Check for updates
Prognostic role of pretreatment [18F]FDG PET/CT in patients affected by adrenocortical carcinoma and treated with chemotherapy
Francesco Dondi1,2(D . Davide Lorenzo Bettini1,3 . Deborah Cosentini1,3(D . Roberta Ambrosini 1,4D . Sara Rodella1,3(D . Benedetta Trevisan1,3 . Andrea Abate1,50D . Mariangela Tamburello 1,5(D . Valentina Cremaschi1,3D. Giovanni Casole1,6 . Guido Alberto Massimo Tiberio1,6D . Sandra Sigala1,5D . Salvatore Grisanti 1,3D . Francesco Bertagna1,2(D . Alfredo Berruti1,3(D . Marta Lagana 1,3[D
Received: 11 September 2025 / Accepted: 26 January 2026 @ The Author(s) 2026
Abstract
Purpose [18F]-fluorodesoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) is used for diagnosis and staging of adrenocortical cancer (ACC), its prognostic role needs to be explored. This study aimed to investi- gate the prognostic role of pre-EDP-M [18F]FDG PET/CT parameters in ACC patients treated with first line chemotherapy (ChT) in term of progression free survival (PFS) and overall survival (OS).
Method this retrospective, monocentric study included metastatic ACC patients treated with EDP-M after [18F]FDG PET/ CT staging. Clinico-pathological features and PET/CT semiquantitative parameters such as standardized uptake value (SUV- max), metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmax/liver ratio (SL) and SUVmax/blood-pool ratio (SBP) were collected.
Results forty-one ACC patients were included. Median PFS was 9.3 months and median OS was 14.3 months. PET/CT parameters did not correlate with the response to ChT, while they were affordable prognosticators. Lower MTV (HR 0.36, CI: 0.17-0.74; p<0.01), lower TLG (HR 0.31, CI: 0.15-0.64; p<0.01), lower tumour burden (HR 0.45, CI: 0.23-0.94; p=0.03), attained the statistical significance in univariable analysis in terms of longer PFS, lower TLG (HR 0.33, CI: 0.15-0.71; p<0.01) confirmed its independent role in multivariable analysis. At univariable analysis lower MTV (HR 0.36, CI: 0.16-0.82; p=0.01) correlated with longer OS. Lower TLG confirmed its role in the multivariate analysis (HR 0.28, CI 0.11-0.69; p<0.01).
Conclusion pretreatment TLG was reported as independent prognostic tools for ACC patients treated with EDP-M. No cor- relations between PET/CT parameters and response to ChT were reported.
Keywords [18F]FDG . ACC . Adrenocortical carcinoma . PET . Positron emission tomography . Prognostic factor
☒ Francesco Dondi francesco.dondi@unibs.it
1 Adrenal Cancer Unit ASST Spedali Civili, Piazzale Spedali Civili 1, Brescia 25123, Italy
2 Nuclear Medicine, Università Degli Studi di Brescia and ASST Spedali Civili di Brescia, Brescia 25123, Italy
3 Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia 25123, Italy
4 Radiology, ASST Spedali Civili, Piazzale Spedali Civili 1, Brescia 25123, Italy
5 Department of Molecular & Translational Medicine, Section of Pharmacology, University of Brescia, Brescia 25123, Italy
6 Surgery, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili, Brescia 25123, Italy
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malig- nancy with an estimated incidence of 0.7-2 new cases per million people per year [1]. Surgery is the gold standard for localized ACC and adjuvant therapy is indicated for cases with higher risk of recurrence basing on Ki67 expression, age, cortisol hypersecretion or stage, which define the prog- nostic GRAS score [2-3]. Mitotane combined with poly- chemotherapy (EDP-M) is the current first line treatment for metastatic ACC [4-5]. This treatment strategy has a limited efficacy, although a proportion of patients can obtain a long term disease control [6]. Identifying prognostic markers and predictive parameters of efficacy is therefore crucial. Prolif- erative activity measurement in ACC patients before initiat- ing EDP-M could serve as a valuable prognostic factor and predictive parameter of treatment efficacy. Proliferative sta- tus can be assessed by evaluating the immunohistochemical expression of Ki67, but it is an invasive procedure that is not commonly performed. The use of a non-invasive diagnos- tic tool to evaluate tumor proliferation and aggressiveness before systemic treatment is therefore of great importance. Several studies have shown a positive correlation between [18F]-fluorodesoxyglucose ([18F]FDG) uptake (measured as standardized uptake value [SUV]) and tissue Ki-67 expres- sion in many malignancies [7]. Higher Ki-67 expression often corresponds to higher [18F]FDG uptake, reflecting a more metabolically active, rapidly proliferating tumors [8]. Ki-67 is routinely available and reproducible at diag- ☒ nosis. However, in metastatic ACC, repeat biopsy to reas- sess Ki-67 during progression is not always feasible. While limited data exist on its temporal variation, some studies suggest that Ki-67 may increase at relapse, reflecting tumor dedifferentiation or decrease after response to cytoreductive chemotherapy (ChT) [6].
Current international guidelines suggest [18F]FDG posi- tron emission tomography/computed tomography (PET/CT) as complementary tool in addition to conventional imaging techniques to define extension of the adrenal tumour and evidence for metastases, especially bone. [18F]FDG PET/ CT uptake has been shown to be prognostic in different neo- plasms [9-10].
The prognostic role of [18F]FDG PET uptake in patients with ACC has been assessed in a few studies involving newly diagnosed patients, but the results have been conflicting. In two studies, a higher SUVmax, body metabolic tumor vol- ume, and total lesion glycolysis (TLG) were associated with shorter survival [11-12]. However in 2 more recent studies, quantitatively derived PET and CT parameters, failed to be significantly associated with OS [13-14].
To our knowledge there are no studies that have assessed the role of [18F]FDG PET/CT as a prognostic and predictive
parameter of efficacy in metastatic patients treated with ChT. In this paper we report the results of a retrospective study conducted at the Adrenal Unit of ASST-Spedali Civili in which we evaluated the prognostic and predictive role of [18F]FDG PET/CT in a consecutive series of metastatic ACC patients uniformly treated with the EDP-M scheme. In particular, two major points were analyzed in the paper: the predictive ability of pre-treatment [18F]FDG PET/CT with respect to the response to ChT and the prognostic role of pre-treatment PET on the long-term outcome of patients treated with ChT.
Patients and methods
Patients selection
Our database was retrospectively screened to retrieve advanced patients submitted to EDP-M who had performed [18F]FDG PET/CT for the baseline staging of ACC from January 2014 to December 2023. Among 83 metastatic ACC patients treated with EDP-M in our centre who underwent at least one [18F]FDG PET/CT scan, 41 had this baseline-scan available, performed before starting ChT and were included in the study (Fig. 1).
Clinicopathological information about gender, age, func- tional status of ACC, European Network for the Study of Adrenal Tumours (ENSAT) stage, tumor burden, Ki67
108 advanced ACC 18FDG/PET performed in our center
25 excluded non treated with EDP-M (clinical conditions, previously treated)
83 treated with EDP-M in our center
42 excluded non available baseline PET before I cycle EDP-M
41 baseline PET scan available
value, type of ChT were collected. Informed consent was obtained from all individual participants included in the study.
[18F]FDG PET/CT acquisition and interpretation
Before PET/CT acquisition patients fasted for at least 6 h and they had a glucose blood level below 150 mg/dl at the time of injection; 3.5-4.5 MBq/kg of [18F]FDG were intravenously injected to the patients and before images acquisition they were instructed to void. No contrast agent, intestinal preparation with purge or enteric contrast were used. Images were acquired 60 min after radiotracer injec- tion, from the skull base to the midthigh on a Discovery ST or Discovery 690 PET/CT tomograph (General Electric Company, GE, Milwaukee, Wisconsin) in the same depart- ment with standard parameters (CT: 80 mA, 120 kV; PET: 2.5-4 min per bed position, PET step of 15 cm). Images were reconstructed with a 256×256 matrix and a 60 cm field of view. On Discovery 690 tomograph time of flight (TOF) and point spread function (PSF) algorithm were used for the reconstruction of images, with filter cut-off 5 mm, 18 subsets and 3 iterations. For Discovery ST tomograph, an ordered subset expectation maximization (OSEM) algo- rithm with filter cut-off 5 mm, 21 subsets and 2 iterations was used.
PET/CT images were visually and semiquantitatively analyzed by two experienced nuclear medicine physicians by consensus. Every focal tracer uptake deviating from physiological distribution and from the background was regarded as suggestive of disease localization. The semi- quantitative analysis of images was performed by measuring SUVmax of the most hypermetabolic lesion. Furthermore, the SUVmax of the liver was calculated at the VIII hepatic segment from transaxial PET images using a spheric vol- ume of interest (VOI) with 1 cm diameter. The SUVmax of the blood-pool was calculated at the aortic arch by using transaxial PET images with a similar VOI, paying attention to not involve the vessel’s walls. These values were used to calculate a ratio between SUVmax of the lesion with the highest uptake and these two parameters (SL and SBP, respectively).
An SUV-based automated contouring program (Advan- tage Workstation 4.6, GE HealthCare) was used to measure metabolic tumor volume (MTV) from attenuation corrected [18F]FDG PET/CT images, using an isocontouring thresh- old method based on 41% of the SUVmax, as recommended by the European Association of Nuclear Medicine guideline [15]. Furthermore, total lesion glycolysis (TLG) was calcu- lated as the sum of the product of the MTV of each lesion and its SUVmean.
Statistical analysis
All statistical analyses were performed using SPSS v29.0.1.0 for Windows (SPSS Inc, Chicago, USA). The descriptive analysis of categorical variables comprised the calculation of simple and relative frequencies. The numeric variables were described as median and minimum and maximum (range).
Overall Survival (OS) was defined as the time in months from the date of the initiation of ChT to the date of death for any cause or to the date of last documented follow-up. Progression Free Survival (PFS) was calculated as the time in months between the initiation of ChT and the date of first documented disease progression, based on radiological imaging (x-ray, CT, magnetic resonance and PET/CT).
Logistic regression analysis was used to evaluate a cor- relation between PET parameters and the response to ChT, considering stable and responding patients vs. progressing disease defined with the combination of PET/CT and con- ventional imaging data.
Kaplan-Meier analysis was used to draw survival curves which were compared using the log-rank test. A p-value<0.05 was considered as statistically significant. In order to perform such analyses, continuous quantitative parameters were dichotomized based on their median value. This decision has been made given the small sample of our cohort, retaining that a median-based dichotomization could avoid model overfitting. Furthermore, Cox regres- sion model was applied to identify independent prognostic factors between clinicopathological and PET/CT features. In particular, these features were retained for multivariable analysis if they had a significant prognostic value at uni- variable analysis (p-value<0.05) or they were near the limit of statistical significancy (p-value<0.10). Estimates of the predictive effect for OS and PFS were expressed as hazard ratios (HRs) in univariable and multivariable Cox regres- sion analyses with a 95% confidence interval (CI).
Results
ACC patients characteristics and [18F]FDG PET/CT scan semiquantitative parameters
All the patients included in the study were metastastic at the moment of [18 F]FDG PET/CT performed before ChT start. Among 41 included patients, the median age at time of base- line-PET was 53 years (range 24-77) and 27 (66%) patients were female. Thirty-one patients (75%) were not metasta- stic at ACC diagnosis while 6 (14%) presented a mEnsat stage IVa, 2 (5%) stage IVb and 2 (5%) stage IVc. ACC was
Table 1 Patients characteristics
N=41
| Clinicopathological charachteristics | N (%) |
|---|---|
| or Median (range) | |
| Age at baseline-PET | 53 |
| (24-76) | |
| Sex | |
| - Male | 14 (34) |
| - Female | 27 (66) |
| Diagnosis | |
| - Hormonal related symptoms | 15 (37) |
| - Mass related symptoms | 12 (30) |
| - Both hormonal and mass related symptoms | 3 (7) |
| - Incidentaloma | 11 (26) |
| Cortisol secretion at PET pre CHT* | |
| - Yes | 14 (50) |
| - No | 14 (50) |
| Serum cortisol levels at PET pre CHT | 7.00 |
| (1.00- | |
| 29.00) | |
| mENSAT stage at diagnosis | |
| -1 | 2 (5) |
| -2 | 17 (41) |
| -3 | 12 (29) |
| -4a | 6 (14) |
| -4b | 2 (5) |
| -4c | 2 (5) |
| Ki67 at ACC diagnosis ** | |
| -< 20 | 18 (46) |
| -≥20 | 21 (54) |
| Surgery on primary ACC | 30 (73) |
| Adjuvant mitotane treatment | 20 (49) |
| Tumor burden at the start of CHT and PET evaluation | |
| - 1 site | 18 (44) |
| -2 sites | 11 (27) |
| -3 sites | 6 (15) |
| -4 sites | 5 (12) |
| -5 sites | 1 (2) |
| Disease site | |
| - Liver | 22 (54) |
| - Lung | 22 (54) |
| - Adrenal lodge | 13 (32) |
| - Peritoneum | 11 (27) |
| - Lymphnodes | 5 (12) |
| - Bone | 4 (10) |
| - Kidney | 2 (5) |
*Data available for 28 patients
** Data available for 39 patients
N number, ENSAT European Network for the Study of Adrenal Tumours, ACC adrenocortical carcinoma, PFS progression free survival, OS Overall survival, CHT chemotherapy, EDP etoposide, doxorubicine and cisplaTin.
diagnosed due to hormone hypersecretion symptoms in 15 (37%) patients and due to tumor mass effect in 12 (30%), while 3 (7%) patients presented both hormone hypersecre- tion and mass effect symptoms; in 11 (26%) patients the diagnosis was incidental. Among 28 patients for whom the
| Parameter | All patients (N: 41) | Non respond- ers (N: 18) | Responders (N: 23) | p value |
|---|---|---|---|---|
| SUVmax | 12.2 (3.3-42.2) | 12.7 (3.3-31.3) | 11.6 (4.8-42.2) | 0.475 |
| MTV | 41.1 | 42.1 | 41.1 | 0.352 |
| (2.6-2011.8) | (2.6-374.7) | (4.3-2011.8) | ||
| TLG | 239.9 | 213.0 | 322.9 | 0.263 |
| (11.6-8800.0) | (11.6-2662.7) | (13.7-8800.0) | ||
| SL | 3.9 (1.1-16.3) | 4.9 (1.1-8.4) | 3.7 (1.7-16.3) | 0.362 |
| SBP | 5.9 (2.1-27.4) | 5.9 (2.3-11.8) | 5.6 (2.1-27.4) | 0.347 |
Non responders: progression of disease burden at imaging at the end of CHT.
Responders: stability or reduction of disease burden at the end of CHT.
N number, SUVmax maximum standardized uptake value, MTV metabolic tumour volume, TLG total lesion glycolysis, SL SUVmax/ Liver ratio, SBP SUVmax/blood-pool ratio.
plasma cortisol value was available at the time of the PET pre-ChT, 14 patients (50%) had cortisol hypersecretion. At diagnosis, median Ki-67 value was 20% (range 3-65), 5 (6%) patients had a lower value less than 10% (ki67 value was available in 39 patients). At ChT start 18 patients (44%) presented 1 metastatic site while 23 (56%) had the involve- ment of 2 or more organs other than the adrenal gland. These patients were defined as having high tumour burden (Table 1).
The median time interval between [18F]FDG PET/CT and first line ChT start was 1 day [1-30]. Most of the patients (34/41, 82.9%) performed PET/CT imaging on Discovery 690 tomograph.
As for the [18F]FDG PET/TC semiquantitative param- eters, median SUVmax was 12.2 (range 3.3-42.2), median MTV was 41.1 (range 2.6-2011.8), median TLG was 239.9 (range 11.6-8800), median SBP was 5.9 (range 2.1-27.4) and median SL was 3.9 (range 1.1-16.3). No significant differences were reported for such parameters between responders patients and non responders subjects (Table 2). Additionally, PET/CT semiquantitative parameters at chi- square analysis showed a statistically significant correla- tion between higher TLG and tumor burden (p-value 0.03) (Table 3).
[18F]FDG PET/CT pre-chemotherapy scan parameters correlation with response
All patients started ChT according to the EDP-M regimen (median number of cycles 5, range 1-10) after [18F]FDG PET/CT scan [16]. Thirty-one (76%) patients presented mitotane level in range during the ChT treatment. The best response was complete response in 3 subjects (7%), partial
| Variable | SUVmax | SL | SBP | MTV | TLG |
|---|---|---|---|---|---|
| Cortisol | 0.154 | 0.165 | 0.064 | 0.239 | 0.265 |
| Ki67% | 0.008 | 0.0003 | -0.011 | 0.031 | 0.089 |
| Tumor burden | 0.083 | 0.108 | 0.127 | 0.038* | 0.458 ** |
* p value 0.012
** p value 0.002
SUVmax maximum standardized uptake value, MTV metabolic tumour volume, TLG total lesion glycolysis, SL SUVmax/Liver ratio, SBP SUVmax/blood-pool ratio.
response in 13 patients (32%), stable disease in 7 (17%), progression in 18 (44%).
Logistic regression analysis revealed that none of the assessed PET parameters demonstrated a statistically sig- nificant correlation with the response to ChT, considering stable and responding patients vs. progressing disease. In particular, TLG had an odds ratio (OR) of 2.365 (95% con- fidence interval [CI] 0.200-27.929) with a p value of 0.494, MTV an OR of 1.953 (95% CI 0.452-8.442) with a p value of 0.370 and SUVmax an OR of 0.118 (95% CI 0.009- 1.628) with a p value of 0.111.
Prognostic role of [18 F]FDG PET/CT pre- chemotherapy scan parameters
The median follow-up of this patient series was 42 months (range 8-161), during which 34 (83%) patients experienced
disease progression and 27 (66%) died. The median PFS after ChT start was 9.3 months (range 1.8-64.9) and the median OS was 14.3 months (range 1.5-79.6).
Lower MTV (HR 0.36, CI: 0.17-0.74; p<0.01), lower TLG (HR 0.31, CI: 0.15-0.64; p<0.01), lower tumour bur- den (HR 0.45, CI: 0.23-0.94; p=0.03), were significantly associated with a lower risk of disease progression. Since the value of MTV is included in the calculation of TLG, subsequent multivariable analysis was performed includ- ing only the latter. Lower TLG (HR 0.33, CI: 0.15-0.71; p=0.005) confirmed to be an independent parameter associ- ated with PFS at multivariable analysis (Fig. 2).
As regards as OS, univariable analysis revealed that lower MTV (HR 0.36, CI: 0.16-0.82; p=0.01) and lower TLG (HR 0.30, CI: 0.12-0.69; p<0.01) correlated with lower risk of death while lower tumour burden was near the statistical significance value (HR 0.48, CI: 0.21-1.07; p=0.07). Lower TLG did achieve statistical significance as an independent prognostic factor in terms of OS in the multivariable analysis (HR 0.28, CI 0.11-0.69; p<0.01) (Table 4).
Discussion
[18F]FDG PET/CT is a well established tool for the diagno- sis and the assessment of recurrence of malignant adrenal tumors and its prognostic role has also been investigated in
A
PFS
B
PFS
100
100
80
80
Survival probability (%)
Survival probability (%)
60
60
40
40
MTV<41.1
TLG<239.9
20
20
MTV≥41.1
TLG≥239.9
0
0
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
Time
Time
C
OS
100
D
OS
100
80
80
Survival probability (%)
Survival probability (%)
60
60
40
MTV<41.1
40
TLG<239.9
20
20
MTV≥41.1
TLG≥239.9
0
0
0
20
40
60
80
0
20
40
60
80
Time
Time
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| p-value | HR (95% CI) | p-value | HR (95% CI) | |
| PFS | ||||
| SUVmax lower than | 0.38 | 0.74 | – | – |
| median | (0.37-1.45) | |||
| MTV lower than | 0.006 | 0.36 | – | – |
| median | (0.17-0.74) | |||
| TLG lower than | 0.002 | 0.31 | 0.005 | 0.33 |
| median | (0.15-0.64) | (0.15- | ||
| 0.71) | ||||
| SL lower than median | 0.15 | 0.60 | – | – |
| (0.30-1.21) | ||||
| SBP lower than | 0.19 | 0.62 | – | – |
| median | (0.30-1.26) | |||
| No cortisol secretion | 0.27 | 1.60 | – | – |
| (0.69-3.72) | ||||
| Age at diagnosis lower | 0.54 | 0.81 | – | – |
| than 50y | (0.41-1.59) | |||
| Tumour burden <2 | 0.03 | 0.45 | 0.107 | 0.54 |
| (0.23-0.94) | (0.26- | |||
| 1.13) | ||||
| OS | ||||
| SUVmax lower than | 0.64 | 0.83 | – | – |
| median | (0.39-1.78) | |||
| MTV lower than | 0.01 | 0.36 | – | – |
| median | (0.16-0.82) | |||
| TLG lower than | 0.005 | 0.30 | 0.006 | 0.28 |
| median | (0.12-0.69) | (0.11- | ||
| 0.69) | ||||
| SL lower than median | 0.31 | 0.67 | – | – |
| (0.30-1.47) | ||||
| SBP lower than | 0.75 | 0.88 | – | – |
| median | (0.40-1.92) | |||
| No cortisol secretion | 0.40 | 0.65 | – | – |
| (0.24-1.75) | ||||
| Age at diagnosis lower | 0.79 | 0.90 | – | – |
| than 50y | (0.42-1.93) | |||
| Tumour burden <2 | 0.07 | 0.48 | 0.21 | 0.59 |
| (0.21-1.07) | (0.25- | |||
| 1.35) | ||||
PFS progression free survival, OS overall survival, CHT chemother- apy, SUVmax maximum standardized uptake value, MTV metabolic tumour volume, TLG total lesion glycolysis, SL SUVmax/Liver ratio, SBP SUVmax/blood-pool ratio.
the past [17, 18-19]. In this paper we specifically focused on the predictive ability of this imaging modality to evaluate the efficacy of ChT. In this retrospective study of patients with metastatic ACC, all uniformly treated with EDP-M, baseline pre-ChT [18F]FDG PET/CT parameters were dem- onstrated as independent prognostic predictors, while they did not demonstrate a correlation with response to ChT. In particular, TLG was demonstrated to be a significant
independent prognostic parameter. In addition, since the calculation of TLG comprehends MTV, also this param- eters can be considered as an affordable prognostic factor. These parameters reflects the disease burden of the patients in terms of both metabolic activity and volumetric dis- semination, indicating that subjects with higher amount of neoplastic mass and metabolic active disease have a worst prognosis in terms of disease progression and death. A rep- resentative case that demonstrates this correlation is shown in Fig. 3.
Our data confirm previously reported correlations between [18F]FDG PET/CT findings and OS [11-12, 20], with the addition that in our study the correlation was also demonstrated with PFS. This study’s results are in conflict with those of two papers that found no prognostic value of this imaging modality in ACC patients [13-14, 21]. The prognostic insights of [18F]FDG PET/CT in patients with ACC has been previously reported by Leboulleux et al. [20] that reported SUVmax and the volume of uptake of the tracer, a parameter similar to MTV, significantly asso- ciated with survival however without a confirmation at multivariable analysis. Similarly, Satoh et al. [12] demon- strated that subjects with higher MTV, TLG or SUVmax had a worse OS; interestingly, no significant differences in terms of OS were underlined between patients who performed ChT prior to operative intervention and those who did not perform it. More recently, Wrenn et al. [11], revealed a strong negative association between SUVmax and OS. Our results demonstrated and confirmed the prog- nostic role of baseline [18F]FDG PET/CT, in particular in the setting of patients treated with ChT. However, it should be noted that the patients included in the present study, all of whom were metastatic and treated with ChT, are differ- ent from other published case series, and this may explain the observed differences. As a matter of fact, the median SUVmax, MTV and TLG values of [18F]FDG PET/CT scans of our cohort were generally higher compared to the same values reported in literature for ACC patients, even though differences in acquisition and reconstruc- tion parameters and extraction of volumetric metrics may explain these differences [11-12, 14, 20-21].
As expected, in our series there was a statistically signifi- cant correlation between TLG and tumor burden: these two parameters reflect the quote of neoplastic tissue, strengthen- ing the fact that the total burden of disease, considering both metastases numbers and metabolism, predict the prognosis of ACC subjects. However TLG maintained its prognostic role after adjustment for the extension of the disease, and this evidence supports the distinct prognostic significance of the aggressiveness of the disease measured by TLG, that includes also the metabolic activity, compared to its extension.
A
B
Despite the [18F]FDG uptake reflects the aggressiveness of the disease, our findings did not confirm a correlation between SUVmax and Ki-67 expression. The reason for this discrepancy may be related to the fact that the major- ity of patients had their Ki-67 evaluation performed dur- ing the diagnosis of the disease, many months before the start of systemic treatment and before performing PET/CT evaluation.
Regarding the potential predictive role of [18F]FDG uptake on the efficacy of EDP-M, our data showed that none of the baseline PET parameters predicted tumor response. This underlines that the aggressiveness of the disease alone does not significantly affect sensitivity to ChT.
The present study’s strengths lie in its monocentric design and the fact that the CT and PET/CT scans were evaluated by board-certified radiologists and nuclear medicine phy- sicians, respectively. Whereas the retrospective nature and the small sample of patients are the main limitations. In this setting, the relatively small sample size is mainly due to the rarity of metastatic ACC and additionally, because of the retrospective design, no formal sample size calculation was performed. In addition, even though our systems received regular cross-calibration, the fact that the PET/CT acquisi- tions were not performed with the European Association of Nuclear Medicine Research Ltd. (EARL) accreditation and therefore no harmonization between them was performed is an issue that might be kept in mind when considering the
reproducibility of our findings. Despite that, several internal control measures (such as for example regular calibration with phantoms, uniformity of protocols and periodic quality controls) have been implemented to minimize this effect. Furthermore, even though the reproducibility of PET semi- quantitative parameters has been underlined in the past [22], another limitation of this study is the fact that two different PET/CT tomographs have been used, although this might be the condition in different departments. In addition, another important point is that, as mentioned, the assessment of response to therapy was performed by considering both PET/CT and conventional imaging data instead of RECIST evaluation to better capture metabolic changes of the dis- ease; this fact might introduce biases and it could be one of the reasons why no correlation has been found between baseline PET parameters and early response to treatment.
Conclusion
[18 F]FDG PET/CT, performed prior to ChT treatment for advanced/metastatic ACC patients, provides useful predic- tive information on patient PFS and OS. However, the results of this imaging modality did not correlate with response to ChT. Changes in tracer uptake before and after treatment provide complementary information to the radiological response for a better definition of the efficacy of treatment
in the individual patient. Validation study is needed to deter- mine whether [18 F]FDG PET/CT is a valuable imaging test to complement routine CT scan in patients eligible for sys- temic antineoplastic treatment.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Francesco Dondi, Marta Laganà, Davide Bettini and Alfredo Berruti. The first draft of the manuscript was written by Fran- cesco Dondi and Marta Laganà and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding Open access funding provided by Università degli Studi di Brescia within the CRUI-CARE Agreement. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Data availability The datasets generated during and/or analysed dur- ing the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of Brescia. Patients were enrolled and ad- hered to the ENS@T registry (European Network for the Study of Ad- renal Tumors), in compliance with registry guidelines and under the oversight of the registry’s coordinating center.
Consent to participate Informed consent was obtained from all indi- vidual participants included in the study.
Consent to publish The authors affirm that human research partici- pants provided informed consent for publication of the images in Fig- ure 3.
Competing interests The authors have no relevant financial or non- financial interests to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.o rg/licenses/by/4.0/.
References
1. Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Foucha- rdiere C, Haak HR, de Krijger R, Porpiglia F, Terzolo M, Ber- ruti A; ESMO Guidelines Committee. Electronic address:
clinicalguidelines@esmo.org. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1476-1490. https://doi.org/10.1016/j.annonc .2020.08.2099
2. S-GRAS score for prognostic classification of, Elhassan YS, Alt- ieri B, Berhane S, Cosentini D, Calabrese A, Haissaguerre M, Kastelan D, Fragoso MCBV, Bertherat J, Al Ghuzlan A, Haak H, Boudina M, Canu L, Loli P, Sherlock M, Kimpel O, Laganà M, Sitch AJ, Kroiss M, Arlt W, Terzolo M, Berruti A, Deeks JJ, Libé R, Fassnacht M, Ronchi. Adrenocortical carcinoma: an international, multicenter ENSAT study. CL Eur J Endocrinol. 2021;186(1):25-36.
3. Terzolo M, Fassnacht M, Perotti P, Libé R, Kastelan D, Lacroix A, Arlt W, Haak HR, Loli P, Decoudier B, Lasolle H, Quinkler M, Haissaguerre M, Chabre O, Caron P, Stigliano A, Giordano R, Zatelli MC, Bancos I, Fragoso MCBV, Canu L, Luconi M, Puglisi S, Basile V, Reimondo G, Kroiss M, Megerle F, Hahner S, Kimpel O, Dusek T, Nölting S, Bourdeau I, Chortis V, Ettaieb MH, Cosentini D, Grisanti S, Baudin E, Berchialla P, Bovis F, Sormani MP, Bruzzi P, Beuschlein F, Bertherat J, Berruti A. Adju- vant mitotane versus surveillance in low-grade, localised adre- nocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol. 2023;11(10):720-30.
4. Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical car- cinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12(3):657-66.
5. Advances in adrenocortical, Abate A, Cosentini D, Grisanti S, Rossini E, Laganà M, Tamburello M, Turla A, Sigala S, Berruti AE. Carcinoma pharmacotherapy: what is the current state of the art?Cremaschi V. Opin Pharmacother. 2022;23(12):1413-24.
6. Laganà M, Grisanti S, Cosentini D, Ferrari VD, Lazzari B, Ambrosini R, Sardini C, Volta AD, Palumbo C, Poliani PL, Terzolo M, Sigala S, Tiberio GAM, Berruti A. Efficacy of the EDP-M scheme plus adjunctive surgery in the management of patients with advanced adrenocortical carcinoma: the Bres- cia experience. Cancers (Basel). 2020;12(4):941. https://doi .org/10.3390/cancers12040941. PMID: 32290298; PMCID: PMC7226395.
7. Vesselle H, Salskov A, Turcotte E, Wiens L, Schmidt R, Jordan CD, Vallières E, Wood DE. Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 pro- liferation index. J Thorac Oncol. 2008;3(9):971-8. https://doi.org /10.1097/JTO.0b013e31818307a7
8. Bellini P, Albano D, Dondi F, Bertagna F, Giubbini R Different glucose metabolism behavior relating to histotypes in synchro- nous breast cancers evaluated by [18F]FDG PET-CT. Nucl Med Rev Cent East Eur. 2022;25(1):64-5. . https://doi.org/10.5603/N MR.a2022.0012.
9. Dondi F, Albano D, Bellini P, Cerudelli E, Treglia G, Bertagna F. Prognostic role of baseline 18F-FDG pet/CT in stage I and stage Ii non-small cell lung cancer. Clin Imaging. 2023;94:71-8. Epub 2022 Dec 2. PMID: 36495848.
10. Dondi F, Pasinetti N, Guerini A, Piazza C, Mattavelli D, Bossi P, Berruti A, Ravanelli M, Farina D, Albano D, Treglia G, Ber- tagna F. Prognostic role of baseline 18 F-FDG pet/CT in squa- mous cell carcinoma of the paranasal sinuses. Head Neck. 2022;44(11):2395-406. https://doi.org/10.1002/hed.27145. Epub 2022 Jul 12. PMID: 35818852.
11. Wrenn SM, Moore AL, Shah HJ, Barletta JA, Vaidya A, Kilbridge KL, Doherty GM, Jacene HA, Nehs MA. Higher SUVmax on FDG-PET is associated with shorter survival in adrenocortical
carcinoma. Am J Surg. 2023;225(2):309-14. Epub 2022 Sep 8. PMID: 36137821.
12. Satoh K, Patel D, Dieckmann W, Nilubol N, Kebebew E. Whole body metabolic tumor volume and total lesion Glycolysis pre- dict survival in patients with adrenocortical carcinoma. Ann Surg Oncol. 2015;22(Suppl 3):S714-20. https://doi.org/10.1245/s1043 4-015-4813-8. Epub 2015 Aug 18. PMID: 26282908.
13. Schlötelburg W, Hartrampf PE, Kosmala A, Fuss CT, Serfling SE, Buck AK, Schirbel A, Kircher S, Hahner S, Werner RA, Fassnacht M. Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma. Endocrine. 2024;84(3):1172-81. h ttps://doi.org/10.1007/s12020-024-03695-6. Epub 2024 Feb 21. PMID: 38381353; PMCID: PMC11208261.
14. Tessonnier L, Ansquer C, Bournaud C, Sebag F, Mirallié E, Lifante JC, Palazzo FF, Morange I, Drui D, de la Foucardère C, Mancini J, Taïeb D (18)F-FDG uptake at initial staging of the adrenocortical cancers: a diagnostic tool but not of prognostic value. World J Surg. 2013;37(1):107-12. . https://doi.org/10.100 7/s00268-012-1802-y.
15. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, Verzijlbergen FJ, Barrington SF, Pike LC, Weber WA, Stroobants S, Delbeke D, Donohoe KJ, Holbrook S, Gra- ham MM, Testanera G, Hoekstra OS, Zijlstra J, Visser E, Hoek- stra CJ, Pruim J, Willemsen A, Arends B, Kotzerke J, Bockisch A, Beyer T, Chiti A, Krause BJ. European association of nuclear medicine (EANM). FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2015;42:328-54. https://doi.org/10.1007/s00259-014-2961-x.
16. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboul- leux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlum- berger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B, FIRM-ACT Study Group. Combination che- motherapy in advanced adrenocortical carcinoma. N Engl J Med.
2012;366(23):2189-97. https://doi.org/10.1056/NEJMoa120096 6. Epub 2012 May 2. PMID: 22551107.
17. Deandreis D, Leboulleux S, Caramella C, Schlumberger M, Baudin E. FDG PET in the management of patients with adre- nal masses and adrenocortical carcinoma. Horm Cancer. 2011;2(6):354-62. https://doi.org/10.1007/s12672-011-0091-5. PMID: 22076881; PMCID: PMC10358045.
18. Krishnaraju VS, Kumar R, Subramanian K, Mittal BR, Singh H, Chatterjee D, Walia R. Fluoro-2-deoxyglucose-positron emission tomography/computed tomography in the diagnosis and manage- ment of adrenocortical carcinoma: a 10-year experience from a tertiary care Institute. Indian J Nucl Med. 2022;37(3):227-35.
19. Hahner S, Higuchi T, Serfling SE, Samnick S, Fuss CT, Heinze B, Buck AK, Schirbel A, Fassnacht M, Werner RA. Exploring theranos- tic avenues in adrenocortical carcinoma using chemokine receptor and Prostate-Specific membrane Antigen-Directed PET/CT. Clin Nucl Med. 2024;49(4):369-70. Epub 2024 Feb 9. PMID: 38350087.
20. Leboulleux S, Dromain C, Bonniaud G, Aupérin A, Caillou B, Lumbroso J, Sigal R, Baudin E, Schlumberger M. Diagnostic and prognostic value of 18-fluorodeoxyglucose positron emission tomography in adrenocortical carcinoma: a prospective com- parison with computed tomography. J Clin Endocrinol Metab. 2006;91(3):920-5. https://doi.org/10.1210/jc.2005-1540. Epub 2005 Dec 20. PMID: 16368753.
21. Takeuchi S, Balachandran A, Habra MA, Phan AT, Bassett RL Jr, Macapinlac HA, Chuang HH Impact of 18F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients. Eur J Nucl Med Mol Imaging. 2014;41(11):2066-73. . h ttps://doi.org/10.1007/s00259-014-2834-3.
22. Lodge MA. Repeatability of SUV in oncologic 18F-FDG PET. J Nucl Med. 2017;58(4):523-32. https://doi.org/10.2967/jnum ed.116.186353. Epub 2017 Feb 23. PMID: 28232605; PMCID: PMC5373499.
Publisher’s Note Springer Nature remains neutral with regard to juris- dictional claims in published maps and institutional affiliations.