DOI: 10.1148/rg.246045701
RadioGraphics 2004;24:1611-1616
© RSNA, 2004
Spectrum of Thymic Uptake at 18F-FDG PET1
Brett Ferdinand, MD,
Pramod Gupta, MD and
Elissa L. Kramer, MD
1 From the Department of Radiology, NYU School of Medicine, Rm HW231, Nuclear Medicine/Radiology, Tisch Hospital, 550 First Ave, New York, NY 10016. Received February 6, 2004; revision requested April 7 and received May 19; accepted May 20. All authors have no financial relationships to disclose. Address correspondence to E.L.K. (e-mail: elissa.kramer@med.nyu.edu).
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Abstract
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Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as a strong diagnostic tool for the diagnosis and staging of neoplasms. Uptake in the thymus at 18F-FDG PET complicates the assessment of mediastinal involvement by tumor in children and young adults. Increased thymic 18F-FDG uptake may represent normal physiologic uptake but may also indicate the presence of thymic hyperplasia, lymphomatous infiltration, primary thymic neoplasm, or metastatic disease. Familiarity with the patterns of 18F-FDG uptake that characterize these pathologic conditions is crucial to the interpretation of PET findings in the thymus. In addition, awareness of the subsets of patients in whom physiologic uptake may be seen and of the normal morphologic features and 18F-FDG PET appearance of the thymus, along with a general sense of the upper limits of metabolic activity for physiologic thymic uptake, will aid in differentiating between physiologic thymic uptake and mediastinal disease. In equivocal cases, correlation with morphologic data from computed tomography or magnetic resonance imaging will likely continue to play a key role in diagnosis and will aid in differentiating benign thymic uptake from malignancy.
© RSNA, 2004
Index Terms: Fluorine, radioactive, 675.12163 • Positron emission tomography (PET), in infants and children, 675.12163 • Thymus, CT, 675.1211 Thymus, neoplasms, 675.3154, 675.321 • Thymus, PET, 675.12163
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Introduction
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Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as a powerful diagnostic tool for the diagnosis, staging, and restaging of neoplasms. In the evaluation of malignancy, a potential pitfall in the evaluation of the anterior mediastinum is mistaking normal uptake within the thymus for disease such as adenopathy or local invasion by tumor. The thymus can be infiltrated secondary to a number of mediastinal neoplasms, involved by metastatic disease, and involved most commonly by lymphoma, usually nodular sclerosing Hodgkin disease. Indeed, the rate of thymic involvement by mediastinal Hodgkin disease has been reported to be as high as 70% (1). Even in the absence of lymphomatous infiltration, thymic enlargement may coexist with lymphoma and has been reported to be present in 30%–56% of patients who present with intrathoracic Hodgkin disease (2). Increased uptake within the thymus may also be due to a primary thymic malignancy such as a thymoma or thymic carcinoma. Therefore, understanding the PET appearance of physiologic thymic uptake, the appearance of thymic malignancy, and the potential distinctions between the two is essential.
In this article, we discuss and illustrate the normal thymic appearance at 18F-FDG PET, the thymic response to chemotherapy, the differentiation of normal and hyperplastic thymus from malignant involvement, and various thymic neoplasms.
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Normal Thymic Appearance
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One of the key elements of assessing the thymus at 18F-FDG PET is realizing which subsets of patients typically exhibit thymic 18F-FDG uptake. In general, it is accepted that the thymus can be seen at computed tomography (CT) in virtually every pediatric patient (1). Some investigators have reported that the thymus can be seen at CT in all patients under the age of 30 years (3). In an early report on the physiologic thymic uptake of 18F-FDG, Patel et al (4) extrapolated from their experience with CT and hypothesized that thymic uptake could be a normal finding in patients under the age of 20 years. Of the 14 patients in that study, all of whom had undergone whole-body 18F-FDG PET with no evidence to suggest a thymic abnormality, seven patients—all under the age of 13 years—had normal physiologic thymic uptake (Fig 1). Thymic uptake was deemed "normal" on the basis of morphologic features, size, and contour at 18F-FDG PET. Because normal uptake was not seen in any patients over 13 years old, the authors suggested that metabolic activity in the thymus ceases at puberty, which is the point at which the thymus undergoes fatty infiltration and involution.
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Figure 1. Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in an 11-year-old boy with lymphoma demonstrate an inverted V-shaped area of anterior mediastinal uptake on the transaxial view with a maximum standardized uptake value (SUV) of 3.0. Given the morphologic features, this finding is typical of normal thymic uptake.
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Subsequent studies, however, have shown that physiologic thymic uptake can be seen in patients well beyond puberty. One study examined thymic uptake at 18F-FDG PET in 94 patients ranging from 18 to 29 years of age and found that 32 of these patients exhibited normal physiologic thymic uptake (5). The criteria for "normal" in these patients included a normal thymus identified at CT, absence of clinical symptoms of thymus-related disease, and absence of mediastinal tumor at follow-up ranging from 6 to 69 months. This study also found a correlation between the degree of thymic uptake and the attenuation of the thymus at CT (measured in Hounsfield units), a finding that supports the idea that the disappearance of thymic uptake is related to the degree of fatty infiltration of the thymus (Fig 2). In a more recent study—to our knowledge, the only study to date to confirm physiologic thymic 18F-FDG uptake with histologic findings—three patients (aged 29, 32, and 44 years, respectively) with histologically normal thymic tissue were retrospectively found to have physiologic uptake at 18F-FDG PET as well as thymic enlargement at CT (6). In one of these patients, increased uptake was attributed to thymic hyperplasia in response to chemotherapy; the cause of increased uptake and thymic enlargement in the other two patients was unknown.
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Figure 2. Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 64-year-old man with fatty infiltration of the thymus demonstrate a region of near-absent 18F-FDG uptake corresponding to the expected location of the thymus.
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Thymic Response to Chemotherapy
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Although it is evident that both pediatric patients and (more rarely) adult patients can exhibit normal physiologic thymic uptake of 18F-FDG, the subset of patients who undergo chemotherapy deserves particular attention. Thymic hyperplasia has been reported to occur following chemotherapy, especially in young patients treated for testicular malignancy or malignant lymphoma (Fig 3). It has been proposed that this finding is due to an immunologic rebound phenomenon characterized by lymph follicles with large nuclear centers and infiltration of plasma cells following thymic aplasia secondary to steroid-induced apoptosis and inhibition of lymphocyte proliferation (7). The phenomenon of thymic hyperplasia following chemotherapy is particularly important to recognize in young adults, in whom the thymus may not be visualized. This point is illustrated in a study by Brink et al (7), which examined 18F-FDG PET findings in four sets of patients with malignancy: (a) children with malignancy prior to chemotherapy (n = 15; mean age, 11.9 years ± 3.7), (b) children with malignancy following chemotherapy (n = 12; mean age, 10.3 years ± 5), (c) adults with lymphoma prior to chemotherapy (n = 37; mean age, 43.9 years ± 16.7), and (d) adults with lymphoma following chemotherapy (n = 104; mean age, 40.9 years ± 14.6). The authors found increased 18F-FDG uptake in 73% of the children with malignancy prior to chemotherapy and in 75% of the children with malignancy following chemotherapy. However, they also found increased uptake in 5% of the adults with lymphoma following chemotherapy (of whom the oldest patient with increased uptake was 25 years of age). None of the adults with lymphoma prior to chemotherapy exhibited increased thymic uptake. These findings support the idea that, although thymic uptake may be a normal finding in children, it may also be expected in young adults after therapy. Of note is a reported case of increased thymic uptake in a 54-year-old woman following radioiodine ablation of a follicular thyroid carcinoma (8).
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Figure 3. Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 17-year-old girl who was being treated for lymphoma demonstrate linear uptake in the anterior mediastinum with a maximum SUV of 3.8. Differentiation of lymphoma from thymic hyperplasia is difficult in such cases. A repeat study performed 5 months later showed continued absence of lymphoma with persistent anterior mediastinal uptake in the same triangular configuration. This finding was believed to represent thymic hyperplasia.
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Differentiating Normal and Hyperplastic Thymus from Malignant Involvement
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Although it is important to recognize those subsets of patients in whom physiologic thymic uptake may be a normal or expected finding, these are the very patients in whom differentiation of thymic uptake from disease such as malignant adenopathy is often most difficult. Differentiation of thymic uptake from malignancy may be made in part on the basis of morphologic features. Much of the literature regarding the morphologic characteristics of the thymus derives from experience with cross-sectional imaging, in particular CT. In patients under the age of 5 years, the thymus is generally quadrilateral with convex or straight margins. As the patient ages, the thymus becomes more triangular with concave or straight margins and should be triangular in configuration by the age of 15 years in most patients (1). Thickness of the gland measured perpendicular to the length of a lobe has been used as a criterion for abnormal thymic enlargement, with 1.8 cm being the upper limit of "normal" in patients under 20 years old and 1.3 cm the upper limit in older patients (5,9,10). Although PET does not offer the same resolution as CT or magnetic resonance (MR) imaging, the appearance of physiologic thymic uptake at PET is characteristic. The thymus appears as a triangular retrosternal region of increased uptake, a finding that corresponds to the bilobed configuration of the thymus (Fig 4). In questionable cases, correlation with findings at cross-sectional imaging modalities such as CT or MR imaging may better delineate the contour of the pertinent region.
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Figure 4a. (a) Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 14-year-old boy with lymphoma involving the right arm demonstrate a triangular area of anterior mediastinal uptake. This area was believed to represent normal thymic uptake on the basis of morphologic features and a maximum SUV of 2.8. The maximum SUV of the mass in the right upper extremity was 15.6. (b) CT scan demonstrates a normal-appearing thymus corresponding to the area of anterior mediastinal uptake seen at 18F-FDG PET.
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Figure 4b. (a) Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 14-year-old boy with lymphoma involving the right arm demonstrate a triangular area of anterior mediastinal uptake. This area was believed to represent normal thymic uptake on the basis of morphologic features and a maximum SUV of 2.8. The maximum SUV of the mass in the right upper extremity was 15.6. (b) CT scan demonstrates a normal-appearing thymus corresponding to the area of anterior mediastinal uptake seen at 18F-FDG PET.
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Although morphologic features may help define the presence of physiologic thymic uptake, to our knowledge, no study is available to support this assertion. PET also provides information regarding the metabolic rate of thymic tissue. Several investigators have examined the relationship between the rate of glucose metabolism and the presence of thymic neoplasia or mediastinal malignancy using SUVs to measure 18F-FDG uptake. SUVs have gained wide acceptance as a method of assessing 18F-FDG uptake by tissue, despite the fact that they may be affected by various factors, including time elapsed between 18F-FDG injection and imaging; the patient’s body fat content, body weight, and serum glucose level; and use of a maximum pixel value versus an average pixel value for the region of interest (11). SUV is defined as Q x W/Qinj, where Q is the decay-corrected activity in the region of interest in Becquerels per milliliter, W is the body weight of the patient in kilograms, and Qinj is the injected dose in Becquerels. The available data indicate that SUVs may have a limited role in the differentiation of a normal thymus from thymic neoplasia or adenopathy. In an examination of the 18F-FDG PET findings in three patients with a histologically proved normal thymus, the SUV of the thymus was found to be 1.8 ± 0.55. This value overlaps with the values found in a study by Sasaki et al (12) for noninvasive thymoma (3.0 ± 1), indicating that SUVs may not reliably help differentiate between physiologic thymic uptake and thymic neoplasia. However, further examination of SUVs in the normal thymus is necessary.
It is also important to get a sense of the upper limit of normal physiologic thymic uptake. In the study by Brink et al (7), the highest average SUV occurred in the group of adults with lymphoma following chemotherapy (mean, 2.74 ± .66) with a maximum SUV of 3.83 in a pediatric patient following chemotherapy for osteosarcoma. In a study by Wittram et al (6), the highest SUV value for normal thymus was 2.2. Although more research and experience are necessary before declaring an upper SUV limit for physiologic thymic uptake, it appears that a maximum SUV above 4.0 may be cause to at least reconsider before attributing an area of 18F-FDG accumulation in the mediastinum to physiologic uptake within the thymus.
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Thymic Neoplasms
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One area in which SUVs may be useful in evaluating the thymus is the differentiation of thymic carcinoma from other thymic neoplasms, thymic hyperplasia, and normal physiologic uptake. Although thymic carcinoma can often be differentiated from hyperplasia at CT or MR imaging on the basis of morphologic characteristics, it is useful to assess the capacity of 18F-FDG PET to help differentiate thymic malignancy from other entities in terms of metabolic activity. Thymic epithelial tumors tend to occur in the anterior mediastinum and are most prevalent in the 5th and 6th decades of life (13). That thymic carcinoma and thymoma can be differentiated on the basis of metabolic activity follows from the pathophysiologic features of these entities and from prior studies that have demonstrated a higher degree of 18F-FDG uptake in malignant mediastinal tumors than in benign entities (14). Both thymic carcinoma and thymoma derive from neoplasia of thymic epithelial elements. Thymoma is typically classified as either invasive (Fig 5) or noninvasive. Both invasive and noninvasive thymomas are cytologically benign appearing and can be differentiated from each other on the basis of the biologic behavior of invasive thymomas, which have a propensity for local invasion and, in rare cases, distant spread. In contrast, thymic carcinoma (Fig 6) is cytologically malignant and behaves aggressively, with a propensity for distant metastasis (15).
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Figure 5. Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 55-year-old man demonstrate an anterior mediastinal mass with a maximum SUV of 4.5. The lesion was resected and proved to be an invasive thymoma.
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Figure 6. Transaxial (left), coronal (middle), and sagittal (right) 18F-FDG PET scans obtained in a 55-year-old man with a thymic carcinoma demonstrate anterior mediastinal uptake with a maximum SUV of 7.5.
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Sasaki et al (12) found a mean SUV of 7.2 ± 2.9 for patients with thymic carcinoma (n = 9). This value was significantly greater than the values found for invasive thymoma (3.8 ± 1.3) and noninvasive thymoma (3.0 ± 1.0). By using an SUV of 5.0 as a cutoff, the authors achieved reasonable sensitivity (84.6%), specificity (92.3%), and accuracy (88.5%) in differentiating thymic carcinoma from thymoma. They found no statistically significant difference in SUV between invasive and noninvasive thymomas, a finding that is consistent with the histologic similarity of the two tumors. This finding is also consistent with earlier work by Liu et al (16), which failed to demonstrate a significant difference in 18F-FDG uptake between different stages of thymoma. Brink et al (7) also presented one case of thymic carcinoma with an SUV of 9.6. On the basis of these limited data, it appears that 18F-FDG PET will prove to be effective in differentiating thymic carcinoma from other entities within the thymus but will likely prove equivocal in differentiating invasive and noninvasive thymoma from each other and from thymic hyperplasia.
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Conclusions
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As the number of clinical applications of 18F-FDG PET grows, the recognition of physiologic thymic uptake and its differentiation from mediastinal disease will remain important. Awareness of the subsets of patients in whom physiologic uptake may be seen and of the normal morphologic features and 18F-FDG PET appearance of the thymus, as well as a general sense of the upper limits of metabolic activity for physiologic thymic uptake, will aid in this differentiation. In addition, correlation with treatment history (eg, in patients who have undergone chemotherapy) will suggest the possibility of rebound thymic hyperplasia. In equivocal cases, it is likely that correlation with morphologic data from CT or MR imaging will continue to play a key role in diagnosis and will aid in differentiating benign thymic uptake from malignancy.
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Footnotes
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Abbreviations: FDG = fluorodeoxyglucose,
SUV = standardized uptake value
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Abstract
Introduction
