The Prognostic Role of CD8+ T Lymphocytes in Childhood Adrenocortical Carcinomas Compared to Ki-67, PD-1, PD-L1, and the Weiss Score.

Thiago Demetrius Woiski,Denise Brentan Silva ,Marco Volante,Roberto Rosati,Ivy Zortéa S Parise ,Ana Luiza M R Fabro,Mirvat Surakhy,Gareth Bond,Diancarlos Pereira De Andrade ,Gislaine Custódio ,Melyssa Grignet Ribeiro,Maria Helena C P Del-Valle ,Marjorana Martini R Galvão ,Guilherme A Parise ,Heloísa Komechen ,Mirna M O Figueiredo ,Mariana M Paraizo ,Tatiana Ei-Jaick B Costa ,Marilza Leal Nascimento,Lúcia De Noronha ,Enzo Lalli,Bonald C Figueiredo,José Antônio De Souza,Miriam Lacerda Barbosa,João Batista Barbosa

doi:10.3390/cancers11111730

Abstract

Adrenocortical carcinoma (ACC) is a rare disease among children. Our goal was to identify prognostic biomarkers in 48 primary ACCs from children (2.83 ± 2.3 y; mean age ± SD) by evaluating the tumor stage and outcome for an age of diagnosis before or after 3 years, and association with ACC cluster of differentiation 8 positive (CD8+) cytotoxic T lymphocytes (CD8+-CTL) and Ki-67 immunohistochemical expression (IHC). Programmed death 1(PD-1)/Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in ACC was analyzed in a second, partially overlapping cohort (N = 19) with a similar mean age. All patients and control children were carriers of the germline TP53 R337H mutation. Survival without recurrence for less than 3 years and death unrelated to disease were excluded. Higher counts of CD8+-CTL were associated with patients diagnosed with ACC at a younger age and stage I, whereas a higher percentage of the Ki-67 labeling index (LI) and Weiss scores did not differentiate disease free survival (DFS) in children younger than 3 years old. No PD-1 staining was observed, whereas weakly PD-L1-positive immune cells were found in 4/19 (21%) of the ACC samples studied. A high CD8+-CTL count in ACC of surviving children is compelling evidence of an immune response against the disease. A better understanding of the options for enhancement of targets for CD8+ T cell recognition may provide insights for future pre-clinical studies.

Highlights

The germline TP53 R337H mutation is associated with a cluster of pediatric adrenocortical carcinoma (ACC) that is reported in Southern [1] and Southeastern Brazil [2], and accounts for the highest global incidence of childhood ACC [3,4]
Stage assessment and treatment were performed according to the Children’s Oncology Group (COG) protocol [10] except for stage 2 retroperitoneal lymph node dissection (RPLND), which was not performed in the present study
These findings suggest thatthat the the Programmed death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) pathway does does not play a major role in ACC, and, given the modest results obtained for PD-1 and PD-L1, no not play a major role in ACC, and, given the modest results obtained for PD-1 and PD-L1, no further further were performed to correlate those data to tests weretests performed to correlate those data to ACC

Summary

Introduction

The germline TP53 R337H mutation is associated with a cluster of pediatric adrenocortical carcinoma (ACC) that is reported in Southern [1] and Southeastern Brazil [2], and accounts for the highest global incidence of childhood ACC [3,4]. Features of adult ACC include secretory syndromes (60%) that are either a mixture of CS and VS (35%), CS (30%), or VS (20%) alone, feminizing syndrome (10%), and aldosterone-secreting carcinomas (2%) [6]. Older children (without a clear cut-off age) commonly exhibit features observed more often in adult ACC patients than in young children, which is consistent with the hypothesis that the ACC phenotype found in very young children is probably embryonic in origin [7,8,9].

Objectives

Methods

Results

Discussion

Conclusion