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Current Management Strategies and Outcomes in Children With Adrenocortical Carcinoma
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Ioannis A. Ziogas, MD, MPH,a,b,* Jonathan L. Hills-Dunlap, MD, MPH,a,b Kristine S. Corkum, MD,a,b Nicholas G. Cost, MD,b,c Ankush Gosain, MD, PhD,a,b and Jonathan P. Roach, MDa,b
ª Division of Pediatric Surgery, Department of Surgery, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colorado
b Surgical Oncology Program, Children’s Hospital Colorado, Aurora, Colorado
“Division of Urology, Department of Surgery, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colorado
ARTICLE INFO
Article history: Received 29 February 2024 Received in revised form 22 April 2024 Accepted 29 April 2024 Available online 25 June 2024
Keywords:
Adrenalectomy Adrenocortical carcinoma National Cancer Database Pediatric adrenal tumors Pediatric cancer
ABSTRACT
Introduction: Adrenocortical carcinoma (ACC) is a rare but aggressive pediatric endocrine tumor. However, there is no recent US national report on the management or outcomes of pediatric ACC. We aimed to examine the clinical characteristics, current management strategies, and outcomes of pediatric ACC.
Methods: In this retrospective National Cancer Database study between 2004 and 2019, children (<18 y) with ACC were included. Overall survival was examined by means of Kaplan-Meier method, log-rank tests, and Cox regression modeling.
Results: Seventy-eight children with ACC were included. The median age was 10 y, the median tumor size was 10.2 cm, and 35.9% had metastasis at diagnosis. Most patients underwent surgical treatment (84.6%), 56.4% received chemotherapy, and 7.7% received radiation. The 1-, 3-, and 5-y overall survival rates were 87.0%, 62.0%, and 60.1%, respectively. In unadjusted analysis, surgical treatment was associated with improved overall survival (log-rank test, P < 0.001). In multivariable Cox regression, metastasis at diagnosis was associated with inferior overall survival (hazard ratio: 2.72, 95% confi- dence interval: 1.15-6.40, P = 0.02), when adjusting for age, tumor size, receipt of sur- gical treatment, and chemotherapy. In patients with nonmetastatic ACC, increasing age was associated with inferior overall survival (hazard ratio: 1.12, 95% confidence interval: 1.00-1.24, P = 0.04), when adjusting for tumor size, receipt of surgical treat- ment, and chemotherapy.
* Corresponding author. Division of Pediatric Surgery, Department of Surgery, University of Colorado School of Medicine, Children’s Hospital Colorado, 12631 East 17th Avenue, Room 6111, Aurora, CO 80045. E-mail address: ioannis.ziogas@cuanschutz.edu (I.A. Ziogas).
Conclusions: Most children with ACC in the USA undergo surgical treatment with about half of these also receiving chemotherapy. Metastasis at diagnosis was independently associ- ated with inferior overall survival; in patients with nonmetastatic ACC, increasing age was independently associated with inferior overall survival.
@ 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Introduction
Adrenocortical carcinoma (ACC) is a rare yet aggressive ad- renal malignancy. The reported incidence is 0.2-0.3 new cases per 1 million children annually, thus accounting for 0.2% of all pediatric cancers.1-3 It typically presents within the first 5 y of life and has a strong female predominance (61%-76%).4,5 Pe- diatric ACC is mostly sporadic but can often be associated with certain mutations, such as the germline TP53 mutation (Li-Fraumeni syndrome).3,5,6 Pediatric ACC is almost always functional and presents typically with virilization alone or in combination with hypercortisolism.4,5 Additionally, pediatric ACC is associated with >90% long-term survival in patients with small localized tumors compared with 10% in patients with metastasis.3,7 Notably, Wieneke’s index has been broadly used as a histopathological tool to predict outcomes in chil- dren with ACC and is comprised of tumor weight >400 g, size >10.5 cm, extension into adjacent organs, venous or capsular invasion, invasion to the vena cava, >15 mitoses per 20 high power fields, and the presence of atypical mitotic figures.8 Nevertheless, the differentiation between adrenocortical tu- mors and ACC in children is a matter of debate since most tumors are classified as carcinomas or histology of undeter- mined malignant potential.9,10
The mainstay of treatment for pediatric ACC is complete surgical resection for patients with stage I disease with the addition of lymph node dissection for those with stage II-IV disease, while stage III and IV disease also warrants sys- temic treatment with chemotherapy (cisplatin, etoposide, doxorubicin) and mitotane.11 Given the rarity of pediatric ACC, most of the data have been derived from single-center studies. The most recent comprehensive US report on pediatric ACC examined data between 1998 and 201112, thus a more contemporary analysis is warranted.
This study aimed to describe the characteristics, manage- ment, and outcomes of pediatric ACC in the contemporary era.
Materials and Methods
Study design and setting
This was a retrospective cohort study of children with ACC in the National Cancer Database (NCDB), which is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The NCDB in- corporates approximately 70% of all newly diagnosed cancers in more than 1500 hospitals accredited by the Commission on Cancer in the US.13 It includes data on demographic, clinical, and pathological characteristics, as well as tumor
characteristics (histology, behavior, stage, sequence of ma- lignancy, etc.), treatment, and overall survival. The Institu- tional Review Board of the University of Colorado deemed the study exempt from review (nonhuman subjects research).
Study participants
Patients <18 y old with ACC were identified from the NCDB Pediatric Adrenal Participant User File between January 2004 and December 2019 using the combination of International Classification of Diseases for Oncology, 3rd Edition adrenal gland site code “C74”, and histology code: “8370”. Patients were excluded if data regarding the time from diagnosis to last patient contact, vital status at last patient contact, or key sociodemographic (race and ethnicity, insurance status, in- come level) and clinical or treatment (unknown metastatic disease status, tumor laterality, receipt of surgery, chemo- therapy, or radiation therapy) variables were unavailable.
Exposure classification and predictor variables
Surgical treatment was defined as any type of surgical resec- tion (total or partial adrenalectomy, radical resection, local excision, or not otherwise specified). Lymph node dissection was defined as surgical removal and pathologic evaluation of at least one lymph node. Predictor variables captured for all patients included: age; sex; race and ethnicity, stratified into White, Black, Hispanic, and Other; household income by quartile (adjusted for 2020 inflation); insurance status, strati- fied into private, Medicaid, or other government; linear dis- tance between patient’s residence and treating hospital; tumor size; metastasis at diagnosis; disease stage; receipt of surgical treatment and/or lymph node dissection and/or chemotherapy and/or radiation therapy; surgical margin sta- tus; systemic therapy (chemotherapy)-surgery sequence; and Charlson/Deyo score as a proxy for medical comorbidities. The Charlson/Deyo score14,15 is a validated clinical comor- bidity index (0 equals no comorbidities) based on International Classification of Diseases diagnosis/procedure and Current Procedural Terminology codes with higher scores correlated with worse survival outcomes. When data on the systemic therapy (chemotherapy)-surgery sequence were missing, the number of days from diagnosis to chemotherapy initiation was used.
Statistical analysis
Two age groups were generated with a cutoff at 4 y of age based on data from previous studies.12,16 Continuous variables were expressed as median (interquartile range) and between- group comparisons were evaluated with the Mann-Whitney
3,482 Children in the National Cancer Database Pediatric Adrenal Participant User File from January 2004 to December 2019 assessed for eligibility
3404 Excluded
3371 Histology other than adrenocortical carcinoma
19 Unknown race and ethnicity, insurance status, income quartile
6 Multiple cancer diagnoses
4 Unknown tumor laterality
2 Unknown metastasis at diagnosis
2 Unknown receipt of surgery, chemotherapy, radiation
78 Children included in the primary analysis
U-test. Categorical variables were expressed as frequency (percentage) and between-group comparisons were evaluated with the chi-square test. Overall survival was the primary outcome of interest and was determined as the duration from the date of diagnosis until the date of last patient contact or death. The Kaplan-Meier method was used to determine the 1-, 3-, and 5-y overall survival rates. The log-rank test was used to assess differences in univariable analysis, while Cox regression modeling was implemented in multivariable analysis to adjust for a priori selected clinically important variables. Cohort development and statistical analyses were conducted using Stata IC 16.0 (StataCorp LLC, College Station, Texas).
Results
Patient demographic and clinical data
A total of 78 children with ACC were included (Fig. 1). The me- dian age was 10 y and followed a bimodal distribution (Fig. 2) with 34 patients being ≤4 y old (43.6%) and 44 patients being >4 y old (56.4%). Most patients were female (61.5%) and 69.2% were White without any significant differences between those ≤4 y versus > 4 y old. All children had insurance and most commonly private insurance (≤4 y: 41.2% versus > 4 y: 70.5%, P = 0.02). Only 9.0% had Charlson/Deyo Score ≥1 and all but one had unilateral ACC. The median tumor size was smaller in the ≤4 y versus the >4 y group (median: 8.4 cm versus 12.5 cm, P < 0.001). Metastasis at diagnosis was seen in a smaller proportion in the ≤4 y versus the >4 y group (20.6% versus 47.7%, P = 0.01). Data on stage were only available in 45 (57.7%) patients and the stage distribution was the following: stage I one patient; stage II 10 patients; stage III eight patients; stage IV 26 patients.
Sixty-six patients (84.6%) underwent surgical treatment (≤4 y: 94.1% versus > 4 y: 77.3%, P = 0.04), which was most commonly total adrenalectomy (63.6%), partial adrenalectomy (16.7%), and radical resection (13.6%). Positive surgical margins were seen in 3.7% in those ≤4 y compared to 35.5% in those >4 y (P = 0.003) and all but one of the patients with positive surgical margins received chemotherapy. Data on the surgical approach
were available for 33 (50.0%) surgically treated patients, most of whom underwent an open procedure while <10 patients un- derwent a minimally invasive procedure. Lymph node dissec- tion was performed in 41.3% without any difference between the two age groups. More than half (56.4%) received chemo- therapy (<4 y: 35.3% versus > 4 y: 72.7%, P = 0.001) and mostly in the adjuvant setting (78.8%) in surgically treated patients. Ra- diation therapy was only administered in a small proportion of the cohort and only in older children (<4 y: 0.0% versus > 4 y: 13.6%, P = 0.03). Immunotherapy was not offered in any patient. Detailed patient demographic and clinical data by age group are presented in Table 1.
Overall survival
The 1-, 3-, and 5-y overall survival rates were 87.0%, 62.0%, and 60.1%, respectively. In unadjusted analysis, age ≤4 y was associated with improved overall survival (log-rank test, P < 0.001; Fig. 3A). In unadjusted analysis, surgical treatment was associated with improved overall survival (log-rank test, P < 0.001; Fig. 3B). Notably, compared to patients who under- went surgical treatment alone, patients who underwent both surgical treatment and lymph node dissection were not found to have a statistically significant improvement in overall
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Age at Diagnosis
| Table 1 - Patient demographic and clinical data in children with ACC by age group. | ||||
| Variable | Total (n = 78) | ≤4 Y (n = 34) | >4 Y (n = 44) | P value |
| Age (years) | 10.0 (2.0-15.0) | 1.0 (0.0-2.0) | 14.5 (11.5-16.0) | <0.001 |
| Sex | 0.97 | |||
| Male | 30 (38.5%) | 13 (38.2%) | 17 (38.6%) | |
| Female | 48 (61.5%) | 21 (61.8%) | 27 (61.4%) | |
| Race/ethnicity | 0.64 | |||
| White | 54 (69.2%) | 21 (61.8%) | 33 (75.0%) | |
| Black | 5 (6.4%) | 3 (8.8%) | 2 (4.6%) | |
| Hispanic | 15 (19.2%) | 8 (23.5%) | 7 (15.9%) | |
| Other | 4 (5.1%) | 2 (5.9%) | 2 (4.6%) | |
| Median household income quartile | 0.26 | |||
| < $46,277 | 10 (12.8%) | 6 (17.6%) | 4 (9.1%) | |
| $46,277-$57,856 | 16 (20.5%) | 4 (11.8%) | 12 (27.3%) | |
| $57,857-$74,062 | 21 (26.9%) | 11 (32.4%) | 10 (22.7%) | |
| $74,063+ | 31 (39.7%) | 13 (38.2%) | 18 (40.9%) | |
| Insurance status | 0.02 | |||
| Not insured | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Private insurance | 45 (57.7%) | 14 (41.2%) | 31 (70.5%) | |
| Medicaid | 32 (41.0%) | 20 (58.8%) | 12 (27.3%) | |
| Other government | 1 (1.3%) | 0 (0.0%) | 1 (2.3%) | |
| Distance between patient's residence and hospital (miles) | 24.1 (11.6-41.1) | 24.7 (12.2-55.0) | 22.2 (11.4-35.8%) | 0.78 |
| Charlson/Deyo score ≥1 | 7 (9.0%) | 2 (5.9%) | 5 (11.4%) | 0.40 |
| Unilateral tumor | 77 (98.7%) | 34 (100.0%) | 43 (97.7%) | 0.38 |
| Tumor size (cm) (n = 75) | 10.2 (7.4-14.0) | 8.4 (6.1-10.4) | 12.5 (9.7-16.0) | <0.001 |
| Metastasis at diagnosis | 28 (35.9%) | 7 (20.6%) | 21 (47.7%) | 0.01 |
| Receipt of surgical treatment | 66 (84.6%) | 32 (94.1%) | 34 (77.3%) | 0.04 |
| Lymph node dissection (n = 75) | 31 (41.3%) | 17 (50.0%) | 14 (34.2%) | 0.17 |
| Receipt of chemotherapy | 44 (56.4%) | 12 (35.3%) | 32 (72.7%) | 0.001 |
| Receipt of radiation | 6 (7.7%) | 0 (0.0%) | 6 (13.6%) | 0.03 |
| Surgical margin status | 0.003 | |||
| Negative | 46 (79.3%) | 26 (96.3%) | 20 (64.5%) | |
| Positive | 12 (20.7%) | 1 (3.7%) | 11 (35.5%) | |
| Type of surgery (n = 66) | 0.052 | |||
| Local excision | 3 (4.6%) | 3 (9.4%) | 0 (0.0%) | |
| Partial adrenalectomy | 11 (16.7%) | 3 (9.4%) | 8 (23.5%) | |
| Total adrenalectomy | 42 (63.6%) | 23 (71.9%) | 19 (55.9%) | |
| Radical resection | 9 (13.6%) | 2 (6.3%) | 7 (20.6%) | |
| Surgery, not otherwise specified | 1 (1.5%) | 1 (3.1%) | 0 (0.0%) | |
| Surgery-chemotherapy sequence (n = 33) | 0.69 | |||
| Neoadjuvant only | 2 (6.1%) | 1 (10.0%) | 1 (4.4%) | |
| Adjuvant only | 26 (78.8%) | 7 (70.0%) | 19 (82.6%) | |
| Neoadjuvant and adjuvant | 5 (15.2%) | 2 (20.0%) | 3 (13.0%) | |
| Categorical variables expressed in frequency (%) and compared with chi-square test, continuous variables expressed in median (interquartile range) and compared with Mann-Whitney U-test. | ||||
survival (hazard ratio [HR]: 0.98, 95% confidence interval [95% CI]: 0.43-2.28, P = 0.97). In surgically treated patients, having positive surgical margins was not associated with inferior overall survival (HR: 2.44, 95% CI: 0.89-6.66, P = 0.08). Detailed patient demographic and clinical data by survival status are presented in Table 2.
In multivariable Cox regression (Table 3), metastasis at diagnosis was associated with inferior overall survival (HR: 2.72, 95% CI: 1.15-6.40, P = 0.02), when adjusting for age, tumor size, receipt of surgical treatment, and chemotherapy. In patients with nonmetastatic ACC (Table 3), increasing age was associated with inferior overall survival (HR: 1.12, 95% CI: 1.00-1.24, P = 0.04),
A
Kaplan Meier Overall Survival Estimates
B
Kaplan Meier Overall Survival Estimates
100
100
No surgical treatment
90
90
Surgical treatment
80
Log-rank test, p < 0.001
80
Overall Survival (%)
70
Overall Survival (%)
70
60
60
50
50
Log-rank test, p < 0.001
40
40
30
30
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≤ 4 years
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0
> 4 years
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36
48
60
72
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60
72
Number at risk
Time After Diagnosis (Months)
Number at risk No surgical treatment 12 Surgical treatment 66
Time After Diagnosis (Months)
≤ 4 years
34
28
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22
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8
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1
1
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> 4 years
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38
26
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58
50
37
32
29
25
when adjusting for tumor size, receipt of surgical treatment, and chemotherapy.
Discussion
This contemporary NCDB cohort study was able to demon- strate that pediatric ACC in the USA demonstrates a bimodal age distribution with most children presenting with large tu- mors (>10 cm). It also demonstrated that the management of pediatric ACC includes surgical treatment with the addition of chemotherapy when indicated. Moreover, about one-third of children with ACC present with metastasis at diagnosis, which is independently associated with inferior overall survival. Increasing age was independently associated with inferior overall survival likely due to more advanced disease stage at the time of diagnosis in patients with nonmetastatic ACC.
The previous comprehensive NCDB report by Gulack et al. included 111 children with ACC between 1998 and 2011 and similar to that study,12 we observed a female predominance for pediatric ACC. In addition, we demonstrated a bimodal age distribution (peaks <5 y and >10 y), which has been previously reported for pediatric ACC but not with data from the NCDB.4,17 Gulack et al.12 reported that 31% of patients had metastasis at diagnosis (versus ~36% in our study) and that the median tumor size was 9.5 cm (versus 10.2 cm in our study), which shows that a similar to slightly higher propor- tion of patients in the more recent era present with more advanced disease. Interestingly, similar to slightly higher proportions of patients in their study12 underwent surgical treatment (86.5% versus 84.6%) and lymph node dissection (45% versus 41.3%) when compared to our study. This may also explain their reported 3-y overall survival rate of 64%,12 which is similar to the 62% reported in our study. These findings are alarming and indicate that no significant improvement has been made in management or outcomes for pediatric ACC in the USA over the past decade.
The treatment algorithm for pediatric ACC is of major in- terest and is guided by tumor stage. Stage I is comprised of patients with tumors <100 g and normal postoperative hor- mone levels and stage II of patients with tumors >100 g and normal postoperative hormone levels.11 Stage III is comprised
of patients with incomplete resection or unresectable tumors or stage I/II tumors with spillage and persistently elevate postoperative hormone levels or retroperitoneal lymph node involvement, and stage IV of patients with distant metastasis.11 Although surgery alone with or without lymph node dissection may be adequate for stage I or II ACC, the Children’s Oncology Group guidelines indicate the need for chemotherapy in stage III or IV ACC, in case of unresectable tumors, positive surgical margins, and tumor spillage during resection.11 The findings of the prospective ARAR0332 study suggest that the addition of lymph node dissection for stage II ACC does not provide suffi- cient improvement in outcomes to warrant adoption.11 Although our study could not incorporate stage-based ana- lyses, our findings concur with those of the ARAR0332 study showing no survival benefit with the addition of lymph node dissection in all children with ACC undergoing surgical treat- ment. Therefore, further evaluation of the potential benefit of lymph node dissection in children with ACC is warranted.
Another notable observation of our study is the inferior overall survival in older children with nonmetastatic ACC independent of tumor size. Kerkhofs et al.16 reported population-based data from the Netherlands and showed better outcomes for children ≤4 y old compared to older children. This may be attributed to the earlier clinical mani- festations of hormone excess, such as hirsutism, enlarged genitalia, increased height, or moon facies in younger chil- dren. Another cohort of 95 children with ACC from Brazil also showed that overall and disease-free survival were signifi- cantly better in patients ≤3 y old.18 These findings were also confirmed by a systematic review of 137 studies and 3680 ACC pediatric patients, which hypothesized that the different hormonal production profile and earlier stage presentation in younger patients may be related to fetal zone-derived tumorigenesis in early childhood.19 In addition to that hy- pothesis, our data indicate that children >4 y had larger tu- mors, were more likely to have metastasis at diagnosis, were less likely to be offered surgical treatment and if offered more likely to have positive surgical margins, and were more likely to be offered chemotherapy and radiation therapy, which is the case for patients with more advanced disease stage. Although our analysis has a great deal of missing data for tumor stage which limits stage-based survival analysis, our
| Table 2 - Patient demographic and clinical data in children with ACC by survival status. | ||||
|---|---|---|---|---|
| Variable | Total (n = 78) | Deceased (n = 32) | Alive (n = 46) | P value |
| Age (years) | 10.0 (2.0-15.0) | 13.5 (9.5-16.0) | 2.5 (1.0-13.0) | <0.001 |
| Sex | 0.42 | |||
| Male | 30 (38.5%) | 14 (43.8%) | 16 (34.8%) | |
| Female | 48 (61.5%) | 18 (56.2%) | 30 (65.2%) | |
| Race/ethnicity | 0.06 | |||
| White | 54 (69.2%) | 27 (84.4%) | 27 (58.7%) | |
| Black | 5 (6.4%) | 2 (6.2%) | 3 (6.5%) | |
| Hispanic | 15 (19.2%) | 3 (9.4%) | 12 (26.1%) | |
| Other | 4 (5.1%) | 0 (0.0%) | 4 (8.7%) | |
| Median household income quartile | 0.83 | |||
| < $46,277 | 10 (12.8%) | 4 (12.5%) | 6 (13.0%) | |
| $46,277-$57,856 | 16 (20.5%) | 5 (15.6%) | 11 (23.9%) | |
| $57,857-$74,062 | 21 (26.9%) | 9 (28.1%) | 12 (26.1%) | |
| $74,063+ | 31 (39.7%) | 14 (43.8%) | 17 (37.0%) | |
| Insurance status | 0.09 | |||
| Not insured | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Private insurance | 45 (57.7%) | 22 (68.8%) | 23 (50.0%) | |
| Medicaid | 32 (41.0%) | 9 (28.1%) | 23 (50.0%) | |
| Other government | 1 (1.3%) | 1 (3.1%) | 0 (0.0%) | |
| Distance between patient's residence and hospital (miles) | 24.1 (11.6-41.1) | 22.9 (12.2-36.4) | 24.3 (11.2-41.8) | 0.84 |
| Charlson/Deyo score ≥1 | 7 (9.0%) | 5 (15.6%) | 2 (4.4%) | 0.09 |
| Unilateral tumor | 77 (98.7%) | 31 (96.9%) | 46 (100.0%) | 0.23 |
| Tumor size (cm) (n = 75) | 10.2 (7.4-14.0) | 12.3 (9.8-16.5) | 9.4 (6.1-12.5) | <0.001 |
| Metastasis at diagnosis | 28 (35.9%) | 19 (59.4%) | 9 (19.6%) | <0.001 |
| Receipt of surgical treatment | 66 (84.6%) | 22 (68.8%) | 44 (95.6%) | 0.001 |
| Lymph node dissection (n = 75) | 31 (41.3%) | 10 (32.3%) | 21 (47.7%) | 0.18 |
| Receipt of chemotherapy | 44 (56.4%) | 26 (81.2%) | 18 (39.1%) | <0.001 |
| Receipt of radiation | 6 (7.7%) | 4 (12.5%) | 2 (4.4%) | 0.18 |
| Surgical margin status | 0.15 | |||
| Negative | 46 (79.3%) | 13 (68.4%) | 33 (84.6%) | |
| Positive | 12 (20.7%) | 6 (31.6%) | 6 (15.4%) | |
| Type of surgery (n = 66) | 0.004 | |||
| Local excision | 3 (4.6%) | 0 (0.0%) | 3 (6.8%) | |
| Partial adrenalectomy | 11 (16.7%) | 3 (13.6%) | 8 (18.2%) | |
| Total adrenalectomy | 42 (63.6%) | 11 (50.0%) | 31 (70.4%) | |
| Radical resection | 9 (13.6%) | 8 (36.4%) | 1 (2.3%) | |
| Surgery, not otherwise specified | 1 (1.5%) | 0 (0.0%) | 1 (2.3%) | |
| Surgery-chemotherapy sequence (n = 33) | 0.30 | |||
| Neoadjuvant only | 2 (6.1%) | 1 (6.2%) | 1 (5.9%) | |
| Adjuvant only | 26 (78.8%) | 11 (68.8%) | 15 (88.2%) | |
| Neoadjuvant and adjuvant | 5 (15.2%) | 4 (25.0%) | 1 (5.9%) | |
| Categorical variables expressed in frequency (%) and compared with chi-square test, continuous variables expressed in median (interquartile range) and compared with Mann-Whitney U test. | ||||
findings suggest that older children are more likely to present with more advanced disease, which may be contributing to their inferior overall survival outcomes.
Intrinsic downsides of using NCDB data have imposed certain limitations on the current study, such as the retro- spective nature of the data. NCDB also lacks certain clinically
important parameters, including patient presentation, tumor mutations/syndromes, the use of mitotane, and disease-free or recurrence-free survival. The data on disease stage were only available in <60% of the cohort, which limited our ability to perform stage-based analyses. Additionally, the staging system provided by NCDB does not exactly match up with the
| Table 3 - Multivariable Cox regression models. | ||||||
|---|---|---|---|---|---|---|
| Variable | Multivariable model - All | Multivariable model - Nonmetastatic | ||||
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Age | 1.06 | 0.99-1.14 | 0.11 | 1.12 | 1.00-1.24 | 0.04 |
| Tumor size | 0.54 | 0.99-1.01 | 0.54 | 1.00 | 0.99-1.02 | 0.56 |
| Metastasis at diagnosis | 2.72 | 1.15-6.40 | 0.02 | |||
| Receipt of surgical treatment | 0.53 | 0.22-1.28 | 0.16 | 0.34 | 0.04-2.93 | 0.33 |
| Receipt of chemotherapy | 2.26 | 0.85-5.99 | 0.10 | 1.79 | 0.45-7.20 | 0.41 |
Children’s Oncology Group ACC staging system, which high- lights the need for better national pediatric surgical oncology datasets that reflect accurate staging to be able to better un- derstand rare pediatric tumors. Furthermore, the relatively small sample size may increase the risk of a type II error, which may explain the lack of statistically significant differ- ence in overall survival according to surgical margin status. Finally, data included in the NCDB are only collected from institutions accredited by the Commission on Cancer, yet the data are still likely generalizable since these patients require focused high-level comprehensive care.
Conclusions
The majority of children with ACC in the USA undergo surgical treatment with about half of these also receiving chemo- therapy without significant improvements in management and survival outcomes over the past decade. The addition of lymph node dissection to surgical treatment is of unclear survival benefit and warrants further investigation. Metas- tasis at diagnosis appears to be independently associated with inferior overall survival, while in patients with nonmetastatic ACC increasing age was independently associated with infe- rior overall survival likely due to more advanced disease stage at the time of diagnosis.
Study Type
Retrospective Cohort Study.
Level of Evidence
Level III.
Disclosure
The authors have no conflicts of interest to disclose.
Funding
No funding was received for this study.
Availability of Data
The data that support the findings of this study are available from the National Cancer Database. Restrictions apply to the availability of these data, which were used under license for this study. Data from the National Cancer Database Patient User Data Files are available upon request at https://ncdbapp. facs.org/puf/.
Meeting Presentation
Oral Presentation at the Academic Surgical Congress in Washington, D.C., on February 8, 2024.
CRediT authorship contribution statement
Ioannis A. Ziogas: Writing - original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Jonathan L. Hills-Dunlap: Writing - review & editing, Resources, Methodology, Investigation. Kristine S. Corkum: Writing - review & editing, Resources, Methodology, Investigation. Nicholas G. Cost: Writing - review & editing, Resources, Methodology, Investigation. Ankush Gosain: Writing - review & editing, Supervision, Resources, Project administration, Methodology, Investigation. Jonathan P. Roach: Writing - re- view & editing, Supervision, Resources, Project administra- tion, Methodology, Investigation.
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