Received: 1 October 2020 Revised: 27 October 2020 Accepted: 14 November 2020

DOI: 10.1002/pbc.28836 Pediatric

Blood &
Cancer The American Society of
Pediatric Hematology/Oncology
O N C O LO G Y: R E S E A R C H A RT I C L E

Clinical prognostic factors in pediatric adrenocortical tumors:

A meta-analysis

Elisa Zambaiti1 Miriam Duci1 Federica De Corti1 Piergiorgio Gamba1

Patrizia Dall’Igna2 Filippo Ghidini1 Calogero Virgone1

1
Department of Women’s and Children’s
Health, University Hospital of Padua, Padua,
Italy
2
Department of Emergencies and Organ
Transplantation, Azienda
Ospedaliero-Universitaria Consorziale
Ospedale Pediatrico Giovanni XXIII, Bari, Italy
Correspondence
Calogero Virgone, Department of Women’s
and Children’s Health, University Hospital of
Padua, Via Giustiniani 3, 35128 Padua, Italy.
Email: calogero.virgone@unipd.it
Abstract
Pediatric adrenocortical tumors (ACT) are rare and sometimes aggressive malignan-
cies, but there is no consensus on the outcome predictors in children. A systematic
search of MEDLINE, SCOPUS, Web of Science, and the Cochrane Library for studies
from 1994 to 2020 about pediatric ACT was performed. In 42 studies, 1006 patients,
aged 0-18 years, were included. The meta-analyses resulted in the following predictors
of better outcome: age <4 years (P < .00001), nonsecreting tumors (P = .004), complete
surgical resection (P < .00001), tumor volume (P < .0001), tumor weight (P < .00001),
tumor maximum diameter (P = .0009), and Stage I disease (P < .00001). Moreover,
patients affected by Cushing syndrome showed a worse outcome (P < .0001). Inter-
national prospective studies should be implemented to standardize clinical prognostic
factors evaluation, together with pathological scores, in the stratification of pediatric
ACT.

KEYWORDS
adrenocortical carcinoma, adrenocortical tumors, children, meta-analysis, prognosis study, prog-
nostic factors, systematic review

1 INTRODUCTION
Pediatric adrenocortical tumors (ACTs) are rare and sometimes aggres-
sive endocrine malignancies, frequently associated with Li-Fraumeni
syndrome, a familial cancer predisposition disorder caused by germline
mutations in the tumor suppressor gene TP53, and account for approx-
imately 0.38% of all childhood cancer cases.1 ACT develop from the
adrenal cortex, with an estimated incidence of one per million each
year, and comprise benign adrenocortical adenomas (ACA) and highly
malignant adrenocortical carcinomas (ACC), whose pathogenesis is
incompletely understood. Patients with ACC generally have a poor
clinical outcome, because there is no effective therapy for advanced
and metastatic forms, accounting for a 5-year overall survival of less
than 40%.2 On the other hand, ACA is associated with excellent prog-
nosis, but only about 20% of pediatric ACTs are classified as ACA.
Abbreviations: ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma; ACT,
adrenocortical tumor; CI, confidence interval; RR, risk ratio
As a matter of fact, children with ACC seem to have a better out-
come when compared with adults, and some authors attributed this
finding to an overestimation of malignancy based on the use of adult
scores, which may be not fully applicable to the pediatric population.3,4
The Wieneke index has been reported to have a prognostic value
more reliable in comparison with adult scores,5,6 and lately the five-
item score7 was described to be useful when stratifying patients
with ACT.
In this scenario, it is still difficult to establish which patients may
benefit from a more aggressive medical approach after surgery, and the
use of pediatric pathology scores could be a valid option if considered
together with clinical risk factors, as it happens in the management of
other pediatric tumors as neuroblastoma or rhabdomyosarcoma.
In the past, various clinical features were variably reported to asso-
ciate with a poor outcome: age >4 years, volume, weight, size, Cushing
syndrome, R1 resections, initial biopsy, and stage are the clinical fea-
tures more commonly taken into account to define risk stratification.8,9

Pediatr Blood Cancer. 2021;68:e28836. wileyonlinelibrary.com/journal/pbc © 2020 Wiley Periodicals LLC 1 of 9

https://doi.org/10.1002/pbc.28836
2 of 9
Unfortunately, there is no consensus on which clinical features may be
determinant to predict the outcome in pediatric ACT, as most of the
features described above did correlate with prognosis in a univariate
analysis but were not confirmed at the multivariate analysis.8
2 METHODS
2.1 Protocol, eligibility criteria, information
sources, and search
This review was performed according to an a priori designed protocol
and recommended for systematic reviews and meta-analysis.10–12
MEDLINE, SCOPUS, Web of Science, and the Cochrane Library,
including the Cochrane Database of Systematic Reviews (CDSR),
Database of Abstracts of Reviews of Effects (DARE), and the Cochrane
Central Register of Controlled Trials (CENTRAL), were searched elec-
tronically in April 2020 utilizing combinations of relevant medical
subject heading (MeSH) terms, keywords, and word variants for
“adrenocortical tumors,” “adrenocortical adenoma,” “adrenocortical
carcinoma,” “prognostic factors,” and “children” (Supporting Informa-
tion S1). The search and selection criteria were restricted to English
language. Reference lists of relevant articles and reviews were manu-
ally searched for additional reports. The Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines13 were
followed.
The study was registered with the PROSPERO database (registra-
tion number CRD42020180970).
2.2 Study selection, data collection, and data
items
Studies were assessed according to the following criteria: population,
outcome, clinical features, and tumor features. Inclusion criteria
were: studies reporting pediatric cases of ACTs with available data
on treatment, histology, and follow up; publication span including
the last 25 years (1994-2020). Four authors, divided in two groups
(Filippo Ghidini, Calogero Virgone and Elisa Zambaiti, Miriam Duci)
reviewed all abstracts independently. Agreement about potential
relevance was reached by consensus, and full-text copies of those
articles were obtained. The same reviewers independently extracted
relevant data regarding study characteristics and ACT features
and outcomes. Case reports or case series without outcome data
and/or clinical data were excluded. Inconsistencies were discussed
by the reviewers and consensus reached. If more than one study was
published for the same cohort with identical end points, the report
containing the most comprehensive information on the population was
included to avoid overlapping populations. For those articles in which
information was not reported but the methodology was such that
this information would have been recorded initially, the authors were
contacted. Quality assessment of the included studies was performed
using the Newcastle-Ottawa Scale for cohort studies (Supporting
Information S2).14
ZAMBAITI ET AL .
2.3 Summary measures, synthesis of the results,
and risk of bias
The clinical prognostic factors analyzed in this review were age, sex,
tumor secreting status, tumor volume, tumor weight, tumor maxi-
mum diameter, surgical results, and stage. Age greater than or less
than 4 years was considered according to previous reports, which
showed that children under 4 years of age usually show a favorable
outcome. Indeed, distant metastases are observed at a higher rate in
adolescents.7,8
Secretion pattern has been sporadically reported to associate with
outcome: Cushing syndrome and nonsecreting tumors were reported
to have worse prognosis.2
Cut-off values for tumor volume (200 cm3 ), for tumor weight (100 or
400 g), and for tumor maximum diameter (<5 cm, between 5 and 10 cm,
>10 cm) were established in previous literature data.1,8,9 Although size
in the ACT literature has been described with different units of mea-
surement, the evidence that larger tumors may present a dismal out-
come at higher rates is widely recognized.
Surgical results were defined as complete resection or incom-
plete resection (microscopic or macroscopic residuals) in patients who
underwent surgery on the primary tumor. A complete resection at
diagnosis is considered to be a major prognostic factor, since ACTs
are localized in greater part. Stage was assessed on the basis of COG
staging system for ACT proposed by Sandrini et al15 and later mod-
ified by Michalkiewicz et al2 and Ribeiro et al,1 as it represents the
most currently used worldwide: studies in which stage assessment
was performed with different systems were not included into this
analysis.
The outcome analyzed in this systematic review was the reported
patient’s status (alive or dead).
2.4 Statistical analysis
Overall, we evaluated separately the association between eight clinical
prognostic factors and the outcome for a total of 17 separated meta-
analyses.
Data were analyzed by using Review Manager (RevMan, Version
5.3, Cochrane Collaboration). For categorical variables risk ratio (RR)
with 95% confidence intervals (CIs) were generated. We performed
descriptive statistics, and calculated the pooled RR and 95% CI for
each prognostic factor that was studied in more than one different
study. The RRs were pooled using the fixed-effects model. The hetero-
geneity was assessed by the chi-square test and quantified using the I2
statistic. The I2 statistic represents the percentage of between-study
variation that is due to heterogeneity rather than chance: a value of
0% indicates no observed heterogeneity, whereas I2 values of ≥50%
indicate a substantial level of heterogeneity. A fixed-effects model
was used if substantial statistical heterogeneity was not present.
Publication bias was examined by funnel plot analysis. A P-value of less
than .05 was considered statistically significant.
ZAMBAITI ET AL . 3 of 9

3.2 Sex

Thirty-six papers2,5,16–18,20–47,49,50 allowed the evaluation of gender

effect on outcome: females were found to have RR of 1.21, without
reaching a significance (P = .14; 95% CI 0.94-1.55; I2 0%).

3.3 Tumor secreting status

Three different meta-analyses were performed in order to deter-

mine the effect of secretion pattern on outcome. Firstly, the
patients affected by Cushing syndrome versus those without
Cushing syndrome were compared (Figure 3A). Twenty-seven
studies2,5,16–19,23,24,26,29–34,36–41,43,45,46,48,51 assessed the outcomes
between these two groups, and being affected by Cushing syndrome
resulted in a worse outcome (P < .0001; RR 1.88; 95% CI 1.38-2.58;
I2 6%). Secondly, 19 studies5,18,20,26,30–33,36–38,40,41,43,45,46,49,51 com-
pared the secreting tumors and nonsecreting masses, identifying
hormonal secretion as a negative prognostic factor (P = .004; RR
1.63; 95% CI 1.17-2.27; I2 0%). Finally, the comparison between
patients affected by Cushing syndrome and nonsecreting tumors was
performed in 17 studies5,18,20,26,30–33,37,38,40,41,43,45,46,49,51 and no
difference in outcome was found (P = .40; RR 1.19; 95% CI 0.79-1.79;
I2 0%) (Figure 3B).

3.4 Tumor volume

F I G U R E 1 Flowchart summarizing inclusion of studies in the
systematic review
Five papers reported tumor volume.5,18,20,30,31 The meta-analysis
(Supporting Information S3) showed a worse outcome for the tumors
3 RESULTS
more than 200 cm3 of volume (P < .0001; RR 3.37; 95% CI 1.93-5.88; I2
60%).
A total of 2233 articles were identified and 275 were assessed
with respect to their eligibility for inclusion. Forty-two studies were
included in the systematic review (Figure 1), accounting for a total of
3.5 Tumor weight
1006 pediatric patients with diagnosis of an ACT. The general charac-
teristics of the studies included in the systematic review are reported
Tumor weight was reported in 15 studies. Two meta-analyses were
in Table 1.
performed for the two different cutoffs. Either tumors weighing more
Quality assessment of the included studies was performed using
than 400 g17–21,27,31,33,35,37–40,42,52 or tumors weighing more than
Newcastle-Ottawa Scale for cohort studies. Almost all the included
100 g17,18,20,21,31,33–35,37–40,42,45,52 were considered as risk factor for
studies showed an overall good rate with regard to the selection and
a worse outcome (respectively, P < .00001; RR 4.29; 95% CI 3.19-5.78;
comparability of the study groups and to the ascertainment outcome
I2 0% and P < .00001; RR 5.46; 95% CI 3.24-9.20; I2 0%) (Figure 4A,B).
of interest (Supporting Information S2). The major weaknesses of these
studies were represented by their retrospective design, a lack of homo-
geneity of the clinical features evaluated, and the different thresholds
3.6 Tumor maximum diameter
adopted to define clinical features (as age, tumor volume, weight, max-
imum diameter, and stage).
Three different meta-analyses were performed, considering tumor
maximum diameter as a risk factor. The different groups were com-
3.1 Age pared as follows. First, tumors <5 cm versus tumors >5 and <10 cm
were included in 11 studies,5,25,29,32–35,37,42,45,52 showing a worse
Thirty-three papers entered this meta-analysis.2,5,16–45 An age of more outcome for the tumors >5 and <10 cm (P = .008; RR 2.85; 95%
than 4 years was found to have RR of 3.07 (P < .00001; 95% CI 2.35- CI 1.31-6.17; I2 0%). Second, tumors <5 cm versus tumors >5 cm
4.02; I2 0%) (Figure 2). were included in 15 studies,5,19,22,23,25,28,29,32–35,37,42,45,52 resulting
4 of 9 ZAMBAITI ET AL .

TA B L E 1 General characteristics of the included studies

Mean age at Mean

Sample diagnosis Number of follow-up
Author, year (location) Study design size Period M;F (years) deaths years (range)
Federici, 1994 (Italy) Cohort 12 1976-1989 5;7 5.0 2 6.4 (1.5-14)
Damiani, 1995 (Brazil) Cohort 33 1975-1993 11;22 3.7 17 6.7 (0-20)
Bergadà, 1996 (Argentina) Cohort 20 1970-1991 5;15 7.1 2 10 (0-23)
Mendonca, 1996 (Brazil) Cohort 18 1980-1992 5;13 3.1 2 5.1 (0.5-9.5)
Michalkiewicz, 1997 (USA, Brazil, Cohort 20 1988-1994 18;1 2.0 1 2.5 (0.1-6.2)
Canada, Uruguay, Norway, Chile)
Mayer, 1997 (Canada) Cohort 11 1972-1996 3;8 7.0 1 5.6 (0.8-15)
Driver, 1998 (UK) Cohort 18 1954-1995 3;15 5.6 12 4.3 (0.1-26)
Teinturier, 1999 (France) Cohort 54 1973-1993 27;27 4.0 28 3.2 (0.1-20)
Wolthers, 1999 (UK) Cohort 30 1976-1996 7;23 4.9 4 3.8 (0.4-75)
Wilkin, 2000 (Canada) Cohort 10 - 2;8 5.7 1 7.5 (0.5-18)
Mishra, 2001 (India) Cohort 10 1990-1999 4;6 7.4 5 2.2 (0-7.6)
Misu, 2001 (Japan) Cohort 4 - 3;1 2.5 1 5.9 (3.0-12)
Ciftici, 2001 (Turkey) Cohort 30 1970-1999 11;19 6.7 11 2.5
Latronico, 2001 (Brazil) Cohort 18 - 5;13 2.2 1 5.3 (0.2-13)
McDonnell, 2003 (Australia) Cohort 12 1976-2001 6;6 2.5 3 10 (1.0-25.8)
Narasismhan, 2003 (India) Cohort 8 1989-2000 2;6 2.5 2 2.3 (0.5-5.0)
Sandrini, 2005 (Brazil) Cohort 21 - 7;14 3.7 4 8.6 (0.3-19)
Figuereido, 2005 (Brazil) Cohort 9 - 3;6 2.6 2 -
Barbosa, 2004 (Brazil) Cohort 7 - 4;3 5.1 1 5.8 (1.2-8.2)
Pinto, 2005 (Brazil) Cohort 16 - 6;10 4.4 1 4.4 (1.0-10)
Rosati, 2008 (Brazil) Cohort 12 - 3;9 3.6 5 6.6 (2.4-15.8)
Loncarevic, 2008 (Germany) Cohort 14 1998-2007 6;8 3.8 6 4.4 (4.3-9.8)
Lorea, 2012 (Brazil) Cohort 60 1991-2009 15;45 3.4 10 5.7 (0.7-14)
Waldmann, 2012 (Germany) Cohort 2 - 1;1 16 1 4.2 (1.9-6.5)
Fragoso, 2012 (Brazil) Cohort 24 1990-2010 7;17 3.8 5 6.7 (0.6-14)
Custodio, 2013 (Brazil) Cohort 19 2005-2010 4;15 1.5 4 3.8 (2.0-5.8)
Borges, 2013 (Brazil) Cohort 57 1991-2009 14;43 3.4 10 5.2 (0-14)
Wendt, 2014 (USA) Cohort 5 1975-2011 3;2 3.1 3 7.6 (0.5-32)
Nazli Gonç, 2014 (Turkey) Cohort 18 1999-2013 8;10 5.7 6 6.0 (1.0-11)
Kerkhofs, 2014 (The Netherlands) Cohort 12 1989-2013 3;9 4.1 5 6.4 (0.1-14.8)
Dall’Igna, 2014 (Italy) Cohort 58 1982-2011 19;39 5.1 12 5.9 (0.2-9.9)
Sakoda, 2014 (UK) Cohort 29 1987-2011 14;15 2.2 10 2.1 (0.1-15)
Chatterjee, 2015 (India) Cohort 13 2005-2014 4;9 2.9 3 2.2
Das, 2016 (India) Cohort 14 2005-2015 5;9 2.1 3 4.1 (0.5-5)
Bulzico, 2016 (Brazil) Cohort 27 1997-2015 8;19 5.1 10 2.3 (0.1-12.8)
Pinto, 2017 (USA) Cohort 59 2006-2013 17;42 3.3 14 4.0 (0-23)
Picard, 2018 (France) Cohort 95 2000-2018 28;67 5.0 16 5.3 (0.2-17)
Jehangir, 2019 (India, Australia) Cohort 22 2006-2016 12;10 6.3 2 6.0 (2.1-6.7)
Monteiro, 2019 (Brazil) Cohort 12 2004-2015 2;10 2.0 1 4.5 (0.4-11)
Parise, 2019 (Brazil) Cohort 48 - 18;30 2.8 15 7.0 (0.2-21)
Zekri, 2020 (Egypt) Cohort 18 2007-2016 6;12 4.0 8 3.2
Pinto, 2020 (USA) Cohort 11 - 3;8 4.5 3 -
ZAMBAITI ET AL . 5 of 9

F I G U R E 2 Forest plot showing risk ratio (RR) according to age (<4 years vs >4 years) for each study and pooled for all studies. Only first
author of each study is given

F I G U R E 3 Forest plots showing risk ratio (RR) (A) according to Cushing’s syndrome (Cushing vs non-Cushing); and (B) secretion status
(secreting vs nonsecreting tumors), for each study and pooled for all studies. Only first author of each study is given
6 of 9
F I G U R E 4 Forest plots showing risk ratio (RR) according to tumor weight for each study and pooled for all studies in (A) <100 g versus >100 g,
and (B) <400 g versus >400 g. Only first author of each study is given
F I G U R E 5 Forest plots showing risk ratio (RR) according to tumor size diameter for each study and pooled for all studies: (A) maximum size
<5 cm versus >5 cm, and in (B) maximum size <10 cm versus >10 cm. Only first author of each study is given
in a worse outcome for those >5 cm (P = .0009; RR 2.98; 95% CI
1.56-5.67; I2 0%) (Figure 5A). Finally, the last meta-analysis among 15
studies5,19,22,23,25,28,29,32–35,37,42,45,52 showed that tumors larger than
10 cm had worse outcome (P < .00001; RR 3.87; 95% CI 2.51-5.96; I2
0%) (Figure 5B).
3.7 Surgery results
A meta-analysis (Supporting Information S3) including 13
studies5,20,23,36,27,32,33,37,38,42,51,53,54 compared the outcome between
patients undergone complete resection and those undergone incom-
plete resection. The first ones showed a better outcome (P < .00001;
RR 3.50; 95% CI 2.51-4.88; I2 16%).
3.8 Stage
Five different meta-analyses assessed the impact on the outcome of
the different stage of disease at diagnosis (Supporting Information S4).
The stages were compared as follows. Stage I versus Stage II, III, and
IV included eight studies.7,18,20,31,36,38,40,46 The meta-analysis showed
a better outcome for Stage I (P < .00001; RR 6.94; 95% CI 3.35-
14.4; I2 12%). Then, Stage I versus Stage II and III included seven
studies.7,18,20,31,38,40,46 This resulted in a better outcome for patients
with Stage I disease (P < .00001; RR 4.69; 95% CI 2.11-10.4; I2 28%).
Stage I versus Stage II, including six studies,7,18,20,31,38,40 showed a bet-
ter outcome once again for Stage I (P < .002; RR 5.02; 95% CI 1.82-13.9;
ZAMBAITI ET AL .
I2 53%). Stage II was compared to Stage III in six studies,18,20,31,38,40,46
and no difference was found (P < .12; RR 1.93; 95% CI 0.84-4.47; I2
39%). Lower stages (Stage I and II) versus advanced disease (Stage III
and IV) showed RR of 4.99 for advanced tumors (95% CI 3.57-6.98;
P < .00001; I2 0%).7,18,20,31,36,38,40,46
4 DISCUSSION
4.1 Main findings
The findings from this systematic review partially confirmed the previ-
ous reports. Age <4 years, R0 resection, tumor diameter <5 cm, tumor
volume <200 cm3 , tumor weight <100 g and <400 g, and lower stage
at diagnosis strongly correlated with good outcome. An association
with worse outcome was also found when patients presenting with
Cushing syndrome were compared with patients without Cushingoid
features (secreting and nonsecreting together), but not when com-
pared with nonsecreting tumors only. Secreting tumors showed a slight
increase in the RR when compared with nonsecreting tumors. Lower
stages are associated with a better outcome independently from the
inclusion of metastatic patients into the analysis.
4.2 Limitations
Limitations and bias derived from the features of the studies are
included in this review. The main weaknesses of these series were
ZAMBAITI ET AL .
represented by their retrospective design, small sample size, dif-
ferent thresholds or classifications used (such as to describe vol-
ume and weight, or stage), and by the fact that most of the stud-
ies did not explore all the clinical features taken into account by
this systematic review. The variability in the thresholds limited the
evaluation of some clinical features, as it lowered the number of
patients who entered the single analysis, decreasing the rate of
events. In this scenario, it is plausible that the relationship between
a given clinical feature and the outcome may have been under- or
overestimated.
4.3 Implications for clinical practice
The current pathological scores may not be sufficient to determine the
malignant behavior of localized ACTs, especially in case of a Stage II-III
disease. The Wieneke index seems to be the most reliable score in pedi-
atric age so far,5,6,27 but because it addresses a group of tumors with
indeterminate malignancy, it still leaves partially unsolved the deci-
sion on which may be the best postoperative treatment (chemotherapy
associated to mitotane or mitotane alone) for this subset of patients.
In the past, various clinical features have been considered to be
associated with poor outcome, but they varied depending on the study:
age >4 years, size, Cushing syndrome, incomplete resections, and stage
have been more commonly reported. Additionally, initial biopsy is con-
sidered to be an unfavorable prognostic factor and it should be avoided
as much as possible.2,8,47,55,56 Moreover, few attempts have been made
to overcome this variability of evidence before the present study, but
they retrospectively took into account a limited number of patients and
without reaching a wider consensus on a possible risk stratification.
A paper published by the European group (EXpERT) tried to define a
subset of “high-risk” tumors based on the presence of one of the fol-
lowing features: age at diagnosis, volume more than 200 cm3 , Cushing
syndrome, initial biopsy (open or tru-cut), surgical excision with resid-
uals or spillage, regional lymph node involvement, histologic vascular
invasion, and distant metastases at diagnosis.8 An analysis performed
on 111 patients of the American National Cancer Data Base suggested
including in the risk stratification age, extension into adjacent organs,
metastases, and incomplete resection.55
Identifying some clinical features, in order to stratify patients who
are at major risk of relapse, could lead to identifying a subgroup of
ACT which may be elected to a systemic treatment after surgery,
but also in which a mini-invasive approach at diagnosis should be
avoided.
The use of adjuvant mitotane for 24-36 months in some Stage II
and III patients, alone or in combination with standard chemotherapy,
has been found to be determinant56–59 to improve overall survival and
event-free survival. In these cases, a distinction between benign and
malignant forms may in turn avoid important and unnecessary side
effects, or represent a possible improvement in terms of survival.
Indeed, the use of a mini-invasive approach (laparoscopic or robotic-
assisted) in ACT is also the object of debate: some authors suggested
that it could be associated with a higher rate of incomplete resection
7 of 9
or spillage60 and discouraged this technique.61,62 The definition of pre-
operative clinical risk factors (eg, age >4 years, Cushing syndrome, or
nonsecreting tumor), aside from size and suspicious nodes or exten-
sion into adjacent organ at imaging, could drive the surgeon’s decision
in order to avoid unnecessary hazards with potentially fatal outcomes.
4.4 Implications for research
Despite the presence of national registries and large studies, and a
considerable number of ACT patients reported in the literature, the
prognostic value to be attributed to a given clinical feature is currently
extremely variable. For this reason, international cooperative studies
or registries prospectively aimed at defining a risk stratification for
pediatric ACT, ideally based both on clinical and histological features,
are needed. These studies should consider prospectively the predictive
accuracy of the different features, alone and in combination. The opti-
mal cutoffs of quantitative variables, such as size and volume, should
be investigated in order to provide a precise estimation of the pre- and
postsurgical risk of localized ACT. Furthermore, such studies should
provide standardization for qualitative variables in order to homoge-
nize data collected in different countries (eg, staging or tumor scores).
5 CONCLUSIONS
As expected, localized small tumors did show a better prognosis: a low
stage, size <10 cm, and weight under 100 g seem to have lesser risk of
death. Some clinical factors (age >4 years, Cushing syndrome) corre-
lated with a worse outcome and, despite the biological reasons being
far from clear, they could be considered when stratifying patients or
before planning the surgical approach at diagnosis. Notwithstanding its
limitations, this systematic review strengthened in part the evidence
coming from the previous literature, and it could be considered a step
forward for risk stratification for pediatric ACT.
ACKNOWLEDGMENTS
We thank Carlos Alberto Scrideli (Pediatrics Department, Ribeira õ
Preto Medical School, University of Saõ Paulo, Brazil) for his contribu-
tions to this systematic review in terms of additional explanations on
their published data and unpublished data supplied.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request
from the corresponding author.
ORCID
Elisa Zambaiti https://orcid.org/0000-0002-9610-1708
Patrizia Dall’Igna https://orcid.org/0000-0002-3822-3272
Calogero Virgone https://orcid.org/0000-0002-3651-9416
8 of 9
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SUPPORTING INFORMATION
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ing Information section at the end of the article.
How to cite this article: Zambaiti E, Duci M, De Corti F, et al.
Clinical prognostic factors in pediatric adrenocortical tumors:
A meta-analysis. Pediatr Blood Cancer. 2021;68:e28836.
https://doi.org/10.1002/pbc.28836