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Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma
Wiebke Schlotelburg 1 . Philipp E. Hartrampf1 . Aleksander Kosmala1 . Carmina T. Fuss2 . Sebastian E. Serfling1 . Andreas K. Buck1 . Andreas Schirbel1 . Stefan Kircher3 . Stefanie Hahner2 . Rudolf A. Werner1,4,5 . Martin Fassnacht2
Received: 5 October 2023 / Accepted: 10 January 2024 / Published online: 21 February 2024 @ The Author(s) 2024
Abstract
Purpose We aimed to evaluate the prognostic potential of baseline [18F]FDG PET/CT for overall survival (OS) in patients with adrenocortical carcinoma (ACC).
Methods We performed a retrospective analysis of 67 treatment-naïve ACC patients with available [18F]FDG PET/CT at time of initial diagnosis. Pretherapeutic PETs of primary tumors were manually segmented and quantitative parameters (maximum/mean/peak standardized uptake value (SUVmax/mean/peak), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG, defined as TV*SUVmean) were derived. Based on a visual read, absence (M0) or presence of metastatic disease (M1) were evaluated. Kaplan-Meier and Cox regression analyses were used to determine the prognostic value of the above mentioned markers on overall survival adjusted for established prognostic markers.
Results 24/67 patients (36%) presented with M0 based on PET/CT, while the remaining 43/67 (64%) had M1-status. 32/67 patients died during follow-up and median OS was 48 months. In 12% of patients FDG-PET detected additional metastatic lesion not clearly visible by CT only. In univariable analysis, all quantitatively derived PET parameters failed to reach significance (P ≥0.1), and only PET/CT-based M1-status and Ki-67 were associated with increased mortality (M1: HR 13.89, 95% CI 4.15-86.32, P<0.001; Ki-67 HR 1.29, 95% CI 1.16-1.42; P <0.0001). Using multivariable Cox regression analyses, M1-status (HR 9.69, 95% CI 2.82-60.99) and Ki-67 index (HR 1.29, 95% CI 1.13-1.04; P <0.05) remained significant associated with OS.
Conclusion In treatment-naïve ACC patients, the quantitative PET parameter failed to predict OS, but presence of metastases detected by [18F]FDG PET/CT and Ki-67 index were independently associated with shorter OS. Therefore, a simple visual PET-based read-out is of prognostic value at initial diagnosis, while time-consuming PET-based quantification can be omitted.
Keywords Endocrine . ACC . Survival . SUV max · Treatment-naïve
These authors contributed equally: Rudolf A. Werner, Martin Fassnacht
☒ Wiebke Schlötelburg schloetelb_W@ukw.de
1 Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany
2 Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany
3 Institute for Pathology, University of Würzburg, Würzburg, Germany
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy (incidence of 0.7-2 cases per million popula- tion/year) [1, 2]. Five-year survival rates are heterogeneous,
4 Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Goethe University Frankfurt, University Hospital, Department of Nuclear Medicine, Clinic for Radiology and Nuclear Medicine, Frankfurt, Germany
ranging from 0% to 80%, and depend mainly on tumor stage, resection status, hormone excess and proliferative activity/tumor grade [3-5]. Reliable non-invasive prog- nosticators for patients, such as imaging parameters, would be favorable, as they would allow treatment to be modified or intensified early in the course of the disease.
To date, the European Network for the Study of Adrenal Tumors (ENSAT) tumor staging system is commonly used to stage patients with ACC [3, 5, 6]. Recent modifications have made this standardized framework also applicable to wide- spread metastatic disease [7, 8]. Not surprisingly, recent years have seen an increased use of the glucose consumption- reflecting positron emission tomography/computed tomo- graphy (PET/CT) biomarker 2-[18F]fluoro-2-deoxy-D-glu- cose ([18F]FDG) in patients with unclear adrenal lesions, as well as confirmed ACC. This approach is also endorsed by current guidelines and reviews [5, 9-11]. Beyond accurate staging in indeterminate cases [12, 13], [18F]FDG reflects the metabolism of the tumor lesions and also provides the ability to quantify radiotracer accumulation in disease sites. This enables a virtual biopsy of every single lesion within the field-of-view [14]. The potential of the quantitatively derived PET signal in ACC patients has recently been evaluated in terms of the relationship between [18F]FDG uptake, clin- icopathological and outcome data [15].
By investigating the up-to-date largest, long-term fol- lowed-up cohort of ACC patients imaged with [18F]FDG PET/CT prior to any guideline-directed treatment, we aimed to determine the predictive value of the [18F]FDG signal.
Material and methods
Patient characteristics
This retrospective single center study, 67 treatment-naïve patients with afterwards histologically confirmed ACC (n =66) or metastatic ACC with tumor-induced autono- mous hormone excess (n = 1) were included. They under- went [18F]FDG PET/CT prior to any ACC-related treatment between September 2011 and September 2022 (Supple- mentary Fig. 1). Other inclusion criteria were: age ≥18 years, available clinical/histopathological data and follow- up data (Table 1). Metastatic status was determined by pre- therapeutic [18F]FDG PET/CT performed as part of routine care according to current guidelines [5, 9]. In addition, the following clinical data were obtained from the ENSAT registry or our medical archive: sex, age at time of diag- nosis, hormonal assessment, ENSAT stage, Weiss-Score and Ki-67 index of the primary tumor [5, 7, 16]. Tumor size was measured on the pre-treatment CT scan.
The study was performed in accordance with the Declaration of Helsinki and the German Medical Products
Act, AMG §13.2b. All patients provided written informed consent for the present retrospective data analysis, as they were included in the ENSAT registry. The local Ethics Committee waived the need for further approval because of the retrospective character of the study (waiver no. 20220519 03).
Imaging procedures
Patients fasted for at least 6 h before image acquisition and their blood glucose levels were less than 160 mg/dL. A mean activity of 275.8 MBq (±51 MBq) [18F]FDG was injected intravenously. After 1 h, scanning was performed using a hybrid PET/CT scanner with an extended field-of- view for the PET and a 64- or 128-slice spiral CT (Bio- graph64 or 128, Siemens Healthineers; Erlangen, Ger- many). A whole-body PET scan covered the area from the skull to the upper thighs. Diagnostic CT scans were per- formed for attenuation correction and diagnostic purposes using the CT protocol with (n =53) or without (n = 14) iodine contrast administration (depending on patient’s pre- vious images). For CT-scans, automatic tube current mod- ulation was activated, with reference mAs of 35 mAs for low-dose scans, and 160 mAs for full-dose scans. The tube voltage was set to 120 keV on the 64-slice CT-scanner, and 100 keV on the 128-slice CT-scanner. For collimation, we used 64/128 × 0.6 mm, while rotation time was 0.5 s. Axial slices were reconstructed with a thickness of 3.0 or 5.0 mm. After decay and scatter correction, the PET data underwent iterative reconstruction with attenuation correction, using the algorithm supplied by the scanner manufacturer using 3D mode with a 200 x 200 matrix, 3 iterations and 24 sub- sets for the mCT64 and 21 subsets for the mCT128. Additionally, Gaussian filtering of 2 mm was applied [17, 18].
Visual and quantitative image interpretation
Tumor size of the adrenal tumor was measured according to the modified Response Evaluation Criteria in solid tumors (version 1.1) by using the trans-axial slice with the largest diameter [19]. Hounsfield Units (HU) of the primary tumor were measured on the unenhanced CT scan using a circular region of interest that include at least two-thirds of the lesion, carefully recessing the lesion’s margins to minimize partial volume effects [20].
All PET/CT images were reviewed by a board-certified radiologist with three years of experience in reading PET/ CT (W.S.) and supervised by a board-certified nuclear medicine physician (R.A.W.) using a dedicated workstation and software package (syngo.via; V60A; Siemens Healthi- neers, Erlangen, Germany). Based on a visual PET/CT readout, we defined the absence (M0) or presence of
| Patient characteristics | Entire cohort | M0 at time of diagnosis | M1 at time of diagnosis |
|---|---|---|---|
| N | 67 | 24 | 43 |
| Age at time of diagnosis in years, | 50.5± 16.2 (18-79) | 51.8 ± 15.7 (25-79) | 49.7 ±16.6 (18-79) |
| Sex (F:M) | 40 (60%): 27 (40%) | 14 (58%): 10 (42%) | 26 (60%): 17 (40%) |
| Location of ACC (R:L) | 27 (40%): 40 (60%) | 10 (42%): 14 (58%) | 17 (40%): 26 (60%) |
| Tumor characteristics | |||
| Size, cm, mean ± SD Median (range) | 9.9 ±3.4; 9.7 (3.4-16.4) | 8.7 ±3.5; 9.1 (3.4-14.8) | 10.6±3.2; 10.6 (3.5-16.4) |
| HU in unenhanced CT, mean ± SD median (range) | 33 ±6; 33 (21-54) | 35 ±7; 34 (23-54) | 33 ±6; 33 (21-44) |
| Autonomous hormone excess | 55 (83%) (1 not known) | 17 (74%) (1 not known) | 38 (88%) |
| Histopathological parameters/ENSAT | |||
| Ki-67 Index, % | 28.3 ±18.7; 25 (1-90) | 20.1 ±18.9; 15 (1-80) | 34.3 ±16.4; 30 (10-90) |
| Weiss Score | 6.7±2; 7 (4-10) | 6±2; 6 (4-9) | 7.3 ±2; 8 (4-10) |
| ENSAT stage | |||
| 1 | 5 (7.5%) | 5 (21%) | – |
| 2 | 8 (12%) | 8 (33%) | – |
| 3 | 11 (16.5%) | 11 (46%) | – |
| 4 | 43 (64%) | – | 43 (100%) |
| Metastasized at initial diagnosis (M1) | 43/67 (64%) | – | 43 |
| In one organ compartment (M1-1) | 19/67 (28%) | – | 19/43 (44%) |
| In ≥2 organ compartments (M1-2) | 24/67 (36%) | – | 24/43 (56%) |
| Location of metastases | n =77 | – | n =77 |
| Lung | 27 (35.1%) | – | 27 (35.1%) |
| Liver | 24 (31.2%) | – | 24 (31.2%) |
| Lymph node | 17 (22.1%) | – | 17 (22.1%) |
| Bone | 5 (6.5%) | – | 5 (6.5%) |
| Other locationsª | 4 (5.1%) | – | 4 (5.1%) |
| Patients with additional findings in PET/CT compared to CT aloneb | 8/67 (12%) | – | 8/43 (19%) |
| Therapy | |||
| Adrenalectomy | 56 (84%) | 24 | 32 |
| Mitotane | 45 (67%) | 10 | 35 |
| Chemotherapy | 27 (40%) | 3 | 24 |
| Others | 6 (9%) | 1 | 5 |
| Median OS, months | 48 (1-139) | n.r. (9-136) | 31 (1-139) |
| Dead | 32/67 (44.8%) | 2/24 | 30/43 |
| Median PFS, months | 11 (1-131) | 37 (5-136) | 7 (1-99) |
Total amount or mean ± SD; median (range or percentages are indicated in parentheses)
M0 patients with no evidence of metastases at initial diagnosis, M1 patients with presence of metastatic disease at initial diagnosis, OS Overall survival, PFS progression-free survival, ENSAT European Network for the Study of Adrenal Tumors, n.r. not reached
ªIncluding local recurrence, peritoneal and cerebral metastases
bIncluding mediastinal lymphnodes (n =3), metastases located in bones or extremities (n =2), liver (n =2), vascular tumor invasion (n=1)
metastatic disease (M1), with M1-1 was defined as one and M1-2 as at least two affected organ compartments. More- over, to quantify of the primary adrenal tumor, an
isocontour volume of interest (VOI) with a threshold SUV of 3.0 was drawn using a three-dimensional segmentation method that allows semi-automatic volumetric assessment
L13VO11 PT
Max 12,30 SUV-BW Peak 9.08 SUV-BW / Große: 1 cm3
Mittelwert 5.24 SUV-BW
TLG 1737,03 SUV-bw xcm3 Vol.mon (MTV): 331,68 cm2
Schwel: PICO SUV-BW / 24 %
0
5
SUV
0
5
(Fig. 1) [17]. We calculated mean, maximum and peak standardized uptake values (SUV mean/max/peak). In addition, the metabolic tumor volume (MTV in cm3) of the primary adrenal tumor was also assessed, while tumor lesion gly- colysis (TLG) was calculated using the following equation [21]:
TLG = SUV mean * MTV (1)
Tumor-to-background ratios (TBR) were determined to quantify the image contrast and defined as follows:
TBR = SUV max (of the adrenal tumor) /SUV mean (unaffected liver parenchyma) (2)
As previously used in several studies, we also determined the Adrenal-to-liver SUVmax ratio (ALR) [15, 22, 23]:
ALR = SUVmax (of the adrenal tumor) /SUV max (unaffected liver parenchyma) (3)
Statistical analysis
For statistical analysis, GraphPad Prism (GraphPad Soft- ware, version 9.4.1, San Diego, CA, USA) was used. Continuous variables were presented as mean ± SD or median and range, as appropriate. Mann-Whitney U test was used to compare groups regarding continuous variables.
Overall survival (OS) was defined as time from first diag- nosis to death or last follow-up and progression-free sur- vival (PFS) was scored as time interval from first day of treatment to first documented disease progression. Kaplan-Meier survival curves were calculated using the median of the parameter to illustrate separation. Uni- and multivariable Cox regressions were used for survival pre- diction and to identify independent prognostic factors. Hazard ratio (HR) along with 95% confidence intervals (95% CI) are displayed. Spearman rank order correlation test was used to assess correlation between [18F]FDG PET parameter and Ki-67. P <0.05 was considered statistically significant.
Results
The detailed characteristics of the patients are summarized in Table 1 and the flowchart of the study design is shown in Supplementary Fig. 1. Briefly, the entire cohort consisted of 67 patients (mean age 50.5±16.2 years), of whom 40 (60%) were female. In 43/67 (64%), ENSAT stage was IV. A Ki-67 index ≥20% was observed in 35/56 (63%) of cases, while 26/47 (55%) had a Weiss-Score ≥7. According to PET/CT findings, 43/67 patients (64%) had metastatic dis- ease (M1) (ENSAT stage IV), with 19/43 (44%) having one affected organ compartment (M1-1) and 24/43 (56%) hav- ing two affected organ compartments (M1-2). Compared to CT alone [18F]FDG PET/CT detected additional metastatic
| N | Entire cohort | M0 24 | M1 43 | M0 vs. M1 | |
|---|---|---|---|---|---|
| p-value | |||||
| SUV peak | Mean ± SD | 15.9±11.3 | 13.7±13.2 | 22.4 ±10.2 | |
| Median (range) | 12.4 (3-57) | 10 (3-57) | 14 (7-51) | <0.05 | |
| SUV max | Mean ± SD | 20.6 ± 14.5 | 17.2±16 | 22.4 ±13.5 | |
| Median (range) | 17.1 (4-71) | 11.8 (4-71) | 17.5 (8-71) | <0.05 | |
| SUV mean | Mean ± SD | 7.0±3.8 | 6.4±4.3 | 7.4 ±3.4 | |
| Median (range) | 6.2 (3-22) | 5.5 (3-22) | 6.5 (4-21) | <0.05 | |
| TLG | Mean ± SD | 3629 ±5562 | 2265 ±2545 | 4391 ±6588 | |
| Median (range) | 2007 (25-42545) | 1579 (25-9469) | 2231 (144-42545) | <0.05 | |
| MTV | Mean ± SD | 470 ±469 | 336 ±323 | 545 ±522 | |
| Median (range) | 319 (8-2952) | 258 (8-1205) | 348 (25-2952) | 0.06 | |
| TBR | Mean ± SD | 9.2±7.5 | 7.6±7.7 | 10.1±7.3 | |
| Median (range) | 6.6 (2-33) | 4.9 (2- 31) | 7.6 (4- 33) | <0.05 | |
| Adrenal-to-liver | Mean ± SD | 6.2±4.9 | 5.3±5.5 | 6.7 ±4.5 | <0.01 |
| SUV max ratio | Median (range) | 4.8 (1.1-23.6) | 3.6 (1.1-23.0) | 5.0 (2.8-23.6) |
MO patients with no evidence of metastases at initial diagnosis, MI patients with presence of metastatic disease at initial diagnosis, Comparison of [18F]FDG PET-parameters of MO and M1 using Mann-Whitney U test, SUV standardized uptake value, TLG tumor lesion glycolysis, MTV metabolic tumor volume, TBR target to background ratio
lesions in eight patients (8/43) (19%). [18F]FDG PET/CT, treatment included adrenalectomy in 56/67 (84%), mitotane in 45/67 (67%), and chemotherapy in 27/67 (40%). Tumor characteristics of the primary tumors are shown in Tables 1 and 2. The median follow-up of surviving patients was 40 months. Median PFS and OS were 10 and 48 months, respectively. 32/67 patients (45%) died during follow-up.
All ACC presented with high SUVs: The lowest adrenal SUV max was 4.2 in a patient with an incidentally discovered ACC (M0, 44 mm diameter) and all other patients showed SUV max 6.0 or higher. Dividing the cohort into patients with (M1) and without (M0) presence of metastases at initial diagnosis, SUVpeak/max/mean, TLG, TBR and ALR were significant different with higher values in the patient group with M1-status (P<0.05) (Table 2).
Associations between quantitative PET results and clinical outcome
In Kaplan-Meier analyses, none of the quantitative PET parameters were associated with PFS or OS, although there was a trend towards improved PFS for SUVmax values < 17.1 (HR 1.68, 95% CI 0,95-2,97, p = 0.06). The PET/CT- based metastatic status was associated with shorter survival (M1, median OS, 30 months vs. M0, not reached; HR 12.85, 95% CI 6.41-25.74, P<0.0001). Specifically, a higher number of organ compartments involved correlated negatively with OS: patients with M1-1 had a median OS of 48 months and patients with M1-2 survived only 14 months
(Fig. 2). Regarding the proliferation index Ki-67, a higher Ki-67 correlated with shorter OS (Ki-67> 25%, median OS 30 months vs. Ki-67 < 25%, not reached; HR 4.32, 95% CI 2.15-8.66, P<0.0001) (Fig. 2). Figure 3 presents two illustrative cases with treatment-naïve ACC with corre- sponding findings on immunohistochemistry and [18F]FDG PET/CT.
In univariable Cox regression analysis for OS, quanti- tatively derived PET and CT parameters, failed to reach significance (P≥0.09; Table 3). Presence of metastases (M1) at initial diagnosis (HR 13.89, 95% CI 4.15-86.32, P <0.001) and an increase in Ki-67 (per 5%, HR 1.29, 95% CI 1.16-1.42, P<0.0001) were the only variables that were significantly associated with shorter overall survival. In multivariable Cox regression analyses only M1-status (HR 2.27, 95% CI 1.04-4.11; P <0.01) and Ki- 67 (HR 1.29, 95% CI 1.13-1.47; P<0.001) remained significant (Table 3). In univariable Cox regression ana- lyses for PFS only higher Ki-67 was associated with shorter PFS, while all other parameters failed to reach statistical significance (Table 4).
Regarding the location of metastases at time of first diagnosis, presence of liver metastases is more indicative for a worse prognosis than lung metastases. In Kaplan-Meier analyses, combination of both and in addi- tion other locations, e.g. lymph node metastases, are con- nected with shortest OS (Fig. 2). In univariable Cox regression analyses presence of liver and then lung metas- tases was linked to shorter survival (HR 5.36, 95% CI
100
Median OS (months)
100
Median OS (months)
Probability of Survival
- SUVmax <17.1
55
Ki67 <25%
SUVmax >17.1
not reached
38
Probability of Survival
Ki67>25%
30
Hazard ratio for death (95%CI)
50
SUVmax 1.74 (0.87 - 3.51); P=0.11
50
Hazard ratio for death (95%CI)
4.32 (2.15 - 8.66); P<0.0001
0
0
0
50
100
0
50
100
OS in months
OS in months
100
100
Probability of Survival
Median OS (months)
Probability of Survival
Median OS (months)
MO, n=24
not reached
MO, n=24
not reached
M1, n=43
30
M1-1, n=19
48
50
50
- M1-2, n=24
14
Hazard ratio for death (95%CI)
Hazard ratio for death (95%CI)
MO vs. M1-1
8.42 (2.91 - 24.4);
16.53 (6.61 - 41.33);
P<0.001
12.85 (6.41 - 25.74); P< 0.0001
MO vs. M1-2
M1-1, vs. M1-2 3.06 (1.43 - 6.55);
P<0.0001
P<0.001
0
0
0
50
100
0
50
100
OS in months
OS in months
100
Median PFS (months)
100
SUVmax <17.1
- Lung only (n=8)
Probability of Survival
12
SUVmax >17.1
9.5
Probability of Survival
- Liver only (n=6)
Hazard ratio for death (95%CI) SUVmax 1.68 (0.95 - 2.97); P=0.06
only Lung and Liver (n=5)
- Lung and Liver and others (n=8)
50
50
- LK with lung or liver (n=10)
others than Liver or lung (n=6)
0
0
0
50
100
0
50
100
PFS in months
OS in months
1.67-7.16, P<0.0001; respectively HR 3.38, 95% CI 1.67-7.16, P<0.001) (Table 3).
Discussion
As reported in previous studies, the ability of [18F]FDG PET/ CT to discern between benign and malignant adrenal lesions ranges from 85% to 100% for both sensitivity and specificity [22, 23]. Nevertheless, the prognostic value of [18F]FDG PET/CT at the time of diagnosis of ACC has received little attention. In a previous study, we highlighted glucose trans- porter 1 (GLUT1) as a stage-independent prognostic bio- marker for ACC, determined by assessing GLUT1 expression in tissue sections from ACC patients [24]. At the cellular level, the uptake of [18F]FDG is facilitated by GLUT1. Consequently, our investigation focused on this radiotracer reflecting glucose consumption in ACC patients before treatment, with the aim of validating its prognostic value.
In our study none of the quantitative PET parameters was of prognostic value, but in 8 patients (12%), additional
shortest survival relative to M1-1, defined as only one affected com- partment. Regarding the localization of affected organ compartment, presence of liver metastases is linked to shorter survival (22 months) compared to presence of lung metastases (25 months)
metastases, not identified by CT, were detected by FDG- PET. Using multivariate regression analyses only the pre- sence of [18F]FDG PET/CT-positive metastases and a higher Ki-67 index were associated with shorter OS. Thus, a simple visual PET-based read-out is probably as good as the time-consuming quantification of different sophisticated PET parameters in ACC.
A correlation between adrenal SUVmax and the pro- liferation marker Ki-67 has recently been described by Libé et al. [15]. In our study, we are able to confirm these findings. Intriguingly, individuals with metastases at time of initial diagnoses had significantly elevated quantitative PET parameters in their primary tumor (except MTV) compared to those without metastases. The clinical implications of this observation need be evaluated in a prospective study.
Considering outcome data, Takeuchi et al. showed that SUVmax and TLG were also not associated with survival, but their study cohort with [18F]FDG PET/CT for primary staging consisted of only 22 patients with ACC [25]. Beyond such conventional metrics, a previously published pilot study added radiomics to the quantitative armamentarium, but these
A
B
0
5
SUV
0
5
| Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | |
| PET and CT parameters: | ||||||
| Ki-67 index (per 5%) | 1.285 | 1.160-1.423 | <0.0001 | 1.294 | 1.134-1.039 | <0.0001 |
| M1 | 13.89 | 4.147-86.32 | 0.0003 | 9.690 | 2.815-60.99 | 0.0023 |
| ENSAT stage | 3.189 | 1.569-10.82 | 0.06 | 1.403 | 0.315-10.17 | 0.68 |
| Weiss-Score | 1.311 | 1.024-1.726 | 0.09 | |||
| TLG | 1.000 | 1.000-1.000 | 0.09 | |||
| HU on unenhanced CT | 0.947 | 0.881-1.017 | 0.14 | |||
| MTV | 1.000 | 0.9997-1.001 | 0.17 | |||
| SUV max | 1.011 | 0.987-1.031 | 0.31 | |||
| Tumor size | 1.005 | 0.995-1.016 | 0.31 | |||
| TBR | 1.019 | 0.972-1.060 | 0.40 | |||
| SUV peak | 1.010 | 0.978-1.036 | 0.49 | |||
| SUV mean | 1.027 | 0.939-1.110 | 0.55 | |||
| ALR | 1.019 | 0.945-1.083 | 0.58 | |||
| Metastases in: | ||||||
| Liver | 5.357 | 2.609-11.23 | <0.0001 | 4.741 | 2.211-10.4 | <0.0001 |
| Lung | 3.379 | 1.665-7.159 | 0.0009 | 2.487 | 1.122-5.649 | 0.0258 |
| Lymphnodes | 3.290 | 1.482-6.999 | 0.0024 | 1.816 | 0.777-4.154 | 0.19 |
| Bone | 3.722 | 1.242-9.115 | 0.0085 | |||
Significant P-values are marked in bold
HR Hazard ratio, CI confidence interval. M1 presence of metastases at first diagnosis, ENSAT European Network for the Study of Adrenal Tumors, TLG tumor lesion glycolysis, MTV metabolic tumor volume, SUV standardized uptake value, TBR target to background (Liver) ratio, ALR adrenal to liver SUV max ratio
| Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | |
| Ki-67 index (per 5%) | 1.035 | 0.996-1.069 | 0.04 | 1.018 | 0.938-1.072 | 0.55 |
| HU on unenhanced CT | 1.089 | 0.914-1.267 | 0.29 | 1.070 | 0.871-1.26 | 0.45 |
| MTV | 0.999 | 0.995-1.001 | 0.46 | |||
| TLG | 0.999 | 0.998-1.000 | 0.49 | |||
| Tumor size | 0.994 | 0.967-1.019 | 0.64 | |||
| TBR Liver | 0.990 | 0.798-1.095 | 0.89 | |||
| SUV peak | 0.996 | 0.881-1.055 | 0.93 | |||
| ALR | 1.008 | 0.779-1.149 | 0.93 | |||
| SUV mean | 1.009 | 0.725-1.185 | 0.93 | |||
| SUV max | 1.001 | 0.916-1.048 | 0.96 | |||
| Weiss-Score | 1.005 | 0.615-1.562 | 0.98 | |||
Significant P-values are marked in bold
HR Hazard ratio, CI confidence interval, M1 presence of metastatic disease, TLG tumor lesion glycolysis (defined as tumor volume x SUV mean), MTV metabolic tumor volume, SUVpeak/mean/max peak/mean/maximum Standard uptake value, TBR tumor-background ratio
PET-based mathematically extracted features also failed to predict outcome [14]. While these analyses included a rather limited number of subjects, Tessonnier et al. investigated the prognostic value of pre-therapeutic PET/CT in 37 patients and also did not report on predictive capabilities of SUVmax or tumor/liver SUV max ratio (ALR) [24].
As initially described by Tessonnier et al., an ALR of 1.8 demonstrated 100% sensitivity and specificity for differ- entiating between benign and malignant adrenal tumors, but their study cohort was heterogeneous and only 3 ACC were included [22]. Later this ALR value was slightly modified by Groussin et al. after prospective evaluation of the role of [18F]FDG PET/CT excluding pheochromocytoma and other non-adrenal malignancies. A ratio below 1.45 showed the best negative predictive value for ACC [23]. Using these ratios on our cohort we would have missed two ACCs (ALR of 1.12, M0, 44 mm diameter and ALR of 1.4, M0, 49 mm diameter). Comparing ALR and TBR (= SUVmax adrenal/SUV mean liver) which is more established in clinical nuclear medicine routine as it is the more stable and meaningful parameter [21], we see comparable results regarding the differentiation between patients with and without metastases and no significant association between survival parameters (OS and PFS).
In the present single-center experience, with the largest number of treatment-naïve ACC patients an increasing number of affected organ compartments (≥2) was associated with shorter OS. This is in contrast to the results of Leboulleux et al. who performed a [18F]FDG PET/CT study in a cohort of 28 mainly metastatic patients after various previous treatment options at a median of 3 years after ACC tumor surgery. In their study the number of affected organs (>2) did not determine the prognosis, but in univariable
analysis SUVmax > 10 was associated with decreased sur- vival [26]. The differences to our study may be related to previous treatments. We only included patients who had not received any anti-cancer-related treatment. This ensures that the molecular and biological characteristics of the tumor tissue were not affected by treatment-induced dediffer- entiation, which could otherwise lead to increased expres- sion of glucose transporters and glycolytic enzymes. Consequently, this could result in an elevated FDG-PET signal.
Regarding the location of metastases, Ettaieb et al. found that OS was not different between their subgroups with only one affected organ system [27]. In our cohort, the presence of liver metastases was associated with a worse outcome than the presence of lung metastases, but the small number of these subgroups limits the significance of this observa- tion. Compared to this a visual assessment of involved organs, time-consuming segmentation and quantification of glucose consumption in the primary failed to reach sig- nificance. As such, a simple PET-based read-out of affected organ compartments may be sufficient to identify indivi- duals with a less favorable outcome, thereby rendering molecular imaging as a valuable tool for identifying patients who may benefit from intensified treatment early in the course of the disease.
Of note, in our study investigating PET/CTs prior to treatment on-set, HU derived from conventional unen- hanced CT failed to reach significance even in univariable analysis.
However, novel artificial intelligence approaches may also enable for providing sufficient number of PET/CTs, as those Deep Convolutional Generative Adversarial Networks require only a relatively small number of existing scans to
create novel images that closely resemble their real-world equivalents. Such a deep learning-based augmentation, how- ever, may be of particular interest in the context of orphan diseases such as ACC or in scenarios chosen in the present study, which focused exclusively on untreated subjects [28]. Last, a recent study investigated 690 patients affected with 35 different tumor types, which were all imaged with chemokine receptor PET. In the subgroup of solid cancers, ACC showed the highest in vivo uptake. Thus, future studies may also determine the value of such novel radiotracers for outcome prediction in treatment-naïve ACC patients [29].
Our study has some obvious limitations. First, it is limited by its retrospective nature. Secondly, the sample size is still rather small. Regarding the patient cohort itself, the large number of patients with metastases at time of initial diagnosis, resulting in a large group with ENSAT stage IV, could be a limitation as they often show a more unfavorable outcome. This can be attributed to the fact that advanced patients were sent to our specialized ACC center, whereas non-metastatic patients were often operated in peripheral hospitals without preoperative molecular imaging. As such, future prospective studies should also include more patients with ENSAT stage I and II. However, our study also has strengths: the detailed characterization of all PET/CT images by a board-certified radiologist and a board-certified nuclear medicine physician, the comprehensive clinical annotation of the patient cohort, and long-term follow-up of our study cohort.
Conclusion
In this largest analysis to date of treatment-naïve ACC patients scheduled for [18F]FDG PET/CT, quantitative PET- parameters such as SUV peak/max/mean, tumor-to-background ratio failed to predict OS. However, a higher SUV peak/max/mean of the primary tumor correlated with presence of metastases and might identify patients that deserve special attention in the search for metastases. Accordingly, in 12% of patients FDG- PET detected a metastatic lesion not clearly visible by CT alone. Furthermore, molecular imaging-based M1-status was independent of other prognostic markers associated to shorter OS, especially when two or more organ compartments were involved. As such, a simple read-out of affected organ com- partments may be sufficient to identify patients at higher risk of shorter survival, making molecular imaging a valuable tool for identifying patients who may benefit from intensified treatment early in the course of their disease.
Data availability
Detailed information about the image analysis or the overall survivals of the subjects presented in this study are available on reasonable request from the corresponding author.
Supplementary information The online version contains supplemen- tary material available at https://doi.org/10.1007/s12020-024-03695-6.
Author contributions Conceptualization, W.S., R.A.W., M.F .; meth- odology, W.S. R.A.W .; software, W.S., P.E.H .; validation, W.S., R.A.W, M.F .; formal analysis, W.S., P.E.H., R.A.W, S.H., S.K .; investigation, W.S. A.K .; resources, A.K.B .; data curation, W.S., R.A.W .; writing-original draft preparation, W.S., R.A.W .; writing of the first draft, W.S .; review and editing, P.E.H., M.F., A.K.B., A.K., A.S., S.H., S.K. S.E.S .; visualization, W.S., A.K., S.K .; supervision, R.A.W., M.F .; project administration, W.S., R.A.W., A.K.B., M.F .; funding acquisition, W.S. All authors have read and agreed to the published version of the manuscript.
Funding This work was supported by the Interdisciplinary Center for Clinical Research (IZKF), University Hospital of Wuerzburg (grant Z- 2/91 to W.S.) and the Deutsche Forschungsgemeinschaft (project numbers: 314061271 - CRC/TRR 205). Open Access funding enabled and organized by Projekt DEAL.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethics approval The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived for this study by the local Ethics Committee due to the ret- rospective character of the study (# 20220519 03).
Informed consent All procedures have been conducted as part of clinical routine care. Informed consent has been obtained from all subjects.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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. org/licenses/by/4.0/.
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