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Nuclear Medicine |
1 All authors: Division of Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 57, Houston, TX 77030.
Received December 12, 2003;
accepted after revision March 4, 2004.
Address correspondence to M. T. Truong
(mtruong{at}mdanderson.org).
Abstract
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MATERIALS AND METHODS. All PET/CT scans obtained at our cancer institution from August to October 2003 were retrospectively reviewed for increased FDG uptake in the mediastinum localized to fat on CT. The following features were recorded: location, appearance, maximal standard uptake value (SUVmax) of hypermetabolic mediastinal brown fat, and presence of extramediastinal brown fat.
RESULTS. PET/CT scans were obtained in 845 oncologic patients. Fifteen patients (1.8%) with focal hypermetabolic mediastinal brown fat were identified: nine women and two men (age range, 27–79; mean, 55.1 years) and four children (age range, 5–16 years; mean, 10 years). Hypermetabolic mediastinal brown fat (mean SUVmax, 5.7) was more common in children (4/8) than in adults (11/837) and more common in women (9/372) than in men (2/465). Foci of hypermetabolic brown fat were localized to the paratracheal, paraesophageal, prevascular, and pericardial regions; interatrial septum; and azygoesophageal recess. Five patients had focal hypermetabolic brown fat isolated to the mediastinum. Ten patients also had extramediastinal hypermetabolic brown fat in the neck, thorax, and abdomen. There was no difference in the body weight (p = 0.876) or body mass index (p = 0.538) of patients with hypermetabolic brown fat compared with age- and sex-matched control subjects.
CONCLUSION. Hypermetabolic brown fat can be localized to the mediastinum and manifests as focal increased FDG uptake. Knowledge of this potential pitfall and precise localization with fusion PET/CT are important in preventing misinterpretation as malignancy.
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In terms of adipose tissue, there are two types in the human body: white adipose tissue that stores energy and serves as insulation and brown adipose tissue. Brown adipose tissue plays an important role in cold-induced and diet-induced thermogenesis [4]. The brown color is attributed to the high vascularity and mitochondrial density. The mitochondria in brown adipose tissue exclusively express the thermogenic protein responsible for uncoupling respiration from adenosine triphosphate synthesis, dissipating heat. FDG uptake in hypermetabolic brown fat can occur as glucose transporters have been shown in brown adipose tissue [5]. Because hypermetabolic brown fat is typically bilateral, symmetric, and elongated in the supraclavicular area on PET (Fig. 1), the appearance is seldom confused with malignancy [1]. However, when brown fat occurs in the mediastinum, focal FDG uptake in this region can be misinterpreted as primary malignancy or nodal metastases. The purpose of this study was to evaluate the prevalence, location, and appearance of hypermetabolic mediastinal brown fat in patients imaged with FDG PET/CT.
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The PET and CT images were reviewed on a workstation (Xeleris, GE Healthcare) in all standard planes along with maximum-intensity-projection images and were analyzed visually and quantitatively by two reviewers experienced in interpreting PET/CT scans. Findings were recorded by consensus. When needed, a third experienced reviewer resolved differences in interpretations of the scans. All cases with FDG uptake in the mediastinum localized to fat were selected for this study. All cases in which patient breathing or motion resulted in misregistration of increased FDG uptake because of primary malignancy or vascular or nodal abnormality localized to mediastinal fat were excluded. FDG uptake was considered abnormal on visual analysis when it was substantially greater than mediastinal blood pool activity on the attenuation-corrected images. In addition, a pixel region of interest (ROI) was outlined in the regions of increased FDG uptake, and after correction for radioactive decay, the ROI was semiquantitatively analyzed according to the following formula:
The following features were recorded: location, appearance (focal, spherical, elongated), and SUVmax of the FDG uptake in mediastinal brown fat, and the presence of extramediastinal brown fat. The body weight and body mass index (BMI) of the patients with FDG uptake in mediastinal fat and those of patients in a control group, matched for age and sex who had PET/CT scans during the same period, were recorded. BMI, an estimate of total body fat, is calculated by dividing the weight (in kilograms) by the square of the height (in meters squared). The two-sample Student's t test was used to compare the body weight and BMI of the study group and control group.
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Increased FDG uptake in mediastinal brown fat occurred more commonly in children (50% [4/8]) than in adults (1.3% [11/837]) (p = 0.001, Pearson's chi-square test). In adults, it occurred more often in women (2.4% [9/372]) than in men (0.43% [2/465]) (p = 0.012, Pearson's chi-square test). The mean body weight of adult patients showing FDG uptake in mediastinal brown adipose tissue was 71.9 kg (range, 48–103 kg) and the mean BMI was 24.9 (range, 20–32). No statistically significant difference was found with age- and sex-matched control groups (mean, 72.9 kg and 25.9, respectively) for body weight (p = 0.876) or for BMI (p = 0.538).
Hypermetabolic brown fat was localized to the paratracheal, paraesophageal, prevascular (Figs. 2A, 2B, and 2C), and pericardial regions; and azygoesophageal recess (Figs. 3A, 3B, and 3C); interatrial septum (Figs. 4A, 4B, and 4C), adjacent to the brachiocephalic arteries (Figs. 5A, 5B, and 5C); and azygos and hemiazygos veins (Table 1). The appearance of FDG uptake in mediastinal brown fat was focal and spherical. An elongated appearance of FDG uptake in the mediastinum was not seen in any of our patients. Five patients had an isolated single focus of hypermetabolic brown fat in the mediastinum—that is, without hypermetabolic brown fat elsewhere in the body. Ten patients had associated extramediastinal hypermetabolic brown fat in the cervical region (n = 2); paravertebral region (n = 1); cervical and paravertebral regions (n = 1); cervical, paravertebral, and axillary regions (n = 4); and cervical, axillary, paravertebral, and abdominal regions (n = 2) (Table 2). The SUVmax of the hypermetabolic brown fat in the mediastinum ranged from 3.4 to 13 (mean, 5.7). The SUVmax of the hypermetabolic brown fat in the extramediastinal sites noted in 10 patients ranged from 2.4 to 20 (mean, 7.2).
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Of the five patients with isolated FDG uptake in mediastinal brown fat, two patients had PET/CT performed 1 and 3 months after the initial study. In the first patient, follow-up examination showed no malignancy in the mediastinum and no hypermetabolic brown fat. In the second patient, who had isolated hypermetabolic brown fat adjacent to the brachiocephalic arteries, the follow-up studies showed hypermetabolic brown fat similar to the first study. There was no interval development of an anatomic abnormality in the region of the brachiocephalic arteries. However, the 3-month follow-up study did show new metastatic disease localized to the hilum.
Of the remaining 10 patients, two patients had follow-up PET/CT scans. In one patient, a study performed 2 months after the initial study did not show any increased FDG uptake in the mediastinum. In the second patient, a child, diffuse hypermetabolic brown fat distributed in the neck, chest, and abdomen was noted on four serial studies performed over a 9-month period.
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Since the advent of whole-body PET in the mid 1990s, elongated fusiform areas of FDG uptake in the neck and shoulders have been observed and attributed to muscle activity, particularly because these findings usually resolved after the administration of a benzodiazepine, a muscle relaxant [6]. However, fusion PET/CT images subsequently showed that, in some patients, these foci of FDG uptake were localized to adipose tissue rather than to muscle. The increased FDG uptake in brown adipose tissue in the neck has been reported as a false-positive result in 2.3–4% of patients [1, 3]. Typically, the increased FDG uptake in brown fat in the neck is bilateral and symmetric and is seldom confused with malignancy. The acronym "USA-fat" (uptake in supraclavicular area fat) has been used to describe this characteristic appearance [1].
In the fetus and neonate, brown adipose tissue is abundant because it serves an important role in thermoregulation. Its location is principally cervical, axillary, paravertebral, mediastinal, and abdominal [8]. Likened to a high-collared vest arranged so that the heat generated warms the blood supply to vital organs, the cervical fat and axillary fat protect the blood supply to the head, the paravertebral fat protects the spinal cord, the mediastinal fat and pericardial fat protect the great vessels and heart, and the perirenal fat protects the kidneys.
Brown fat deposits diminish with age because of reduced demands for thermogenesis. This correlates to the finding in our study of hypermetabolic brown fat being more common in children than in adults. It is note-worthy that the diffuse pattern of hypermetabolic brown fat distributed in the neck, thorax, and abdomen that was seen in two children in our study was not seen in any of the adults in our study. In addition, FDG uptake in mediastinal brown fat was more common in women than in men, similar to findings in previous studies [1, 3]. One explanation for female predominance can be drawn from a study of rodents that showed sex-related differences in morphologic and functional features of brown adipose tissue for cold-induced thermogenesis [9]. In this study, brown adipose tissue in female rats under usual rodent housing temperature (22°C) showed bigger mitochondria and higher density of cristae, resulting in increased thermogenic capacity and activity.
Although FDG uptake in brown fat has been reported to occur more commonly in underweight patients with low BMI [2], in our study no difference in the body weight or BMI of patients with hypermetabolic brown fat compared with those of a control group was detected. This finding is similar to more recently published data [1, 3].
Our finding of hypermetabolic brown fat in the mediastinum occurring in 1.8% of patients in our study was higher than that reported by Yeung et al. [3] (0.9%). This difference is due to the differences in patient inclusion criteria for the two studies. In the study of Yeung et al., patients were selected on the basis of the initial observation of increased FDG uptake in the neck; consequently, the prevalence of isolated FDG uptake in mediastinal brown fat could not be determined. In addition, to our knowledge, the occurrence of focal hypermetabolic brown fat in the mediastinum in the absence of FDG uptake in brown fat in the more typical locations (supraclavicular, paravertebral, and axillary regions) has not been reported. Isolated focal FDG uptake in mediastinal brown adipose tissue is particularly misleading in interpreting PET scans. In our study, five patients had an isolated brown fat deposit in the mediastinum that could have been misinterpreted as malignancy. The mean SUVmax of the hypermetabolic mediastinal brown fat was 5.7, which is well within the commonly accepted abnormal range.
With PET alone, focal increased uptake of FDG in brown adipose tissue in the mediastinum could have been misinterpreted as primary esophageal malignancy, primary lymphoma, or nodal metastases, leading to tumor upstaging or unnecessary medical or surgical intervention. The integration of functional PET data with anatomic CT data has been reported to increase diagnostic accuracy in the staging of nodal metastases in patients with non–small cell lung cancer [10, 11]. Staging was correctly determined in more patients using PET/CT than using either PET alone or CT alone [10]. Furthermore, integrated PET/CT has been reported to be superior to visual correlation of PET with CT in staging non–small cell lung cancer [11]. When correlative PET/CT fails to reveal abnormalities in areas showing focal increased FDG uptake in the mediastinum, brown adipose tissue needs to be considered. In our experience, fusion PET/CT images are useful in avoiding this pitfall by precisely localizing the focal FDG uptake.
Our study has several limitations. The retrospective nature of the study introduces inherent biases. Misregistration of focal increased FDG uptake caused by primary malignancy, vascular or nodal abnormalities, patient breathing or motion, or mechanical malalignment could have resulted in incorrect localization to the mediastinal fat. However, in our patient group, the fusion PET/CT images were reviewed in their entirety to determine accurate coregistration of PET and CT data sets. Patients with focal increased uptake of FDG localized to fat were excluded if there was misregistration of adjacent mediastinal structures. Finally, for ethical reasons, biopsy confirmation of brown fat in the mediastinum was not possible. However, our findings correlate to those of autopsy reports of the distribution of brown fat in adults and children [12, 13].
Because hypermetabolic brown fat can complicate the interpretation of FDG PET scans, attempts have been made to suppress this activity using benzodiazepine and maintaining a warm environment. The ability of benzodiazepine to suppress brown adipose tissue metabolism may be explained by studies of brown adipose tissue in rats that have shown benzodiazepine receptors to be under the control of the sympathetic nervous system [14, 15]. Of the two known stimuli for brown adipose tissue thermogenic activation— namely, cold exposure and food intake—the diet-induced thermogenesis is unlikely because patients are instructed to fast before scanning. Cold exposure remains a viable consideration as a means to activate brown adipose tissue nonshivering thermogenesis stimulated by the sympathetic nervous system. Although additional studies need to be performed to elucidate this process, instructing patients to stay warmly dressed and maintain fairly high ambient household temperature (75°C) for 48 hr before scanning to suppress brown adipose tissue metabolic activity and potentially reduce misinterpretation of FDG PET scans has been suggested (Morton K et al., unpublished data).
In summary, hypermetabolic brown fat in the mediastinum is uncommon in adults but can manifest as focal increased FDG uptake that can be misinterpreted as malignancy. Knowledge of this potential pitfall and the use of fusion PET/CT to precisely localize FDG uptake are important in improving diagnostic interpretation and accurate staging.
Acknowledgments
We thank Lyle D. Broemeling for statistical analysis, Gloria Mendoza for
manuscript preparation, and Brooke Lening for photography.
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