Aaditya Daga, Siddhant Dahale, Aditya Phadte, Vijay Sarathi, Saba Memon, Anurag Lila*, Chethan Yamichannaiah, Virendra Patil, Manjiri Karlekar, Rohit Barnabas, Nalini Shah, Amey Rojekar, Gwendolyn Fernandez, Pragati Sathe, Padma Badhe and Tushar Bandgar
Clinical spectrum, imaging characteristics, and treatment outcomes of pediatric adrenocortical tumors: a 24-year experience from Western India
https://doi.org/10.1515/jpem-2025-0162
Received March 20, 2025; accepted August 15, 2025; published online August 25, 2025
Abstract
Objectives: This study aims to characterize the clinical spectrum of pediatric adrenocortical tumors (P-ACTs) in in- dividuals aged <20 years and to compare the distinguishing features of pediatric adrenocortical adenomas (P-ACAs) and carcinomas (P-ACCs).
Methods: This retrospective study consisted of P-ACT pa- tients who presented to our institute over the past 24 years (2001-2024). They were categorized as P-ACC or P-ACA based on Wieneke score. Data on clinical presentation, hormonal evaluation, imaging, management, and outcomes were recorded.
Results: A total of 30 (22 females) P-ACT patients (7 P-ACA and 23 P-ACC) were identified. The median age at presenta- tion was 7 (range, 1.0-20) years, with a median symptom duration of 6.0 months (range 0.6-42 months). All patients, except one 16-year-old having P-ACC, had hormonal hyper- secretion. Cortisol and androgen co-secretion was most common (56.6 %), followed by isolated cortisol (26.6 %) and
Aaditya Daga and Siddhant Dahale contributed equally to this work and share first authorship.
*Corresponding author: Anurag Lila, MBBS, MD, DM, Department of Endocrinology and Metabolism, Seth G S Medical College and KEM Hospital, Parel, Mumbai, 400012, Maharashtra, India, E-mail: anuraglila@gmail.com. https://orcid.org/0000-0002-9623-4471
Aaditya Daga, Siddhant Dahale, Aditya Phadte, Saba Memon, Chethan Yamichannaiah, Virendra Patil, Manjiri Karlekar, Rohit Barnabas, Nalini Shah and Tushar Bandgar, Department of Endocrinology and Metabolism, Seth G S Medical College and KEM Hospital, Mumbai, India. https://orcid.org/0000-0002-6902-4639 (T. Bandgar)
Vijay Sarathi, Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, India
Amey Rojekar, Gwendolyn Fernandez and Pragati Sathe, Department of Pathology, Seth GSMC and KEMH, Mumbai, India
Padma Badhe, Department of Radiology, Seth GSMC and KEMH, Mumbai, India
androgen hypersecretion (13.3 %). On steroid profiling by LCMS/MS, P-ACC patients had raised levels of multiple ste- roid metabolites (6-9) as compared to P-ACA (2-5). P-ACA patients were relatively older (17.0 vs. 6.0 years, p=0.045), more often had isolated cortisol secretion (57.1 vs. 17.3 %, p=0.060), had smaller tumors (2.8 vs. 8.5 cm, p=0.002), a lower incidence of calcification (0 vs. 80 %) and a lower percentage venous enhancement (PVE 109.6 vs. 187.8 %, p=0.008) and achieved higher disease remission rates (100 vs. 21.4 %, p=0.005).
Conclusions: CECT features, particularly PVE, may aid in differentiating P-ACT from P-ACC. Serum steroid panels may have a role in preoperative assessment, but their utility re- mains to be validated.
Keywords: pediatric adrenocortical tumors; adrenal cush- ings; hyperandrogenism; Wieneke score
Introduction
Pediatric adrenocortical tumors (P-ACTs) constitute less than 0.2 % of all pediatric neoplasms with an estimated annual incidence of 0.3 per million children [1, 2]. Pediatric adrenal cortical tumors (ACTs) are primarily linked to Li-Fraumeni Syndrome as well as the more inclusive Li-Fraumeni spec- trum. Other genetic conditions associated with ACTs include Beckwith-Wiedemann syndrome, Lynch syndrome, and multiple endocrine neoplasia (MEN) Type 1 [3]. P-ACTs usu- ally present with features of androgen and/or cortisol excess and, rarely, aldosterone or estrogen hypersecretion [4, 5]. They may also present with tumor mass-related symptoms, particularly in older children and adolescents [4]. Based on histological features, these ACTs are classified as adenomas (ACA) or carcinomas (ACC); discriminating benign vs. ma- lignant behavior is even more challenging in P-ACT than in adults. In P-ACT, despite having histological characteristics (higher Weiss scores), some patients have good outcomes; hence, the Wieneke index has been proposed to have a more accurate prognostication [6, 7]. Preoperative investigations like adrenal mass imaging characteristics by contrast-
enhanced computerized tomography (CECT) and serum steroid panel by LCMS/MS assay may help differentiate ACA from ACC [8, 9]. Such data are mainly validated in the adults, and data in the pediatric age group are scarce. Cross- sectional imaging with CT, magnetic resonance imaging (MRI), and/or 18-fluorodeoxyglucose positron emission to- mography (18FDG-PET) scan is essential for determining the extent of local and distant tumor spread. Surgery remains the first-line treatment for localized/regional disease, with age, tumor size, and resection status as key prognostic fac- tors [4]. Recent data have validated the previous observa- tions and also highlighted the additional role of the Ki67 index [10]. They also suggested that detailed hormonal profiling at baseline may unfold the predictive utility of these biomarkers in the future. Systemic chemotherapy and mitotane therapy are the therapeutic options in the treat- ment of advanced P-ACC patients, though outcomes are dismal [11]. Few Indian centers have reported their experi- ence managing P-ACT patients [12, 13, 14]. This study aims to describe the clinical spectrum of P-ACTs (age <20 years) pa- tients managed at our center in western India in the last 24 years and compare the features of P-ACAs vs. P-ACCs.
Materials and methods
A retrospective analysis of P-ACT patients, aged <20 years at diagnosis, managed from 2001 to 2024, at our tertiary care institute in Western India, was performed after Ethical Committee approval. Data on clinical presentation, hor- monal evaluation, imaging, management, and outcome were recorded. ACC diagnosis was based on Wieneke scores >3, while scores <2 indicated ACA, and a score of 3 was classified as uncertain malignant potential. In patients with metastatic disease where tissue diagnosis was un- available, ACC was diagnosed based on hormonal hyper- secretion and normal plasma metanephrines. ACT was diagnosed as cortisol secreting if overnight dexamethasone suppression test (ODST) serum cortisol ≥1.8 ug/dL and basal plasma ACTH <10 pg/mL. Androgen excess was defined by serum DHEAS and/or testosterone levels above age-specific cutoffs. Cortisol levels were assessed using a solid-phase competitive chemiluminescent enzyme immunoassay (Siemens Healthcare). Plasma ACTH was determined using a solid-phase, two-site sequential chemiluminescent assay. The Siemens Immulite assay was supplemented with the Liaison (Diasorin) assay, which started in December 2017. Serum DHEAS levels were measured using the chem- iluminescence microparticle immunoassay (CMIA) on the Roche Cobas platform. LCMS/MS serum steroid panel re- sults (available after 2017), with assay methodology
detailed in our previous work, were compared against pediatric age and sex-specific reference [15-18]. CECT ad- renal imaging features included basal and enhanced phase Hounsfield units (HUs), with region-of-interest measure- ments of the central solid two-thirds. The scanning pa- rameters included a tube voltage of 120 kVp, with automatic exposure control set between 140 and 220 mA, a rotation time of 0.75 s, a pitch of 0.797, and a detector configuration of 0.625 mm, with a beam width of 40 mm. The initial phase was captured at baseline (UP). A total of 1- 1.5 mL/kg of iodinated contrast (Iohexol: Omnipaque 300, GE Healthcare) was administered. The early venous phase (EVP) and delayed venous phase (DVP) were acquired at 1 and 15 min, respectively. Washout characteristics including absolute percentage washout (APW), relative percentage washout (RPW), and percentage venous enhancement (PVE) were calculated as follows: APW=(EVP HU - DVP HU) × 100/(EVP HU - UP HU), RPW=(EVP HU - DVP HU) × 100/EVP HU and PVE=(EVP HU - UP HU) ×100/UP HU. CECT/MRI of the chest and abdomen and/or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed for disease mapping. Disease staging was performed according to the International Pe- diatric Adrenocortical Tumor Registry (IPACTR) system, validated by the Children Oncology Group (COG) and Eu- ropean Network for Study of Adrenal Tumors (ENSAT) system, with outcomes classified as remission (no evidence of disease), alive with disease, and deceased. pS-GRAS scores, 5-item microscopic score, were calculated where the Ki-67 index was available. Inflammatory scores (neutrophil to lymphocyte ratio (NLR), derived lymphocyte ratio (dNLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR)) were calculated as described by Riedmeier et al. [19] Outcome analysis included patients with a minimum one-year follow-up.
Statistical analysis
Data analysis was conducted using SPSS version 26. Cate- gorical variables were compared with Chi-square or Fisher’s exact test, while continuous variables (reported as medians with ranges or interquartile ranges [IQR]) were compared using an unpaired t-test. ROC curve analysis determined optimal CECT parameter cutoffs for distinguishing P-ACC from P-ACA. Statistical significance was set at p<0.05. Sur- vival analysis was performed with the Kaplan-Meier method to estimate overall survival (OS) and event-free survival (EFS). The log-rank test was used to compare sur- vival distributions across different subgroups, including IPACTR stage, ENSAT stage, Wieneke score (≤3 vs. >4), and
age groups (<4 years vs. ≥4 years). Cox regression analysis calculated the hazard ratio and prognostic significance of IPACTR stage III-IV vs. stage I-II, ENSAT stage III-IV vs. stage I-II, pS-GRAS, 5-item score and inflammatory scores. Statis- tical significance was defined as a two-tailed p-value <0.05.
Results
A total of 30 (22 females) P-ACT patients (7 P-ACA and 23 P-ACC) were identified, and their data is summarized in Ta- ble 1. The median age at presentation was 7 (range, 1.0-20) years, with median symptom duration of 6.0 months (range 0.6-42 months). All except one 16-year-old having P-ACC, had hormonal hypersecretion. Cortisol and androgen co- secretion (as evidenced by clinical and/or hormonal levels) was most common (56.6 %), followed by isolated cortisol (26.6 %) and androgen hypersecretion (13.3 %). A 13-year-old
boy with P-ACA and Cushing syndrome had gynecomastia (Tanner stage B4, both sides) at presentation, and his serum estradiol and luteinizing hormone levels were 246 pg/mL and 0.1 mIU/mL, respectively. Hypertension was observed in 15/30 patients (50.0 %), and none had dysglycemia. All tumors were unilateral (17 right-sided), with median diameter of 7.5 (range 2.1-15) cm. IPACTR stages 1, 2, 3, and 4 were seen in 33, 20, 23.3, and 23.3 %, respectively, with seven patients showing lung and/or liver metastases at presentation. ENSAT stages 1, 2, 3, and 4 were seen in 30, 30, 16.6, and 23.3 %, respectively.
The clinical details of P-ACA (n=7) and P-ACC (n=23) pa- tients are summarized in Table 1. P-ACA patients were relatively older (17.0 vs. 6.0 years, p=0.045), more often had isolated cortisol secretion (57.1 vs. 17.3 %, p=0.06), had smaller tumors (2.8 vs. 8.5 cm, p=0.002), and achieved higher remission rates (100 vs. 21.4 %, p=0.005). Two P-ACA patients had tumors ≥4 cm, while four P-ACC had tumors <4.0 cm. LC-MS steroid profile was available for seven P-ACC and two
| Pediatric adrenocortical tumors P-ACT (n=30) | Pediatric adrenocortical adenoma P-ACA (n=7) | Pediatric adrenocortical carcinoma P-ACC (n=23) | p-Value | |
|---|---|---|---|---|
| Age, yearsª | 7 (1, 20) | 17 (4.75, 20) | 6 (1, 18) | 0.045 |
| Gender (male:female) | 1:2.75 | 1:2.5 | 1:2.8 | 1.000 |
| Duration of symptoms, monthsª | 6 (0.6, 42) | 9 (4, 24) | 5.5 (0.6, 42) | 0.720 |
| Symptoms/biochemistry | ||||
| Androgen excess | 4 (13.3) | – | 4 (17.3) | 0.320 |
| Cortisol excess | 8 (26.6) | 4 (57.1) | 4 (17.3) | 0.060 |
| Androgen+cortisol excess | 17 (56.6) | 3 (42.8) | 14 (60.8) | 0.143 |
| Non-secretory | 1 (3.3) | – | 1 (4.34) | – |
| Hypertension | 15 (50) | 3 (42.8) | 12 (52.1) | 1.000 |
| Maximum tumor diameter, cmª | 7.5 (2.1, 15) | 2.8 (2.1, 6) | 8.5 (2.1, 15) | 0.002 |
| IPACTR staging | ||||
| 1 | 10 (33.3) | 7 (100) | 3 (13) | 0.001 |
| 2 | 6 (20) | 6 (26) | ||
| 3 | 7 (23.3) | 7 (30.4) | ||
| 4 | 7 (23.3) | 7 (30.4) | ||
| ENSAT staging | ||||
| 1 | 9 (30) | 5 (71.4) | 4 (17.3) | 0.038 |
| 2 | 9 (30) | 2 (28.5) | 7 (30.4) | |
| 3 | 5 (16.6) | – | 5 (21.7) | |
| 4 | 7 (23.3) | – | 7 (30.4) | |
| Resection status (n=25) | ||||
| RO | 14 | 7/7 | 7 | 0.067 |
| R | 4 | 4 | ||
| R2 | 7 | 7 | ||
| Outcome at follow-up of minimum 1 year (n=19) | ||||
| Remission | 8 (42.1) | 5 (100) | 3 (21.4) | 0.005 |
| Living with disease | 3 (15.7) | – | 3 (21.4) | 0.530 |
| Deceased | 8 (42.1) | – | 8 (57.2) | 0.106 |
Data expressed as n (%) or ªmedian (range). ENSAT, European Network for the Study of Adrenal Tumors; IPACTR, International Pediatric Adrenocortical Tumor Registry. Bold values indicate statistically significant p-values (p<0.05).
P-ACA patients; the details are summarized in Table 2. All P-ACC patients had raised levels of multiple (n=6 to 9) steroid metabolites. Higher aldosterone (2/6), progesterone (1/7), 11- deoxycorticosterone (3/6), corticosterone (5/7), 17-hydroxy- progesterone (6/7), 11-deoxycortisol (6/7), cortisol (3/7), cortisone (3/5), DHEA (3/7), DHEAS (5/7), androstenedione (7/ 7), and testosterone (6/7) was observed. All five patients where serum 21-deoxycortisol was available had normal levels. P-ACA patients with Cushing syndrome, aged 6.6 years boy and 18 years female, had an elevation of five and two steroid metabolites, respectively. Detailed CECT character- istics (available for ten P-ACC and five P-ACA patients) are summarized in Table 3. The tumor size (9.0 vs. 2.8 cm) and proportion of tumors with calcification (80 vs. 0 %) were significantly higher for P-ACCs. Basal HU was >10 HU for all P-ACTs. 2/10 P-ACC had RPW≥40 %, and amongst P-ACA, 1/5 had RPW <40 %. PVE (109.6 vs. 187.8 %, p=0.008, AUC=0.875) was higher for P-ACA vs. P-ACC, with a cutoff value of 157.8 %, yielding a sensitivity of 87.5 % and a specificity of 90 %. Figure 1 shows basal and venous phase CT images of patients with P-ACC and P-ACA. Per-patient clinical, biochemical, histopathological (modified Weiss, Wieneke, and 5-item microscopic score), and prognostic markers (pS-GRAS scores and inflammatory scores) of P-ACC as per age are summa- rized in Supplementary Data.
Twenty-five patients underwent surgery for the pri- mary tumor. Wieneke scoring classified 18 tumors as P-ACC and seven as P-ACA. pS-GRAS scores were calculated for eight patients (six P-ACC and two P-ACA) with an available Ki67 index. The score was two for both P-ACA patients, while all P-ACC patients except one had a score greater than two. Of the 25 patients with available surgical data, R0 (complete) resection was achieved in 14 cases, including all seven pa- tients with P-ACA and seven of the 18 patients with P-ACC. R1 (microscopic residual) and R2 (macroscopic residual) re- sections were observed exclusively among carcinoma cases, in four and seven patients, respectively. All P-ACA patients achieved remission post-surgery, with no recurrence at a median follow-up of 48 months. Eighteen of the twenty-three P-ACC patients underwent adrenal mass surgery. Of the 11
patients who had residual disease (R1 and R2) and one with extensive local disease, three patients received local bed radiation, five patients were treated with the cisplatin, eto- poside, and doxorubicin (CED) regimen, and two received mitotane plus CED. One patient declined further treatment, while another was lost to follow-up.
Among patients with ≥1 year follow-up, outcomes (remission, living with disease, deceased) were significantly associated with IPACTR stage (p<0.001), ENSAT stage (p=0.006), and resection status (p<0.001). No significant dif-
ferences were observed for age, treatment period, or
| P no. | Age, years | Sex | Aldosterone, ng/L | Progesterone, µg/L | -Deoxy corticosterone, µg/L | Corticosterone, µg/L | 17-OH progesterone, ng/dl | -Deoxy- cortisol, µg/L | Cortisol, µg/dL | Cortisone, µg/L | 21- Deoxy- cortisol, µg/L | DHEA, µg/L | DHEAS, µg/dL | Androstenidione, ng/dL | Testost- erone, ng/dL | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P-ACC | 16 | 1.0 | F | – | 0.27 | – | 4.09 | 175 | 1.25 | 3.82 | – | – | 21,800 | 328.2 | 880 | 163 |
| 21 | . | F | 11.4 | 0.15 | 0.02 | 0.53 | 252 | 10.7 | 25.4 | 51.8 | 0.027 | 2.13 | 526 | 666 | 204 | |
| 13 | 2.7 F | 383 | 0.06 | 0.24 | 1.19 | 158 | 12.6 | 26.4 | 38 | 0.11 | 7.89 | 1,530 | 3,770 | 3,540 | ||
| 3 | 6.0 F | 365 | 0.2 | 0.09 | 4.48 | 32 | 0.61 | 8.0 | 19.9 | 0.03 | 9.29 | 2,010 | 330 | 57 | ||
| 4 | 6.0 F | 94.7 | 0.27 | 0.96 | 4.14 | 92 | 1.56 | 9.9 | 16.5 | 0.02 | 0.91 | 10.9 | 120 | 160 | ||
| 22 | 17.0 | F | 58.2 | 1.55 | 4.96 | 8.31 | 755 | 88.5 | 46.0 | 36.5 | 0.31 | 3.58 | 645 | 3,300 | 706 | |
| 18 | 18.0 M | 21.3 | 0.23 | 16.2 | 50 | 267 | 16.20 | 26.1 | – | – | 2,657 | 96.4 | 900 | 170 | ||
| P-ACA | 27 | 6.6 M | 99 | 0.23 | 0.04 | 1.31 | 67 | 1.3 | 14.8 | 38.8 | 0.02 | 0.23 | 21.5 | 160 | 45 | |
| 26 | 18.0 | F | 16.8 | 0.14 | 0.3 | 7.63 | 40 | 2.61 | 24.6 | 23.5 | 0.027 | 0.7 | 17.9 | 70 | 13 | |
DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone-sulfate; F, female; LCMS/MS, liquid chromatography tandem mass spectrometry; M, male; P-ACA, pediatric adrenocortical adenoma; P-ACC, pediatric adrenocortical carcinoma; P no., patient no. Bold values indicate steroid hormone levels above the upper limit of age and sex matched reference range.
| Pediatric adrenocortical carcinoma, (n=10) | Pediatric adrenocortical adenoma, (n=5) | p-Value | |
|---|---|---|---|
| Location: left/right side | 7/3 | 2/3 | 1.000 |
| Largest diameter, cmª | 9.05 (4.72, 13.4) | 2.80 (2.45, 4.40) | 0.019 |
| Necrosis | 9 (90 %) | 1 (20 %) | 0.176 |
| Calcification | 8 (80 %) | 0 (0 %) | 0.021 |
| Baseline, HUª | 42.4 (33.8, 46.1) | 37.0 (24.8, 40.5) | 0.206 |
| Early venous phase | 81.3 (74.5, 97.3) | 100.0 (77.6, | 0.254 |
| attenuation, HUª | 131.0) | ||
| Delayed venous phase | 52.6 (49.9, 61.2) | 60.0 (39.1, 69.0) | 0.768 |
| attenuation, HUª | |||
| APWª | 71.4 (51.3, 76.4) | 68.2 (60.2, 78.5) | 0.859 |
| RPWª | 35.5 (19.5, 38.9) | 49.1 (40.5, 50.9) | 0.028 |
| RPW≥40 % | 2 (20 %) | 4 (80 %) | 0.089 |
| PVEª | 109.6 (68.3, | 187.8 (158.3, | 0.008 |
| 148.9) | 282.6) |
Data expressed as n or ªmedian (IQR). APW, absolute percentage washout; HU, Hounsfield unit; PVE, percentage venous enhancement; RPW, relative percentage washout. Bold values indicate statistically significant p-values. (p<0.05).
secretion type (Table 4). Kaplan-Meier analysis showed significantly poorer overall survival (OS) and event-free survival (EFS) with advancing IPACTR and ENSAT stage (log-rank p<0.001). Survival also differed significantly by Wieneke score (≤3 vs. >3; p=0.007), but not by age group (<4 vs. >4 years; p=0.997 and 0.840) (Figure 2). Hazard ratio for IPACTR stage III-IV against stage I-II was 26.3 (95 % CI: 3.1- 220.8); for ENSAT stage III-IV against ENSAT stage I-II was 10.9 (2.6-44.7). On univariate Cox regression, higher NLR, dNLR, MLR, PLR, 5-item score, and pS-GRAS score were all associated with hazard ratios >1, indicating a trend toward poorer prognosis. However, none reached statistical signif- icance (p>0.05).
Discussion
Our study provides valuable insights into P-ACT management from Western India. As per our cohort’s observation, CECT characteristics, such as PVE, may help to discriminate P-ACT from P-ACC. While our findings do not directly support the use
A
B
C
D
| Variable | Outcomes | p-Value | ||
|---|---|---|---|---|
| Remission | Living with disease | Deceased | ||
| Age, years | ||||
| ≤4 | 3 | 1 | 2 | 1.000 |
| >4 | 5 | 2 | 6 | |
| IPACTR staging | <0.001 | |||
| 1 | 7 | 0 | 0 | |
| 2 | 1 | 3 | 0 | |
| 3 | 0 | 0 | 4 | |
| 4 | 0 | 0 | 4 | |
| ENSAT staging | 0.006 | |||
| 1 | 5 | 0 | 0 | |
| 2 | 3 | 2 | 2 | |
| 3 | 0 | 1 | 2 | |
| 4 | 0 | 0 | 4 | |
| Resection status | ||||
| RO | 8 | 1 | 0 | <0.001 |
| Rx, R1, R2 | 0 | 5 | 2 | |
| Time-period | 0.586 | |||
| Earlier (2001-2016) | 3 | 1 | 5 | |
| Recent (2016-2024) | 5 | 2 | 3 | |
| Secretion | 0.298 | |||
| Androgen | 0 | 1 | 1 | |
| Mixed | 8 | 2 | 7 | |
ENSAT, European Network for the Study of Adrenal Tumors; IPACTR, International Pediatric Adrenocortical Tumor Registry. Bold values indicate statistically significant p-values (p<0.05).
of serum steroid panels for preoperative discrimination, previous studies have suggested their potential role in un- derstanding tumor behavior. Further research is needed to validate these biomarkers in clinical practice.
P-ACT is a rare pediatric neoplasm, and geographical variation in its incidence has been noted. The highest number of P-ACTs is reported from Southern Brazil pri- marily due to the prevalent germline TP53 gene mutation [20]. SEER database reported an incidence of only ~0.2 per million individuals aged <20 years [21]. Few tertiary care centers from India have reported experience managing P-ACT cohorts, with patients ranging from 9 to 23 [12, 13, 14]. Our series, a single-center experience from western India over the last 24 years, identified only 30 patients. These ob- servations suggest that the incidence of P-ACT is low in India, similar to the rest of the world, except for South Brazil. Biphasic age distribution (<5 years and > 10 years) in P-ACT has been observed in many series [1]. The first peak is represented by tumors arising from the fetal (embryonal) adrenal gland, and the other peak is represented by those arising from the cortex of the definitive adrenal gland [22].
At our center, ~30 % (including three infantile cases) and ~50 % of cases presented <5 and >10 years, respectively. Fe- male preponderance (65-70 %), another consistent feature of the P-ACT, was also seen in our series [23]. The exact reason for the female sex bias is not known. Similar to most reports, in our series, clinical signs of androgen and/or cortisol excess (median duration of six months) initiated the diagnostic work-up for most (~90 %) patients [4]. This stresses that signs of hormonal excess in a child should be brought to prompt medical attention. Apart from the typical clinical features of virilization, precocity, and/or Cushing syndrome, a rare observation of feminization due to estro- gen hypersecretion was seen in a 13-year-old boy.
The modified Weiss score standardized for adult ACC overestimates the malignant potential of these tumors in the pediatric age group. Hence, Wieneke score has been used with score >3 suggesting malignancy [4]. In our cohort, two patients classified as P-ACC by modified Weiss were reclassified as P-ACA by Wieneke staging. As defined based on the Wieneke score, P-ACA constituted a smaller fraction (~1/4) of P-ACTs, which is similar to the series from Turkey [24]. Picard et al. recently proposed a pathological scoring system (5-item microscopic score) incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection [25]. In our cohort, 3 out of 4 patients with a 5-item score less than 2 were in remission. Except for P-ACT with distant metastasis at presentation, the preoperative diagnosis of P-ACA vs. P-ACC remains speculative. In our series, higher age at presentation, smaller tumors, and isolated cortisol secretion were more common in P-ACA vs. P-ACC. Nevertheless, the youngest P-ACA patient presented at 4.75 years, with both cortisol and androgen hypersecretion, and harbored an adrenal mass with a maximum tumor dimension of 6.0 cm. Moreover, 5/16 P-ACC without metastasis at presen- tation were below 5 cm in size. Besides the large size, a study reported a heterogeneous enhancement, and calcification fa- vors the diagnosis of P-ACC (n=12) over P-ACA (n=8) [9]. In adults with an adrenal mass, lipid-rich (basal HU <10) and/or higher RPW >40 % favors ACA over ACC. Such data in children with an adrenal mass is scarce. As per our study results, all P-ACTs (5: PACA and 10: P-ACC) were lipid-poor with basal HU >20, and basal HUs in non-contrast imaging were non- discriminatory. Similar results have been observed in the previous series where 4/5 P-ACA and 3/3 P-ACC had basal ad- renal mass HU >30. They have reported a good RPW for two P-ACA masses (59 and 68 %, respectively) [9]. A review by Melo- Leite et al. concluded that it is difficult to discriminate benign from malignant lesions in children in the absence of vascular invasion or metastasis [26]. Our series reports good RPW in 4/5 (80 %) P-ACA, but 2/10 (20 %) P-ACC masses also exhibited good
Survival Functions
Survival Functions
A)
1.0
IPACTR
B) 1.0
IPACTR
1.00
2.00
1.00
0.8
3.00
O.S
2.00
4.00
3.00
4.00
Cum Survival
1.00-censored
Cum Survival
0.6
1.00-censored
0.6
2.00-censored
3.00-censored
2.00-censored
4.00-censored
3.00-censored
0.4
4.00-censored
0.4
0.2
0.2
0.0
0.0
.00
20.00
40.00
60.00
$0.00
100.00
00
20.00
40.00
60.00
$0.00
100.00
Time to event (in months)
Max follow up
Survival Functions
Survival Functions
C) 1.0
ENSAT staging
D) 1.0
ENSAT staging
0.8
1.00
0.8
1.00
Cum Survival
2.00
Cum Survival
2.00
3.00
3.00
0.6
4.00
0.6
4.00
1.00-censored
1.00-censored
2.00-censored
2.00-censored
0.4
3.00-censored
0.4
3.00-censored
4.00-censored
4.00-censored
0.2
0.2
0.0
0.0
00
20.00
40.00
60.00
$0.00
100.00
.00
20.00
40.00
60.00
$0.00
100.00
Max follow up
Time to event (in months)
Survival Functions
Survival Functions
E)
1.0
Age <4=1, >4=2
F)
1.0
Age <4=1, >4=2
O.S
1.00
0.8
1.00
2.00
Cum Survival
2.00
1.00-censored
Cum Survival
1.00-censored
0.6
2.00-censored
0.6
2.00-censored
0.4
0.4
0.2
0.2
0.0
0.0
00
20.00
40.00
60.00
80.00
100.00
.00
20.00
40.00
60.00
$0.00
100.00
Max follow up
Time to event (in months)
Survival Functions
Survival Functions
G) 1.0
Wieneke ≤ 3=1, >3=2
H)
1.0
Wieneke ≤ 3=1, >3=2
O.S
1.00
O.S
1.00
2.00
Cum Survival
Cum Survival
2.00
1.00-censored
1.00-censored
0.6
2.00-censored
0.6
2.00-censored
0.4
0.4
0.2
0.2
0.0
0.0
.00
20.00
40.00
60.00
80.00
100.00
.00
20.00
40.00
60.00
$0.00
100.00
Max follow up
Time to event (in months)
washout. Best discrimination was observed with higher PVE favoring P-ACA, with a cutoff of 157.8 %, which was discrimi- natory with a sensitivity of 87.5 % and specificity of 90 %. Overall, these observations suggest a non-contrast image to see the presence of calcification along with the portal venous phase to look at PVE, and the pattern of contrast enhancement may discriminate P-ACA from P-ACC. The automatic exposure con- trol and voltage reduction can minimize radiation exposure if two phases are used. Such an approach will be in coherence with “Image Gently” and “as low as reasonably achievable” (ALARA) principles and give optimum results. Accurate pre- operative diagnosis of P-ACA vs. P-ACC may guide the preop- erative (using neoadjuvant treatment) and operative (laparoscopic/radical open resection) management.
ACCs are known to produce multiple forms of steroids due to disorganized steroidogenesis. With the availability of the LCMS technique, these various forms of steroids and their metabolites can be measured accurately. Few studies, mainly in adults, have reported more steroid metabolites are elevated in either urine or serum samples of patients with ACC than ACA [8, 27, 28]. Data on serum steroid profile by LCMS/MS in P-ACT is scarce. In our series, P-ACC patients had raised levels of multiple (6-9) metabolites compared to P-ACA. Androstenedione was raised in all (n=7) and 11- deoxycortisol in 6/7 P-ACA patients. Androstenedione can be particularly helpful in diagnosing androgen excess in post- pubertal boys. There have been reports of P-ACT patients who may be misdiagnosed as 21-OH deficiency. Notably, some patients with P-ACC had mild elevations of serum 17- OH progesterone levels, but none had an elevated 21- dexoycortisol, a sensitive biomarker for 21-OH deficiency. Some P-ACT patients had elevated aldosterone, corticoste- rone, and/or 11-deoxycorticosterone levels, but renin levels were not available for most patients. Corresponding plasma renin levels may have helped us to characterize the patho- physiology of hypertension in these cases. Besides being a tumor maker, further studies are required to understand the utility of steroid panels in diagnosis (P-ACC vs. P-ACA), and they may also allow specific treatment with hormonal an- tagonists to alleviate symptoms.
Recently, the pS-GRAS (stage, grade, resection status, age, secretion) score has been validated to prognosticate P-ACTs [10]. Similarly, a recent review by Riedmeier et al. suggested that inflammation-based scores could serve as prognostic tools [19]. In our cohort, these markers showed hazard ratios above 1, indicating a consistent directional trend toward worse survival with higher scores. However, the lack of sta- tistical significance in our analysis is likely attributable to the limited sample size. Despite this limitation, our findings are
consistent with previous studies that have suggested the po- tential prognostic utility of systemic inflammatory markers.
Due to a lack of prospective randomized controlled tri- als, there is no consensus on the optimal chemotherapy regimen in P-ACTs. The Children Oncology Group (COG) evaluated mitotane with CED in the ARAR0332 protocol for unresectable or metastatic disease [29]. Stage III tumors had a good outcome with surgery plus chemotherapy, while stage IV tumors had poor outcomes. Similar regimens used by European groups (TREP, FRACTURE) have shown com- parable outcomes [30,31]. In our cohort, only two patients received mitotane due to limited availability in India.
The study has the inherent limitation of a retrospective case record data collation over the last 24 years. Molecular genetic testing and tumor grading as per the Ki67 criteria were not available. Nevertheless, this study reports the clinical data of this rare pediatric neoplasm, and it has the highest number of patients compared to reports from other Indian centers. CECT characteristics of adrenal mass and serum steroid panel data are distinct features of this series. Further studies on serum steroid panels and CECT adrenal mass characteristics are needed for the preoperative discrimination of the benign vs. malignant nature of P-ACTs.
Conclusions
CECT features, particularly PVE, may aid in differentiating P-ACT from P-ACC. Serum steroid panels may have a role in preoperative assessment, but their utility remains to be validated.
Research ethics: Ethical approval was obtained from the Institutional Ethics Committee (EC/OA-01/2025).
Informed consent: Waiver of consent was granted in view of retrospective nature of the study.
Author contributions: All authors contributed to the study conception and design. Data collection and analysis were per- formed by Siddhant Dahale and Aaditya Daga. The first draft of the manuscript was written by Siddhant Dahale and Aaditya Daga. All authors commented on previous versions of the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest. Research funding: None declared.
Data availability: Not applicable.
References
1. Ilanchezhian M, Varghese DG, Glod JW, Reilly KM, Widemann BC, Pommier Y, et al. Pediatric adrenocortical carcinoma. Front Endocrinol 2022;13:961650.
2. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical Tumors1. J Clin Endocrinol Metab 1997;82:2027-31.
3. O’Neill AF, Ribeiro RC, Pinto EM, Clay MR, Zambetti GP, Orr BA, et al. Pediatric adrenocortical carcinoma: the nuts and bolts of diagnosis and treatment and avenues for future discovery. Cancer Manag Res 2024; 16:1141-53.
4. Gupta N, Rivera M, Novotny P, Rodriguez V, Bancos I, Lteif A. Adrenocortical carcinoma in children: a clinicopathological analysis of 41 patients at the mayo clinic from 1950 to 2017. Horm Res Paediatr 2018;90:8-18.
5. Kerkhofs TMA, Ettaieb MHT, Verhoeven RHA, Kaspers GJL, Tissing WJE, Loeffen J, et al. Adrenocortical carcinoma in children: first population- based clinicopathological study with long-term follow-up. Oncol Rep 2014;32:2836-44.
6. Riedmeier M, Thompson LDR, Molina CAF, Decarolis B, Härtel C, Schlegel P-G, et al. Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC - a mini review. Endocr Relat Cancer 2023;30:e220259.
7. Wieneke JA, Thompson LDR, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003;27:867-81.
8. Taylor DR, Ghataore L, Couchman L, Vincent RP, Whitelaw B, Lewis D, et al. A 13-steroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma. Clin Chem 2017;63:1836-46.
9. Flynt KA, Dillman JR, Davenport MS, Smith EA, Else T, Strouse PJ, et al. Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas? Pediatr Radiol 2015;45:1160-8.
10. Riedmeier M, Agarwal S, Antonini S, Costa TEIJB, Diclehan O, Fassnacht M, et al. Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group. Eur J Endocrinol 2024;191:64-74.
11. Redlich A, Boxberger N, Strugala D, Frühwald M, Leuschner I, Kropf S, et al. Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Pädiatr 2012;224:366-71.
12. Narasimhan KL, Samujh R, Bhansali A, Marwaha RK, Chowdhary SK, Radotra BD, et al. Adrenocortical tumors in childhood. Pediatr Surg Int 2003;19:432-5.
13. Mukhopadhyay B, Ganguly D, Chowdhury S, Maji D, Sarkar AK, Mukhopadhyay M, et al. Paediatric adrenocortical neoplasia - a study of 25 cases. Pediatr Surg Int 1996;11:550-3.
14. Mishra A, Agarwal G, Misra AK, Agarwal A, Mishra SK. Functioning adrenal tumours in children and adolescents: an institutional experience. ANZ J Surg 2001;71:103-7.
15. Kulle AE, Riepe FG, Melchior D, Hiort O, Holterhus PM. A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone, and dihydrotestosterone in pediatric blood samples: age- and sex-specific reference data. J Clin Endocrinol Metab 2010;95:2399-409.
16. Kulle AE, Welzel M, Holterhus P-M, Riepe FG. Implementation of a liquid chromatography tandem mass spectrometry assay for eight adrenal C-21 steroids and pediatric reference data. Horm Res Paediatr 2013;79: 22-31.
17. Fanelli F, Baronio F, Ortolano R, Mezzullo M, Cassio A, Pagotto U, et al. Normative basal values of hormones and proteins of gonadal and adrenal functions from birth to adulthood. Sex Dev Genet Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ 2018;12:50-94.
18. Karlekar MP, Sarathi V, Lila A, Rai K, Arya S, Bhandare VV, et al. Expanding genetic spectrum and discriminatory role of steroid profiling by LC-MS/MS in 11ß-hydroxylase deficiency. Clin Endocrinol 2021;94:533-43.
19. Riedmeier M, Idkowiak J, Frey H, Antonini SRR, Canali GFL, Classen CF, et al. Inflammation-based score in pediatric adrenocortical carcinoma. Endocr Relat Cancer 2025;32:e240244.
20. Figueiredo BC. Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 2005;43:91-6.
21. McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 2013;48:1025-31.
22. Michalkiewicz E, Sandrini R, Figueiredo B, Miranda ECM, Caran E, Oliveira-Filho AG, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the international pediatric adrenocortical tumor Registry. J Clin Oncol 2004;22:838-45.
23. Riedmeier M, Decarolis B, Haubitz I, Müller S, Uttinger K, Börner K, et al. Adrenocortical carcinoma in childhood: a systematic review. Cancers 2021;13:5266.
24. Ciftci AO, Şenocak ME, Tanyel FC, Büyükpamukçu N. Adrenocortical tumors in children. J Pediatr Surg 2001;36:549-54.
25. Picard C, Orbach D, Carton M, Brugieres L, Renaudin K, Aubert S, et al. Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: results from a national cohort study with pathological review. Mod Pathol Off J U S Can Acad Pathol Inc 2019;32:546-59.
26. Melo-Leite AFD, Elias PCL, Teixeira SR, Tucci S, Barros GE, Antonini SR, et al. Adrenocortical neoplasms in adulthood and childhood: distinct presentation. Review of the clinical, pathological and imaging characteristics. J Pediatr Endocrinol Metab JPEM 2017;30:253-76.
27. Vogg N, Müller T, Floren A, Dandekar T, Riester A, Dischinger U, et al. Simplified urinary steroid profiling by LC-MS as diagnostic tool for malignancy in adrenocortical tumors. Clin Chim Acta 2023;543:117301.
28. Yu K, Athimulam S, Saini J, Kaur RJ, Xue Q, Mckenzie TJ, et al. Serum steroid profiling in the diagnosis of adrenocortical carcinoma: a prospective cohort study. J Clin Endocrinol Metab 2024:dgae604. https://doi.org/10.1210/clinem/dgae604.
29. Rodriguez-Galindo C, Pappo AS, Krailo MD, Pashankar F, Monteiro Caran EM, Hicks J, et al. Treatment of childhood adrenocortical carcinoma (ACC) with surgery plus retroperitoneal lymph node dissection (RPLND) and multiagent chemotherapy: results of the Children’s Oncology Group ARAR0332 protocol. J Clin Oncol 2016; 34:10515.
30. Dall’Igna P, Virgone C, Salvo GLD, Bertorelle R, Indolfi P, Paoli AD, et al. Adrenocortical tumors in Italian children: analysis of clinical characteristics and P53 status. Data from the national registries. J Pediatr Surg 2014;49:1367-71.
31. Picard C, Faure-Conter C, Leblond P, Brugières L, Thomas-Teinturier C, Hameury F, et al. Exploring heterogeneity of adrenal cortical tumors in children: the French pediatric rare tumor group (Fracture) experience. Pediatr Blood Cancer 2020;67:e28086.
Supplementary Material: This article contains supplementary material (https://doi.org/10.1515/jpem-2025-0162).