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

Abstract

Background: Ectopic adrenocorticotropic hormone (ACTH)-secreting lung tumors represent the most common cause of ectopic Cushing syndrome (ECS). Pulmonary opportunistic infections are associated with ECS and occasionally difficult to differentiate from tumors by using computed tomography (CT) alone. The present study aimed to evaluate the usefulness of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/CT (¹⁸F-FDG PET/CT) for differentiating ectopic ACTH-secreting lung tumors from tumor-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 tumors and underwent ¹⁸F-FDG PET/CT between 2008 and 2019. Part of the 24 patients underwent ^99mTc-HYNIC-TOC scintigraphy and ⁶⁸Ga-DOTA-TATE PET/CT.

Results: In total, 18 patients had lung tumors and six had pulmonary infections. The primary source of ECS remained occult in the six patients with pulmonary infections. The maximum standardized uptake value (SUV_max) for pulmonary infections was significantly higher than that for tumors (P = 0.008). Receiver operating characteristic analysis was performed, and it was found that a cut-off SUV_max of 4.95 helped in differentiating lung tumors from infections with 75% sensitivity and 94.4% specificity. In a subgroup analysis of 12 typical and five atypical carcinoids, there was no significant between-group difference with respect to SUV_max, the lesion size, the ACTH level, and the prevalence of regional lymph node metastasis. Four out of 6 patients with 5 infectious lesions and 16 out of 18 patients with 16 ACTH-secreting tumors underwent ^99mTc-HYNIC-TOC scintigraphy, and 1/6 patients with 1 infectious lesion, and 6 out of 18 patients with 6 ACTH-secreting tumors underwent ⁶⁸Ga-DOTA-TATE PET/CT. There is no significant difference in sensitivity between tumor lesions and infections using ^99mTc-HYNIC-TOC scintigraphy.

Conclusions: Our findings suggest that pulmonary infections exhibit significantly higher FDG uptake than do well-differentiated ACTH-secreting lung tumors in ¹⁸F-FDG PET/CT. Therefore, SUV_max (cut-off 4.95) may be useful for differentiating the two conditions. However, ^99mTc-HYNIC-TOC scintigraphy is of no value in distinguishing the focus of well-differentiated ACTH-secreting lung tumors from that of infection. Typical and atypical ACTH-secreting lung carcinoids may show similar clinical behavior and appearance on ¹⁸F-FDG PET/CT.

Background

10%-15% of Cushing syndrome is caused by ectopic adrenocorticotropic hormone (ACTH)-secreting tumors. In such cases, resection of the tumors can have curative effects. The most common tumors associated with ECS are pulmonary carcinoids and small cell lung carcinoma (SCLC), followed by thymic carcinoids, pancreatic neuroendocrine tumors, 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 localizing ectopic ACTH-secreting tumors 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 localization [2].

ECS due to ectopic ACTH-secreting tumors 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 tumors [7]. Thus, it could be difficult to differentiate tumor-like pulmonary infections from lung tumors 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 tumors can deteriorate the patient’s condition. Therefore, discrimination of infections and tumors 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 tumors from tumor-like pulmonary infections in patients with ECS.

Materials And Methods

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. The intensity of tumor uptake and ^99mTc-HYNIC-TOC scintigraphy was graded on a scale from 0 to 3 by comparing them with the tracer uptake intensity of the normal liver (0: background activity, negative scan; 1: mild uptake, abnormal uptake higher than the background but less than that in the normal liver; 2: moderate uptake, abnormal uptake equal to that in the normal liver; and 3: intense uptake, abnormal uptake greater than that in the normal liver). Tumors with a score of 1, 2, or 3 were considered positive. The uptake and anatomical changes of suspicious sites on ⁶⁸Ga-DOTA-TATE PET/CT were recorded and analyzed. The high-intensity uptake is defined as the uptake of the focus that is significantly higher than that of the surrounding tissue.

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 tumors 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).

Results

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 analyzed in this study. The patient characteristics are shown in Table 1. After surgical resection of the lesions, all patients in the tumor 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 patients with pulmonary infections. The mean SUV_max for all 18 lesions in the patients with ectopic ACTH-secreting lung tumors 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 tumors (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 tumors 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 a 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 the histopathological analysis (P = 0.951; Table 3). No distant metastases were detected on ¹⁸F-FDG PET/CT in either group. 

In our retrospective study, 4 out of 6 patients with 5 infectious lesions and 16 out of 18 patients with 16 ACTH-secreting tumors underwent ^99mTc-HYNIC-TOC scintigraphy, and 1/6 patients with 1 infectious lesion, and 6 out of 18 patients with 6 ACTH-secreting tumors underwent ⁶⁸Ga-DOTA-TATE PET/CT. There is no significant difference in sensitivity between tumor lesions and infections using ^99mTc-HYNIC-TOC scintigraphy (18.75%, 3/16 vs. 40%, 2/5, respectively; P = 0.553; Fig. 9). For infectious lesions, the sensitivity of ⁶⁸Ga-DOTA-TATE PET/CT is 0% (0/1), and for tumor lesions, the sensitivity of ⁶⁸Ga-DOTA-TATE PET/CT is 83.3% (5/6). (Table 4)

The pathological and immunohistochemical results of ECS patients are listed in Table 4. All TC and AT are classified as well-differentiated neuroendocrine tumors (4 are graded G1, 13 are graded G2), and 1 SCLC is classified as poorly differentiated neuroendocrine tumors (G3). (Table 4)

Discussion

Ectopic ACTH-producing tumors account for 15–20% of cases of ACTH-dependent Cushing syndrome. Lung carcinoids and SCLC represent the most common tumors associated with ECS, and the resection of the responsible tumors can have curative effects [14]. There is no consensus regarding the usefulness of ¹⁸F-FDG PET/CT for localizing 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 tumor and is subjected to surgical resection. However, in clinical practice, the resected pulmonary ‘tumor’ 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 tumors 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 tumors and pulmonary infectious pseudotumors using ¹⁸F-FDG PET/CT. This discrimination is important because the two conditions require entirely different treatment plans.

We found that a cut-off SUV_max of 4.95 maximized the sensitivity and specificity for the differentiation of pulmonary infections from ACTH-secreting tumors. Specifically, the findings indicated that a pulmonary nodule or mass-like lesion with a 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 a SUV_max of > 4.95 in the tumor group (SUV_max, 7.7). SCLCs generally exhibit high FDG uptake on PET/CT because of their aggressiveness and high metabolic activity [15]. 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 localization [2]. ^99mTc-HYNIC-TOC scintigraphy is of no value in distinguishing the focus of tumor from that of infection. Although 4 patients were negative in ^99mTc-HYNIC-TOC scintigraphy and positive in ⁶⁸Ga-DOTA-TATE PET/CT, the number of cases was too small to clearly explain the value of ⁶⁸Ga-DOTA-TATE PET/CT. However, we can speculate that the sensitivity of ^99mTc-HYNIC-TOC scintigraphy is lower than that of ⁶⁸Ga-DOTA-TATE PET/CT because ⁶⁸Ga-DOTA-TATE has a higher affinity for somatostatin receptor 2 (SSTR2) [16] and the spatial resolution of PET/CT is higher. In addition, inflammatory cells also express SSTR2[17], so the role of ^99mTc-HYNIC-TOC scintigraphy and ⁶⁸Ga-DOTA-TATE PET/CT in the differentiation of ACTH-secreting tumours and pulmonary infections is not bright.

The present study showed significantly higher FDG accumulation in infectious lesions than in pulmonary carcinoids. The reason for the low FDG uptake of pulmonary carcinoids is that most of the lesions (17/18) are well-differentiated neuroendocrine neoplasms. [18] As mentioned in our preface, patients with poorly differentiated neuroendocrine neoplasms such as SCLC are rarely examined by FDG PET/CT, which is why we have fewer patients in this group. Among the eight infectious lesions, only two showed low FDG uptake with a 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 pseudotumors (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 necrotizing aspergillosis, and invasive pulmonary aspergillosis (IPA) [19]. The first three subtypes are also considered to be non-invasive pulmonary aspergillosis (NIPA) [19]. 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 [20]. 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 [21–24]. Tatci et al. also observed a higher SUV_max for atypical carcinoids than for typical carcinoids, although the difference was not statistically significant [25]. Fink et al analyzed 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 [26]. 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 [27, 28]. 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 behavior and PET/CT findings, in contrast to previous findings concluding that atypical carcinoids generally exhibit higher FDG uptake, more aggressive behavior, and a worse prognosis [26]. 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 the imaging diagnosis of neuroendocrine tumors, ¹⁸F-FDG PET/CT and ⁶⁸Ga-DOTA-Peptides PET/CT are complementary. However, ⁶⁸Ga-DOTA-Peptides PET/CT is still in the preclinical stage in China, so not all patients suspected of having ECS undergo this examination. In our retrospective study, 7 patients (4#, 10#, 12#-15#, 20# showed in Table 1) underwent ⁶⁸Ga-DOTA-TATE PET/CT. The results showed that the lesions of Patient 4# and 20# were negative and the lesions of Patient 10#, 12#-15# lesions were positive. Because this data is very small, there is no value for discussion, and our study mainly wants to highlight the value of the auxiliary diagnosis of ¹⁸F-FDG PET/CT, so the results of ⁶⁸Ga-DOTA-Peptides PET/CT are not discussed in this study.

Conclusion

In conclusion, although pulmonary infectious lesions associated with ECS and well-differentiated ACTH-secreting lung tumors 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. However, ^99mTc-HYNIC-TOC scintigraphy is of no value in distinguishing the focus of well-differentiated ACTH-secreting lung tumors from that of infection. Moreover, typical and atypical ACTH-secreting lung carcinoids may show similar clinical behavior and appearance on ¹⁸F-FDG PET/CT. Further large-scale studies with adequate follow-up data are necessary to validate our findings.

Abbreviations

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

Declarations

Acknowledgements

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

Authors’ contributions

GH, YJ, FL, and XC contributed to the design and implementation of the research, to the analysis of the results, and to the writing of the manuscript. All authors contributed to the article and approved the submitted version.

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

The dataset of the current study was available from the corresponding author on reasonable request.

Declarations

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

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

Author details

¹ Department of Nuclear Medicine, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

² Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing 100730, China

Guozhu Hou and Yuanyuan Jiang contributed equally to this work

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