Patients
The main characteristics of the patients are summarized in Table 1. Symptoms of adrenal steroids hypersecretion (42.8%) was the most common type of clinical presentation. Over half of the patients (54%) had a localized tumor larger than 5 cm (ENSAT stage 2). Among the 55 operated patients, 41 (75%) underwent an open surgery. Forty-eight (87.3%) operated patients had a complete resection (R0). The Ki67 labeling index was available for 46 out of the 55 operated patients. High expression of Ki67 (> 10%) and an excessive number of mitosis (> 5), both criteria associated with poorer survival, were present respectively in 61% and 78% of the patients. The median follow-up period was 3.3 years (range 8 days-11.7 years) from the diagnosis of ACC. Mean SUVmax and mean adrenal-to-liver SUVmax ratios ± standard deviation were 12.6 ± 6.9 and 5.2 ± 3.2, respectively.
Adrenal-to-liver SUVmax ratios and Weiss scores
As the adrenal-to-liver SUVmax ratio is considered to have the best diagnostic performance for characterizing adrenal tumors, this parameter is shown in Fig. 2 in relation to Weiss scores obtained for the 55 operated ACC. The indicated threshold value of 1.45 represents the lowest published cutoff ratio to diagnose ACC with a sensitivity of 100% [7]. In accordance, the ratio was ≥ 1.45 for the 8 non-operated metastatic ACC and for most of the operated patients (48/55, 87%). Conversely, 7 patients (representing 13% of the operated ACC, and 11% of all ACC) had an adrenal-to-liver SUVmax ratio < 1.45, between 0.7 and 1.36, four of them with a ratio less than 1. Among these 7 patients, the Ki67 was available for 6. Five out of these 6 patients (83%) had a Ki67 ≤ 10%, whereas only 13 out of 39 patients (32.5%) with an adrenal-to-liver SUVmax ≥ 1.45 had a Ki67 ≤ 10%. The difference was statistically significant (p < 0.03). Despite a low adrenal-to-liver SUVmax ratio two patients died from their metastatic ACC after 4 months or 3 years, respectively.
Correlation of [18F]-FDG PET parameters with clinical and histological criteria
We next assessed whether the metabolic cancer activity derived from [18F]-FDG PET uptake correlates with disease histology and/or clinical outcomes. Among the analyzed criteria (Fig. 1), a statistically significant positive correlation was found between tumor SUVmax or adrenal-to-liver SUVmax ratio and five clinical or histological parameters (Table 2). Considering individually the nine items of the Weiss score, a positive correlation was only found between tumor SUVmax and capsular invasion (p = 0.05).
The strongest linear relationship was observed between the proliferation marker Ki67 and the tumor SUVmax (r = 0.47, p = 0.0009) or the adrenal-to-liver SUVmax ratio (r = 0.45, p = 0.0015). The significant correlation between adrenal-to-liver SUVmax ratio and Ki67 is shown in Fig. 3. The Ki67 threshold value at 10% represents the known cutoff value predicting ACC with a worse prognosis. Indeed, only 2 out of 18 (11%) patients with Ki67 < 10% died from their metastatic ACC compared to 15 out of 28 (53.5%) patients with Ki67 > 10% (p < 0.004).
To illustrate the relationship between [18F]-FDG PET and the Ki67 we chose images from patients with three different uptake intensity correlating with an increased proliferating marker (Fig. 4).
Tumor SUVmax and adrenal-to-liver SUVmax ratio were associated with reduced overall survival, albeit not achieving significance (hazard ratios [HR] for death, 1.04 per unit; 95% confidence interval [CI], 0.99 to 1.10, p = 0.16; and HR = 1.10, 95% CI 0.98 to 1.23, p = 0.11 respectively). Associations of tumor SUVmax and adrenal-to-liver SUVmax ratio with progression free survival were weaker (HR = 1.03, 95% CI 0.96 to 1.20, p = 0.42 and HR = 1.05, 95% CI 0.90 to 1.24, p = 0.38 respectively).