Horm Res Paediatr 2022;95:347-353 DOI: 10.1159/000524892
Histopathological Criteria for Paediatric Adrenocortical Carcinoma
Victor P. Paschoalinª Silvio Tucci Júniorª Andrey G. Estevanatoª Ricardo B. Tiraboschib Sonir R. Antoninic Valdair F. Mugliad Fernando Chahude Livia M. Mermejof José de Bessa Júniorb Carlos A. Fernandes Molinaª
ªDepartment of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; bDepartment of Surgery, Feira de Santana State University, Feira de Santana, Brazil; “Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; dDepartment of Medical Images, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; eDepartment of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; ‘Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Keywords
Adrenal glands . Pathology . Neoplasms . Classification . Carcinoma · Paediatrics
Abstract
Introduction: Adrenocortical carcinoma (ACC) is diagnosed in paediatric patients at 5 months after symptom onset on average, and 38% die during the first 2.5 years of follow-up. This study aimed to compare the accuracy of Weiss, Van Slooten, and Wieneke histopathological ACC classifications for predicting follow-up prognosis in a paediatric popula- tion. Methods: Data were retrieved from medical records of 57 patients aged <18 years who underwent surgical treat- ment for ACC with surgical follow-up over 6 months or death due to ACC. They were classified into either good (without recurrence/death due to ACC) or poor (with recurrence/ death due to ACC) prognosis group. Two expert pathologists classified the ACC surgical specimens according to the Weiss, Van Slooten, and Wieneke criteria. Results: The median fol- low-up duration was 126 (18-225) months in 38 males (66.7%) and 19 females (33.3%) (median age: 3 [1-6.5] years).
The good prognosis group was younger than the poor prog- nosis group (median age: 3 [1.5-6.2] years vs. 5 [2-10] years). Seventeen (29.8%) patients in the poor prognosis group died due to ACC within the first 50 months of surgical follow- up; the earliest death occurred in the fourth follow-up month, and the majority of deaths occurred within 24 months of follow-up. The accuracies of Weiss, Van Slooten, and Wieneke classification systems were 40%, 47%, and 77%, respectively. Discussion/Conclusion: The Wieneke classifi- cation showed the best accuracy but was not sufficiently precise to establish reliable prognosis for ACC in the paedi- atric population. The Wieneke classification had approxi- mately 95% sensitivity and negative predictive value.
@ 2022 The Author(s).
Published by S. Karger AG, Basel
Introduction
Adrenal tumours, excluding neuroblastoma, are spo- radic in childhood and adolescence, with an incidence of 1.5 million/year, corresponding to 0.2% of all malignant tumours in this age group [1, 2]. The International Pedi-
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atric Adrenocortical Tumor Registry (IPACTR) revision in 2004 reported that adrenocortical carcinoma (ACC) is diagnosed at 5 months after symptom onset on average, and 38% of patients do not survive during the first 2.5 years of follow-up, reaching only 54% of the overall sur- vival during the first 5 years of follow-up [3, 4]. The IPACTR was created to be specific and develop knowl- edge of the epidemiological and clinical patterns of pae- diatric ACC. By using specific histopathological criteria from the paediatric population, the IPACTR improved outcomes by updating the ACC prognostic staging spe- cific to this population, which had followed those avail- able for adults [5].
ACC in childhood and adolescence is still being clas- sified according to the histopathological Weiss criteria developed for adults, which have no specificity for prog- nostic issues and are not entirely recommended for the paediatric population [6-8]. In an attempt to create a classification for the paediatric population, Wieneke es- tablished specific criteria by modifying the Weiss criteria and adding morphometric data to build a new algorithm that achieves superior specificity for the diagnosis and prognosis of ACC. The Wieneke criteria were validated by three retrospective studies [9-12].
Considering the importance of clinical prognosis based on histopathological diagnosis for the establish- ment of therapeutic management, this study aimed to prospectively assess and compare the accuracy of three histopathological ACC classifications - namely, Weiss, Van Slooten, and Wieneke criteria - for predicting fol- low-up outcomes of this disease in the paediatric popula- tion. This study is a 35-year series of surgical patients with ACC.
Materials and Methods
After receiving exemption for disclosure and consent to re- trieve the medical records and after obtaining approval from our Institutional Review Board (protocol number: HCFMRP-USP 3019/2010), data were retrieved from the medical records of 63 patients who underwent surgical treatment for ACC and followed up at a single academic institution in the countryside of São Paulo, Brazil, from January 1975 to December 2010. Six patients were ex- cluded from this study, because they did not attain the minimum surgical follow-up or did not have surgical specimens at the insti- tutional pathology laboratory for the review of histopathological criteria.
We evaluated age, ethnicity, sex, clinical characteristics, patient follow-up, functionality (laboratory tests), histopathological pat- terns (established criteria for ACC), and morphological traits (size, weight) of the surgically removed tumours. Any recurrence of the disease was identified at patient follow-up.
| Histopathological criteria | Follow-up | |
|---|---|---|
| poor prognosis | good prognosis | |
| Weiss | ||
| Malignant | 16 | 33 |
| Benign | 1 | 7 |
| Van Slooten | ||
| Malignant | 17 | 30 |
| Benign | 0 | 10 |
| Wieneke | ||
| Malignant | 16 | 12 |
| Benign | 1 | 28 |
The inclusion criteria were as follows: age <18 years, confirmed histological ACC diagnosis, surgical treatment for ACC, and surgi- cal follow-up after surgery for at least 6 months or death due to ACC before 6 months of follow-up. Only two children received a follow-up that was less than 12 months in the poor prognosis group. The exclusion criteria were as follows: age ≥18 years, surgi- cal follow-up shorter than 6 months except for death due to ACC, and histological diagnosis for other tumours of the adrenal gland (neuroblastoma, ganglioneuroma, pheochromocytoma, and me- tastasis).
Two expert pathologists from the same academic institution, who were not aware of the patients’ clinical status, reviewed the ACC surgical specimens of all 57 patients included in this study. The slides for surgical specimens were constructed from 5-mm paraffin block slices of the sample stained with haematoxylin and eosin. The pathologists classified the specimens according to the Weiss, Van Slooten, and Wieneke criteria. Subsequently, the 57 patients were assigned to either the good prognosis group (without recurrence/decease due to ACC) or poor prognosis group (with recurrence/decease due to ACC).
Statistical Analyses
Quantitative variables are presented as medians and interquar- tile ranges. The ability of each classification to distinguish the evo- lution of patients was based on sensitivity, specificity, positive and negative prognostic values, and positive and negative likelihood ratios. Statistical significance was set at p < 0.05, and 95% confi- dence intervals were presented as a measure of precision. Data analyses were performed using GraphPad Prism version 8.0.3 (GraphPad Software, San Diego, CA, USA).
Results
The median follow-up time in 57 patients included in this study was 126 [18-225] months in 38 females (66.7%) and 19 males (33.3%) (median age: 3 [1-6.5] years). The median age was lower in the good prognosis group (3 [1.5-6.2] years) than in the poor prognosis group (5 [2-
100
90
% survival
80
70
60
50
0
50
100
150
200
250
300
350
Months
| Classification parameters | |||
|---|---|---|---|
| Weiss | Van Slooten | Wieneke | |
| Sensitivity, % | 100 | 94 | 94 |
| Specificity, % | 17 | 25 | 70 |
| Positive predictive value, % | 36 | 32 | 57 |
| Negative predictive value, % | 100 | 87 | 96 |
| Likelihood ratio + | 1.33 | 1.14 | 3.13 |
| Likelihood ratio - | 0 | 0.35 | 0.08 |
| Accuracy, % | 40 | 47 | 77 |
| +, positive; - , negative. | |||
10] years). Ethnically, 52 patients (91.2%) were white, 5 (8.8%) were black, and none were Asian. The patients were allocated to either the good prognosis group or the poor prognosis group according to their follow-up out- comes and were designated as having benign or malig- nant ACC following the Weiss, Van Slooten, and Wieneke histopathological system scores (p < 0.001) (Table 1).
Overall, 17 (29.8%) patients in the poor prognosis group died because of ACC. All deaths occurred within the first 50 surgical months of follow-up; the earliest death occurred in the fourth follow-up month, and the majority of deaths occurred within 24 months of follow- up (Fig. 1). The relapse rate with 24 and 50 months of follow-up was 43 and 40 patients, respectively (Fig. 1). The accuracy of evaluation for each histopathological sys- tem score revealed that the Wieneke score was superior to the Weiss and Van Slooten scores (Table 2).
Discussion/Conclusion
Histopathological diagnosis of an adrenal cortical tu- mour strives to define whether it is malignant. Such diag- nosis has been carried out using a multiparametric scor- ing system developed for adults but used as well for chil- dren and adolescents worldwide (i.e., Weiss and Van Slooten criteria), with only one system developed for chil- dren and adolescents only, but not for adults (i.e., Wieneke criteria) [13]. The histopathological patterns used to de- scribe the malignant potential of adrenal cortical tumours in the paediatric population differ from those used in adults. However, diagnosing ACC remains challenging in children. Immunohistochemistry and genomic tests have been used to collaborate with the identification of adrenal cortical tumour prognosis, but with no meaningful achievement yet [13]. This study identified a mortality rate of 29.8%, which is in the range of 20-50% [14-16]. The high mortality rate of ACC calls attention to the im- portance of developing a reliable prognostic classification that provides better guidance to patients, families, and healthcare providers. In 2016, Bulzico et al. [17] analysed the database of the National Cancer Institute (INCA) of Brazil and found that almost 30% of patients considered sufficiently treated with surgery for ACC presented with disease recurrence during follow-up.
Weiss et al. [18] developed the largest scoring system available for diagnosing ACC in 1984, using the following nine histopathological parameters: high nuclear grade (Fuhrman III or IV), mitotic index >5/50 high-power field, atypical mitosis, lack of clear cytoplasm ≥25%, dif- fuse architecture >1/3 of tumour, necrosis, venous inva- sion, sinusoidal invasion, and capsular invasion. Each pa-
rameter receives a score of 0 if it is absent and 1 if it is present, providing a total score ranging from 0 to 9. Ana- lysing 43 patients with ACC for 5 years, Weiss identified those who scored ≥4 developed metastasis, therefore con- sidered ACC, while those who scored ≤2 did not develop metastasis were considered to have nonmalignant neopla- sia. In 1989, Weiss et al. [19] reviewed their study and re- duced the score threshold to ≥3 for a diagnosis of ACC. In 1985, Van Slooten et al. [20] proposed their own score for adrenal cortical tumours based on seven histological pa- rameters and designated different weights to each param- eter: regressive changes (necrosis, haemorrhage, fibrosis, calcification), 5.7; lack of normal structure, 1.6; moderate or marked nuclear atypia, 2.1; nuclear hyperchromasia, 2.6; abnormal nucleoli, 4.1; mitotic index >2/10 high- power field, 9.0; and capsular/vascular invasion, 3.3. Hence, the score can range from 0 to 28.4, and if it reach- es >8, it suggests a malignant adrenal cortical tumour. Lat- er, using the same parameters as those by Van Slooten, Aubert et al. [21], van’t Sant et al. [22] and Pennanen et al. [23] (Helsinki score) attributed different weights to the criteria of Weiss et al. [19], modifying the final score and its threshold to define the adrenal cortical tumour as ma- lignant or not, in an attempt to increase the accuracy of the method. All of these efforts work for adults.
ACC in the paediatric population suggests different carcinogenic mechanisms than those in adults. In addi- tion, adrenal cortical tumours present with a less aggres- sive pattern in children and adolescents than in adults, even though they are malignant more than 80%-90% of the time in the paediatric population [4]. In 2003, Wieneke et al. [9] provided a scoring system to diagnose ACC in the paediatric population (<20 years) supported by the following parameters: tumour weight >400 g, tumour size >10.5 cm, extension into periadrenal soft tissue and/or adjacent organs, invasion into the vena cava, venous inva- sion, capsular invasion, presence of tumour necrosis, mi- totic index >15/20 high-power field, and presence of atypical figures. The presence of up to two of these criteria supports a benign evolution, three open evolution, and four or more ACC [9].
In this 35-year series with 57 patients under 18 years of age, we identified a higher incidence of ACC in fe- males, approximately 2/3 of all cases, similar to the Sur- veillance, Epidemiology, and End Results (SEER) data- base with 85 patients in a series of 35 years. The median age of the patients in our series was 3 years; however, the median age in the poor prognosis group was 5 years, again similar to the SEER data. The National Cancer Database (NCDB) and population studies in Europe identified a
worse prognosis for ACC in a paediatric population ≥4 years old [24-27]. In a study of 58 patients, an Italian group showed a survival free of disease for patients ≥12 years, 9.44 times worse than those <4 years and 7.79 over- all [11].
In 2018, Erickson demonstrated the challenge of diag- nosing ACC by using the criteria provided by Weiss, Van Slooten, and Wieneke, their variants, complements, and/ or upgrades developed in an attempt to increase the ac- curacy of the methods; even adding immunohistochem- istry and genomic tests did not enable them to reach their goal [13]. In our 35-year series with 57 patients, 17 died who were classified as having poor prognosis and com- prised almost 1/3 of the poor prognosis group. All pa- tients died in the first 50 months after surgery, and the majority died within the first 24 months after surgery, similar to those reported in the literature.
All three scoring systems used to diagnose ACC in this series showed high sensitivity (94-100%) despite their low specificity (17-70%). In this scenario, despite the high positive predictive value, the low specificity resulted in a large number of children treated surgically by only two experienced surgeons and classified by the three scoring systems, as ACC had a benign follow-up with good prog- nosis. By taking this into account, the Wieneke criteria showed the best performance, placing a low number of patients (n = 12) who were considered to have ACC in the good prognosis group. However, based on the Wieneke criteria, one patient was considered to be “non-ACC” who developed the malignant pattern and was therefore placed in the poor prognosis group. In our series, the Wieneke criteria showed an accuracy of 77% for classifying adrenal cortical tumours in children, which was not as good as ex- pected. However, Gupta et al. [28] analysed 41 patients at the Mayo Clinic in a 67-year series and showed an accu- racy of 100% for the Wieneke index, as compared to 29% and 33% for the Weiss and modified Weiss criteria, re- spectively. Although the Wieneke index in our series was much better than the Weiss and Van Slooten criteria de- veloped to classify adrenal cortical tumours in the adult population, the Wieneke index exhibited a performance less than that of flipping a coin, achieving an accuracy of 77%, as compared to an accuracy of 40% for the Weiss cri- teria and 47% for the Van Slooten criteria (Fig. 2).
Jehangir et al. [29] reported that the Wieneke criteria accurately predict the clinical course in childhood ACC considering the gold standard in their pathological char- acterization. However, Picard et al. [30] stated that they believe the Wieneke scoring system is not sufficient enough to guide perioperative treatment recommenda-
| Criteria | Clinically and pathologically malignant | Clinically benign pathologically malignant | Clinically malignant pathologically benign | Clinically and pathologically benign |
|---|---|---|---|---|
| Wieneke et al. [9] | 18 | 10 | 0 | 37 |
| Chatterjee et al. [12] | 5 | 0 | 0 | 9 |
| Magro et al. [10] | 6 | 1 | 0 | 13 |
| Ru et al. | 6 | 1 | 0 | 13 |
| Giovannoni et al. | 5 | 0 | 0 | 2 |
| Jehangir et al. [29] | 7 | 0 | 0 | 14 |
| Total (n = 81) | 48 | 12 | 0 | 87 |
| Paschoalin et al. [this study] | 16 | 11 | 1 | 29 |
100
*
80
Accuracy, %
60
40
20
0
Van Slooten
Weiss
Wieneke
tions, calling attention to the requirement of small series and urging for further independent studies to validate the conclusion made by Jehangir et al. [29]. We do agree with Picard et al. [30] and have added our series results to the table published by Jehangir et al. [29], showing clinically malignant/pathologically benign and clinically benign/ pathologically malignant tumours (Table 3).
All three histopathological criteria for diagnosing ACC showed very good sensitivity, making them reliable in terms of appropriately predicting and defining patients in the good prognosis group. Only the Van Slooten crite- ria placed all ACC patients with ACC in the poor prog- nosis group, whereas the Weiss and Wieneke criteria di- agnosed one patient as “non-ACC” who belonged to poor prognosis group. However, with respect to all patients in-
cluded in the good prognosis group, almost 75% of them were diagnosed by the Weiss and Van Slooten criteria as having ACC, whereas the Wieneke criteria diagnosed ACC in only 33%. The need for close follow-up in all chil- dren diagnosed with ACC is usually not welcome among families and healthcare providers. We understand that the allocation in the good prognosis group may have oc- curred owing to adequate surgical treatment and not be- cause of a lack of histopathological classification. We also understand that, if possible, we should spare families from such a psychological burden. Therefore, despite the lack of the best histological criteria for diagnosing ACC in the paediatric population, we must use the best avail- able criteria for that population.
This study has many limitations, starting with being a retrospective design. Surgery is a unique treatment that can modify the natural history of the adrenal cortical tu- mour, and biopsy is not recommended for this disease, making a prospective study to check the accuracy of the scoring system impossible. We also know that many chil- dren allocated as having an ACC had good prognosis be- cause the disease was adequately treated with the surgery, which makes the accuracy of these three systems unreli- able. However, this is a 35-year series of 57 patients with a rare disease, turning it into one of the largest series in the world with a long follow-up.
The accuracy of the Weiss and Van Slooten classifica- tions were not greater than that of the odds of flipping a coin, and these criteria should be avoided to classify ad- renal cortical tumours in the paediatric population. The Wieneke classification was better than the Weiss and Van Slooten, but the accuracy was not good enough to estab- lish a reliable prognosis for ACC in the paediatric popula- tion. However, the Wieneke classification has been the best for the child and adolescent population to date.
Acknowledgements
The authors acknowledge all members from the Department of Pathology and Legal Medicine at Ribeirão Preto Medical School of University of São Paulo, who worked in collaboration to separate and provide the reviewed samples.
Statement of Ethics
This study protocol was reviewed and approved by our Institu- tional Review Board: Hospital Das Clinicas Da Faculdade De Me- dicina De Ribeirao Preto Da Universidade De Sao Paulo (protocol number HCFMRP-USP 3019/2010). The study was granted with an exemption by the Research Ethics Committee of Ribeirão Preto Clinical Hospital of Ribeirão Preto Medical School of University of São Paulo regarding the requirement for the acquisition of writ- ten informed consent from patients.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Contributions
Dr. Victor P. Paschoalin substantially contributed to data ac- quisition, analysis, and interpretation for the work. Dr. Silvio Tuc- ci Júnior was involved in study conception, data interpretation, and manuscript drafting. Dr. Andrey G. Estevanato substantially contributed to the study design. Dr. Ricardo Brianezi Tiraboschi interpreted the data for the work. Dr. Sonir R. Antonini critically revised the manuscript for important intellectual content. Dr. Val- dair F. Muglia was involved in the final approval of the version of the manuscript to be published. Dr. Fernando Chahud analysed and interpreted the data for the work. Dr. Livia M. Mermejo was involved in the final approval of the version of the manuscript to be published. Dr. José de Bessa Júnior interpreted the data for the work and was involved in the final approval of the version of the manuscript to be published. Dr. Carlos A. Fernandes Molina crit- ically revised the manuscript for important intellectual content, provided final approval of the version of the manuscript to be pub- lished, and agree to be accountable for all aspects of the work and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Data Availability Statement
All data were retrieved from the medical records of all 57 in- cluded patients at the Ribeirão Preto Clinical Hospital of Ribeirão Preto Medical School of University of São Paulo. The research data that support the findings of this study are not publicly available due to ethical grounds that require permission from the research ethics committee of the Ribeirão Preto Clinical Hospital of Ribeirão Pre- to Medical School of University of São Paulo.
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Weiss, Van Slooten, and Wieneke Criteria for Paediatric ACC