THE WIENEKE SCORING SYSTEM AND THE PD-L1 STAINING: WHICH IS MORE EFFECTIVE TO PREDICT PROGNOSIS IN CHILDHOOD ADRENOCORTICAL TUMORS?

THE WIENEKE SCORING SYSTEM AND THE PD-L1 STAINING: WHICH IS MORE EFFECTIVE TO PREDICT PROGNOSIS IN CHILDHOOD ADRENOCORTICAL TUMORS? | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 6 March 2025 V1 Latest version Share on THE WIENEKE SCORING SYSTEM AND THE PD-L1 STAINING: WHICH IS MORE EFFECTIVE TO PREDICT PROGNOSIS IN CHILDHOOD ADRENOCORTICAL TUMORS? Authors : Gül Özyüksel [email protected] , Elif Yüksel 0000-0003-3417-9689 , Diclehan Orhan , Bilgehan Yalçın 0000-0003-2840-0308 , Burak Ardicli 0000-0002-1630-7029 , Idil User , and Saniye Ekinci Authors Info & Affiliations https://doi.org/10.22541/au.174124662.23511205/v1 267 views 156 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Adrenocortical tumors (ACTs) are exceedingly rare in children. The Wieneke scoring system is commonly used for malignancy classification; however, the prognostic role of immune checkpoint markers, particularly programmed death-ligand 1 (PD-L1), remains uncertain. Given the emerging role of immune checkpoints in cancer progression, this study evaluates PD-L1 expression in pediatric ACTs and its correlation with clinical outcomes. Procedure: A retrospective review was conducted on 23 pediatric ACT patients diagnosed between 2000 and 2020. Clinical, pathological, and immunohistochemical data were analyzed. Tumor samples were stained for PD-L1 using immunohistochemistry, with a positivity threshold set at ≥3%. Malignancy classification was performed using the Wieneke scoring system, and correlations between PD-L1 expression, malignancy classification, and patient outcomes were assessed. Results: Among the 23 patients, 12 had adrenocortical carcinoma (ACC) and 11 had adrenocortical adenoma (ACA). PD-L1 positivity was observed in three patients: one with ACA and two with ACC. One patient demonstrated PD-L1 positivity in both primary and metastatic tumor samples. Wieneke scoring classified 11 patients as malignant, one as intermediate, and 11 as benign. No significant correlation was found between PD-L1 expression and Wieneke scores. Conclusions: Although PD-L1 expression was more frequent in ACC cases, it did not demonstrate a significant prognostic impact. This finding aligns with broader variations in PD-L1 significance across different cancers. While immune checkpoint markers are implicated in tumor progression, their role in pediatric ACT remains unclear. Further multi-center studies are required to determine their prognostic relevance and therapeutic potential, particularly in the context of immunotherapy. INTRODUCTION Adrenocortical tumors (ACTs) are exceedingly rare in children, accounting for approximately 0.2% of all pediatric malignancies [1,2,3]. The estimated annual incidence of ACTs in individuals under 15 years of age ranges from 0.03% to 0.038%[4,5,6]. Unlike their adult counterparts, most pediatric ACTs are hormonally active, with 40% of cases manifesting isolated androgen secretion[4,5,7,8]. Furthermore, a significant proportion (80-90%) of ACTs in children are malignant[9]. Surgical resection remains the primary curative approach, offering the best chance for prolonged survival[9,10]. However, the prognosis is notably poor in cases with metastasis or incomplete tumor removal, even with aggressive surgical approaches and intensive chemotherapy. Determining malignancy in childhood ACTs poses a unique challenge, as standard histopathological criteria established for adults may not reliably predict outcomes in pediatric cases. Tumors that appear high-risk based on adult malignancy parameters can sometimes exhibit a more favorable prognosis in children[11]. To address this discrepancy, the Wieneke scoring system was introduced in 2003, providing a structured classification method to categorize childhood ACTs as benign, intermediate, or malignant. This system evaluates tumors based on nine histopathological parameters and has demonstrated effectiveness in malignancy prediction among pediatric patients (Table 1) [12]. Despite advancements in histopathological classification, the biological mechanisms underlying ACTs progression remain poorly understood. Recent research has highlighted the significance of immune checkpoint pathways, particularly programmed death-1 (PD-1) and its ligand PD-L1, in tumor immune evasion[13,14]. These molecules play a crucial role in modulating T-cell responses and facilitating tumor progression by suppressing anti-tumor immunity. Given the rarity of ACTs, however, the impact of immune checkpoint mechanisms on prognosis in pediatric cases remains largely unexplored. This study aims to evaluate the prognostic significance of PD-L1 expression in childhood ACTs and compare its predictive power with the Wieneke scoring system. By integrating immune checkpoint markers with established histopathological criteria, we hope to contribute to a more comprehensive approach to risk stratification and prognosis in pediatric patients with ACT. METHODS The data of the patients with ACT in our department between 2000 and 2020 were analyzed retrospectively. Age, gender, medical and family history, clinical features, laboratory tests including hormone analysis, radiological examinations, stage of the disease, preoperative and postoperative pathological findings, and follow-up information were recorded for each patient. At the time of diagnosis, tumor size and extension were determined by cross-sectional imaging data. These data were confirmed by surgical findings and pathology reports. The patients were examined under two headings: Adrenocortical adenoma (ACA) and Adrenocortical carcinoma (ACC). The pathology specimens were obtained from the primary tumor, metastases, and the recurrent lesions. Patients whom we could not obtain a specimen from primary tumor were excluded from the study. The sections for PD-L1 staining were deparaffinized in Bond dewax solution at 72 degrees. The primary antibody (Leica PA0832, rabbit monoclonal antibody, clone 73-10, Newcastle, United Kingdom) was pre-treated in Epitope Retrieval Solution 2 at 100 degrees for 20 minutes. Blocking was done with hydrogen peroxide for 10 minutes. The antibody was incubated at a dilution of 1:400 for 40 minutes. Sections were then treated with post-primary solution for 7 minutes, polymer for 7 minutes, and 3,3’-Diaminobenzidine chromogen for 7 minutes before being passed through alcohol and xylene and coverslipped. Only membranous staining was considered to be positive for determining the percentage of PD-L1. Using the 200X magnification field of an Olympus BX50 light microscope, the area covered by PD-L1-positive stained cells in the tumor was calculated. This area was divided by the total area of the tissue, multiplied by 100 to determine the staining percentages. A ≥3% staining rate was accepted for PD-L1 positivity. The Wieneke scoring system was used for the malignancy classification. RESULTS Twenty-three patients with ACT were included in our study. The median age at the onset of symptoms was 7.5 years. There were 12 females and 11 males. Clinical features of the patients are presented in Table 2. The most common finding of physical examination was a palpable mass in the abdomen (n=14, 61%). This was followed by isolated virilization findings (n=6, 26%), isolated Cushing’s Syndrome findings (n=6, 26%), mixed virilization and Cushing’s Syndrome findings (n=3, 13%), hypertension (n=3, 13%), and feminization (n=1, 4%). Twelve patients had ACC, and 11 had ACA. At the time of diagnosis, two patients with ACC had lung metastases, and one had both lung and liver metastases. Two patients with ACC could be managed with partial resection, and local recurrence occurred in both during follow-up. Ten patients with ACC had complete resection. Three patients had tumor spillage due to rupture during the surgery, and one of these patients had local recurrence. Three patients with ACC have been re-operated because of recurrent disease or new metastases. Operative mortality was not seen in our series. In long-term follow-up, four patients died due to progressive disease. Five-year overall survival was 70.1%, while disease-free survival was 43.6%. Total excision without spillage was performed in all patients with ACA. There was no perioperative mortality, and the postoperative period of the patients was uneventful. No recurrence was observed in the patients. The percentage of PD-L1 staining obtained from the primary tumors of the patients, metastases at the time of diagnosis and new metastases and recurrent masses appear during follow-up were evaluated. Twelve patients with ACC and 11 patients with ACA were included in PD-L1 staining (Table 3). One patient with ACA had 3% positivity for PD-L1 staining. Two patients with ACC had two different primary tumor samples belonging to before and after chemotherapy. Thus, we evaluated 14 samples with ACC for PD-L1 positivity. One patient with ACC and its lung metastasis had a 5% positivity of PD-L1 staining (4%) (Fig. 1-2). Also, one patient with ACC had a 3% positivity of PD-L1 staining (4%). According to the Wieneke scoring system, 11 patients are in the benign category, one in the intermediate category, and 11 in the malignant category. Eleven of the patients with ACC were evaluated in the malignant category, and one of them was in the benign category. One of the patients diagnosed with ACA was in the intermediate category, and 10 of them were in the benign category (Table 4). When we compare the Wieneke scoring system results with PD-L1 staining, we detected PD-L1 positivity (5%) in the primary tumor and the lung metastasis of a patient, placed in the malignant category according to Wieneke scoring system. Primary tumor of one patient in the benign category and one patient in the malignant category had 3% positivity for PD-L1. Eight patients in benign category and nine patients in malignant category had <3% positivity for PD-L1. We did not find significant correlation between Wieneke scoring system results and the PD-L1 positive staining. DISCUSSION The unique characteristics of ACT in children created the need for a new scoring system. Wieneke scoring system created in 2003 has proven to be an effective tool for predicting malignancy in pediatric ACT (12). This system provides a reliable means of stratifying patients into benign, intermediate, and malignant categories, offering valuable prognostic insights, particularly in pediatric cases where adult criteria are not applicable. However, while the Wieneke criteria are highly effective for most pediatric cases, certain rare instances, such as metastatic or recurrent tumors, may require additional parameters for more accurate prognosis. In such cases, combining the Wieneke system with other clinical or molecular markers could enhance its predictive accuracy. (12) According to this scoring system, ten of 11 patients with benign tumor were diagnosed with ACA (90.9%) and no disease recurrence was observed during the follow-up period. One patient in benign category with ACC is alive without evidence of disease for 5 years. Our patient in the intermediate category was diagnosed with ACA and was followed up uneventfully for 10 years. Follow-up information of three of 11 malignant patients could not be obtained. Eight had a malignant course and four of them died due to the disease. The Wieneke scoring system, which is recommended to be used in patients with childhood ACT (15,16), achieved a high malignancy prediction rate and in our series. When considering the prognostic significance of PD-L1 positivity, it is essential to acknowledge the variability in cut-off values across different cancers. Studies by Liu and Fay have shown that PD-L1 positivity in adult ACC is associated with improved survival, but the thresholds used to define positivity vary (17,18). Fay et al. used a 5% cut-off, while Liu’s study showed significant outcomes with a 1% cut-off (17). This variability underscores the importance of carefully selecting the optimal cut-off value for pediatric cases. Standardizing a cut-off value for PD-L1 positivity in pediatric adrenocortical tumors is crucial for accurately assessing its prognostic value and guiding therapeutic decisions. Liu et al. determined the cut-off value for PD-L1 positivity as 1%. As a result of the study in which they evaluated 92 adult ACC patients, they found that PD-L1 positivity was associated with increased survival (18). In another series of adult ACC cases, the cut-off value for PD-L1 positivity was 5% and PD-L1 positivity was observed in tumor cells of only three of 28 patients. In addition, no significant relationship was found between PD-L1 positivity and tumor stage and hormone production of the tumor (17). Billon et al. studied PD-L1 mRNA (messenger ribonucleic acid) results in ACC, a significant correlation was found between PD-L1 and disease-free survival independently from other prognostic factors (19). In the series presented by Parise et al., PD-L1 positivity was not observed in tumor cells in any of 19 patients with childhood ACC, while weakly positive PD-L1 staining in the range of 1% to 5% was found in only four of the immune cells staining (20). Also in our study, statistically significant data showing the relationship between the PD-1/PD-L1 pathway and prognosis could not be obtained. However, it was observed that PD-L1 staining was more intense in ACC than in ACA. The fact that PDL-1 staining can be demonstrated in both primary and metastatic tumors of patients with ACC may be promising for immunotherapy approaches targeting the PD-1/PD-L1 pathway. While our study found that PD-L1 positivity had a limited effect on prognosis, other studies in the literature, such as those by Weber and Hodi, indicate that response rates to immunotherapy may vary depending on PD-L1 expression (21,22). This highlights the potential value of PD-L1 as a biomarker for future research, even though it may not currently play a significant role in predicting prognosis in pediatric ACC. Further functional studies are necessary to better understand the biological role of PD-L1 in pediatric tumors, as this could lead to the development of more precise, biology-driven treatment strategies. The study by Zhang et al. highlights the significance of immune checkpoint markers such as VISTA (V-domain Immunoglobulin Suppressor of T-cell Activation) and PD-L1 in ACC, showing their association with tumor progression and patient outcomes. Although their research focuses on adult patients, the findings are also relevant to pediatric ACT (23). In our study, however, PD-L1 positivity did not demonstrate a significant prognostic impact in pediatric ACT, leaving its role uncertain. This reflects the broader variability of PD-L1’s significance across different cancers. While immunotherapy holds promise in adult cancers, its potential in pediatric ACT remains unclear, necessitating further large-scale, multi-center studies to better understand the prognostic value of immune checkpoint markers in this rare malignancy. This study has several limitations. First, the small sample size limits the statistical power of the study and may affect the generalizability of the results. The retrospective design inherently introduces biases such as selection bias and information bias. The interpretation of PD-L1 staining and the setting of positivity cut-off values are controversial, and our chosen cut-off value of ≥3% may not universally reflect the prognostic value of PD-L1. Furthermore, this study does not include functional assessments of the biological role of PD-L1 in ACT progression or treatment response, limiting our understanding of the underlying mechanisms. The external validity of our findings is limited due to the single-center study and multi-institutional studies are needed to validate our results in different settings. Finally, exclusion of patients without available pathology specimens may have introduced selection bias and reduced the diversity of tumor presentations in our sample. In conclusion, the Wieneke scoring system found that childhood ACT requires different prognostic factors than the adult population. Wieneke scoring system captured a correlation with the clinical outcome. It should be preferred because of its high rate of predicting malignancy in childhood ACT. Due to the complex nature of childhood ACT, it does not seem possible to predict prognosis with a single factor as PD-L1. Nevertheless, multicenter studies examining larger patient groups will be helpful to understand the importance of immune check points and to improve outcomes in childhood ACT. CONFLICT OF INTEREST STATEMENT None. ACKNOWLEDGEMENTS None. REFERENCES 1. Custódio G, Komechen H, Figueiredo FR, Fachin ND, Pianovski MA, Figueiredo BC. Molecular epidemiology of adrenocortical tumors in southern Brazil. Mol Cell Endocrinol. 2012;351:44-51. 2. Stiller C. International variations in the incidence of childhood carcinomas. Cancer Epidemiology and Prevention Biomarkers. 1994;3:305-10. 3. Miller RW, Young JL, Jr., Novakovic B. Childhood cancer. Cancer. 1995;75:395-405. 4. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. The Journal of Clinical Endocrinology & Metabolism. 1997;82:2027-31. 5. Rodriguez‐Galindo C, Figueiredo BC, Zambetti GP, Ribeiro RC. Biology, clinical characteristics, and management of adrenocortical tumors in children. 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Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. Journal of Clinical Oncology. 2004;22:838-45. 10. Stewart JN, Flageole H, Kavan P. A surgical approach to adrenocortical tumors in children: the mainstay of treatment. J Pediatr Surg 2004;39:759–63 11. Weiss LM, Medeiros LJ, Vickery ALJ. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202–6. 12. Wieneke JA, Thompson LD, 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. 13. Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., Lennon, V. A., Celis, E., & Chen, L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. 14. Reiss KA, Forde PM, Brahmer JR. Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy. Immunotherapy. 2014;6:459–475. 15. Chatterjee G, DasGupta S, Mukherjee G, Sengupta M, Roy P, Arun I, Datta C, Mishra PK, Banerjee S, Chatterjee U. Usefulness of Wieneke criteria in assessing morphologic characteristics of adrenocortical tumors in children. Pediatr Surg Int. 2015;31:563-71. 16. Riedmeier M, Thompson LDR, Molina CAF, Decarolis B, Härtel C, Schlegel PG, Fassnacht M, Wiegering V. Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC - a mini review. Endocr Relat Cancer. 2023;30:e220259. 17. Liu S, Ding G, Zhou Z, Feng C. β-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion. Onco Targets Ther. 2018;11:2029-36. 18. Fay AP, Signoretti S, Callea M, Telό GH, McKay RR, Song J, et al. Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer. 2015;3:3. 19. Billon, E., Finetti, P., Bertucci, A., Niccoli, P., Birnbaum, D., Mamessier, E., Bertucci, F. PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma. OncoImmunology. 2019;8:e1655362. 20. Parise IZS, Parise GA, Noronha L, Surakhy M, Woiski TD, Silva DB, Costa TEB, Del-Valle MHCP, Komechen H, Rosati R, Ribeiro MG, Nascimento ML, Souza JA, Andrade DP, Paraizo MM, Galvão MMR, Barbosa JRS, Barbosa ML, Custódio GC, Figueiredo MMO, Fabro ALMR, Bond G, Volante M, Lalli E, Figueiredo BC. The prognostic role of CD8+ T lymphocytes in childhood adrenocortical carcinomas compared to Ki-67, PD-1, PD-L1, and the Weiss score. Cancers. 2019;11:1730. 21. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or-naive melanoma. Journal of clinical oncology. 2013;31:4311. 22. Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP, Topalian SL, Atkins MB, Powderly JD, Sharfman WH, Puzanov I, Smith D, Leming PD, Lipson EJ, Taube JM, Anders RA, Horak CE, Kollia GD, Gupta AK, Sosman JA. Long-term survival of ipilimumab-naive patients with advanced melanoma treatedwith nivolumab in a phase I trial. J Clin Oncol. 2014;32:9002. 23. Zhang Z, Li M, Wang J, Liu M, Chen H, Lou Y, Wang Y, Sun Q, Zhu D, Li P, Bi Y. Expression and clinical significance of VISTA and PD-L1 in adrenocortical carcinoma. Endocr Relat Cancer. 2022;29:403–13. TABLES TABLE 1 Wieneke scoring system Tumor weight of >400 g Tumor size >10.5 cm Extension into periadrenal soft tissues and/or adjacent organs Invasion into vena cava Venous invasion Capsular invasion Presence of tumor necrosis >15 mitoses per 20 HPF* Presence of atypical mitotic figures Abbreviations: HPF: high-power field (400×). TABLE 2 Clinical Features Age(months) 114 63 Sex -Male 5 6 -Female 7 5 Site -Left 7 7 -Right 5 4 Surgery -Total 10 11 -Partial 2 0 Outcame -Disease free 4 11 -Dead of disease 4 0 -Alive with disease 4 0 Abbreviations: ACC: Adrenocortical carcinoma, ACA: Adrenocortical adenoma TABLE 3 PD-L1 staining rates ACA (n=11) 0 4 (%16) 6 (%24) 0 1 (%4) 0 ACC (n=14) 4 (%16) 6 (%24) 0 2 (%8) 1 (%4) 1 (%4) Abbreviatinos: PD-L1: Programmed Death-Ligand 1, ACC: Adrenocortical carcinoma, ACA: Adrenocortical adenoma TABLE 4 Results according to Wieneke scoring system WIENEKE SCORING SYSTEM + - + - Tumor weight of >400 g 0 11(100%) 7 (58%) 5 (42%) Tumor size >10.5 cm 0 11 (100%) 7 (58%) 5 (42%) Extension into periadrenal soft tissues and/or adjacent organs 0 11 (100%) 7 (58%) 5 (42%) Invasion into vena cava 0 11 (100%) 1 (8%) 11 (92%) Venous invasion 0 11 (100%) 10 (83%) 2 (17%) Capsular invasion 0 11 (100%) 10 (83%) 2 (17%) Presence of tumor necrosis 1(9,1%) 10 (90,9%) 11 (92%) 1 (8%) >15 mitoses per 20 HPF 2 (18,2%) 9 (81,8%) 12 (100%) 0 Atypical mitotic figures 2 (18,2%) 9 (81,8%) 10 (83%) 2 (17%) Abbreviations: HPF: high-power field (400×). FIGURE LEGENDS Figure 1. The microscopic image of PD-L1 staining, evaluated as 5% positive in the section prepared from the primary tumor of the patient by immunohistochemistry (A: heterogeneous pattern at ×40 magnification; B: membranous staining noticeable at ×200 magnification). Figure 2 . The microscopic image of PD-L1 staining, evaluated as 5% positive in the section prepared from the lung metastasectomy specimen excised during the same surgery from the same patient by immunohistochemistry (A: heterogeneous pattern at ×40 magnification; B: membranous staining noticeable at ×200 magnification). Information & Authors Information Version history V1 Version 1 06 March 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords pediatric oncology rare tumors solid surgery tumor markers tumors Authors Affiliations Gül Özyüksel [email protected] Hacettepe Universitesi Tip Fakultesi View all articles by this author Elif Yüksel 0000-0003-3417-9689 Hacettepe Universitesi Tip Fakultesi View all articles by this author Diclehan Orhan Hacettepe Universitesi Tip Fakultesi View all articles by this author Bilgehan Yalçın 0000-0003-2840-0308 Hacettepe Universitesi Tip Fakultesi View all articles by this author Burak Ardicli 0000-0002-1630-7029 Hacettepe Universitesi Tip Fakultesi View all articles by this author Idil User Hacettepe Universitesi Tip Fakultesi View all articles by this author Saniye Ekinci Hacettepe Universitesi Tip Fakultesi View all articles by this author Metrics & Citations Metrics Article Usage 267 views 156 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Gül Özyüksel, Elif Yüksel, Diclehan Orhan, et al. THE WIENEKE SCORING SYSTEM AND THE PD-L1 STAINING: WHICH IS MORE EFFECTIVE TO PREDICT PROGNOSIS IN CHILDHOOD ADRENOCORTICAL TUMORS?. Authorea . 06 March 2025. DOI: https://doi.org/10.22541/au.174124662.23511205/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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