Imaging Features of Sarcoidosis on MDCT, FDG PET, and PET/CT

AJR Integrative Imaging LIFELONG LEARNING FOR RADIOLOGY Imaging Features of Sarcoidosis on MDCT, FDG PET, and PET/CT Hima B. Prabhakar 1, Chad B. Rabinowitz 1, Fiona K. Gibbons 2, Walter J. O Donnell 2, Jo-Anne O. Shepard 3, and Suzanne L. Aquino 3 Objective The objectives of this article are to discuss the epidemiology and natural history of sarcoidosis; to review the classic imaging features of sarcoidosis on radiography, CT, and 67 Ga nuclear medicine scans; and to present clinical examples of sarcoidosis as seen on PET and PET/CT in the chest, abdomen and pelvis, and bones. Conclusion The imaging features of sarcoidosis are diverse and can be seen on a variety of imaging techniques. It is important for radiologists and nuclear medicine physicians to recognize the common imaging features and patterns of sarcoidosis in order to raise the possibility in the appropriate clinical setting. Introduction Sarcoidosis is a multiorgan granulomatous disease with a wide variety of imaging features. Imaging abnormalities can commonly be seen on chest radiography, MDCT, 67 Ga scans, FDG PET, and PET/CT. FDG uptake from sarcoidosis is nonspecific and can mimic other disease processes, including lymphoma and diffuse metastatic disease. When combined with imaging features on other techniques, such as MDCT, FDG uptake can be useful in monitoring therapeutic response in patients with known sarcoidosis. Because imaging features of sarcoidosis can overlap considerably with those of malignant disorders, it is important for both radiologists and nuclear medicine specialists to be aware of the many varied presentations of sarcoidosis in order to suggest the diagnosis in the appropriate clinical setting. Sarcoidosis is a systemic and chronic disease of unknown cause [1]. The characteristic histologic lesion, a noncaseating granuloma, has been described as affecting all organ systems, although they are most frequently seen affecting the lungs [2]. The imaging features of sarcoidosis are protean and can be shown with a variety of imaging techniques. Diagnostic imaging can not only help suggest a diagnosis in asymptomatic patients, but can also help in monitoring therapeutic response in symptomatic patients. FDG uptake on PET in patients with sarcoidosis is nonspecific and can mimic that in malignancies such as lymphoma and diffuse metastatic disease [2]. Epidemiology Sarcoidosis has a worldwide distribution and typically affects young to middle-aged adults. The highest prevalence of the disease is found in African-Americans, Swedes, and Danes. In the United States, the incidence rate of sarcoidosis is 35.5 cases per 100,000 in blacks and 10.9 cases per 100,000 in whites. Additionally, the disease incidence is slightly higher in women than in men [3]. Clinical Presentation and Natural History Because sarcoidosis affects multiple organ systems, presentation varies from nonspecific constitutional symptoms to those related to specific organ involvement. Symptoms related to lung involvement (dyspnea and cough) can lead to chest radiographs that eventually yield the diagnosis of sarcoid. One third of patients have peripheral lymphadenopathy, most commonly involving the cervical, axillary, and inguinal lymph nodes. One quarter of patients show characteristic skin lesions, including erythema nodosum and lupus pernio [3]. The natural history of sarcoidosis varies significantly from patient to patient. The disease spontaneously remits in up to one third of patients, but is chronic and progressive in up to 30%. There is a 1 5% fatality rate from the disease, most commonly resulting from severe respiratory or cardiac involvement [3]. Keywords: CT, FDG PET, MDCT, PET/CT, sarcoidosis DOI:10.2214/AJR.07.7001 Received March 8, 2007; accepted after revision June 11, 2007. 1 Abdominal Imaging and Interventional Radiology, Department of Radiology, Massachusetts General Hospital, 55 Fruit St., FND 270, Boston, MA 02114. Address correspondence to H. B. Prabhakar (himaprab@gmail.com). 2 Department of Pulmonary/Critical Care Medicine, Massachusetts General Hospital, Boston, MA. 3 Thoracic Radiology, Department of Radiology, Massachusetts General Hospital, Boston, MA. AJR 2008;190:S1 S6 0361 803X/08/1903 S1 American Roentgen Ray Society AJR:190, March 2008 S1

Prabhakar et al. Fig. 1 Stage 1 sarcoidosis in 54-year-old man with biopsy-proven sarcoidosis. Frontal chest radiograph shows right paratracheal and bilateral hilar lymphadenopathy (arrows) and clear lungs. Fig. 3 Abdominal lymphadenopathy in 38-year-old man with biopsy-proven sarcoidosis. Contrast-enhanced axial CT image of upper abdomen shows multiple periaortic lymph nodes (arrows). Classic Imaging Features of Sarcoidosis Radiography Chest radiographic features include mediastinal and bilateral hilar lymphadenopathy, parenchymal opacities, and, in more advanced cases, parenchymal fibrosis. A clinical staging system based on the chest radiograph has been devised to monitor disease in patients with sarcoidosis as well as to predict patient prognosis. The five-part staging system ranges from stage 0 (no radiographic abnormality) to stage 4 (pulmonary fibrosis), with varying degrees of lymphadenopathy and pulmonary parenchymal abnormalities in between. Spontaneous remission is more commonly seen in patients with stage 1 disease (Fig. 1) than in patients with more advanced stages [3]. Fig. 2 Pulmonary nodules in peribronchovascular distribution in 44-year-old woman with sarcoidosis. High-resolution chest CT image shows multiple tiny pulmonary nodules centered in peribronchovascular distribution (upper arrow). Small pulmonary nodules can also be seen lining right major fissure (lower arrow). Fig. 4 Lambda (λ) sign on 67 Ga scan in 26-year-old man with biopsy-proven sarcoidosis. Anterior image of chest shows increased tracer uptake in right paratracheal and bilateral hilar lymph nodes, in configuration known as lambda sign. MDCT Lymphadenopathy and parenchymal involvement in the neck and chest are more readily shown on MDCT. In the neck, palpable cervical lymphadenopathy is identified in one third of patients, usually in the posterior triangle. In the chest, paratracheal, mediastinal, and bilateral hilar lymphadenopathy are most commonly identified. Characteristic parenchymal lesions include pulmonary nodules, typically in a peribronchovascular distribution or along fissures [2] (Fig. 2). Less commonly, alveolar consolidation can be seen with air bronchograms, cavitation, and fibrosis [4]. In the abdomen, lesions are less characteristic, mimicking systemic diseases such as lymphoma, diffuse metastatic disease, or granulomatous or mycobacterial infection. In S2 AJR:190, March 2008

Imaging Features of Sarcoidosis Fig. 5 Palpable submental lymph node with FDG uptake in 56-year-old woman with palpable submental lymph node. Axial fused contrast-enhanced PET/CT image shows enlarged left submental lymph node (arrow) with increased FDG uptake. Lesion was biopsied and was consistent with sarcoidosis. addition to diffuse lymphadenopathy (Fig. 3), nonspecific parenchymal lesions have been described, usually in the spleen and liver [4]. Diffuse hepatic involvement can progress in some cases to confluent hepatic fibrosis [2]. Gallium-67 Scanning Gallium-67 imaging has been widely used in the diagnosis of sarcoidosis. Gallium-67 is taken up in lesions with increased blood flow, typically in lesions having an inflammatory or infectious cause. In sarcoidosis, a characteristic pattern of uptake in the chest has been described as the lambda sign: paratracheal and bilateral hilar uptake [5] (Fig. 4). Another pattern of uptake is called the panda sign, caused by uptake in the lacrimal and parotid glands. Although this pattern can be seen in other entities, such as lymphoma and HIV, the bilateral symmetric involvement of the glands is more typical of sarcoidosis [6]. Additionally, when the panda sign is seen in conjunction with the lambda sign, it is highly specific for sarcoidosis [5]. FDG PET and PET/CT FDG PET is an important clinical tool in the evaluation of known or suspected malignancy. Uptake of the tracer is nonspecific, however, and is related to tissue metabolism. Thus, the agent is also readily taken up in some infectious and inflammatory conditions. Prior studies show increased FDG uptake in active sarcoidosis [7, 8]. FDG uptake in sarcoidosis is nonspecific in both intensity and pattern, and is not generally useful in making an initial diagnosis. Additionally, marked FDG uptake in lymph nodes and parenchymal organs can be an important mimic of malignancy, specifically lymphoma and diffuse metastatic disease. Despite this, FDG uptake can decrease when sarcoidosis is treated, and PET can be useful in monitoring the effectiveness of therapy [8, 9]. Although FDG uptake is nonspecific in sarcoidosis, combining the imaging features of sarcoidosis on CT with uptake on PET can make combined FDG PET/CT a useful technique in monitoring disease progression or remission. Additionally, if characteristic patterns of chest CT lesions are identified (as described previously), along with typical patterns of lymphadenopathy, the disease can be suggested on the basis of FDG PET/CT findings. Histologic proof, however, often is still required because of the importance of excluding malignancies, particularly lymphoma [10]. Clinical Examples on FDG PET and PET/CT Head and Neck Head and neck involvement by sarcoidosis is usually identified as cervical lymphadenopathy, seen in approximately one third of patients [2]. On FDG PET, increased uptake has been described in these lymph nodes (Fig. 5), as well as in the parotid glands, in a similar distribution to that seen with 67 Ga scanning [7]. Chest Although the radiographic and CT features of sarcoidosis have been well described in the chest, few articles have specifically addressed patterns of FDG uptake in the lungs. Mediastinal and hilar lymphadenopathy from sarcoidosis shows increased FDG uptake, as in other parts of the body (Fig. 6). Lung parenchymal involvement and FDG uptake is less well described; however, it has been shown that FDG PET can detect lung involvement by sarcoidosis in patients after transplantation [9]. Abdomen Again, as elsewhere in the body, abdominal lymph nodes secondary to sarcoidosis can show increased FDG activity [7]. Parenchymal lesions in the abdomen have also been described as showing increased FDG uptake. For example, sarcoidosis is known to cause splenomegaly and low-density focal lesions in the spleen that have been reported to have increased FDG uptake on PET [11] (Fig. 7). Musculoskeletal Bone involvement in sarcoidosis can be seen in up to one third of patients, usually in the hands and feet. Less commonly, axial skeletal involvement can be seen. In both cases, lesions of sarcoid can be either osteolytic or osteosclerotic, and their nonspecific appearance can make diagnosis difficult. Increased activity can be seen on bone scintigraphy. AJR:190, March 2008 S3

Prabhakar et al. A C Fig. 6 Confluent parenchymal lung nodules and mediastinal and bilateral hilar lymphadenopathy with increased FDG uptake in 56-year-old woman with biopsyproven sarcoidosis. A C, Axial CT image (A) shows confluent parenchymal lung nodules (yellow arrows) and mediastinal and bilateral hilar lymphadenopathy (blue arrows). These abnormalities show increased FDG uptake on fused PET/CT (B) and unfused PET (C) images. B A B C Fig. 7 Splenic lesions with uptake from sarcoidosis in 43-year-old woman with history of Hodgkin s lymphoma. A C, Images from combined PET/CT show low-density lesions (arrows, A and C) in spleen on coronal CT image (A). Lesions show increased FDG uptake on fused PET/ CT (B) and unfused PET (C) images. Because of patient s history of lymphoma, she underwent splenectomy to assess cause of lesion, and pathology revealed noncaseating granulomas consistent with sarcoidosis. Sarcoidosis is known to cause splenomegaly and low-density focal lesions in the spleen and has been reported to have increased FDG uptake on PET scans [11]. S4 AJR:190, March 2008

Imaging Features of Sarcoidosis Fig. 8 Skeletal uptake in 56-year-old woman with known sarcoidosis in neck, who presented with pelvic bone pain. A C, Images from combined PET/CT scan show multiple subtle sclerotic lesions (arrows) in bilateral iliac bones on axial CT image (A). These lesions show increased FDG uptake on fused PET/CT (B) and unfused PET (C) images. Biopsy of left iliac bone lesion was consistent with sarcoidosis. Fig. 9 Follicular lymphoma and asymptomatic pulmonary sarcoidosis in 44-year-old woman with history of grade 3 follicular lymphoma that is now in remission. Patient underwent transbronchial biopsy to evaluate small lymph nodes in chest, which revealed noncaseating granulomas consistent with sarcoidosis. Whole-body PET image shows marked FDG uptake in bilateral axillae and left paratracheal regions (upper arrows), as well as in abdomen (lower arrows). Distribution of adenopathy is more consistent with lymphoma than with sarcoidosis, especially because of lack of significant hilar or mediastinal lymphadenopathy. Biopsy of left axillary lymph node revealed follicular lymphoma. A B C AJR:190, March 2008 S5

Prabhakar et al. Additionally, case reports have described increased FDG uptake in skeletal sarcoidosis (Fig. 8). In conjunction with the more characteristic findings of sarcoidosis, such as mediastinal lymphadenopathy, bone involvement from sarcoid can be suggested in patients with increased focal bone FDG uptake rather than diffuse metastatic disease [12, 13]. Sarcoidosis as a Mimic of Malignancy The most common radiologic finding in sarcoidosis is intrathoracic lymphadenopathy, seen in up to 85% of patients [2]. Abdominal lymphadenopathy is seen 30% of cases, with massive lymphadenopathy (lymph nodes > 2 cm) seen in 10% of patients [4]. Given the presence of lymphadenopathy in such a large percentage of patients with sarcoidosis, it is not surprising that one of the more common differential considerations in these patients is lymphoma. Additionally, as described previously, musculoskeletal involvement in sarcoidosis can manifest as increased focal uptake throughout the skeleton, which can mimic diffuse metastatic disease [12, 13]. To further complicate matters, a known association exists between sarcoidosis and lymphoma, described in 1986 by Brinker and called sarcoidosis lymphoma syndrome [14]. Several cases studies have been published describing the association of chronic active sarcoidosis and systemic lymphoma, both Hodgkin s and non-hodgkin s lymphoma [15, 16] (Fig. 9). Using data from patients with respiratory sarcoidosis who had registered with the Danish Institute of Clinical Epidemiology, Brinker determined that patients with sarcoidosis are at 5.5 times increased risk of developing a lymphoproliferative disorder as other patients in the same age group [14]. Conclusion The imaging features of sarcoidosis are diverse and can be shown on a variety of imaging techniques. FDG uptake on PET in patients with sarcoidosis is variable and can mimic malignancies such as lymphoma and diffuse metastatic disease. It is important for radiologists and nuclear medicine physicians to recognize the common imaging features and patterns of sarcoidosis in order to raise the possibility in the appropriate clinical setting. References 1. Cox CE, Davis-Allen A, Judson MA. Sarcoidosis. Med Clin North Am 2005; 89:817 828 2. Koyama T, Ueda H, Togashi K, Umeoka S, Kataoka M, Nagai S. Radiologic manifestations of sarcoidosis in various organs. RadioGraphics 2004; 24:87 104 3. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS), and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999; 160:736 755 4. Warshauer DM, Lee JK. Imaging manifestations of abdominal sarcoidosis. AJR 2004; 182:15 28 5. Sulavik SB, Spencer RP, Weed DA, Shapiro HR, Shiue ST, Castriotta RJ. Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis. J Nucl Med 1990; 31:1909 1914 6. Kurdziel KA. The panda sign. Radiology 2000; 215:884 885 7. Lewis PJ, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. J Nucl Med 1994; 35:1647 1649 8. Nishiyama Y, Yamamoto Y, Fukunaga K, et al. Comparative evaluation of 18 F FDG PET and 67 Ga scintigraphy in patients with sarcoidosis. J Nucl Med 2006; 47:1571 1576 9. Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. RadioGraphics 2005; 25:1357 1368 10. Hollister D Jr, Lee MS, Eisen RN, Fey C, Portlock CS. Variable problems in lymphomas: Case 2. Sarcoidosis mimicking progressive lymphoma. J Clin Oncol 2005; 23:8113 8116 11. Vento JA, Arici M, Spencer RP, Sood R. F-18 FDG PET: mottled splenomegaly with remission of symptoms after splenectomy in sarcoidosis. Clin Nucl Med 2004; 29:103 104 12. Aberg C, Ponzo F, Raphael B, Amorosi E, Moran V, Kramer E. FDG positron emission tomography of bone involvement in sarcoidosis. AJR 2004; 182:975 977 13. Ludwig V, Fordice S, Lamar R, Martin WH, Delbeke D. Unsuspected skeletal sarcoidosis mimicking metastatic disease on FDG positron emission tomography and bone scintigraphy. Clin Nucl Med 2003; 28:176 179 14. Brinker H. The sarcoidosis-lymphoma syndrome. Br J Cancer 1986; 54:467 473 15. Schmuth M, Prior C, Illersperger B, Topar G, Fritsch P, Sepp N. Systemic sarcoidosis and cutaneous lymphoma: is the association fortuitous? Br J Dermatol 1999; 140:952 955 16. Dunphy CH, Panella MJ, Grosso LE. Low-grade B-cell lymphoma and concomitant extensive sarcoidlike granulomas: a case report and review of the literature. Arch Pathol Lab Med 2000; 124:152 156 S6 AJR:190, March 2008