Clinical Features of Oncocytic Adrenocortical Carcinoma

Table 1 summarizes the clinicopathological features at diagnosis for the 44 patients affected by OAC included in this study. The mean age at diagnosis was 50.1 ± 15.3 years; 30 (68.2%) were female and 14 (31.8%) were male. The median tumor size at diagnosis was 6.7 cm (25–75 IQR = 5.0–10.0). Autonomous adrenal hormonal excess was observed in 22 patients (50.0%). Of these, 10 patients (22.7%) had mixed hormonal secretion (cortisol plus androgens in 9 patients and cortisol plus mineralocorticoid in 1 patient); 8 patients (18.2%) had autonomous cortisol production, and 4 patients (9.1%) had androgen excess. Of the remaining patients, 18 (40.9%) had non-functioning tumors, and in 4 cases (9.1%), this data was not available. The median Ki67 was 13% (25–75 IQR = 6–20), and the median mitotic count was 6/2 mm2 (25–75 IQR = 4–8). Moreover, we found that all patients with OAC except one had a Helsinki score > 8.5; the latter was considered malignant due to the presence of one major criteria (venous invasion) and three minor criteria of LWB (large size, capsular and sinusoidal invasion). After surgery, the majority of patients had R0 status (33 patients, 75.0%). RX status was identified in 7 patients (15.9%), and positive tumor margins (R1) were identified in 4 patients (9.1%). No patients had gross residual tumor (R2).

Table 1 Clinicopathological features at diagnosis in patients with oncocytic adrenocortical carcinoma and conventional adrenocortical carcinoma and comparison between groups

Regarding disease extension at diagnosis, only 6 patients (13.6%) presented with distant metastases: of these, three patients underwent surgery for hormonal control due to the secretion of cortisol and androgens, one patient for curative purposes due to infiltration of the ipsilateral kidney, and two patients to alleviate discomfort caused by the mass effect of the large tumor. According to the ENSAT staging system, 24 patients (55.8%) had localized disease (ENSAT I/II), 13 patients (30.2%) had locally advanced disease (ENSAT III), and 6 patients (14.0%) had metastatic disease at diagnosis (ENSAT IV).

Patients were followed up for a median time of 58.5 months (25–75 IQR = 32.2–81.5). After surgery, 30 patients (68.2%) were disease-free, 6 patients (13.6%) had persistent disease, and 9 patients (20.5%) experienced recurrence, with a median time to progression (TTP) of 31.4 months (25–75 IQR = 23.3–49.7). At the end of the follow-up period, 38 patients (86.4%) were alive. The survival rate at 5 and 10 years was 89.3% (95% CI = 73.3–95.9) and 76.5% (95% CI = 40.8–92.3), respectively.

Comparison Between Oncocytic and Conventional Adrenocortical Carcinoma

The clinical and immunohistochemical characteristics of patients with OAC were compared with those of 145 patients with conventional ACC. Table 1 reports the comparison between the two groups.

At diagnosis, no significant differences were observed between the two groups in terms of male-to-female ratio, age, Ki67 proliferative index, mitotic count, Helsinki score, necrosis, hormonal excess, distant metastases, or stage. However, patients with OAC had a smaller median tumor size (6.7 cm vs. 9.3 cm, p = 0.044) and more favorable status of resection margins. Indeed, compared to conventional ACC, complete tumor resection (R0) was achieved in 75.0% of OAC patients versus 51.7% of conventional ACC patients, while micro- (R1) and macroscopic (R2) residual tumors were observed in 9.1% vs. 19.3%, respectively (p = 0.023). This difference remained statistically significant even when adjusted for tumor size.

Furthermore, patients with OAC had a lower incidence of venous invasion (44.1% vs. 66.3%, p = 0.022) and a lower incidence of persistent/recurrent disease during follow-up (34.1% vs. 51.7%, p = 0.040). As a result of these features indicating less aggressive biological behavior, patients with OAC had a higher likelihood of being alive at the end of the follow-up period (86.4% vs. 69.2%, OR = 0.36, 95% 95% CI = 0.14–0.90, p = 0.029).

Survival analysis demonstrated that patients with OAC had both a longer time to progression (TTP) and overall survival (OS) (78.7 months and not reached, respectively) compared to patients with conventional ACC (45.1 months and 123.7 months, respectively) (Figs. 2 and 3).

Fig. 2

Kaplan–Meier curve for time to progression in patients with oncocytic and conventional adrenocortical carcinoma

Fig. 3

Kaplan–Meier curve for overall survival in patients with oncocytic and conventional adrenocortical carcinoma

Identification of Risk Factors for Persistent/Recurrent Disease and Overall Survival in Patients with OAC

Table 2 summarizes the characteristics associated with the risk of persistent/recurrent disease in patients with OAC. Univariate analysis revealed that progression was associated with the following factors: Ki67 (HR = 1.06, 95% CI = 1.02–1.10; p = 0.001), mitotic count (HR = 1.09, 95% CI = 1.03–1.17; p = 0.006), tumor size (HR = 1.14, 95% CI = 1.01–1.29; p = 0.041), distant metastases at diagnosis (HR = 6.62, 95% CI = 2.09–20.93; p = 0.001), stage III/IV ENSAT (HR = 8.32, 95% CI = 1.84–37.71; p = 0.006), and R1–R2 resection status (HR = 5.24, 95% CI = 1.08–25.47; p = 0.040). Multivariable analysis identified Ki67 (HR = 1.09, 95% CI = 1.04–1.15; p = 0.001) and tumor size (HR = 1.39, 95% CI = 1.08–1.77; p = 0.010) as features independently associated with disease progression during post-surgical follow-up. By ROC curve analysis, we found that a Ki67 cutoff value of 20% had the best performance in predicting the risk of progressive disease in patients with OAC (AUC = 0.73; sensitivity, 67%; specificity, 80%). Median TTP was 20.0 months in patients with Ki67 ≥ 20% and not reached in patients with ki67 < 20% (log-rank p value < 0.001).

Table 2 Cox regression analysis to evaluate factors associated with persistent/recurrent disease in patients with oncocytic adrenocortical carcinoma

Table 3 summarizes the characteristics associated with OS in patients with OAC. Univariate analysis identified the following factors: Ki67 (HR = 1.06, 95% CI = 1.01–1.12; p = 0.015), mitotic count (HR = 1.09, 95% CI = 1.01–1.19; p = 0.036), distant metastases at diagnosis (HR = 8.15, 95% CI = 1.28–51.92; p = 0.026), and R1–R2 resection status (HR = 13.04, 95% CI = 1.76–96.59; p = 0.012). Multivariable analysis confirmed that Ki67 (HR = 1.10, 95% CI = 1.01–1.19; p = 0.030) and distant metastases at diagnosis (HR = 23.84, 95% CI = 1.56–364.7; p = 0.023) were independently associated with OS.

Table 3 Cox regression analysis to evaluate factors associated with overall survival in patients with oncocytic adrenocortical carcinomaIdentification of Factors for Adjuvant Mitotane in Patients with OAC

To identify factors that could help in selecting patients who might benefit from adjuvant mitotane, we analyzed 38 out of 44 (86.4%) patients who had complete tumor resection and negative post-surgical imaging. Among these 38 patients, 22 (57.9%) were treated with adjuvant mitotane, and 16 were not. Recurrent disease was identified in 10 (26.3%) patients, with a median TTP of 29.9 months (25–75 IQR = 20.0–49.7). Among these 10 patients, 7 were treated with adjuvant mitotane and 3 were not. The median Ki67 value was 15 (25–75 IQR = 8–23) in patients treated with adjuvant mitotane, compared to 9 (25–75 IQR = 6–10) in those not treated (p = 0.042). After disease progression on mitotane therapy: 4 patients underwent additional surgery, and at the last follow-up, 2 patients were alive and 2 had died after receiving systemic chemotherapy; 3 patients were treated with systemic chemotherapy, and at the last follow-up, 2 patients were alive and 1 had died; 3 patients were maintained on mitotane therapy because of a very slow tumor progression and were all alive at the last follow-up.

At the univariate analysis, the risk of recurrence was associated with the following: Ki67 (HR = 1.06, 95% CI = 1.02–1.11; p = 0.006), mitotic count (HR = 1.15, 95% CI = 1.04–1.26; p = 0.006), and ENSAT stage III/IV (HR = 5.72, 95% CI = 1.45–22.49; p = 0.013). Multivariable analysis confirmed that Ki67 (HR = 1.10, 95% CI = 1.04–1.17; p = 0.001) and ENSAT stage III/IV (HR = 20.63, 95% CI = 2.37–179.37; p = 0.006) were independent factors associated with recurrent disease (Table 4). By ROC curve analysis, the Ki67 value of 20% was confirmed as the best in predicting the risk of recurrent disease in patients with OAC (AUC = 0.69; sensitivity, 56%; specificity, 83%). Figures 4 and 5 show the Kaplan–Meier curve for the probability of recurrent disease according to the Ki67 and ENSAT stage, respectively. Median TTP was 23.3 months in patients with Ki67 ≥ 20% and 49.7 months in patients with ENSAT stage III/IV (not reached in patients with Ki67 < 20% and ENSAT stage I/II; log-rank p < 0.001 and 0.004, respectively).

Table 4 Cox regression analysis to evaluate factors associated with recurrent disease in patients with oncocytic adrenocortical carcinomaFig. 4

Kaplan–Meier curve for recurrent disease after surgery according to the Ki67 in patients with oncocytic adrenocortical carcinoma

Fig. 5

Kaplan–Meier curve for recurrent disease after surgery according to the ENSAT stage in patients with oncocytic adrenocortical carcinoma