Role of ¹⁸F-FDG PET/CT in the differential diagnosis of primary benign and malignant unilateral adrenal tumors

Introduction

Up to 5% of adrenal masses are identified incidentally on abdominal computed tomography (CT) imaging (1), and most of them are benign adenomas in patients without a primary malignancy (2). Although CT and magnetic resonance imaging (using adrenal lesion-specific techniques) are classically utilized in the evaluation of incidental adrenal lesions, 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT is emerging as an adjunctive imaging test for distinguishing benign from malignant adrenal nodules (3-6). PET/CT is an imaging technology that combines functional qualitative and anatomic localization and is widely used to diagnose adrenal diseases.

Discrimination of benign adrenal lesions from malignant masses is very important for choosing the appropriate treatment approach and assessing prognosis. The application of PET/CT for adrenal tumors includes tumor localization and qualitative diagnosis and locating the primary focus of metastatic tumors. Early ¹⁸F-FDG PET/CT studies (2,7-10) reported high sensitivity, specificity, and accuracy for detecting metastatic adrenal lesions. When patients with unilateral adrenal tumors undergo a PET/CT examination and have malignant tumors and metastases from other parts of the body excluded, the differential diagnosis of benign and malignant tumors becomes critical, and few relevant reports.

Our goal was to evaluate 18F-FDG PET/CT’s value in the differential diagnosis of benign and malignant tumors in patients with unilateral adrenal masses, where other malignant tumors have been excluded.

Methods

Patients

Between January 2018 and December 2019, 26,264 ¹⁸F-FDG PET/CT examinations were evaluated retrospectively. A total of 64 patients (31 male, 33 female; age range: 3–76 years, mean: 48.5) with a confirmed unilateral adrenal tumor underwent ¹⁸F-FDG PET/CT examination for diagnosis and staging. The whole-body ¹⁸F-FDG PET/CT examination excluded metastasis, and all patients were confirmed by operation and biopsy pathology. Their clinical data and pathological results were collected. The inclusion criterion was a primary unilateral adrenal tumor without metastasis, and the exclusion criteria were a history of malignancy and metastasis or bilateral adrenal tumors. The Ethics Committee approved the study of the Chinese PLA General Hospital. Informed patient consent was not required.

Imaging protocol

All patients were instructed to fast for at least 4–6 h, and rested for 10–15 min in a quiet environment before an injection of 2.96–4.44 MBq/kg FDG. Blood glucose was controlled within 6.5 mmol/L. PET/CT scanning was performed 60 min after injection, using an integrated scanner (Siemens Biograph 64 PET/CT, Germany). Whole-body CT scanning was performed without intravenous contrast administration, with parameters of 120 kV, 100 mA, the pitch of 0.9, and section thickness of 5 mm. The CT images were used for subsequent PET attenuation correction. After unenhanced CT scanning, PET scanning was performed immediately, and images were acquired from the skull base to the upper thigh with a 2-min acquisition per bed position using a three-dimensional acquisition mode. The point diffusion method (turex) was used for the PET reconstruction, with 3 iterations and 21 subsets. The image matrix was 172 mm × l72 mm, 4-mm half-height and width Gaussian filtering, plus scattering correction.

Image analysis

After receiving other imaging examinations (e.g., ultrasound, CT, MRI), the patient was found to have adrenal space occupying lesion, and then PET/CT examination was recommended. The PET/CT scans were reviewed by two experienced nuclear medicine doctors who did not know either the other imaging results or the clinical information. The region of interest (ROI) was delineated in the liver and the renal lesion site, and the maximum standardized uptake values (SUV_max) of the renal lesion and liver were measured on a standardized reconstruction. Discrepancies between the two readers, measuring 50% of the larger measurement, were reviewed by a third reviewer. The two most similar SUV_max measurements were then used for calculations. On visual analysis of PET/CT images, adrenal uptake was based on a three-scale grading system (2): (I) Grade I: intensity less than that of the liver; (II) Grade-II: intensity equal to that of the liver; (III) Grade III: intensity higher than that of the liver. The ratio of tumor to the liver was defined as T/L. For the visual interpretation, SUV_max-receiver operating characteristics (ROC) and T/L-ROC methods were used to analyze the diagnostic accuracy.

Statistical analysis

SPSS22.0 was used to analyze the data. Measurement data were expressed as the mean ± standard deviation of the mean (SD). With surgery or biopsy pathology as the gold standard, the patients were divided into benign and malignant groups. SUV_max-ROC method and T/L-ROC method were used to evaluate the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of unilateral adrenal primary tumor diagnosis.

Results

Pathologic findings

All 64 patients had histopathologically proven adrenal lesions. A total of 64 lesions included 48 benign lesions (left adrenal gland: 22; right adrenal gland: 26) and 16 malignant lesions (left adrenal gland: 10; right adrenal gland: 6) (Table 1). Among the benign lesions, pheochromocytoma was the most common, in addition to rare tumors such as ganglioneuroma, hemangioendothelioma, and hemangioma. Cortical adenocarcinoma was the most common of the malignant tumors, which included leiomyosarcoma and Ewing’s sarcoma.

Table 1 Pathologic findings (N=64)
Full table

PET/CT findings

The visual analysis found that 100% of Grade I cases were benign, 90.9% of Grade II cases were benign, and 65.1% of Grade III cases were benign (Table 2). One malignant adrenal lesion (cortical adenocarcinoma) was Grade II.

Table 2 Grades of uptake for benign and malignant
Full table

The SUV_max of the malignant lesions (10.0±5.8) was higher than that of the benign lesions (5.4±5.3, P<0.05) (Table 3). The average size of malignant adrenal lesions was 83.4±27.4 mm, and that of benign lesions was 62.1±33.5 mm (P<0.05) (Table 3). The T/L of malignant lesions was 3.39±1.79, and that of benign lesions was 1.99±2.09 (P<0.05).

Table 3 Size and SUV_max values for adrenal benign and malignant lesions
Full table

In the differentiation of primary benign and malignant unilateral adrenal tumors, the sensitivity, specificity, and accuracy of the SUV_max-ROC method (cut-off value =5.65) were 81.25%, 72.91%, 75.00%, and the positive and negative predictive values were 50.00% and 92.11%, respectively (Table 4). The sensitivity, specificity, and accuracy of the T/L-ROC method (cut-off value =1.52) were 93.73%, 62.50%, 70.31%, and the positive and negative predictive values were 46.88% and 96.77%, respectively (Table 4). ROC curves generated from SUV_max and T/L are illustrated in Figures 1,2, respectively.

Table 4 Differentiation between adrenal benign and malignant lesions using maximum standardized uptake value, and tumor/liver standardized uptake value ratios
Full table

Figure 1 Receiver operating characteristics (ROC) generated from SUV_max information. Using SUV_max cut-off value of 5.65 gave sensitivity of 81.25%, specificity of 72.91%, accuracy of 75.00%, negative predictive value of 92.11%, and a positive predictive value of 50.00%.

Figure 2 Receiver operating characteristics (ROC) generated from T/L information. Using T/L cut-off value of 1.52 gave sensitivity of 93.73%, specificity of 62.50%, accuracy of 70.31%, negative predictive value of 96.77%, and a positive predictive value of 46.88%. T/L, tumor to liver ratio.

Discussion

In patients with incidentally discovered adrenal nodules, so-called adrenal ‘‘incidentaloma’’, FDG PET/CT is emerging as a useful test to distinguish benign from malignant etiology (11). Several reports have documented the effectiveness of standalone ¹⁸F-FDG PET/CT in differentiating benign from malignant adrenal lesions (2,7-10); however, most of those patients had primary cancer. ¹⁸F-FDG PET/CT could be used to stratify patients with a higher risk of malignancy for surgical intervention while recommending surveillance for adrenal masses with low malignant potential (11). Our retrospective study used ¹⁸F-FDG PET/CT to assess the characteristics of primary benign and malignant unilateral adrenal tumors.

Although metastases comprise most malignant adrenal lesions, less common primary adrenal malignancies, such as adrenocortical carcinoma, primary adrenal lymphoma, melanoma, malignant pheochromocytoma, and angiosarcoma, are also occasionally found (11). We reported leiomyosarcoma and Ewing’s sarcoma in this study. Benign lesions include adrenocortical adenoma, benign pheochromocytoma, myelolipoma, ganglioneuroma, adrenal cyst, adrenal hemorrhage, and granulomatous disease (11). In addition to these benign lesions, we reported calcifying fibrous tumor, hemangioendothelioma, hemangioma, neurogenic tumor, angiogenic tumor, and schwannoma.

Most benign adenomas show adrenal FDG uptake equal to or less than the liver background (11). However, in our study, 38.5% (5/13) of the benign adenomas had a higher FDG uptake than that of the liver. The main reason for that finding may be that these were atypical adenomas and pheochromocytoma. The SUV and T/L of most benign lesions were small, but for a few benign lesions they were large, even higher than those of the malignant lesions (Table 1), which led to an increase in the standard deviation of SUV and T/L for benign lesions. On visual analysis, we found that 95.3% (20/21) of the lesions in Grade I and Grade II were benign. Therefore, when the adrenal lesions are Grade I and Grade II, the mass is likely to be benign. Among the malignant lesions, 93.4% (15/16) were Grade III. Among the benign lesions, 58.3% (28/48) were Grade III, and 74.2% (16/21) of pheochromocytoma and 46.2% (6/13) of adenomas were Grade III. Therefore, when the adrenal lesions are Grade III, the malignant tumor should be differentiated from pheochromocytoma and adenoma.

The diagnostic performance of the SUV_max-ROC and T/L-ROC methods were similar. Both methods had high sensitivity and negative predictive value but low specificity and positive predictive value. When the SUV_max-ROC method’s cut-off value is >5.65, or the cut-off value of the T/L-ROC method is >1.52, it may help differentiate malignant tumor from pheochromocytoma by combining ¹⁸F-FDG PET/CT with 6-l-¹⁸F-fluoro-dihydroxyphenylalanine (¹⁸F-DOPA). ¹⁸F-DOPA is approved in several EU countries for the diagnosis and staging of phaeochromocytoma (12). Therefore, ¹⁸F-FDG combined with ¹⁸F-DOPA should assist in the differential diagnosis of pheochromocytoma from a malignant adrenal tumor. However, sometimes even combination imaging has difficulty differentiating malignant adrenal tumors from adenomas, so pathologic confirmation is essential.

Conclusions

The advantage of ¹⁸F-FDG PET/CT is to exclude malignant tumors from other parts of the body. ¹⁸F-FDG PET/CT had a high negative predictive value in differentiating primary benign and malignant unilateral adrenal tumors, which means adrenal lesions with low FDG uptake are likely to be benign. Although the positive predictive value of ¹⁸F-FDG was not high, ¹⁸F-FDG combined with ¹⁸F-DOPA can assist the differential diagnosis of malignant adrenal lesions and pheochromocytoma.

Acknowledgments

Funding: International S&T Cooperation Program of China (2009DFA32960).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-875). The authors have no conflicts of interest to declare.

Ethical Statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Chinese PLA General Hospital. Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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