All patients with unilateral AL should be screened for malignancy. For incidentalomas with a benign appearance on imaging, international guidelines suggest a repeat imaging study at 12 months after initial discovery . The rationale is that several malignant lesions can grow in this time, leading to earlier intervention. In principle, the appropriateness and suitability of surgery should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. Despite the well-established role of imaging, still unclear or borderline unilateral ALs are found, both regarding the hormonal profile and the radiological features. Molecular imaging employing FDG-PET has been proposed for unilateral AL characterization and a systematic review including 29 studies (2421 patients) found a pooled sensitivity for FDG-PET of 91% (95% CI: 88% - 94%) and a pooled specificity of 91% (95% CI: 87% - 93%) for AL characterization . In the current study we enrolled 48 patients with unilateral AL who had undergone ceCT and FDG-PET before adrenalectomy or 24 months follow-up. On the basis of the composite reference standard, approximately 44% of patients had a unilateral adrenal tumor requiring adrenalectomy. Most importantly, regarding the final diagnosis, the cohort of patients was balanced, with about 56% of benign diagnosis (e.g. adenoma, hyperplasia), 25% of pheochromocytoma and 19% of adrenal carcinoma. Here we present a dual approach to the management of unilateral ALs. Firstly an imaging diagnostic score based on ceCT and FDG-PET parameters and, secondly, a diagnostic flow-chart for optimizing patient management and avoiding unneeded FDG-PET procedure. FDG-PET cut-off values have been investigated in previous publications for ALs characterization [13–16]. Tessonnier and colleagues reported the value of FDG-PET in the diagnosis of 41 indeterminate ALs (29% malignant) . They showed that the use of an adrenal-liver ratio SUVmax was more accurate than visual assessment in the distinction between benign and malignant ALs, with an optimal threshold value of 1.8. Altinmakas et al retrospectively enrolled 59 patients with 61 AL and FDG-PET before histologic evaluation, of those 88% were malignant lesions (44% metastasis) . They found a threshold for adrenal-liver ratio SUVmax of 0.83 in discriminating malignant ALs, which yielded accuracy of 87% and sensitivity of 98%. Moreover, when combined with non-contrast CT density of the AL, the diagnostic performance of both individual FDG-PET parameters increased, both combinations yielding essentially the same accuracy of 93% and AUCs of 0.81. However, in this surgical cohort of patients only few of them had benign AL, no pheochromocytoma was found and injection of iodinated contrast medium with multiphase CT was not performed. In our study, considering the maximum lesion diameter, unenhanced HU and adrenal-liver SUVmax ratio, an AUC of 0.809 was found, comparable to the study by Altinmakas and colleagues. FDG-PET made up of a low-dose unenhanced CT part of the scan could thus be a feasible one-stop-shop examination for assessing unilateral ALs in patients where iodinated contrast medium is contraindicated or when incidentally detected firstly by FDG-PET, even if the AUC is lower than the one found for FDG-PET and multi-phase ceCT (AUC=0.904; p=0.110). In a prospective multicenter study on 87 adrenal masses in non-cancer patients, histology was obtained in 74% of cases and 12-months follow-up was performed in the remaining patients . Overall, 83% were benign AL, 2% were pheochromocytoma and tumors diagnosed with uncertain malignant potential on final pathology were considered as benign. The optimal threshold value of the adrenal-liver ratio SUVmax for malignancy was 1.5 with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 86.7%, 86.1%, 56.5%, 96.9%, and 86.2%, respectively. Nevertheless, there is clinical need for a simple and practical diagnostic algorithm able to discriminate patients to follow-up from patients to treat surgically. We developed a two-parameters imaging score based on ceCT delayed phase and FDG-PET SUVmax able to discriminate, in a cohort made up of benign and malignant lesions including pheochromocytoma, patients with adrenal tumors to treat surgically from patients to follow-up with an AUC of 0.904, slightly higher than the AUC of 0.868 found by Guerin et al. Based on these results, a risk score was proposed, showing an excellent predictive value for scores of 5-6. On the other hand, a simple diagnostic flow-chart to address patients to the most accurate management in order to avoid unneeded diagnostic procedures is missing for ALs. Hormonal assessment together with ceCT discriminate most of patients with a unilateral AL and only patients with an uncertain diagnosis would be referred to FDG-PET especially in a cost-effectiveness rationale. Indeed, ESE and ENSAT guidelines suggest to perform non-contrast CT and HA when assessing AL risk of malignancy . If the AL is indeterminate on non-contrast CT and the result of the HA do not indicate significant hormone excess, there are three options that should be contemplated, namely immediate additional imaging (i.e. MRI, ceCT and FDG-PET), interval imaging in 6-12 months or surgery, guidelines say. However, there is lack of evidence and studies reporting direct comparison of these different imaging modalities. We calculated cut-offs for ceCT parameters to distinguish patients with defined diagnosis from patients with uncertain management. Applying the FDG-PET adrenal-liver ratio SUVmax cut-off of 1.7 to those remaining patients with uncertain management, we found an overall accuracy of 83%, sensitivity of 76% and specificity of 89% for adrenal tumors to treat surgically and a manageable diagnostic flow-chart was designed accordingly.
Summarizing, we proposed two distinct tools able to efficiently support clinicians, radiologists and nuclear medicine physicians when assessing ALs and to optimize patient management.
This study has a number of strengths in comparison to prior studies evaluating ceCT and FDG-PET for unilateral ALs characterization. These include the multidisciplinary approach to included patients, ceCT protocol made up of four phases, short timeframe between ceCT and FDG-PET, i.e. one month, implementation of independent readers, and lesions validation by adrenalectomy or clinical follow-up of at least 24 months. Lastly, a reasonably narrow dimensional range of the AL compared to previous studies. However, major limitations are the retrospective design, the imaging approach based solely on ceCT and FDG-PET without including MRI as well as the lack of a systematic hormonal screening in all patients, and the small sample size. In addition, the imaging-based algorithm and the diagnostic flow-chart are not validated in an independent sample. Therefore, further prospective evidence is needed to externally validate both the predictive score and the diagnostic flow-chart in larger cohorts of patients.