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Prognostic factors of adrenocortical carcinoma in children and adolescents: a population-based study
Zhihua Jiang1 · Bi Zhou2 . Caiyun Zhang3 . Chen Wang4
Received: 6 March 2024 / Accepted: 16 April 2024 / Published online: 23 April 2024 @ The Author(s), under exclusive licence to Springer Nature B.V. 2024
Abstract
Purpose Adrenocortical carcinoma (ACC) is an uncommon adrenal gland endocrine tumor that has a poor prognosis in chil- dren. We aimed to conduct a population-based cohort study to predict overall survival (OS) in pediatric patients with ACC. Methods We used the Surveillance, Epidemiology, and End Results (SEER) database to conduct a retrospective cohort research on pediatric patients diagnosed with ACC between 1975 and 2018. We examined demographic characteristics, tumor stage and size, treatment options, and survival results. Kaplane-Meier estimations were used to generate survival curves based on several parameters. To compare survival curves, the log-rank test was applied.Cox proportional-hazards regression was used to determine the variables related with OS. In addition, we created a nomogram to predict overall sur- vival in pediatric ACC patients.
Results A total of 143 pediatric ACC patients were identified. Females were the most impacted (60.8%). Overall 1 year, 3 year, and 5 year survival rates were 75.0%, 57.6%, and 53.7% for all patients, respectively. In comparison to older patients (5-19 years), younger patients (≤4 years) were shown to have more positive characteristics, including a higher likelihood of local disease (29.4% vs. 14%, P<0.001), tumors less than 10 cm (23.1% vs. 14.7%, P<0.001), and improved overall survival (5 year OS 89.6% vs. 27.7%, P <0.001). Age at diagnosis, SEER stage, and surgery were significant independent predictors of OS in this model, according to the results of Cox proportional hazard regression. After that, we developed a nomogram for predicting OS in children with ACC. Patients older than 4 years old had a higher chance of dying. Furthermore, the higher the SEER stage, the higher the risk of death. Patients who do not have surgery have a worse survival rate than those who do. Conclusions Our study revealed that age at diagnosis, SEER stage, and surgery were found to be the most important predic- tors of the overall survival of pediatric ACC. These findings contribute to the existing body of knowledge and emphasize the importance of continued research to advance our understanding of pediatric ACC and improve patient care.
Keywords Pediatric · Adrenocortical carcinoma · Seer · Age · Survival
Zhihua Jiang and Bi Zhou contributed equally to the work.
☒ Chen Wang hzchwc123@163.com
1 Department of Plastic Surgery, Hangzhou Children’s Hospital, Hangzhou 310005, Zhejiang, China
2 Department of Pediatrics, Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, China
3 Department of Pediatric Intensive Care Unit, Hangzhou Children’s Hospital, Hangzhou, China
4 Department of Pediatric Surgery, Hangzhou Children’s Hospital, Hangzhou 310005, Zhejiang, China
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive form of cancer that develops in the adrenal cortex, which is the outer layer of the adrenal glands [1]. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old, accounting for less than 0.2% of all pediatric malignancies [2, 3]. Pediat- ric ACC is frequently associated with cancer predisposition syndromes, with the majority of pediatric ACC connected with germline mutations [4]. Southern Brazil has a 15-20 fold greater incidence of pediatric ACC due to a higher prevalence of the TP53 mutation linked to Li-Fraumeni syn- drome [5]. Pediatric ACC differs from adult ACC in that it frequently manifests symptoms associated with hormone
overproduction, such as high blood pressure, rapid weight gain, early puberty in children, abundant body hair, and changes in genitalia [6, 7].
The clinical features, treatment status, and prognosis of pediatric ACC are poorly understood due to the low inci- dence, limited sample size, and short follow-up period of prior research on pediatric ACC [8, 9]. Here, we investigated the long-term follow-up survival outcomes and prognostic risk analyses of pediatric ACC using the Surveillance, Epi- demiology, and End Results (SEER) database.
Methods
Study population
The Surveillance, Epidemiology and End Results (SEER) database was utilized to identify all pediatric adrenocortical carcinoma diagnosed between 1975 and 2018. Patients with a ACC diagnosis before their 20th year of age (0-19 years) were selected. For ACC, we used the ICD-O-3 Third Edi- tion morphological code (8370/3: Adrenal cortical cancer).
The database was used to extract case data, including demographics, details on the treatment, tumor size, extent of disease, and information about the duration of the follow-up. SEER summary staging was applied to determine the extent of disease, which was classified as localized (limited to the adrenal gland), regional (invasion of surrounding structures or lymph node involvement), or distant (metastatic). The age groups at diagnosis were divided into two categories: 0-4 years old and 5-19 years old. The primary outcome measure was overall survival (OS). The survival period was calculated from the date of diagnosis to the most recent follow-up date, or until death.
Statistical analysis
All statistical analyses were performed using SPSS soft- ware (version 22.0, SPSS Inc., Chicago, IL, USA). Overall survival was calculated using Kaplan-Meier estimates. To compare survival curves across subgroups, log-rank tests were utilized. Different age groups’ distributions of various clinical and demographic characteristics were compared. A Cox proportional hazards model was used in a multivariate analysis, using OS as the outcome of interest. The multivari- ate model incorporated prognostic factors identified in the univariate study, such as age, gender, disease extent, tumor size, and surgical treatment status. Then we developed a nomogram that predicted survival odds. A P <0.05 was used to denote statistical significance.
Ethical statement
We acquired the Data-Use Agreement for the SEER 1975-2018 Research Database File, as well as the SEER Radiation Therapy and Chemotherapy Information. Because the study’s data were taken from the publicly accessible SEER database, the Ethics Committee and Institutional Review Board at Hangzhou Children’s Hos- pital decided that it was exempt.
Results
Patient characteristics
From 1975 to 2018, 143 qualifying cases of ACC in chil- dren or adolescents were reported to SEER registries. Almost half of the patients were diagnosed when they were ≤4 years of age (42.2%). The majority of patients (86%) were white, and the tumors mostly afflicted females (60.8%). The majority of the patients (82.5%) had their primary tumor surgically removed, and 43.3% of them had distant stage. Furthermore, half of the patients (51.1%) underwent chemotherapy, whereas only 9.1% received radiation therapy.
As shown in Table 1, clinical features varied consid- erably depending on the age of diagnosis, SEER stage, tumor size, and surgery, although gender, race, and lat- erality distribution did not differ significantly among age groups. Patients who reported with a distant stage were present in 34.3% of older children, compared to just 9.1% of children under the age of 4 (P <0.001). Additionally, older patients also had considerably larger tumors and no surgery (P <0.001).
Survival and prognosis analysis
All patients had overall 1 year, 3 year, and 5 year survival rates of 75.0, 57.6, and 53.7%, respectively (Table 2). Overall survival did not differ significantly based on gen- der, race, or laterality (P=0.800, P=0.241, and P=0.594, respectively) (Table 3). Survival rates varied greatly across age categories, with the greatest reduction occurring after the age of four years. Overall, 5 year survival was 89.6% for patients aged 0-4, while 27.7% for patients aged 5-19 (Fig. 1A). Patients with localized disease had much better survival than those with distant metastases (5 year OS, 83.2% versus 22.8%, P<0.001) (Fig. 1B). Patients who had smaller primary tumors also had greater survival rates (5 year OS, 69.9% versus 42.2%, P <0.001) (Fig. 1C).
| Characteristics | ≤4-year-old | >4-year-old | P value |
|---|---|---|---|
| n | 60 | 83 | |
| Race, n (%) | 0.203 | ||
| White | 49 (34.3%) | 74 (51.7%) | |
| Others | 11 (7.7%) | 9 (6.3%) | |
| Gender, n (%) | 0.602 | ||
| Male | 25 (17.5%) | 31 (21.7%) | |
| Female | 35 (24.5%) | 52 (36.4%) | |
| Laterality, n (%) | 0.642 | ||
| Right | 28 (19.6%) | 42 (29.4%) | |
| Left | 32 (22.4%) | 41 (28.7%) | |
| SEER stage, n (%) | <0.001 | ||
| Distant | 13 (9.1%) | 49 (34.3%) | |
| Regional | 5 (3.5%) | 14 (9.8%) | |
| Localized | 42 (29.4%) | 20 (14%) | |
| Surgery, n (%) | <0.001 | ||
| No | 3 (2.1%) | 22 (15.4%) | |
| Yes | 57 (39.9%) | 61 (42.7%) | |
| Radiotherapy, n (%) | 0.001 | ||
| No | 60 (42%) | 70 (49%) | |
| Yes | 0 (0%) | 13 (9.1%) | |
| Chemotherapy, n (%) | <0.001 | ||
| Yes | 19 (13.3%) | 54 (37.8%) | |
| No | 41 (28.7%) | 29 (20.3%) | |
| Tumor size (cm), n (%) | <0.001 | ||
| ≤ 10 | 33 (23.1%) | 21 (14.7%) | |
| >10 | 11 (7.7%) | 34 (23.8%) | |
| Unknown | 16 (11.2%) | 28 (19.6%) | |
| Vital status, n (%) | <0.001 | ||
| Dead | 10 (7%) | 59 (41.3%) | |
| Alive | 50 (35%) | 24 (16.8%) |
| Feature | 1 Year os (%) | 3 Year os (%) | 5 Year os (%) |
|---|---|---|---|
| Overall | 75.0 (3.7) | 57.6 (4.2) | 53.7 (4.3) |
| Gender | |||
| Male | 70.8 (6.2) | 57.4 (6.8) | 53.4 (6.9) |
| Female | 77.7 (4.5) | 57.7 (5.5) | 53.8 (5.5) |
| Race | |||
| White | 74.2 (4.0) | 55.7 (4.6) | 52.1 (4.7) |
| Others | 79.7 (9.1) | 69.1 (10) | 63.8 (11) |
| Age at diagnosis | |||
| ≤ 4 year-old | 91.4 (3.7) | 89.6 (4.0) | 89.6 (4.0) |
| > 4 year-old | 63.0 (5.4) | 34.2 (5.4) | 27.7 (5.1) |
| Laterality | |||
| L Left | 77.2 (5.0) | 57.2 (6.1) | 50.7 (6.2) |
| Right | 72.6 (5.4) | 57.8 (6.0) | 56.3 (6.0) |
| Tumor size (cm) | |||
| ≤10 | 83.3 (5.1) | 73.8 (6.0) | 69.9 (6.3) |
| >10 | 73.3 (6.6) | 48.9 (7.5) | 42.2 (7.4) |
| Unknown | 66.0 (7.4) | 45.4 (8.3) | 45.4 (8.3) |
| SEER stage | |||
| L Localized | 95.0 (2.8) | 83.2 (4.8) | 83.2 (4.8) |
| Regional | 77.8 (9.8) | 65.8 (11) | 53.8 (12) |
| Distant | 53.8 (6.4) | 28.5 (6.0) | 22.8 (5.6) |
| Surgery | |||
| Yes | 84.2 (3.4) | 66.6 (4.5) | 61.9 (4.6) |
| No | 32.0 (9.3) | 16.0 (7.3) | 16.0 (7.3) |
| Radiotherapy | |||
| Yes | 69.2 (12) | 46.2 (13) | 38.5 (13) |
| No | 75.6 (3.8) | 58.8 (4.4) | 55.4 (4.5) |
| Chemotherapy | |||
| Yes | 66.1 (5.7) | 38.4 (6.0) | 33.8 (5.8) |
| No | 84.1 (4.4) | 76.6 (5.1) | 73.5 (5.4) |
When it came to treatment, children who did not receive chemotherapy had a better probability of survival (5 year OS, 69.9% versus 42.2%, P <0.001) (Fig. 1D). Surgery resulted in superior survival results as compared to no sur- gery (5 year OS, 69.9% versus 42.2%, P<0.001) (Fig. 1E).
A multivariate analysis was performed using a Cox pro- portional hazards model (Table 3). Age at diagnosis, tumor size, extent of disease, and treatment status were all incor- porated in the model. The most significant independent pre- dictors of OS in this model were age younger than 4 years (hazard ratio (HR) 0.19, P <0.001), localized disease (HR 0.35, P=0.002), and surgery (HR 0.36, P <0.001). In order to forecast OS in pediatric ACC patients, a nomogram was created. The model takes into account age, gender, tumor size, SEER stage, surgery, radiotherapy, and chemotherapy. As seen in Fig. 2, the likelihood of death rose in patients beyond the age of four. Furthermore, the higher the SEER
stage, the higher the risk of death. Patients who do not have surgery have a worse survival rate than those who do.
Discussion
With its incidence rates bordering on the realm of medi- cal curiosity, pediatric ACC remains a rare occurrence, affecting children and adolescents predominantly under the age of 15. The tumor’s proclivity for rapid development and the possibility of metastasis highlight the importance of early discovery and care [10]. Nearly half of pediatric ACC diagnoses occur in children under the age of four [1]. The pediatric ACC shows a bimodal age distribution, with peaks under the age of 5 and beyond the age of 10 [11]. Our results are in line with prior studies, which found that 42% of pediatric patients are children under the age of four. Additionally, there is a 1.5:1 female to male ratio
| Characteristics | Total(N) | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|
| Hazard ratio (95% CI) | P value | Hazard ratio (95% CI) | P value | ||
| Age at diagnosis | 143 | ||||
| >4 year-old | 83 | Reference | Reference | ||
| ≤ 4 year-old | 60 | 0.136 (0.069-0.268) | <0.001 | 0.190 (0.092-0.391) | <0.001 |
| Race | 143 | ||||
| Others | 20 | Reference | |||
| White | 123 | 1.598 (0.731-3.494) | 0.241 | ||
| Gender | 143 | ||||
| Male | 56 | Reference | |||
| Female | 87 | 0.939 (0.579-1.525) | 0.800 | ||
| Tumor size (cm) | 143 | ||||
| >10 | 45 | Reference | Reference | ||
| Unknown | 44 | 1.102 (0.630-1.926) | 0.734 | 1.541 (0.840-2.828) | 0.162 |
| ≤10 | 54 | 0.498 (0.276-0.898) | 0.020 | 0.990 (0.540-1.814) | 0.973 |
| Laterality | 143 | ||||
| Left | 73 | Reference | |||
| Right | 70 | 0.879 (0.547-1.412) | 0.594 | ||
| SEER stage | 143 | ||||
| Distant | 62 | Reference | Reference | ||
| Regional | 19 | 0.336 (0.158-0.717) | 0.005 | 0.421 (0.190-0.931) | 0.033 |
| Localized | 62 | 0.149 (0.081-0.274) | <0.001 | 0.352 (0.181-0.683) | 0.002 |
| Surgery | 143 | ||||
| No | 25 | Reference | Reference | ||
| Yes | 118 | 0.207 (0.123-0.349) | <0.001 | 0.362 (0.206-0.636) | <0.001 |
| Radiotherapy | 143 | ||||
| No | 130 | Reference | |||
| Yes | 13 | 1.603 (0.793-3.238) | 0.189 | ||
| Chemotherapy | 143 | ||||
| No | 70 | Reference | Reference | ||
| Yes | 73 | 2.963 (1.774-4.951) | <0.001 | 1.478 (0.838-2.607) | 0.177 |
among pediatric ACC diagnoses, indicating that women are more likely than men to have this condition.
Our study found no difference in survival rates between the genders, despite the fact that females are more likely than boys to have ACC. In our study, distant tumors were present in 43.3% of all patients; however, this was only 9.1% in those aged 4 years and younger compared to 34.3% in those over the age of 4. Our study also found that older children were less likely to undergo surgical resection and more likely to have bigger tumors. Our findings imply that the patient’s age at diagnosis is a critical prognostic factor. Furthermore, Wang et al. [12] discovered that tumor stage had a significant impact on cancer outcomes. Localized tumors had a 5 year survival rate of 97.7%, while dis- tant tumors had a 5 year survival rate of 52.7%, according to our findings. Although a greater tumor size (> 10 cm) was associated with a worse outcome, as demonstrated in the survival study, multivariate Cox regression analysis
revealed that it was not an independent predictor, which is consistent with a previously published report [13].
The treatment for pediatric ACC is largely extrapolated from adult ACC [14]. A complete surgical excision is a significant component of pediatric adrenocortical carci- noma treatment [15]. The majority of patients in this study had undergone surgery. Surgical excision was not only an independent prognostic predictor, but it also had the great- est impact on the outcomes. In contrast to surgery, radia- tion and chemotherapy are only used as adjuvant or pallia- tive treatments. It’s perplexing that the survival analysis revealed that chemotherapy did not improve patients but actually raised their risk of death, as also shown in another study [16]. One possible explanation for this is a lack of data on chemotherapy patients. For instance, patients in the unknown group may received chemotherapy and sur- vived for a long time. Although the specific mechanism of mitotane’s antitumor effect is unknown, it is the most
A
B
150
- ≤ 4-year-old
150-
- Localized
Overall survival
- >4-year-old
Overall survival
~ Regional
100-
100-
- Distant
50-
50-
0
0
100
200
300
400
500
0
0
100
200
300
400
500
Months
Months
C
D
150-
≤ 10 cm
150-
- No chemotherapy
Overall survival
- >10 cm
Overall survival
- Chemotherapy
100-
Unknown
100-
50-
50-
0
0
0
100
200
300
400
500
0
100
200
300
400
500
Months
Months
E
150
No surgery
Overall survival
Surgery
100-
50-
0
0
100
200
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500
Months
widely investigated and used chemotherapeutic treatment for ACC [17]. The use of radiation therapy in pediatric ACC patients has not been widely studied. Because most pediatric ACC cases have TP53 mutations, which predis- pose them to malignancy, radiation can raise the risk of developing a secondary tumor [18].
This was a retrospective research with some limitations. To begin, the research data is derived from the SEER data- base, which does not include genomic data or treatment protocols. This is significant since it is well recognized that germline TP53 mutations are related to pediatric adrenal cortical carcinoma [14]. Second, there can be some selec- tion bias while the study’s cases are being screened because of missing values. Finally, the tiny sample sizes required by
Localized and regional, P<0.001. C≤10 vs.>10 and Unknown, P=0.02. D Chemotherapy vs. No chemotherapy, P<0.001. E Sur- gery vs. No surgery, P<0.001
such an uncommon disease make detecting more nuanced relationships problematic. To address some of these short- comings, larger and more prospective trials will be required.
In conclusion, we assessed the clinical features and prog- nosis of pediatric ACC using a population-based dataset. Age at diagnosis, SEER stage, and surgery were found to be the most important predictors of the OS. Current treatment algorithms for pediatric ACC patients are based on research in adult populations. Due to the differences in ACC between pediatric and adult populations, we believe additional research in the treatment of childhood ACC is warranted.
Points
0
20
40
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80 100
>4-year-old
Age at diagnosis
Gender
Timor size
SEER stage
Surgery
Radiotherapy
Chemotherapy
Total Points
Linear Predictor
1-year Survival Probability
3-year Survival Probability
5-year Survival Probability
≤4-year-old
Female
Male
≤10
>10
Regional
Unknown
Localized
Distant
No
Yes
No
Yes
Yes
No
0
100
200
300
-2.5
-1.5
-0.5
0.5
1.5
2.5
0.8
0.6
0.4
0.2
0.8
0.6
0.4
0.2
0.8
0.6
0.4
0.2
Acknowledgements We thank the National Cancer Institute for provid- ing the SEER data set.
Author contributions Zhihua Jiang. MD. Conception and design of study, acquisition of data, Drafting and revising the manuscript. Bi Zhou. MD. Conception and design of study, acquisition of data, Draft- ing the manuscript. Caiyun Zhang. MD. Conception and design of study, acquisition of data, Drafting the manuscript. Chen Wang. MD. Conception and design of study, acquisition of data, analysis and/or interpretation of data, Drafting the manuscript. All authors read and approved the final manuscript as submitted.
Funding None.
Data availability The dataset used and analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest The authors declare that they have no competing interests.
Ethical approval None.
Consent to participate None.
Consent for publication None.
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