Combined [18F]Fluorodeoxyglucose PET and [123I]Iodometomidate-SPECT for diagnostic evaluation of indeterminate adrenal neoplasias-the cross-sectional diagnostic test accuracy study FAMIAN

Abstract

Background: Adrenal tumours are frequently detected by conventional imaging. However, computed tomography and magnet resonance imaging have limited specificity in classifying the most prevalent tumour type, adrenocortical adenoma (ACA), which typically does not require surgery. We proposed that combined molecular imaging with [¹⁸F]Fluorodeoxyglucose-positron emission tomography (FDG PET) and [^123I]Iodometomidate-single photon emission tomography (IMTO SPECT) improves non-invasive classification of ACA.

Methods: This cross-sectional, multicentre diagnostic study included patients (≥30 years) with non-functioning indeterminate adrenal masses (>3 cm or increase >1 cm, Hounsfield units [HU] ≥10 on unenhanced computed tomography [CT]) scheduled for surgery. Using histopathology as the reference, we assessed the accuracy of FDG/IMTO imaging as an ACA-test, assuming that low FDG with high IMTO uptake is indicative of ACA, with a focus on high specificity and moderate to high sensitivity. We also investigated its accuracy in detecting or excluding adrenocortical carcinoma (ACC) and evaluated FDG and unenhanced CT in assessing malignancy.

Trial-registration: EudraCT 2012-003604-13; ClinicalTrials.gov-identifier NCT02010957.

Findings: From July 2015 to December 2020, 85 patients were enrolled, with 77 included in the final analysis (53 benign, 30 ACA, 9 ACC). FDG/IMTO-imaging classified ACA with high specificity (95·7% [95% CI 85·2%-99·47%]), high positive predictive value (87·5% [95% CI 61·7%-98·4%]) and high positive likelihood ratio (11·1 [95% CI 3·2-122]). However, sensitivity was low (48·3% [95% CI 29·4%-67·5%]) due to moderate/high FDG uptake in 14 of 30 ACA. Malignant masses were classified with high sensitivity but low-to-moderate specificity by both unenhanced CT (cut-off HU ≥20 sensitivity 100% [95% CI 85·8%-100%], specificity 26·4% [95% CI 15·3%-40·3%]) and FDG (visual analysis sensitivity 95·8% [95% CI 78·9%-99·9%], specificity 62·3% [95% CI 47·9%-75·2%]). All four study-related AEs were grade 1, the seven serious AEs were not study-related.

Interpretation: Combined FDG/IMTO-imaging classifies ACA with high specificity, potentially reducing unnecessary surgery. A sub-group of FDG-positive ACA lowers sensitivity.

Funding: German Research Foundation and EU-FP7.

Keywords: Adrenal incidentaloma; Adrenocortical adenoma; Adrenocortical carcinoma; Computed tomography; Fluorodeoxyglucose positron emission tomography; Indeterminate adrenal masses; Iodometomidate SPECT; Molecular imaging.

Fig. 1

Flow of participants and main histopathological categories. Patients were included at six German study centres and completed 4 study visits: Visit 1: baseline evaluation; Visit 2 and 3: Diagnostic imaging with FDG and IMTO. The order of imaging was left to the decision of the recruiting centre. Visit 4: Follow up including routine laboratory parameters and adverse event assessment, 2–3 weeks after visit 3 or preoperative, whichever came first. In four cases, only FDG PET was available (1 ACA FDG+, 1 ACA FDG−, 1 non-AC benign, FDG−, 1 non-AC malignant, FDG+). For the evaluation of the ACA test, all 73 tumours with combined imaging information and both tumours with missing IMTO but FDG+ (classified as non-ACA) were included. For the evaluation of the ACC test, all 73 tumours with combined imaging information and both tumours with missing IMTO but available FDG- (classified as non-ACC) were included. 1: No IMTO SPECT due to delivery problems or failure of batch in final quality control in 2 ACA, 1 non-AC benign and 1 non-AC malignant tumour. 2: histopathology based on 72 surgical specimens and 5 biopsies. 3: non-AC malignant tumours comprised 8 metastases (2 malignant melanomas, 1 chorion carcinoma, 1 renal cell cancer, 1 breast cancer, 1 hepatocellular cancer, 1 neuroendocrine carcinoma of the lung, 1 rectum carcinoma); 3 sarcomas, 2 cancers of unknown primary (CUP), 1 gastrointestinal stroma tumour (GIST), 1 non Hodgkin lymphoma (NHL). 4: non-AC benign tumours comprised 7 neurogenic tumours, 3 bronchogenic cysts, 3 pheochromocytomas, 3 vascular malformations, 2 haemangiomas, 2 haematomas, 1 myelolipoma, 1 desmoidfibroma, 1 mesenchymal solitary fibrous tumour. Eight patients were excluded from the final analysis: One patient consented but revealed as screen failure as he fulfilled the exclusion criterion of HU <10 and did not receive study-related investigations. Two patients withdrew consent before any study-related investigations were performed; one patient declined further study-related procedures and surgery after the FDG PET result was available; two cases were excluded after completing the study because unenhanced CT tumour attenuation was less than 10 HU upon central imaging analysis; one patient died from heart failure not related to the adrenal tumour before the scheduled adrenalectomy.

Fig. 2

Illustrative imaging examples for the different tumour categories. Examples of the categorization into the four tumour subgroups based on the results of functional imaging using FDG PET and IMTO SPECT: ACA: FDG-negative and IMTO-positive; non-AC benign: FDG-negative and IMTO-negative; ACC: FDG-positive and IMTO-positive; non-AC malignant: FDG-positive and IMTO-negative. Left column: unenhanced computed tomography imaging; tumour is indicated by the red arrow.

Fig. 3

Results of molecular imaging based on visual and quantitative imaging analysis for the histopathological subcategories. a Visual interpretation of FDG PET in histopathological subcategories with scoring system ranging from 1 to 5. 1 = FDG negative (definitely benign), 2 = mildly FDG avid (more likely benign), 3 = indeterminate (rated as FDG positive), 4 = moderately FDG-avid (more likely malignant), 5 = malignant. b Visual interpretation of IMTO SPECT 1 = negative, no adrenocortical origin, 2 = mildly positive, unlikely adrenocortical origin, 3 = indeterminate (rated as IMTO negative), 4 = moderately positive, indicative of adrenocortical origin, 5 = strongly positive, adrenocortical origin. c Quantitative analysis of the FDG uptake in the tumour subcategories based on the measurement of SUVpeak (n = 77). Horizontal line = median. d Quantitative analysis of the IMTO uptake in the tumour subcategories based on the measurement of SUVpeak (n = 58). Horizontal line = median. e ROC analyses for quantitative measures of FDG uptake (SUVmax, SUVpeak and tumour to background ratio TBR adrenal tumour SUVpeak/prevertebral region SUVmax), for visual analysis of FDG uptake using five categories and for attenuation values in unenhanced CT measured in Hounsfield units. Discrimination malignant versus benign tumours. AUCs are reported with 95% CI. f ROC analyses for quantitative measures of IMTO uptake in 58 lesions (SUVmax, SUVpeak and tumour to background ratio TBR adrenal tumour SUVpeak/prevertebral region SUVmax), for visual analysis of the 58 lesions with available quantitative measures and for the all lesions with IMTO SPECT (n = 77). Discrimination adrenocortical versus non-adrenocortical tumours. AUCs are reported with 95% CI.