopic
Approach + Open + Laproscopic
1.00
7
1.00
7
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75
0.75-
2
0.50
0.50
0.25
0.25
p = 0.27
p=0.66
0.00-
0.00-
0
50
100
150
0
50
100
Time From Enrollment (months)
Time From Enrollment (months)
150
Number at risk
Number at risk
Approach
Open-54
22
5
0
Approach
Open
54
18
4
0
Laproscopic-
11
2
0
0
Laproscopic-
11
2
0
0
0
50
100
150
0
50
100
150
Time From Enrollment (months)
Time From Enrollment (months)
F
RPLND + No + Yes
RPLND + No + Yes
1.00-
1.00-
Estimated Proportion Surviving
Estimated Proportion Event-Free
0.75-
0.75-
1
#
0.50-
0.50
0.25
0.25-
p =0.53
0.00-
0.00-
0
50
100
150
Time From Enrollment (months)
0
50
100
Time From Enrollment (months)
150
Number at risk
Number at risk
RPLND
No
35
12
4
0
RPLND
No
35
10
3
0
Yes
8
2
0
0
Yes
8
2
0
0
0
50
100
150
0
50
Time From Enrollment (months)
100
150
Time From Enrollment (months)
metastatic disease at presentation had a 5-year OS of just 18.7% (95% CI: 0.001-40.0%) and a mean survival time of 25.2 months. This was associated with a hazard ratio (HR) of 10.0 compared with patients without metastases, who had a significantly better 5-year OS of 84.5% (95% CI: 72.9-96.2%) and a mean survival of 53.5 months (p < 0.001).
Patients with oligometastatic disease had a 5-year OS of 49.1% (95% CI: 0.001-99.95%) and a mean survival of 34.3 months. Although survival in this group trended lower than in nonmetastatic patients, the difference was not statistically significant (p =0.08). In contrast, patients with extensive metastases (> 5 lesions) had significantly worse outcomes, with a 5-year OS of 11.9% (95% CI: 0.001-29.5%) and a mean survival time of only 19.0 months (p < 0.001).
When outcomes were further stratified by both age and metastatic burden, survival patterns were even more distinct. Among younger children, those with no metastases (n = 22) had a 5-year OS of 95.6% (95% CI: 87.0-100.0%). Those with oligometastatic disease had a 5-year OS of 42.6% (95% CI: 0.001-100.0%) and an HR of 18.78 (95% CI: 1.16-304.39, p = 0.04) compared with those without metas- tases. The younger children with extensive metastatic dis- ease had a 5-year OS of just 2.5% (95% CI: 0.001-20.1%), with a corresponding HR of 81.17 (95% CI: 5.26-1253.48, p = 0.002). Among older children, those without metastases (n = 22) had a 5-year OS of 73.4% (95% CI: 52.9-93.9%), while those with oligometastatic disease (n = 5) had a 5-year OS of 56.3% (95% CI: 0.001-100.0%) and an HR of 1.86 (95% CI: 0.21-16.65, p = 0.58). The older children with extensive metastases had a 5-year OS of 14.5% (95% CI: 0.001-36.6%) and an HR of 6.24 (95% CI: 2.02-19.26, p = 0.001).
DISCUSSION
This study provides one of the most comprehensive analy- ses to date of pediatric adrenocortical carcinoma in a North American cohort, leveraging data from 22 institutions to evaluate age-related differences, surgical management strate- gies, and oncologic outcomes.
Several key observations emerged from this analysis. First, age at diagnosis was associated with distinct clini- cal patterns. Children under 5 years of age more commonly presented with localized tumors and were more likely to achieve complete remission than older children. Despite these favorable features, overall survival between age groups was not statistically different, a finding that may reflect the limited sample size inherent to studies of rare tumors and the relatively short follow-up time noted within our study. Second, complete surgical resection remains paramount to cure. Notably, only one patient with Stage I disease died of
disease, reinforcing the critical importance of early detec- tion and complete tumor resection. Third, metastatic ACC continues to carry a dismal prognosis in children, with cur- rent systemic therapies achieving durable survival in only a small subset of patients. Patients with extensive metastatic burden in our cohort experienced poor outcomes despite aggressive multimodal treatment, underscoring the urgent need for more effective medical therapies. Finally, our data support the oncologic safety of MIS adrenalectomy in care- fully selected pediatric ACC cases. MIS was not associated with worse recurrence rates or survival outcomes. These findings suggest that surgical approach should be tailored to tumor characteristics and surgeon expertise.
Age-Stratified Presentation and Outcomes
Young children tended to have more localized disease at diagnosis in our cohort, consistent with prior population data. In a SEER analysis of pediatric ACC, 76% of patients ≤ 4 years old had localized tumors at presentation, compared with only ~31% of those > 4 years old .13 This stage discrep- ancy likely reflects biological and clinical differences: Pedi- atric ACC is almost always functional in young children, leading to overt endocrine symptoms (e.g., virilization) that prompt earlier diagnosis.1 Indeed, nearly 95% of pediatric ACCs produce hormones, and the most common presentation is androgen excess with virilization in over 80% of cases.3,14 Thus, tumors in toddlers are often detected before wide- spread progression. Consistent with this, previous registry studies found that complete tumor resection is achieved in the majority of young patients and is deemed essential for cure, whereas residual or metastatic disease portends a poor outcome.3 Younger age itself has been associated with more favorable prognosis in some series.15 Klein et al. reported that older age was an independent predictor of tumor-related mortality in pediatric adrenocortical tumors.16 The lack of an age-based survival gap in our study may reflect limited power (given the extreme rarity of ACC) or effective sal- vage therapies in select older patients, but it underscores that younger children can experience relapse and death, while some older children can survive long term. Overall, our findings emphasize that early-stage presentation in infancy and early childhood is advantageous, aligning with known trends. Yet, all pediatric patients, regardless of age, require diligent long-term surveillance and therapy tailored to dis- ease biology.
Surgical Approach: Minimally Invasive Versus Open Adrenalectomy
Surgical resection remains the cornerstone of curative- intent therapy for ACC, and historically, open adrenalec- tomy has been advocated to maximize oncologic clearance.
The role of minimally invasive surgery in ACC has been controversial, especially in adults, due to concerns about inadequate resection and tumor dissemination during lapa- roscopy.3,17 Early reports highlighted risks of capsular rup- ture, tumor fragmentation, peritoneal carcinomatosis, and port-site recurrences when laparoscopic adrenalectomy was applied to ACC.17 As a result, many experts traditionally recommended against MIS for suspected ACC due to tumors often being large and friable, making intraoperative spillage a major concern. 18
However, more recent literature has noted the safety of the laparoscopic approach with the guidelines presented by the International Pediatric Endosurgery Group noting that laparoscopic adrenalectomy is technically feasible in chil- dren with no absolute contraindications so long as oncologic principles are maintained.19 While some single-center stud- ies in adults suggested that laparoscopic adrenalectomy for ACC may be associated with higher rates of tumor recur- rence and reduced survival, raising concern that laparoscopy might compromise oncologic completeness,5,20 others have reported that, in carefully selected early-stage (Stage I-II) ACC, laparoscopic resection can achieve similar oncologic outcomes as open surgery when proper oncologic technique is followed.21,22 A multi-institution report of 152 adult ACC patients found no difference in recurrence-free survival between laparoscopic and open approaches for localized tumors, provided that R0 resection was achieved. 23 Thus, the literature suggests that tumor stage/size and surgical tech- nique are crucial determinants and that minimally invasive adrenalectomy may be oncologically sound in select cases of ACC.
In the pediatric population, data guiding the choice of open versus MIS (laparoscopic or robotic) adrenalectomy are extremely limited. Pediatric surgeons have increasingly adopted minimally invasive surgery for adrenal tumors (such as neuroblastomas and benign lesions) and reported favora- ble experiences.6 However, for confirmed or suspected ACC in children, surgeons often still favor an open approach due to extrapolation of adult ACC guidelines and fear of tumor spillage in a malignancy with high recurrence risk.7,8
Our multi-center data provide important real-world evidence that a minimally invasive approach can be onco- logically safe in carefully selected pediatric ACC cases, primarily those with localized (Stage I/II) disease. We observed zero instances of intraoperative tumor spill in the MIS group, whereas open adrenalectomies had a 22% spillage rate. This finding challenges the assumption that open surgery inherently prevents rupture-in fact, an open approach did not guarantee avoidance of tumor violation in our series. Furthermore, MIS was not associated with worse recurrence or survival outcomes compared with open sur- gery. Although our cohort was not randomized, these results align with growing evidence from adult ACC studies that, in
experienced hands and with proper case selection, laparo- scopic adrenalectomy yields similar oncologic outcomes to open surgery.6,23,24 A meta-analysis of 13 adult ACC stud- ies (1171 patients) found no significant differences between laparoscopic and open adrenalectomy in R0 resection rates, local recurrence, disease-free survival, or overall survival for localized tumors.24 Our pediatric data mirror these findings: when surgeons selected minimally invasive adrenalectomy for appropriately sized, localized tumors, oncologic efficacy was not compromised. It is noteworthy that all MIS cases in this series achieved resection without spill, reflecting careful patient selection and surgical technique; however, these out- comes should be interpreted with caution given the baseline differences between MIS and open cohorts, which differed significantly in stage and other presenting characteristics.
However, a key limitation of the MIS group in our cohort is that no lymph nodes were sampled in any of these cases. This restricts our ability to fully assess the oncologic ade- quacy of MIS resections, particularly with respect to stag- ing and regional disease control. Given that nodal involve- ment can occur in ACC and has prognostic implications, the absence of lymphadenectomy in MIS cases highlights the need for caution in interpreting equivalence with open approaches and underscores the importance of incorporating nodal assessment when feasible. Taken together, these find- ings suggest that MIS adrenalectomy may be feasible and safe for pediatric ACC in select cases-specifically, when tumor characteristics (size, lack of local invasion) and sur- geon expertise support an en bloc resection without violation of the capsule. However, we emphasize that MIS should not be universally applied; it must be limited to centers and surgeons with significant experience in adrenal tumors, and conversion to open surgery should occur at the first sign of compromised oncologic safety.
Metastatic Disease and Prognosis
Despite improvements in survival for localized ACC, the outcome for children with advanced or metastatic dis- ease remains dismal. Pediatric ACC, when detected early and fully resected, can have favorable outcomes; reported all-stage 5-year survival rates ranged from ~50 to 70% in various series.3,25,26 However, survival drops sharply with regional or distant spread; multiple studies report 5-year survival estimates below 20% in the presence of metas- tases. 1,27-29 A report from the IPACTR found a 5-year event-free survival of 54% and identified disease stage and patient age as independent prognostic factors.3 Similarly, a European study of high-risk pediatric ACC reported 3-year overall survival of only ~55% for the entire cohort, with much poorer outcomes in those with metastatic disease.29
Our cohort reflects these findings: patients with wide- spread metastases at diagnosis had poor remission rates
and minimal long-term survival despite aggressive ther- apy. This is in line with prior reports that stage at diagno- sis is the dominant prognostic factor in ACC.3 Analyses of international registries and SEER data confirm that patients with metastatic ACC have dramatically worse outcomes than those with localized disease.1 Even in the modern era, metastatic ACC in children often proves fatal, as reflected in our series and others. 1,3,25-29
The biology of ACC with distant spread likely reflects a more aggressive tumor genotype/phenotype, and such cases are often not amenable to complete resection. Our find- ings underscore that current systemic therapies are largely inadequate to rescue patients with high-volume metastatic ACC. Novel approaches are desperately needed-whether intensification of systemic therapy, incorporation of tar- geted agents or immunotherapy in clinical trials, or perhaps upfront metastatectomy in carefully selected situations. In the meantime, the key to improving survival in ACC is to prevent metastatic presentations through early diagnosis and prompt intervention. This principle was evident in our data: virtually all long-term survivors had either initially local- ized disease or could be rendered free of disease surgically, whereas those with metastases fared poorly. Going forward, multidisciplinary management remains crucial, and enroll- ment of high-risk patients in prospective trials should remain a priority.
Limitations and Future Directions
As with all retrospective studies, this analysis has limita- tions that must temper interpretation. Chief among these is the rarity of pediatric ACC. With an incidence of only ~0.2-0.3 per million, even a multi-institutional cohort of 69 patients may be underpowered to detect small differences. Several comparisons (e.g., survival by age group) showed trends consistent with prior reports but did not reach statisti- cal significance, likely due to the limited sample size. Selec- tion bias is another concern; surgeons may have chosen MIS for smaller, favorable tumors, which could partly explain the excellent outcomes with laparoscopy. Conversely, the higher rate of tumor spill in open cases might reflect the fact that more advanced or invasive tumors were managed via open approach. We attempted to mitigate such biases through subgroup analysis, but unmeasured confounders inherent to retrospective, nonrandomized data remain. Additionally, het- erogeneity in adjuvant therapies and follow-up across institu- tions could influence outcomes: for instance, varying use of mitotane or chemotherapy might affect survival independent of surgery type. Despite these caveats, our findings are bol- stered by their consistency with broader pediatric and adult ACC literature and by the inclusion of multiple high-volume centers, which improves generalizability.
Future research should aim to confirm these observa- tions in prospective trials. Long-term follow-up is needed to ensure that laparoscopic resection truly yields equivalent survival and does not predispose to late abdominal recur- rences. Biological studies comparing tumors from younger versus older children could elucidate why age impacts pres- entation and whether younger patients have inherently less aggressive tumor biology. For example, when comparing our findings with the Children’s Oncology Group (COG) ARAR0332 study, a notable discrepancy in TP53 mutation rates was observed.4 In the COG cohort, TP53 germline mutations were present in 53% of patients, and somatic tumor mutations were detected in 79.7%. In contrast, our cohort demonstrated TP53 mutations in only 29% of cases. This marked difference in mutation prevalence may partially explain the variation in stage-specific survival outcomes between the two studies, suggesting underlying biological differences in tumor genetics between cohorts. Importantly, novel therapeutic approaches for metastatic ACC must be pursued; our data painfully illustrate the limitations of cur- rent treatments in Stage IV disease. Clinical trials exploring targeted therapies or intensified regimens in pediatric ACC are warranted, as are efforts to incorporate molecular profil- ing to guide therapy.
Future studies should also evaluate the role of retroperi- toneal lymph node dissection in ACC, particularly its impact on staging accuracy, recurrence risk, and overall survival. This has been challenging to study, even through the Chil- dren’s Oncology Group. On ARAR0332 where RPLND was recommended for all Stage II patients, the median number of lymph nodes obtained was only four.2 This raised concerns about the completeness of the RPLND for the majority of patients and complicated the interpretation of study out- comes. Our own findings echoed this challenge, with com- pliance rates too low to support meaningful conclusions. In contrast, in adults, RPLND (defined as ≥ 5 nodes resected) has been associated with decreased risk of recurrence and disease-related death.30 These limitations highlight the need for more rigorous and standardized approaches to surgical management in future trials.
CONCLUSIONS
By integrating the insights from our large cohort with evidence from the literature, this study provides a more nuanced understanding of pediatric ACC. It supports cau- tious expansion of minimally invasive surgery in carefully selected patients with small tumors, underscores the prog- nostic importance of early-stage disease and the need for early detection, and reiterates that patients with metastatic ACC require innovative strategies beyond current conven- tional therapy. Ultimately, international cooperation and pro- spective studies will be key to advancing care for children
with ACC, given the rarity of this tumor and the complexity of its management. Our findings lay groundwork for these future efforts and for updated clinical guidelines that balance surgical innovation with oncologic prudence in the treatment of pediatric ACC.
SUPPLEMENTARY INFORMATION The online version con- tains supplementary material available at https://doi.org/10.1245/ s10434-025-18731-6.
FUNDING This work was made possible, in part, with support from the Center for Clinical and Translational Science Center at the Univer- sity of Cincinnati (funded by the National Institute of Health Clinical and Translational Science Award program, grant UL1TR001425) as well as from the Cincinnati Children’s Research Foundation and Data Management and Analysis Center (RRID:SCR_022625). The Univer- sity of Pittsburgh holds a Physician-Scientist Institutional Award from the Burroughs Wellcome Fund.
DISCLOSURE None.
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