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

doi:10.21203/rs.3.rs-16145/v1

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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

https://doi.org/10.21203/rs.3.rs-16145/v1

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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.

Nuclear Medicine & Medical Imaging

ectopic Cushing syndrome

adrenocorticotropic hormone-secreting lung tumours

pulmonary infections

fluorodeoxyglucose

positron emission tomography/computed tomography

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]. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT; ¹⁸F-FDG PET/CT) has been shown to be an effective modality for localising ectopic ACTH-secreting 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 ¹⁸F-FDG PET/CT, although the reported number of ECS-causing SCLCs detected by ¹⁸F-FDG PET/CT is quite small. This is probably because the patients are rapidly diagnosed by conventional cross-sectional imaging and do not undergo ¹⁸F-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 cell-mediated 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 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 ¹⁸F-FDG PET/CT [8–11].

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 ¹⁸F-FDG PET/CT for differentiating ectopic ACTH-secreting lung tumours from tumour-like pulmonary infections in patients with ECS.

Patients

We retrospectively reviewed ¹⁸F-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.

¹⁸F-FDG PET/CT Study

Following 8 h of fasting and confirming the blood glucose level to be less than 120 mg/dL, ¹⁸F-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_max), 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_max for differentiating pulmonary infections from ACTH-secreting tumours was obtained via receiver operating characteristic (ROC) analysis with calculation of areas under the curve (AUCs) and sensitivity and specificity values. A P-value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics (version 21.0, IBM SPSS Inc., IBM, Chicago, IL, USA).

Among the 24 patients, 18 patients with 18 lesions were diagnosed with ectopic ACTH-secreting 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 infections. The mean SUV_max 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_max was significantly higher for infectious lesions than for tumours (P = 0.008; Fig. 1). ROC curve analysis suggested that an SUV_max 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 ACTH-secreting 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). Figures 3, 4, 5, 6, and 7 present representative cases of cryptococcosis (two lesions; SUV_max, 5.7 and 12.4), aspergillosis (SUV_max, 1.0), an atypical carcinoid (SUV_max, 1.1), a typical carcinoid (SUV_max, 2.8), and small cell lung cancer (SUV_max, 7.7), respectively.

In subgroup analysis of the 12 typical carcinoids and five atypical carcinoids, the mean SUV_max 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 ¹⁸F-FDG PET/CT in either group.

Ectopic ACTH-producing tumours account for 15–20% cases of ACTH-dependent Cushing 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 ¹⁸F-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 ¹⁸F-FDG PET/CT, in the absence of abnormal lesions in other areas, tends to be interpreted as an ACTH-secreting tumour and is subjected to surgical resection. However, in clinical practice, the resected pulmonary ‘tumour’ occasionally turns out to be an infectious lesion most often caused by fungus. In such cases, surgery is unnecessary and can deteriorate the patient’s condition, considering the immunosuppression related to ECS. The present study included 18 patients with ectopic ACTH-secreting lung tumours and six patients with pulmonary infections. To the best of our knowledge, this is the first study to describe and compare the features of ACTH-secreting lung tumours and pulmonary infectious pseudotumours using ¹⁸F-FDG PET/CT. This discrimination is important because the two conditions require entirely different treatment plans.

We found that a cutoff SUV_max 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_max 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_max of > 4.95 in the tumour group (SUV_max, 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 require ¹⁸F-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_max of < 4.95. One of the lesions (Patient 1, SUV_max, 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_max, 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 et al. evaluated the FDG PET/CT scans of 24 patients with pulmonary aspergillosis (8 IPA and 16 NIPA) and concluded that an isometabolic pattern on FDG PET/CT most likely represented NIPA [15]. NIPA is a chronic infection with low virulence and a mild inflammatory reaction, which might attribute to the low metabolic activity on ¹⁸F-FDG PET/CT.

Pulmonary carcinoids are histologically classified into typical and atypical carcinoids. Some authors have reported that atypical carcinoids exhibited significantly higher FDG uptake than did typical carcinoids [16–19]. Tatci et al. also observed a higher SUV_max 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 ¹⁸F-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_max 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.

In conclusion, although pulmonary infectious lesions associated with ECS and ACTH-secreting lung tumours occasionally exhibit similar morphological features, the former may show significantly higher FDG accumulation in ¹⁸F-FDG PET/CT. Therefore, SUV_max (cut-off: 4.95) may be a useful parameter for differentiating the two conditions. Moreover, typical and atypical ACTH-secreting lung carcinoids may show a similar clinical behaviour and appearance on ¹⁸F-FDG PET/CT. Further large-scale studies with adequate follow-up data are necessary to validate our findings.

ACTH: adrenocorticotropic hormone; ECS: ectopic Cushing syndrome; SCLC: small cell lung carcinoma; FDG: fluorodeoxyglucose; PET: positron emission tomography; CT: computed tomography; ROC: receiver operating characteristic; AUCs: areas under the curve; SUV_max: maximum standard uptake value; IPA: invasive pulmonary aspergillosis; NIPA: non-invasive pulmonary aspergillosis.

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Availability of supporting data

Not applicable.

Authors’ contributions

Guozhu Hou and Yuanyuan Jiang contributed equally to the present study. All authors read and approved the final manuscript.

Funding: This study was funded by CAMS Initiative for Innovative Medicine (CAMS-2018-I2M-3-001) and the National Natural Sciences Foundation of China (No.81201121).

Availability of data and materials

Not applicable.

Ethics approval and consent to participate: 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.

Consent for publication

All authors consent to the publication of this manuscript.

Competing interests

The authors declare that they have no competing interests.

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Table 2. Imaging and clinical characteristics of ectopic Cushing syndrome patients

	ACTH-secreting tumors (n=18)	Infectious lesions (n=8)	P value
Diameter (mm)	13.8±7.9 (5-37)	20.9±11.0 (7-35)	0.126
SUV_max	2.1±1.8 (0.6-7.7)	5.9±3.8 (1.0-12.4)	0.008

SUV_max, maximum standardized uptake value

Table 3. Characteristics in subgroup analysis of typical carcinoids and atypical carcinoids

	TC	AC	P value
SUV_max	1.9±1.5	1.6±0.8	0.597
Diameter (mm)	11.1±3.7	15.4±8.5	0.165
ACTH level (pg/ml)^*	242.8±240.8	263.6±337.3	0.833
lymph node metastasis	5/12 (41.7%)	2/5 (40%)	0.951

SUV_max, maximum standardized uptake value; AC, atypical carcinoid; TC, typical carcinoid; * Reference range for ACTH: 0-46 pg/ml.

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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

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