Society for Endocrinology
The role of 18F-FDG PET/CT in adrenocortical carcinoma: a systematic review
Domenico Albano 1,2, Salvatore Grisanti3, Deborah Cosentini3, Marta Laganà3, Francesco Dondi1,2, Alfredo Berruti3 and Francesco Bertagna1,2
1Nuclear Medicine, University of Brescia, Brescia, Italy
2Nuclear Medicine Department, ASST Spedali Civili di Brescia, Brescia, Italy
3Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
Correspondence should be addressed to D Albano: domenico.albano@unibs.it
Abstract
Adrenocortical carcinoma (ACC) is a rare and highly aggressive carcinoma with a poor prognosis. The aim of our study is to summarize existing evidence on the potential usefulness of fluorine-18-fluorodeoxyglucose positron/computed tomography (18F-FDG PET/CT) in the management of patients affected with ACC. The current systematic review was registered to the PROSPERO registry (ID1103377). A comprehensive search of the PubMed/MEDLINE, Embase, and Cochrane Library databases was conducted until July 2025. A total of 19 studies that evaluated the role of 18F-FDG PET/CT in ACC were included. One of the fields investigated was the ability of PET/CT to discriminate between adrenal masses, particularly in the differential diagnosis between benign and malignant lesions. 18F-FDG PET/CT demonstrated good sensitivity and specificity but was affected by different cutoff values of SUV and SUV ratio applied. In addition, in the staging/restaging, despite heterogeneity of data, diagnostic performances were good and higher than conventional imaging tools. Moreover, PET/CT modified patient management in 9-21% of cases. The prognostic role of 18F-FDG PET/CT remains controversial, with seven studies reporting heterogeneous findings and different endpoints investigated, primarily OS and PFS. Semiquantitative parameters such as SUVmax and SUV ratio were analyzed, but their prognostic impact was inconsistent. Despite several limitations affecting this analysis, especially related to the heterogeneity of the studies included, 18F-FDG PET/CT seems to be a useful tool for the evaluation of ACC, especially in the differential diagnosis of adrenal masses and in the staging/restaging. Instead, the prognostic impact of PET/CT and its features remains inconclusive.
Keywords: adrenocortical carcinoma; PET/CT; FDG; PET; nuclear medicine
Introduction
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer known for its high recurrence rate and rapid progression. While surgery is the only curative option, other treatments such as mitotane, chemotherapy, and localized therapies primarily offer palliative care (1). Patient prognosis is determined by the disease stage of ACC, radical surgery, proliferation activity, cortisol hypersecretion, and patient age, which are included in
the GRAS score recently validated (2, 3, 4, 5). The risk of relapse or progression in ACC is very high; even after complete initial surgical removal, the disease recurs in up to 80% of patients within the first 2 years (6). Imaging plays a crucial, multifaceted role in managing ACC (7). Initially, it helps detect and characterize primary adrenal tumors, guiding the selection of surgical candidates. After ACC is confirmed, accurate imaging-based staging is
essential for effective treatment planning. Finally, imaging allows for the early detection of recurrent disease, often at a stage where surgical intervention and complete resection are still possible. Currently, computed tomography (CT) scans and magnetic resonance imaging (MRI) are the most commonly used imaging techniques due to their widespread availability. However, fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) is emerging as a promising tool for ACC (8). Beyond complementing morphological imaging for characterizing adrenal masses and identifying tumors, FDG PET can also be valuable for disease staging and evaluating treatment response. Furthermore, PET findings may offer prognostic insights, helping to stratify ACC patients.
Despite its promise, further research is needed to evaluate new tracers and broaden the clinical applications of FDG PET in ACC. This systematic review aims to evaluate the utility of 18F-FDG PET/CT in various clinical scenarios for adrenocortical carcinoma (ACC). In particular, it emphasizes PET/CT’s real-world impact on clinical decision-making. By quantifying management changes and specifying actions (e.g., avoiding futile surgery or redirecting to systemic therapy), we bridge evidence to practice. Highlighting PET/CT’s superiority in detecting adrenal bed recurrence and distant metastases underscores its irreplaceable role in guiding salvage therapies. This addresses a critical gap: clinicians need clarity on when PET/CT adds value beyond conventional imaging.
Methods
Protocol
The current systematic review was carried out following a preset protocol, and the ‘Preferred Reporting Items for a Systematic Review and Meta-Analysis’ (PRISMA 2020 statement) served as a guideline for its development and reporting (9) and was registered to the PROSPERO registry (ID 1103377).
As a first step, a direct review query using the population, intervention, comparator, and outcomes (PICO) framework was done: ‘what is the role (‘outcome’) of 18F-FDG PET or PET/CT (‘intervention’) in patients with ACC (‘population’) compared or not to other imaging methods (‘comparator’)‘? Two investigators (DA and FD) independently performed the literature search, the study selection, the data extraction, and the quality evaluation. In case of disagreements, a third opinion (FB) was asked.
Search strategy
A comprehensive literature search of the PubMed/MEDLINE, Scopus, and Embase databases was
conducted to find relevant published articles about the role of 18F-FDG PET/CT in patients affected by ACC. Moreover, a specific search on the ClinicalTrials.gov database for ongoing investigations (access date: 1 July 2025) was executed.
We used a search algorithm based on a combination of the following terms: i) ‘PET’ OR ‘positron emission tomography’ AND ii) ‘FDG’ OR ‘fluorodeoxyglucose’ AND iii) ‘ACC’ OR ‘adrenocortical’.
No beginning date limit was used for our literature search, which was updated until July 1, 2025. Only articles in the English language were selected. To enlarge our research, references of the retrieved articles were also screened for searching additional papers. For the management of these articles, we used EndNote Basic (Thompson Reuters).
Study selection
Studies or subsets in studies investigating the value of 18F-FDG PET/CT in patients with ACC were eligible for inclusion. Exclusion criteria were: i) articles not in the field of interest; ii) review articles, meta-analyses, letters, conference proceedings, and editorials; and iii) case reports or small case series (less than ten patients with ACC included). Case reports or small case series were excluded to minimize bias from underpowered studies and focus on robust evidence, with the awareness that this can improve evidence quality, but it might omit valuable insights given ACC’s rarity. Two researchers (FD and DA) independently reviewed the titles and abstracts of the articles, applying the above-mentioned inclusion and exclusion criteria, and the same two researchers then independently reviewed the full-text version of the papers to evaluate their suitability.
Data extraction and collection
To avoid potential biases, the researchers separately gathered each of the studies and extracted data from the information in the entire manuscript, figures, and tables. For each included study, we collected data concerning overall study information (first author, year of publication, country, study design, funding sources, number of included subjects, age, gender, stage, and kind of therapy); technical variables (type of scanner, administered radiopharmaceutical dose, uptake time, and image analysis features). Data about sensitivity and specificity of 18F-FDG PET/CT were also extracted. The main findings of the articles included in this review were represented in Tables and in the ‘Results’ section.
Meta-analysis (quantitative synthesis) was not performed, as significant heterogeneity among the selected studies (such as the different samples analyzed and different endpoints investigated) was expected.
Quality assessment (risk of bias assessment)
A quality assessment of included articles was performed to analyze the risk of bias in individual studies to the review query. Four domains (patient selection, index test, reference standard, and flow and timing) were evaluated for risk of bias. At the same time, three sectors were assessed for applicability concerns (patient selection, index test, and reference standard) by using the QUADAS-2 tool (10).
Results
Literature search
Our initial literature search across selected databases yielded 261 records. We then meticulously screened these articles, first by reviewing their titles and abstracts. This initial pass led to the exclusion of 241 articles for several reasons: 176 were outside our specific field of interest, 54 were either small case series or individual case reports, 6 were identified as reviews or editorials, and 5 were preclinical studies. Finally, 19 studies (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29) were deemed relevant enough for a thorough full-text review and were subsequently included in this systematic review (as visually represented in Fig. 1). A final check of the
references within these selected articles did not reveal any additional manuscripts for inclusion.
Studies and patient characteristics
Tables 1, 2, 3 detail the key characteristics of the articles included in our qualitative analysis. Most of the studies were of retrospective nature, while the remaining six were prospective.
The selected articles were published between 2006 and 2024, especially in France (n = 8), followed by the USA (n = 5), Germany (n = 2), Italy (n = 1), India (n=1), Turkey (n = 1), and Portugal (n = 1). Funding sources were reported only in three studies.
Participant ages ranged from a median/mean of 34.6-56.5 years, usually showing a female predominance. The primary research aims were to investigate the role of 18F-FDG PET/CT in differential diagnosis of adrenal masses (n = 8), the diagnostic role of 18F-FDG PET/CT in staging/restaging (n = 9), as well as its prognostic role (n = 6).
Risk of bias and applicability
Figure 2 provides a summary of the overall risk of bias and applicability concerns for the articles included in this systematic review, as assessed using QUADAS-2.
Research question: What is the role of [18F]FDG PET/CT in adrenocortical carcinoma? Research string: (a) “positron emission tomography” OR “PET” AND (b) “FDG” OR “fluorodeoxyglucose"" AND c) “adrenocortical” or “ACC”.
Databases screened: Scopus, PubMed/MEDLINE, Embase
Identification of studies via databases and registers
Identification
Records identified from Databases searching (n =261)
Records removed before screening:
Duplicate records removed (n = 0)
Records screened (n = 261)
Records excluded (n = 241)
176 as not in the field of interest 6 as reviews/editorials
Screening
54 as case report/case series 5 as preclinical studies
Reports assessed for eligibility (n =19)
Included
Studies included in qualitative analysis (systematic review) (n = 19)
| First author | Year | Country | Funding source | Study design | Purpose/s |
|---|---|---|---|---|---|
| Mackie GC (11) | 2006 | USA | None reported | R | Restaging |
| Leboulleux S (12) | 2006 | France | None reported | P | Staging, restaging, prognosis |
| Groussin L (13) | 2009 | France | None reported | P | Diagnosis |
| Ansquer C (14) | 2010 | France | None reported | R | Diagnosis |
| Gust L (15) | 2012 | France | None reported | R | Diagnosis |
| Tessonier L (16) | 2013 | France | None reported | R | Staging, prognosis |
| Takeuchi S (17) | 2014 | USA | None reported | R | Staging, restaging, prognosis |
| Satoh K (18) | 2015 | USA | None reported | P | Prognosis |
| Ardito A (19) | 2015 | Italy | Italian Ministry of University and Scientific Research (grant number FIRB RBAP1153LS_005) and University of Turin (grant number TERMATEN 12) | R | Restaging |
| Launay N (20) | 2015 | France | None reported | R | Diagnosis |
| Werner RA (21) | 2016 | Germany | None reported | P | Prognosis |
| Guerin C (22) | 2017 | France | The French National Cancer Institute (INCa) | P | Diagnosis |
| He X (23) | 2021 | USA | None reported | R | Diagnosis |
| Krishnaraju VS (24) | 2022 | India | None reported | R | Staging, restaging |
| Wrenn SM (25) | 2023 | USA | None reported | R | Prognosis |
| Ozturk H (26) | 2023 | Turkey | None reported | R | Restaging |
| Maciel J (27) | 2023 | Portugal | None reported | R | Diagnosis |
| Libè R (28) | 2023 | France | None reported | R | Diagnosis |
| Schlötelburg W (29) | 2024 | Germany | The Interdisciplinary Center for Clinical Research (IZKF), University Hospital of Wuerzburg (grant Z-2/91 to WS) and the Deutsche Forschungsgemeinschaft (project numbers: 314061271 - CRC/TRR 205) | R | Prognosis |
R, retrospective; P, prospective; na, not available.
Concerning risk of bias, the quality evaluation of the research reviewed indicated a moderate risk for biases in the areas of ‘patient selection’ and ‘flow and timing’. The first can be attributed to the small sample size reported and the inclusion of patients from various clinical settings in individual trials. The latter can be attributed to the different follow-up times among studies.
Technical features
Methodologically, the average injected radiotracer activity varied considerably. When expressed as a relative value, the administered activity ranged from 2.5 to 5.5 MBq/kg; as absolute activities, it ranged from 185 to 370 MBq. Consistently across all investigations, the time between injection and scan was approximately 60 min. PET images were qualitatively assessed in every study, while a semiquantitative evaluation was also performed in 18 studies. Among semiquantitative parameters, maximum standardized uptake value (SUVmax) was the most commonly measured PET feature, followed by SUV ratio (defined as the ratio between SUV measured at the adrenal tumor and SUV measured in the liver), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Only one study investigated the potential role of texture features (21).
Differential diagnosis of adrenal masses
One of the major impacts of PET/CT published in the literature is the ability in the differential diagnosis of adrenal masses. Eight studies focused on the role of PET/CT in the differential diagnosis of ACC (13, 14, 15, 20, 22, 23, 27, 28). Sensitivity reported is good but wide, ranging from 67 to 100%, whereas specificity is slightly lower but still good (range 70-97%). The diagnostic performances are impacted by the method used for the diagnosis, especially by the cutoff of SUV or SUV ratio applied. This variability underscores the need for standardized SUV ratio cutoffs, ideally validated in multicentric cohorts.
In two articles, SUVmax and SUV ratio were compared, and diagnostic rates were equal or in favor of SUV ratio. Groussin et al. (13) used SUVmax (cutoff 3.4) and SUV ratio (cutoff 1.45) with reported sensitivities of 100 and 70%, and specificity of 100 and 88%, respectively. Instead, Launay et al. (20) compared SUV and SUV ratio, deriving identical diagnostic performances in terms of sensitivity and specificity. One of the limitations of these studies is the different thresholds applied that reduce the possibility to compare the studies.
The main findings are summarized in Table 4.
| First author | No pts with ACC | M:F | Average age (range) | Stage early: advanced | Treatment | Mitotane yes (%) |
|---|---|---|---|---|---|---|
| Mackie GC (11) | 12 | 2:10 | 34.6 (5-71) | 0:12 | na | nr |
| Leboulleux S (12) | 28 | 8:20 | 49 (22-73) | nr | Surgery (n = 11)* Chemotherapy (n = 13) Radiotherapy (n = 5) Liver chemoembolization (n = 3) | 19 (68%) |
| Groussin L (13) | 22/77 | 9:68 | (32-81) | 14:8* | Surgery (n = 22) | nr |
| Ansquer C (14) | 10/78 | 37:41 | 55* (19-88) | nr | Surgery (n = 10) | nr |
| Gust L (15) | 22/51 | na | 54 (27-80) | nr | Surgery (n = 22) | nr |
| Tessonier L (16) | 37 | 16:21 | 52 (20-88) | 10:27+ | Surgery (n = 31) Chemotherapy (n = 35) | nr |
| Takeuchi S (17) | 106 | 38:68 | (3-77) | 30:76+ | Surgery (n = 82) Chemotherapy (n = 39) | 14 (13%) |
| Satoh K (18) | 30 | 11:19 | 47 (18-70) | 0:30+ | Surgery (n = 26) Chemotherapy (n = 26) Radiotherapy (n = 3) | nr |
| Ardito A (19) | 57 | 25:32 | 42* (18-68) | 37:20+ | Surgery (n = 57) | 38 (67%) |
| Launay N (20) | 32/66 | 33:33 | 56.5 | nr | Surgery (n = 32) | nr |
| Werner RA (21) | 10 | 8:2 | 50 (17-67) | 2:8+ | Surgery (n = 5) Chemotherapy (n = 4) Radiotherapy (n = 1) | 5 (50%) |
| Guerin C (22) | 11/87 | 34:53 | 55 | nr | Surgery (n = 11) | nr |
| He X (23) | 35/117 | 14:21 | 51 | nr | nr | nr |
| Krishnaraju VS (24) | 30/77 | 36:41 | 40.4 (1-84) | 18:12+ | Surgery (n = 21) Chemotherapy (n = 1) Radiotherapy (n = 1) Surgery + radiotherapy (n = 4) Surgery + radiotherapy + chemotherapy Surgery + chemotherapy (n = 1) | (n = 1) nr |
| Wrenn SM (25) | 26 | 12:14 | 53* (36-81) | 4:19+ (n = 3 stage unknown) | Surgery (n = 20) | 14 (54%) |
| Ozturk H (26) | 11/16 | 10:6 | 53.4 (30-74) | nr | Surgery (n = 11) | nr |
| Maciel J (27) | 12/631 | nr | nr | nr | nr | nr |
| Libè R (28) | 63 | 25:38 | nr | 40:23+ | Surgery (n = 55) | nr |
| Schlötelburg W (29) | 67 | 27:40 | 50.5 (18-79) | 13:54+ | Surgery (n = 56) Chemotherapy (n = 27) | 45 (67%) |
Nr, not reported; M, male; F, female; ACC, adrenocortical carcinoma.
*MacFarlane’s criteria. 1ENSAT stage. * Several patients received combined treatments but not described in the manuscript.
Staging/restaging
Data about the role of 18F-FDG PET/CT in staging and restaging are very heterogeneous. Most studies were mixed, including patients that performed PET/CT both for staging and restaging purposes. One research (12) included only patients at staging, while two articles included only patients at restaging. Samples analyzed ranged from 10 to 106 patients.
In a per-patient analysis, sensitivity reported was very high, ranging from 83 to 100%; similar performances also considered specificity (range 83-100%) (Table 5).
In cases of positive PET/CT, SUVmax reported was relatively high, with a mean value between 6.8 and 13.8.
In three studies (12, 17, 19), the impact of 18F-FDG PET/CT in management was also evaluated. In all these research studies, PET/CT modified the management, ranging from 9 to 21% of the patients included. The most
common impacts were the avoidance of useless treatment, such as surgery, for a watch-and-wait approach, and the lead to systemic therapy (chemotherapy) from local therapy.
Prognostication
Regarding the prognostic role of 18F-FDG PET/CT in ACC, seven studies are present in the literature, reporting the controversial impact of PET/CT features in predicting prognosis (12, 16, 17, 18, 21, 25, 29) (Table 6).
In these studies, different endpoints were investigated, with OS as the most frequent (n = 3), both OS and PFS (n = 3), and only PFS (n = 1).
To investigate the prognostic role of PET/CT, semiquantitative parameters were analyzed in all papers, with SUVmax and SUV ratio as the most common, while MTV and TLG were considered only in
| First author | Device | Mean 18F-FDG injected dose, MBq | Mean uptake time (min) | Image analysis | Semiquantitative variables |
|---|---|---|---|---|---|
| Mackie GC (11) | PET and PET/CT | 296-370 | 45 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Leboulleux S (12) | PET/CT | 5 MBq/kg | 60-120 | Visual and semiquantitative | SUVmax, MTV |
| Groussin L (13) | PET and PET/CT | 2.5-5 MBq/kg | 60 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Ansquer C (14) | PET/CT | 4-7 MBq/kg | 60-80 | Visual and semiquantitative | SUVmax |
| Gust L (15) | PET/CT | 4 MBq/kg | 60 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Tessonier L (16) | PET/CT | 4-5 MBq/kg | 70 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Takeuchi S (17) | PET/CT | 185-370 | 60 | Visual and semiquantitative | SUVmax, TLG |
| Satoh K (18) | PET/CT | 370 | 60 | Visual and semiquantitative | SUVmax, MTV, TLG |
| Ardito A (19) | PET/CT | 222-370 | 60 | Visual and semiquantitative | SUVmax |
| Launay N (20) | PET/CT | 5 MBq/kg | 60 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Werner RA (21) | PET/CT | 339 | 63 | Visual and semiquantitative | SUVmax, SUVpeak, SUV ratio (adrenal to liver) and textural heterogeneity features |
| Guerin C (22) | PET/CT | nr | 60 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| He X (23) | PET/CT | nr | nr | Visual and semiquantitative | SUV ratios (adrenal to liver and adrenal to blood pool) |
| Krishnaraju VS (24) | PET/CT | 5 MBq/kg | 45-60 | Visual and semiquantitative | SUVmax, TLRmax, TLRpeak, TCRpeak |
| Wrenn SM (25) | PET/CT | na | na | Visual and semiquantitative | SUVmax |
| Ozturk H (26) | PET/CT | 370 | 60 | Visual and semiquantitative | SUVmax |
| Maciel J (27) | PET/CT | 3.7 MBq/kg | 60 | Visual and semiquantitative | SUVmax |
| Libè R (28) | PET/CT | 5 MBq/kg | 60 | Visual and semiquantitative | SUVmax, SUV ratio (adrenal to liver) |
| Schlötelburg W (29) | PET/CT | 278 | 60 | Visual and semiquantitative | SUVmax, SUVpeak, SUVmean, SUV ratio (adrenal to liver), MTV and TLG |
na, not available; SUV, standardized uptake value; lbm, lean body mass; MTV, metabolic tumor volume; TLG, total lesion glycolysis; TLRmax, target-to-liver ratio SUVmax; TLRpeak, target-to-liver ratio SUVpeak; TCRpeak, target-to-contralateral adrenal SUVpeak.
three studies. SUVmax with a threshold of ten was the most frequent parameter analyzed, with no significant impact on prognosis in two studies and significant impact in one research, but in this case only univariate analysis was performed.
Only in one study were textural features representing heterogeneity included, but without usefulness.
In the two studies where PET semiquantitative features were investigated as continuous variables and not dichotomized, no prognostic role of these variables was recognized. Prospective studies using harmonized PET protocols, fixed SUV ratio cutoffs (e.g., adrenal-to-liver), and integration of volumetric parameters (MTV/TLG) with molecular biomarkers are needed to clarify prognostic value.
Discussion
18F-FDG PET/CT is a functional imaging tool that has been widely used in the staging, prognosis, and treatment response evaluation of various types of oncological diseases. However, specific studies about the role of PET/CT in ACC are relatively scarce and have heterogeneous results. Thus, the effective value of 18F-FDG PET/CT in evaluating ACC is still under debate because it is not yet understood due to
the low number of studies and patients evaluated in the literature.
One of the potential uses of 18F-FDG PET/CT in the investigation of ACC is the diagnosis and characterization of adrenal masses.
The rate of incidental adrenal masses detected on conventional imaging (incidentalomas) is about 5-10%, and they are more frequently non-secreting adenomas, followed by metastases (31). Instead, malignant primary tumors represent only 2-3% of all adrenal incidentalomas in healthy patients, and among them, the incidence of ACC is very low (<5%) (30, 31).
CT scans are initially used to distinguish between benign and malignant adrenal lesions. Key indicators for benign lesions are low density (≤10 Hounsfield units on unenhanced images), size less than 4 cm, lipid content, and fast washout rate (32). However, about 30% of adrenal lesions are not correctly diagnosed or remain doubtful.
MRI was also investigated in this field with promising initial evidence. Its key strength lies in tissue characterization, particularly through chemical shift imaging, which detects the presence of microscopic intracellular lipids. Lipid-rich adrenal adenomas, the most common benign lesions, exhibit a characteristic signal loss on out-of-phase images compared to
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Figure 2 QUADAS 2 scores of the articles included. A full color version of this figure is available at https://doi.org/10.1530/ERC-25-0356.
in-phase images. While most malignant lesions (e.g., metastases, adrenocortical carcinoma, and pheochromocytoma) lack this lipid and do not show signal drop, some atypical cases or specific metastases
can overlap. Dynamic contrast-enhanced MRI can further aid differentiation by analyzing enhancement patterns and washout, with adenomas typically showing rapid enhancement and washout, while malignant lesions often demonstrate heterogeneous and prolonged enhancement (33, 34).
While conventional imaging (CT, MRI) is the primary method for characterizing adrenal masses (35), 18F-FDG PET/CT can provide valuable functional/ metabolic information. Malignant adrenal lesions, including ACC, typically show increased FDG uptake due to their higher metabolic activity and proliferation. This can help differentiate ACC from many benign adrenal adenomas, which often show lower or no significant FDG uptake. However, the possibilities of false-positive or false-negative reports with FDG are not negligible (36). Some benign conditions (e.g., adrenal hemorrhage, pheochromocytoma, inflammatory reactions) can also show increased FDG uptake, and some ACCs may show low uptake, highlighting the need for careful interpretation in conjunction with other clinical and imaging findings.
The diagnostic performance of PET/CT in the differential diagnosis reported in the literature is very high in terms of both sensitivity and specificity. Both SUVmax as an absolute value and SUV ratio (considering liver as reference) showed optimal accuracy. The major limitation is the different cutoff values proposed by several groups that published. This bias is intrinsically due to the fact that SUVmax is a variable dependent on other parameters related to patient features, protocol, kind of scanner, and technology available (37).
Considering the high FDG-avidity rate of ACC, 18F-FDG PET/CT is an imaging tool potentially useful for the staging
| First author | No patients | No ACC (%) | Comparator | Method | Sensitivity | Specificity |
|---|---|---|---|---|---|---|
| Groussin L (13) | 77 | 22 (29%) | Adrenocortical adenomas | SUVmax 3.4 | 100% | 70% |
| SUV ratio 1.45 | 100% | 88% | ||||
| Ansquer C (14) | 78 | 10 (13%) | Metastases (n = 3), pheochromocytoma (n = 12), | Visual | 89% | 76% |
| lymphomas (n = 4), other malignant lesions (n = 3), benign lesions (n = 46) | SUVmax 3.3 | 93% | 78% | |||
| Gust L (15) | 51 | 22 (43%) | Benign tumors | SUV ratio 1.7 | 95% | 97% |
| Launay N (16) | 66 | 32 (49%) | Adrenocortical adenoma (n = 16), metastases (n = 19) | SUVmax 3.7 | 97% | 83% |
| SUV ratio 1.29 | 97% | 83% | ||||
| Guerin C (22) | 87 | 11 (13%) | Benign tumors (n = 72), sarcomas (n = 3), metastases (n = 1) | SUV ratio 1.5 | 87% | 86% |
| He X (23) | 117 | 35 (30%) | Adrenocortical adenomas (n = 36), other benign tumors (n = 34) metastases (n = 12) | SUV ratio (liver) 2.5 | 85% | 90% |
| SUV ratio (blood pool) 3.4 | 83% | 90% | ||||
| Maciel J (27) | 631 | 12 (19%) | Metastases (n = 355), benign tumors (n = 233) | SUVmax 6.7 | 61% | 95% |
| Libè R (28) | 63 | 63 (100%) | na | SUV ratio 1.45 | 89% | Not |
| possible to calculate |
| First author | Indications | Mean SUVmax | Kind of analysis | Sensitivity | Specificity | Management impact n (%) | Kind of impact |
|---|---|---|---|---|---|---|---|
| Mackie GC (11) | Restaging (n = 12) | 6.9 | Per-patient | 83% | NA | na | na |
| Leboulleux S (12) | Staging (n = 19) | na | Per-patient | 90% | NA | 5 (18%) | Lead to surgery n = 2 |
| Restaging (n = 9) | Per-organs | 93% | NA | Lead to radiotherapy n = 1 Lead to systemic therapy n = 1 Avoid useless therapy n = 1 | |||
| Tessonier L (16) | Staging (n = 37) | 11* | Per-patient | na | na | na | na |
| Takeuchi S (17) | Staging (n = 22) | 13.8 (staging) | Per-organs | 99% | 100% | 10 (9%) | Lead to systemic therapy n = 2 |
| Restaging (n = 91)+ | 8.4 (restaging) | Lead to surgery n = 7 Avoid useless therapy n = 1 | |||||
| Ardito A (19) | Restaging (n = 57) | 6.8* | Per-lesion | 67% | 97% | 12 (21%) | Lead to surgery n = 3 Lead to systemic therapy n = 1 Avoid useless therapy n = 8 |
| Krishnaraju VS | Staging (n = 55) | 10.1 | Per-patient | 100% | 95% | na | na |
| (24) | Restaging (n = 41) | ||||||
| Ozturk H (26) | Restaging (n = 16) | na | per-patient | 100% | 83% | na | na |
NA, not available.
*Median. +Fifteen patients performed both staging and restaging PET/CT.
and restaging of disease, particularly for the study of distant metastases and relapse/recurrence. When compared, PET/CT seems to be superior to CT for the detection of adrenal bed disease, in the liver, and in the bone, but less sensitive for the investigation of lung lesions and peritoneal carcinomatosis. The low detection rate for lung nodules may be explained by the small size of nodules, under the resolution power of the PET scanner (about 5 mm for classical PET scanners). The low sensitivity of FDG PET in detecting peritoneal carcinomatosis can also be correlated with lesion size and with the physiological uptake in the bowel that hides the uptake in the peritoneum (11). These potential limitations could be overcome with the introduction of
new ‘digital’ scanners characterized by the replacement of traditional photomultiplier tubes (PMTs) with silicon photomultipliers (SiPMs) and a potential resolution power of 1-2 mm (38).
The potential prognostic role of 18F-FDG PET/CT parameters remains an unresolved issue, with findings that are heterogeneous and controversial. The inconsistent prognostic results stem from methodological limitations: small cohorts, retrospective designs, and variable statistical approaches (e.g., arbitrary SUVmax dichotomization vs continuous analyses). Volumetric parameters (MTV/TLG) showed promise in two studies but require validation in larger
| First author | No patients | Parameters considered | Cutoffs | Endpoints | Main findings |
|---|---|---|---|---|---|
| Leboulleux S (12) | 21 | SUVmax, MTV | SUVmax:10 MTV: 150 | PFS | SUVmax and MTV significantly correlated with PFS (only univariate analysis performed) |
| Tessonier L (16) | 37 | SUVmax, SUV ratio | SUVmax:10 SUV ratio: 4 | DFS, OS | No PET features correlated with survival |
| Takeuchi S (17) | 106 | SUVmax, TLG | SUVmax:10 TLG: 200 | PFS, OS | No PET features correlated with survival |
| Satoh K (18) | 30 | SUVmax, MTV, TLG | SUVmax: 8.9 MTV: 87 TLG: 229.4 | OS | SUVmax, MTV and TLG significantly correlated with OS |
| Werner RA (21) | 10 | SUVmax, SUVpeak, SUV ratio (adrenal to liver) and textural heterogeneity features | Investigated as continuous variable | PFS, OS | No PET features correlated with survival |
| Wrenn SM (25) | 26 | SUVmax | SUVmax: 8.4 | OS | SUVmax significantly correlated with OS |
| Schlötelburg W (29) | 67 | SUVmax, SUVpeak, SUVmean, SUV ratio (adrenal to liver), MTV and TLG | Investigated as continuous variable | OS | No PET features correlated with OS, only the presence of metastases FDG positive was correlated with OS |
PFS, progression-free survival; DFS, disease-free survival; OS, overall survival.
cohorts. Crucially, no study adjusted for established prognostic markers (e.g., ENSAT stage, Ki-67 index) in multivariate models. Future work should integrate PET parameters with clinical-pathological risk stratification systems and standardize endpoints (e.g., 12-month PFS). Texture analysis, though preliminarily negative, warrants exploration in multicenter datasets using validated software platforms.
Substantial technical heterogeneity was observed across studies, including variations in PET/CT scanners, reconstruction algorithms, administered FDG activity (185-370 MBq), and uptake times (45-120 min). These factors critically influence SUV measurements and limit comparability of semiquantitative thresholds (e.g., SUVmax cutoffs ranged from 3.4 to 6.7 for diagnosis). Future studies should adhere to harmonization protocols (e.g., EANM/EARL accreditation) and prioritize adrenal-to-liver SUV ratios to mitigate technical variability.
Among metabolic features, MTV seems to be promising. MTV represents a combination of tumor volume and metabolism and may be considered an expression of tumor aggressiveness together with tumor size characteristics. In our research, only two articles studied MTV, finding a positive impact.
Another point with potential prognostic role but not yet well investigated is the reduction of PET uptake after treatment. A significant reduction, expressed as SUV, could be a sign of good response to treatment and predictive of positive prognosis (7, 17).
To navigate these challenges, integrating artificial intelligence systems could prove highly beneficial.
Beyond FDG, alternative radiotracers were investigated with the aim to increase sensitivity and specificity. While FDG dominates ACC imaging, novel tracers merit discussion. 11C-metomidate (MTO) offers specificity for adrenocortical tissue. C11-MTO was one of the first studied because it targets the 11ß-hydroxylase enzyme, which is highly expressed in the adrenal cortex and is involved in steroid synthesis. This enzyme is crucial for normal adrenal function and is often overexpressed in ACC (39, 40). 68Ga-Pentixafor (targeting CXCR4) demonstrated superior accuracy vs FDG in advanced ACC and was explored with promising results (41, 42). FDG remains preferred for staging/restaging due to widespread availability, but tracer selection should be individualized (e.g., CXCR4-directed PET for peptide receptor radionuclide therapy eligibility). Artificial intelligence-driven quantification of tumor heterogeneity may further refine risk prediction beyond current semiquantitative metrics.
Limitations
The main limitations of our systematic review include the low number of included studies, the retrospective nature
of the design in most cases, and the heterogeneity of patients, disease characteristics, and treatment. Consistent with the constrained number of included studies and the subsequent small sample analyzed, selection bias cannot be excluded.
These limitations may explain the absence of robust evidence about this topic.
Conclusions
With the limitations of the heterogeneity of the studies included, with this systematic review, we can reason that 18F-FDG PET/CT has a significant role in the evaluation of ACC patients, especially in the diagnosis of adrenal masses and the staging/restaging of ACC. Instead, the prognostic impact of 18F-FDG PET/CT seems to be promising, but the data available are too limited, and its routine use for prognostication requires further validation. Artificial intelligence-driven analysis of PET texture features may unlock novel prognostic insights, and future research should prioritize extensive, potentially prospective and multicentric, studies to determine its suitability for inclusion in routine diagnostic algorithms.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
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