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* From the Division of Pulmonary and Critical Care Medicine (Dr. Daniels), Division of Radiology, Department of Nuclear Medicine (Dr. Lowe), Division of Anatomic Pathology (Dr. Aubry), Division of General Thoracic Surgery (Dr. Allen), and Division of Medical Oncology (Dr. Jett), Mayo Clinic, Rochester, MN.
Correspondences to: Craig E. Daniels, MD, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: daniels.craig{at}mayo.edu
Abstract
Background: Fluorodeoxyglucose positron emission tomography (FDG-PET) is sensitive for detection of neoplastic solitary pulmonary nodules but may have decreased sensitivity for detection of carcinoid tumors. Our purpose was to determine the sensitivity of FDG-PET to detect pulmonary carcinoid tumors.
Methods: We performed a retrospective review of our institutional results regarding FDG-PET in the setting of thoracic carcinoid neoplasms. We identified 16 patients with a pathologic diagnosis of bronchial carcinoid who had an antecedent FDG-PET (from 2000 to 2004). All patients but one presented with pulmonary nodule(s).
Results: Sixteen patients had a diagnosis of carcinoid tumor, typical in 11 patients and atypical in 5 patients. The mean greatest pathologic dimension was 2.08 cm (range, 1.0 to 8.3 cm). Overall positron emission tomography (PET) sensitivity was 75% (12 true-positive and 4 false-negative results). The mean (± SD) size of carcinoids with false-negative PET results was not significantly different from carcinoids with true-positive results (1.6 ± 0.81 cm and 2.35 ± 1.87 cm, p = 0.54). Fifteen of 16 patients were staged pathologically, and positive nodes were found in 2 of these patients. PET lymph node staging agreed with pathologic staging in one stage 4 patient with positive lymph nodes and distant metastasis, but PET results were false negative in the other patient who had N2 with micrometastatic disease; stage IIIA.
Conclusions: FDG-PET imaging is useful for evaluation of typical and atypical thoracic carcinoid tumors. Although overall PET sensitivity for detection of carcinoid tumors is somewhat reduced as compared to non-small cell lung cancer, it is much higher than prior reports suggest.
Key Words: carcinoid • positron emission tomography • sensitivity • solitary pulmonary nodule • thoracic neoplasm
Fluorodeoxyglucose positron emission tomography (FDG-PET) is utilized to detect malignant lung tumors with pooled sensitivity of 96 to 97%.123 Additionally, positron emission tomography (PET) is a useful staging modality for non-small cell lung carcinoma (NSCLC) as a compliment to CT scanning in identifying metastasis to mediastinal lymph nodes as well as extrathoracic metastasis.345 FDG-PET has been reported to show a decreased sensitivity for detection and staging of small or hypometabolic thoracic neoplasms such as bronchoalveolar carcinomas and carcinoid tumors.6
Carcinoid tumors are neuroendocrine malignancies occurring most commonly in the GI tract (90%) followed by the respiratory tract.7 In the chest, carcinoids are rare and account for only 2 to 3% of all primary lung neoplasms.8 While 80% of thoracic carcinoid tumors are endobronchial in origin, 20% present as solitary pulmonary nodules (SPNs) in asymptomatic individuals.8 Evaluation of SPNs is a diagnostic challenge for which clinicians utilize various imaging modalities and algorithms to detect and predict the likelihood of malignancy.9 SPNs are difficult to accurately diagnose based on limited sensitivity of noninvasive imaging, technical limitations of biopsy, and the high frequency of benign lesions. PET is an effective tool that differentiates malignant from benign pulmonary nodules with sensitivity of 95%.210
The sensitivity of FDG-PET for diagnosis of primary pulmonary carcinoids is believed to be reduced due to the low metabolic activity and slow growth of carcinoid tumors. A large series6 evaluating FDG-PET detection of primary pulmonary carcinoids demonstrated PET sensitivity of only 14.2%. This finding led many to believe PET is not effective for diagnosis of pulmonary carcinoid tumors.67 In contrast to this initial report, individual case reports1112 have since demonstrated PET true-positive pulmonary carcinoid tumors of both typical and atypical morphology. These conflicting data led us to investigate the value of FDG-PET for evaluation of primary pulmonary carcinoids. We report our institutional experience with FDG-PET and pulmonary carcinoids from 2000 to 2004.
Materials and Methods
Patients with a histopathologic diagnosis of carcinoid on surgical excisional biopsy and an antecedent FDG-PET scan who were seen at the Mayo Clinic in Rochester, MN, from January 1, 2000, to December 31, 2004, were eligible for the study. We identified 172 unique patients with a histopathologic diagnosis of pulmonary carcinoid tumor. Sixteen of these had a corresponding FDG-PET performed prior to surgical resection.
The following data were abstracted from the clinical records: age, sex, and findings on chest radiography, CT, and FDG-PET. Additionally, cancer information was abstracted including method and date of diagnosis, and gross pathologic tumor size, including largest diameter and surgical stage.
This study was approved by the Mayo Foundation Institutional Review Board. Data are presented as mean ± SD, median, and range for continuous variables. Statistical analysis of PET results was completed using two-tailed, unpaired t test with the independent variable of PET result (positive or negative) and the dependent variable of tumor size. Statistically significant difference was predetermined as a p value of 
0.05. Sensitivity was calculated as the percentage of true-positive results divided by true-positive plus false-negative results. The 95% confidence intervals for sensitivity were calculated using Bayesian analysis of proportions.
FDG-PET Imaging
FDG-PET imaging was performed as part of the clinical evaluation, and PET results were abstracted from the PET report at the time of evaluation. All FDG-PET scans were reviewed (but not reinterpreted) by one of our nuclear medicine experts who was not blinded. PET scan results were interpreted as positive when the nodule or nodal activity was greater than background mediastinal blood pool activity. Only visual interpretation was performed, as it is the accepted general practice method of interpretation and is as accurate as standardized uptake value analysis.13
FDG-PET imaging was performed using a GE Advance PET Tomograph or DLS combined PET/CT scanner (General Electric Medical Systems; Milwaukee, WI). The F-18 fluoride was produced by an on-site GE Trace Cyclotron (GE Medical Systems). FDG synthesis was performed by the standard method. Fluorodeoxyglucose (FDG) was tested for sterility, pyrogenicity, and radiochemical purity on each production run. PET images of the body to include the infracranial head, neck, chest, and abdomen to at least the level of the iliac crest were obtained 60 min after IV injection of 740 MBq of FDG. After voiding, the patients were positioned on the tomographic gantry for imaging. Emission images were reconstructed using iterative reconstruction. Attenuation correction was used on all data. Emission data were corrected for scatter, random events, and dead time losses using the manufacturer’s software. Image pixel size was 4.25 mm displayed in a 128-by-128 array. Standard orthogonal views, as well as maximum intensity projections, were reviewed during scan interpretation. CT image fusion was available on the DLS combined PET/CT images.
Pathology
Routinely processed hematoxylin-eosin–stained sections from all surgical specimens were reviewed. Typical and atypical carcinoid tumors were defined based on established World Health Organization pathologic criteria stipulating typical carcinoids have < 2 mitotic figures per 2 mm2 and no necrosis, while atypical carcinoids have 2 to 10 mitotic figures per 2 mm2 or evidence for necrosis (Fig 1
).14
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Surgical Treatment and Staging
All 16 patients underwent thoracic surgical resection, and 15 of 16 were pathologically staged. Tissue diagnosis was confirmed prior to surgical resection in only four patients (25%), three by bronchoscopic biopsy and one by CT-guided needle aspiration. The mean time from PET scan to tissue diagnosis was 6.3 days (range, 0 to 22 days). The mean time from PET scan to surgical resection was 8.2 days (range, 2 to 23 days). The mean time from false-negative PET result to surgical resection did not differ from the mean time of true-positive PET result to surgical resection: 6.75 days vs 8 days, respectively. Table 1
demonstrates the relevant features of the 16 reported patients.
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FDG-PET Sensitivity for Detection of Pulmonary Carcinoid Tumors
Table 2
reports the FDG-PET sensitivity for the 16 patients with resected carcinoid. Incidentally, two false-positive PET granulomas and one true-positive PET adenocarcinoma were resected in addition to the 16 carcinoid tumors. In one of these cases, a false-positive PET granuloma was resected in conjunction with a false-negative PET carcinoid tumor. Overall sensitivity for FDG-PET detection of carcinoid tumors was 75% (12 of 16 cases). In the 12 true-positive PET cases, 9 were reported as having moderately increased uptake, while 3 were reported as having intense uptake (Fig 2
). Atypical carcinoids were somewhat more likely to be PET true positive than were typical carcinoids (80% vs 72.7%, respectively), but the numbers are small and this difference was not statistically meaningful. While three of six carcinoid lesions measuring 1.3 cm were PET false negative, the mean size of PET false-negative and true-positive carcinoid tumors were similar at 1.6 ± 0.81 cm and 2.2 ± 1.95 cm (p = 0.12), respectively, with similar median values of 1.3 cm and 1.5 cm. The four false-negative PET carcinoid tumors measured 1.0, 1.3, 1.3, and 2.8, respectively.
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Our study suggests that FDG-PET is useful in the evaluation of SPNs that turn out to be carcinoid tumors. We report a significantly higher sensitivity of FDG-PET than other reports, although still comparatively lower than other thoracic malignancies.2 Not all carcinoid tumors in our series were PET true positive. While not statistically significant, smaller lesions appeared more likely to be PET false negative and comprised three of the six smallest thoracic carcinoids. Although PET accurately staged all patients with true-positive carcinoid tumors, the majority of our cohort, 13 of 16 cases, were pathologic stage IA, making conclusions regarding PET utility for nodal disease and distant metastasis uncertain.
Bronchial carcinoids are thought to occur along a spectrum of histopathologic features and clinical behavior from typical carcinoids and intermediate atypical carcinoids to aggressive neuroendocrine large cell and small cell carcinomas.1415 PET uses [18F]-FDG to differentiate tumor cells from surrounding normal cells by utilizing tumor cells avidity for glucose uptake coupled to decreased metabolism of [18F]-FDG, which then becomes trapped intracellularly and serves as the substrate for PET imaging.16 Tumors that are "slow growing" exhibit a lower glucose uptake when compared to other aggressive malignancies.17 Applying these assumptions regarding carcinoid metabolism and FDG-PET imaging, we hypothesized PET sensitivity for detection of thoracic carcinoid tumors would be reduced compared to NSCLC, and atypical carcinoid tumors would more likely be PET true positive.
The findings of our cohort demonstrate a trend toward higher PET sensitivity for atypical carcinoid tumors (80%) compared to typical carcinoid tumors (72.7%), with four of five atypical carcinoid tumors being PET true positive, and a single 1.3-cm atypical carcinoid tumor being PET false negative. Further, we report the overall PET sensitivity for thoracic carcinoid tumors in our cohort was 75%, which is much higher than previously indicated by Erasmus et al6 and in contrast to the assumption that most, if not all, carcinoid tumors are PET false negative. Several possible reasons exist to explain the higher sensitivity we report. While one could say the overall metabolic level of uptake in our group of carcinoids was less intense than would be seen in other lung carcinomas (9 of 12 PET true-positive carcinoids were reported as moderately increased FDG uptake), they were still visually positive. Increased awareness over time of PET appearance for carcinoid tumors by nuclear radiologists has likely led to increased accuracy when distinguishing visual activity compared to background mediastinal blood pool activity, which is at times subtle (Fig 2). Additionally, sensitivity of PET in this cohort may be improved because of higher FDG dose administration (20 mCi).
Several other interesting observations are noted in our cohort. Only 3 of 16 patients had CT or bronchoscopic evidence of airway involvement, whereas 75 to 85% of thoracic carcinoids are reported to arise in the tracheobronchial tree.8 This finding is likely explained by the differing presentations of endobronchial vs peripheral carcinoid tumors. Endobronchial carcinoids are frequently symptomatic, presenting with wheeze, cough, and hemoptysis, and are amenable to diagnostic biopsy utilizing flexible fiberoptic bronchoscopy. Peripheral carcinoids presenting as SPNs are often a diagnostic challenge. Their peripheral location and small size make transthoracic and bronchoscopic biopsy difficult. Thus, the disproportionate number of peripheral carcinoid tumors in our cohort likely reflects the clinician’s inclination to further evaluate indeterminate SPNs prior to surgical resection.21018 An additional and unexplained observation is the disproportionate percentage of women in our cohort (14 of 16 cases, 88%). Prior studies819 have not shown a gender difference.
In this retrospective review, all PET imaging studies were performed as part of the clinical evaluation. Chart review indicated preoperative assessment of indeterminate pulmonary nodule(s) was the clinical indication for PET imaging in 12 of the 16 cases. All but one case had CT imaging prior to PET imaging; in six of these cases, CT was performed with lung nodule enhancement (all six cases were positive for enhancement). In our practice, PET imaging has replaced CT nodule enhancement in the evaluation of indeterminate lung nodules due to the equivalent sensitivity, higher specificity, and additional staging information obtained from PET imaging.20 It is our practice to evaluate patients with nodules, suspected to be NSCLC, with PET imaging prior to surgical resection to exclude metastatic disease and avoid futile thoracotomy.18 While we report 75% sensitivity for PET detection of thoracic carcinoids tumors, we do not advocate routine use of PET in the clinical evaluation of patients with biopsy-proven thoracic carcinoid tumors.
This study has several limitations mostly based on its retrospective pathology-based analysis. Specifically, the data analyzed only included nodules that were resected and therefore may underestimate the number of PET false-negative lesions. However, the mean time from PET to tissue diagnosis of false-negative carcinoids (6.75 days) was actually shorter than true-positive carcinoids (8 days), but not significantly different. Based on this, one may conclude FDG-PET was performed for preoperative evaluation (staging), which lessens the criticism that PET false-negative carcinoid tumors would not be resected.
We report a series with 16 resected carcinoid tumors ranging in size from 1.0 to 8.3 cm. While this study will not likely answer all questions regarding the utility of PET in detecting pulmonary carcinoid tumors, it does suggest a higher sensitivity than has been previously reported, particularly for carcinoid tumors measuring > 1.5 cm. Thoracic carcinoid tumors should not be considered universally as PET false-negative neoplasms.
Footnotes
Abbreviations: FDG = fluorodeoxyglucose; FDG-PET = fluorodeoxyglucose positron emission tomography; NSCLC = non-small cell lung carcinoma; PET = positron emission tomography; SPN = solitary pulmonary nodule
Funding was provided by Mayo institutional funds.
The authors have no conflicts of interest to disclose.
Received for publication March 20, 2006. Accepted for publication July 18, 2006.
References
This article has been cited by other articles:
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  R. L. Young, J. D. Mitchell, C. Cool, and S. P. Nana-Sinkam Wheezing and Exertional Dyspnea in a 25-Year-Old Mountaineer Chest, March 1, 2008; 133(3): 820 - 825. [Full Text] [PDF]
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 S. Dubois, O. Morel, P. Rodien, F. Illouz, S. Girault, A. Cahouet, F. Lacoeuille, M. Brousseau, J. Picquet, and V. Rohmer A Pulmonary Adrenocorticotropin-Secreting Carcinoid Tumor Localized by 6-Fluoro-[18F]L-Dihydroxyphenylalanine Positron Emission/Computed Tomography Imaging in a Patient with Cushing's Syndrome J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4512 - 4513. [Full Text] [PDF]
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