Characteristics of the study cohort

A total of 490 patients was included, divided into 429 patients with ACA (87.55%) and 61 with ACC (12.45%). Among them, 59.5% were women (56.9% in the ACA group and 54.1% in the ACC group). Patients with ACA comprised patients with APA (n = 54), CPA-CS (n = 22), MACS (n = 138), and inactive-ACA (n = 215).

The demographic, hormonal, and radiological data are detailed in Table 1. The groups differed, as expected, in terms of age, size, and cortisol secretion; patients with ACC had higher levels of cortisol after 1 mg-DST and higher UFC levels. Five patients with APA had also a cortisol co-secretion, based on cortisol levels after 1mgDST (range 54–90 nmol/L). Since no other hormonal and clinical differences were found between these patients and APA patients without cortisol excess, these subjects were consider as primarily affected by APA and they were included in the APA group.

Table 1 Demographic, clinical, laboratory, and radiological data as well as inflammation-based scores in patients with adrenocortical adenomas (ACA) or adrenocortical carcinoma (ACC)Correlations between inflammation-based scores and cortisol secretion levels

All inflammation-based scores displayed a significant, although weak, correlation with cortisol levels after 1 mg-DST when considering patients altogether (Table 2). In particular, NLR exhibited the best correlation with cortisol levels after 1 mg-DST, (ρ = 0.3676, p < 0.001, as shown in Fig. 1A). This correlation remained significant even when analyzing ACC and ACA patients separately (ρ = 0.6388, p < 0.001 for ACC; ρ = 0.2905, p < 0.001 for ACA, respectively) (Table 2). UFC showed a positive correlation with NLR (ρ = 0.2675, p < 0.001) and SII (ρ = 0.2272, p < 0.001), and a negative correlation with LMR (ρ = − 0.1150, p = 0.038). The correlation between UFC and NLR (ρ = 0.5553, p < 0.001 for ACC; ρ = 0.1811, p = 0.002 for ACA, respectively) and SII (ρ = 0.3632, p = 0.0348 for ACC; ρ = 0.1391, p = 0.002 for ACA, respectively) remained significant when analyzing ACC and ACA patients separately (Table 2).

Table 2 Correlations between multiple inflammation-based scores and cortisol levels after 1 mg overnight dexamethasone suppression testFig. 1

A Correlation between cortisol levels after 1-mg overnight dexamethasone-suppression test and neutrophil/lymphocyte ratio (NLR). p-values were determined with Spearman’s correlation coefficient. Gray dots represent patients with adrenocortical carcinoma (ACC, n = 61), black dots represent patient with adrenocortical adenoma (ACA, n = 429). B Area under the curve (AUC) of the neutrophil/lymphocyte ratio (NLR) for distinguishing adrenocortical adenomas (ACA) from adrenocortical carcinomas (ACC)

Inflammation-based scores in benign and malignant adrenal tumours

Patients with ACC had higher levels of NLR, PLR, SII and lower levels of LMR and PNI compared to patients with ACA (all p values < 0.001), as shown in Table 1. Importantly, this difference remained significant after adjusting age, tumour maximum diameter, and cortisol after 1 mg-DST (Table 1).

Among the inflammation-based scores, NLR demonstrated the highest accuracy in distinguishing ACC from ACA, with an area under the curve (AUC) of 0.847 (95% CI 0.795–0.894) and an optimal cut-off value of 2.6 (Table 3 and Fig. 1B).

Table 3 Receiver Operator Curves (ROC) with their most discriminant values (Youden’s Index) for multiple inflammation-based scores to distinguish patients with adrenocortical adenomas (ACA, n = 429) from adrenocortical carcinomas (ACC, n = 61)

The logistic regression analysis showed that the presence of NLR > 2.6 was independently associated with the presence of ACC [OR 7.955 (95% CI 1.374–46.058), p = 0.021], cortisol levels after 1 mg-DST (50 nmol/L increase) [OR 1.336 (95% CI 1.185–1.507), p < 0001] and age (1-year increase) [OR 1.035 (95% CI 1.018–1.051, p < 0.001] but not with size (1 cm increase) [OR 0.995 (95% CI 1.185–1.507), p = 0.950]. The results did not change even including UFC levels in the place of cortisol levels after 1 mg-DST or including the presence of hypertension and diabetes in the model (data not shown). Finally, the two-way ANOVA analysis showed that both the presence of malignancy (ACC vs ACA, p < 0.001) and the presence of cortisol excess (cortisol after 1 mg-DST > 50 nmol/L, p < 0.001) were associated with higher NLR values (Fig. 2). Moreover, the same analysis showed that no significant interaction was present between malignancy and cortisol excess (p = 0.21) in influencing NLR values.

Fig. 2

Neutrophil/lymphocyte ratio (NLR) in patients with adrenocortical adenomas (ACA) and adrenocortical carcinomas (ACC). 1-mg DST = 1-mg overnight dexamethasone-suppression test. Data are shown as median and interquartile range, the upper and the lower whiskers represent respectively the 90 and the 10 percentiles

Effect of cortisol excess on inflammation-based scores in adrenocortical carcinomas

The ACC cohort was divided in two groups according to the presence of normal (ACC without cortisol excess, comprising patients with inactive-ACC and androgen-ACC) or pathological levels of cortisol after 1 mg-DST (ACC with cortisol excess, combining both patients with MACS-ACC and CS-ACC), as detailed in Supplementary Table 2.

There were no significant differences in terms of clinical and demographic characteristics between patients with or without cortisol excess, except for ENSAT stage (Table 4). NLR and SII was found to be higher in patients with cortisol excess compared to those without (p = 0.002 and p = 0.007, respectively). On the other hand, PNI was lower in the subgroup with cortisol excess compared to the one without hypercortisolism (p = 0.044) (Table 4).

Table 4 Demographic, clinical, laboratory, and radiological data of patients with adrenocortical carcinoma (ACC), divided according to the presence of normal or pathological levels of cortisol after 1 mg-DSTAssessing inflammation-based scores for distinguishing inactive adrenocortical carcinomas from adenomas

According to our findings, we hypothesized that inflammation-based score might be useful to differentiate inactive ACC from ACA. When specifically analyzing this subgroup of patients, i.e., 215 patients with non-functioning ACA (inactive-ACA) and 10 patients with inactive-ACC, only LMR and NLR were different between the two groups (NLR 2.2 (1.71–2.93) for ACA and 2.82 (2.55–3.35) for ACC, p = 0.040, and LMR 3.66 (2.98–4.6) for ACA and for ACC 2.69 (2.31–3.81), p = 0.031, respectively). We therefore evaluated the discriminatory power of these two inflammation-based scores in differentiating patients with inactive-ACC and inactive-ACA. Here NLR showed an AUC of 0.692 (95% CI 0.563–0.821); the cut-off value with the best compromise between sensitivity and specificity being 2.42 (Se 90%, Sp 59.1%), while LMR showed an AUC of 0.702 (95% CI 0.540–0.865); the cut-off value with the best compromise between sensitivity and specificity was set at 2.71 (Se 60%, Sp 83%) (Fig. 3).

Fig. 3

Neutrophil-to-lymphocyte ratio (NLR, A and lymphocyte-to-monocyte ratio (LMR, B for distinguishing inactive adrenocortical adenomas (ACA) from inactive adrenocortical carcinomas (ACC)