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 . 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 SUVmax 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 SUVmax 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 SUVmax of > 4.95 in the tumor group (SUVmax, 7.7). SCLCs generally exhibit high FDG uptake on PET/CT because of their aggressiveness and high metabolic activity . 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 . 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)  and the spatial resolution of PET/CT is higher. In addition, inflammatory cells also express SSTR2, 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.  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 SUVmax of < 4.95. One of the lesions (Patient 1, SUVmax, 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, SUVmax, 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) . The first three subtypes are also considered to be non-invasive pulmonary aspergillosis (NIPA) . 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 . 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 SUVmax for atypical carcinoids than for typical carcinoids, although the difference was not statistically significant . 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 . 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 SUVmax 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 . 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.