Use of 18F-FDG PET/CT to differentiate ectopic adrenocorticotropic hormone-secreting lung tumours from tumour-like pulmonary infections in patients with ectopic Cushing syndrome


 Purpose: Ectopic adrenocorticotropic hormone (ACTH)-secreting lung tumours represent the most common cause of ectopic Cushing syndrome (ECS). Pulmonary opportunistic infections are associated with ECS and occasionally difficult to differentiate from tumours by using computed tomography (CT) alone. The aim of the present study was to evaluate the usefulness of 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT (18F-FDG PET/CT) for differentiating ectopic ACTH-secreting lung tumours from tumour-like pulmonary infections in patients with ECS.Methods: We retrospectively reviewed the imaging data for 24 patients with ECS who were suspected to have ACTH-secreting lung tumours and underwent 18F-FDG PET/CT between 2008 and 2019.Results: In total, 18 patients had lung tumours (17 carcinoids and 1 small cell lung cancer) and six had pulmonary infections (cryptococcosis, n = 3; aspergillosis, n = 4; pulmonary abscess, n = 1). The primary source of ECS remained occult in the six patients with pulmonary infections. The maximum standardized uptake value (SUVmax) for pulmonary infections was significantly higher than that for tumours (P = 0.008). Receiver operating characteristic analysis was performed, and it was found that a cut-off SUVmax of 4.95 helped in differentiating lung tumours from infections with 75% sensitivity and 94.4% specificity. In subgroup analysis of 12 typical and five atypical carcinoids, there was no significant between-group difference with respect to SUVmax, the lesion size, the ACTH level, and the prevalence of regional lymph node metastasis.Conclusions: Our findings suggest that pulmonary infections exhibit significantly higher FDG uptake than do ACTH-secreting lung tumours in 18F-FDG PET/CT. Therefore, SUVmax (cut-off 4.95) may be useful for differentiating the two conditions. Typical and atypical ACTH-secreting lung carcinoids may show a similar clinical behaviour and appearance on 18F-FDG PET/CT.


Introduction
10%-15% of Cushing syndrome is caused by ectopic adrenocorticotropic hormone (ACTH)secreting tumours. In such cases, resection of the tumours can have curative effects. The most common tumours associated with ectopic Cushing syndrome (ECS) are pulmonary carcinoids and small cell lung carcinoma (SCLC), followed by thymic carcinoids, pancreatic neuroendocrine tumours, medullary thyroid carcinoma, and pheochromocytoma [1]. 18 Ffluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT; 18 F-FDG PET/CT) has been shown to be an effective modality for localising ectopic ACTHsecreting tumours causing ECS. Pulmonary carcinoids generally demonstrate low to moderate metabolic activity because of their low proliferation rate and slow growth.
Meanwhile, ACTH-producing SCLC can show positive findings on 18 F-FDG PET/CT, although the reported number of ECS-causing SCLCs detected by 18 F-FDG PET/CT is quite small. This is probably because the patients are rapidly diagnosed by conventional crosssectional imaging and do not undergo 18 F-FDG PET/CT for source localisation [2]. ECS due to ectopic ACTH-secreting tumours is associated with markedly elevated ACTH levels. This results in high circulating glucocorticoid levels, which primarily affect cellmediated immunity [3] and impair immune function by inhibiting the phagocytic function of alveolar macrophages and reducing neutrophil recruitment to the infected areas. This results in an increased incidence of opportunistic bacterial and fungal infections [4,5].
The four most common infections associated with ECS are cryptococcosis, aspergillosis, nocardiosis, and pneumocystosis [6], with the lung being the most frequently involved site. Pulmonary infections can exhibit varied radiographic findings and may appear as nodules or masses simulating lung tumours [7]. Thus, it could be difficult to differentiate 4 tumour-like pulmonary infections from lung tumours by using conventional cross-sectional imaging. FDG is a nonspecific tracer that accumulates in areas of infection. Pulmonary cryptococcosis, aspergillosis, nocardiosis, and pneumocystosis have been reported to show high metabolic activity and mimic lung malignancies on 18 F-FDG PET/CT [8][9][10][11].
In the setting of immunosuppression resulting from ECS, surgery for the removal of pulmonary infectious lesions misdiagnosed as ectopic ACTH-secreting tumours can deteriorate the patient's condition. Therefore, discrimination of infections and tumours is crucial for avoiding unnecessary surgical intervention. The primary goal of this retrospective study was to evaluate the usefulness of 18 F-FDG PET/CT for differentiating ectopic ACTH-secreting lung tumours from tumour-like pulmonary infections in patients with ECS.

Patients
We retrospectively reviewed 18 F-FDG PET/CT scans obtained for localising the source of ectopic ACTH secretion in all patients with ECS in our department between 2008 and 2019.
Eventually, 24 patients with suspicious ACTH-secreting lung tumours were included in the present study. The diagnosis of ECS was confirmed by clinical presentations combined with laboratory tests. The reference standard was histopathological diagnosis obtained by either lung surgery or biopsy. There were 11 female and 13 male patients aged 9 to 72 years (mean age, 37.8±17.1 years). This retrospective study of existing patient data and images was approved by the institutional review board of Peking Union Medical College Hospital. The requirement for informed consent was waived.

F-FDG PET/CT Study
Following 8 h of fasting and confirming the blood glucose level to be less than 120 mg/dL, 5 18 F-FDG (5.5 MBq/kg) was intravenously injected. An hour later, PET/CT images were acquired from the mid-thigh to the skull base (2 min/bed position) using a combined PET/CT Biograph (Siemens Co.). All scans were obtained in a three-dimensional mode.

Image interpretation and statistical analysis
The PET/CT scans were reviewed by two experienced nuclear medicine physicians, who visually inspected the images and performed semi-quantitative measurements based on the maximum standard uptake value (SUV m ax ), which is determined by selecting the point of maximum FDG uptake within the lesion. All data are expressed as mean ± standard deviation. Differences between groups were analyzed using the Student t test, nonparametric analysis, and χ2 test. The cut-off SUV m ax for differentiating pulmonary infections from ACTH-secreting tumours was obtained via receiver operating characteristic

Results
Among the 24 patients, 18 patients with 18 lesions were diagnosed with ectopic ACTHsecreting tumours (typical carcinoids, n =12; atypical carcinoids, n = 5; SCLC, n =1) while six patients with eight lesions were diagnosed with pulmonary infections (cryptococcosis, n = 3; aspergillosis, n = 4; pulmonary abscess, n = 1). Therefore, a total of 26 lesions were analysed in this study. The patient characteristics are shown in Table 1. After surgical resection of the lesions, all patients in the tumour group were relieved of all symptoms, with serum cortisol and ACTH levels returning to normal. On the other hand, the source of ectopic ACTH secretion remained occult in the patients with pulmonary 6 infections. The mean SUV m ax for all 18 lesions in the patients with ectopic ACTH-secreting lung tumours was 2.1 ± 1.8 (range: 0.6-7.7), while that for the eight lesions in the patients with pulmonary infections was 5.9 ± 3.8 (range: 1.0-12.4). Thus, SUV m ax was significantly higher for infectious lesions than for tumours (P = 0.008; Fig. 1). ROC curve analysis suggested that an SUV m ax of ≥4.95 was predictive of pulmonary infection with 75% sensitivity and 94.4% specificity; AUC was 0.833 (standard error, 0.093; P = 0.008; 95% confidence interval, 0.651-1.000; Fig. 2). The mean diameters of the ectopic ACTHsecreting lung tumours and pulmonary infectious lesions were 13.8 ± 7.9 (range: 5-37) and 20.9 ± 11.0 (range: 7-35) mm, respectively, with no significant between-group difference (P = 0.126; Table 2 In subgroup analysis of the 12 typical carcinoids and five atypical carcinoids, the mean SUV m ax was 1.9 ± 1.5 and 1.6 ± 0.8 mm, respectively, with no significant between-group difference (P = 0.597; Fig 8). Moreover, there were no significant differences between the typical and atypical groups in terms of the lesion size (11.1 ± 3.7 mm vs. 15.4 ± 8.5 mm, respectively; P = 0.165) and ACTH level (242.8 ± 240.8 pg/ml vs. 263.6 ± 337.3 pg/ml, respectively; P = 0.833). Five of the 12 typical carcinoids (41.7%) and two of the five atypical carcinoids (40%) were confirmed with hilar or mediastinal lymph node metastasis in histopathological analysis (P = 0.951; Table 3). No distant metastases were detected on 18 F-FDG PET/CT in either group.

Discussion
Ectopic ACTH-producing tumours account for 15-20% cases of ACTH-dependent Cushing 7 syndrome. Lung carcinoids and SCLC represent the most common tumours associated with ECS, and the resection of the responsible tumours can have curative effects [12]. There is no consensus regarding the usefulness of 18 F-FDG PET/CT for localising the source of ectopic ACTH secretion, even though it is the most commonly used molecular imaging method in clinical practice because of its wide availability. A nodule or mass-like lesion in the lung that demonstrates abnormal activity on 18  We found that a cutoff SUV m ax of 4.95 maximised the sensitivity and specificity for the differentiation of pulmonary infections from ACTH-secreting tumours. Specifically, the findings indicated that a pulmonary nodule or mass-like lesion with an SUV m ax of ≥ 4.95 was more likely to be an infectious lesion. Our study included only one SCLC, and it was the only lesion with an SUV m ax of > 4.95 in the tumour group (SUV m ax , 7.7). SCLCs generally exhibit high FDG uptake on PET/CT because of their aggressiveness and high metabolic activity [13]. The SCLC was underrepresented in our series, probably because most SCLCs are rapidly diagnosed by conventional cross-sectional imaging and do not 8 require 18 F-FDG PET/CT or other nuclear imaging modalities for localisation [2].
The present study showed significantly higher FDG accumulation in infectious lesions than in pulmonary carcinoids. Among the eight infectious lesions, only two showed low FDG uptake with an SUV m ax of < 4.95. One of the lesions (Patient 1, SUV m ax , 1.2) was due to cryptococcosis, and it was the smallest lesion among the infectious pseudotumours (0.7 cm in diameter). The other infectious lesion with low FDG uptake was an aspergilloma (Patient 4, SUV m ax , 1.0). Pulmonary aspergillosis can be divided into four subtypes on the basis of clinical and radiological findings: aspergilloma, allergic bronchopulmonary aspergillosis, chronic necrotising aspergillosis, and invasive pulmonary aspergillosis (IPA) [14]. The first three subtypes are also considered to be non-invasive pulmonary aspergillosis (NIPA) [14]. Kim  Some authors have reported that atypical carcinoids exhibited significantly higher FDG uptake than did typical carcinoids [16][17][18][19]. Tatci et al. also observed a higher SUV m ax for atypical carcinoids than for typical carcinoids, although the difference was not statistically significant [20]. Fink et al analysed the clinicopathological data and outcomes of 142 patients with pulmonary carcinoids (128 typical and 14 atypical) and found that atypical carcinoids were associated with higher rates of nodal involvement and distant metastases [21]. ACTH-secreting lung carcinoids are considered rare variants of pulmonary carcinoids, and 18 F-FDG PET/CT findings for these lesions have only been described in single case reports or small case series, with no study comparing typical and atypical carcinoids [22,23]. In the present study, the mean SUV m ax for atypical carcinoids was unexpectedly (although statistically insignificant) slightly lower than that for typical carcinoids. In addition, the prevalence of lymph node involvement was similar in atypical carcinoids (40%) and typical carcinoids (41.7%). And we did not observe a significant difference between these two groups in terms of the lesion size, ACTH level neither. These results suggested that typical and atypical ACTH-secreting lung carcinoids exhibit similar clinical behaviour and PET/CT findings, in contrast to previous findings concluding that atypical carcinoids generally exhibit higher FDG uptake, more aggressive behaviour, and a worse prognosis [21]. We speculate that this discrepancy was caused by the fact that the pulmonary carcinoids enrolled in the previous studies did not show features of ectopic ACTH secretion.
The main limitations of this study were the small sample size, which does not allow for powerful statistical analysis, and retrospective design. In addition, survival and recurrence rates for ACTH-secreting carcinoids were not evaluated because of inadequate follow-up data. Therefore, a larger study is necessary to investigate whether the pathological subtype of ACTH-secreting lung carcinoids affects the clinical prognosis of these rare variants of pulmonary carcinoids.

Conclusion
In conclusion, although pulmonary infectious lesions associated with ECS and ACTHsecreting lung tumours occasionally exhibit similar morphological features, the former may show significantly higher FDG accumulation in 18      The patient underwent 18F-FDG PET/CT to localise the source of ACTH secretion.
PET/CT images revealed a nodule with mild FDG activity (arrows; SUVmax, 1.1) in the right lung. The lesion was surgically removed, and histopathological analysis indicated an atypical carcinoid with ACTH positivity in immunohistochemistry. SUVmax difference between typical carcinoids and atypical carcinoids was not statistically significant (P = 0.597).