Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-Up

Abstract

Pediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight ≥ 200 g (p < 0.001), tumor size ≥ 5 cm (p < 0.05), Weiss score ≥ 5 (p < 0.05), Wieneke index ≥ 3 (p < 0.001) and Ki67 ≥ 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). Additionally, the subtractions of BUB1B-PINK1 (<6.95) expression (p < 0.05) and IGF-IR overexpression (p = 0.0001) were associated with malignant behavior. These results helped identify patients who are likely to have an aggressive course; further multicenter prospective studies are required to confirm our results. In conclusion, PACTs with these patterns of prognostic factors could be treated using an adjuvant approach that may improve the overall survival in such patients.

Keywords: TP53; pediatric adrenocortical tumor; pediatric cancer; prognostic factors.

Figure 1

Percentage of metastatic and non-metastatic pediatric patients diagnosed with adrenocortical tumor according to age-groups; group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age. Patient aged > 3 years are more likely to develop a malignant evolution (p = 0.03; HR: 2.5; CI 95% 1.07–5.8).

Figure 2

Clinical manifestations of patients with PACTs. 1: male patient (9 months of age) with mixed syndrome (VS and CS); 2: Male patient (5 years of age) with estrogen, androgen and cortisol producing tumor (gynecomastia and an important bone age advance); 3: Female patient (1 year of age) with pubic hair and clitoromegaly (2.7 cm). The parents gave a written informed consent for the publication of the images.

Figure 3

Tumor size and their relative frequencies (%) in each age-group (n = number of cases); group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age. Tumor size ≥ 5 cm was found to be an important predictor of worse prognosis in groups 1 and 3, (p < 0.05; HR: 5.3; CI 95% 1.03–5.4).

Figure 4

Kaplan-Meier curve estimates for overall survival according to each age-group; group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age.

Figure 5

Kaplan-Meier curve estimates for disease-free survival according to each age-group; group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age.

Figure 6

Kaplan-Meier curve estimates for recurrence-free survival according to each age-group; group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age.

Figure 7

Growth pattern of male patient with PACT, 2 years of age, with mixed syndrome (V + CS), tumor weight of 250 g, sized 12 cm, McFarlane IV, Weiss score 7, Wieneke 4, with TP53- p.R337H and overall survival of 11 months. Blue circle is stature for age and red circle is bone-age.

Figure 8

Percentage of patients in each age-groups in the evaluation of pediatric adrenal tumor-related genes; group 1: ≤3 years of age; group 2: 3 < age ≤ 12 years of age; group 3: 12 < age ≤ 18 years of age. Ki67 ≥ 15% increased the risk of developing metastasis in all groups (p < 0.05; HR: 8.1; CI 95% 1.2–8.2). The TP53 Arg337His pathogenic variant, ZNRF3/ ATRX somatic pathogenic variant, MLH1 germline/ likely pathogenic variant, MSH6 germline pathogenic variant and XAF1 E134 pathogenic variant were not associated with a worse outcome, in all groups (p > 0.05).