- Email: [email protected]
CT Interpretative Pitfalls in Thoracic Malignancies
Author’s Accepted Manuscript PET/CT Interpretative Malignancies
Pitfalls
in
image
Thoracic
Girish S. Shroff, Bradley S. Sabloff, Mylene T. Truong, Brett W. Carter, Chitra Viswanathan
www.elsevier.com/locate/bios
PII: DOI: Reference:
S0887-2171(18)30022-2 https://doi.org/10.1053/j.sult.2018.02.007 YSULT809
To appear in: Seminars in Ultrasound, CT, and MRI Cite this article as: Girish S. Shroff, Bradley S. Sabloff, Mylene T. Truong, Brett W. Carter and Chitra Viswanathan, PET/CT Interpretative Pitfalls in Thoracic Malignancies, Seminars in Ultrasound, CT, and MRI,doi:10.1053/j.sult.2018.02.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/CT Interpretative Pitfalls in Thoracic Malignancies Girish S. Shroff MD, Bradley S. Sabloff MD, Mylene T. Truong MD, Brett W. Carter MD, Chitra Viswanathan MD
All authors from: Department of Diagnostic Radiology Division of Diagnostic Imaging University of Texas M.D. Anderson Cancer Center Houston, TX
Corresponding Author:
Girish S. Shroff, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 1478 Houston, Texas 77030 Telephone: (713) 792-5884 Email: [email protected]
Keywords: PET/CT, pitfalls, thorax, lung cancer, staging Keypoints: 1. Misinterpretation in PET/CT can be due artifacts and quantitative errors in the use of CT for attenuation correction of PET data. 2. Normal variants in physiologic uptake of [18F]-fluoro-2-deoxy-D-glucose and technical artifacts are potential pitfalls in PET/CT interpretation. 3. Factors that confound interpretation of PET/CT include malignancies that are PET negative and benign conditions that are PET positive. Abstract Applications of PET/CT in the thorax include the evaluation of solitary pulmonary nodules, staging and restaging of oncologic patients, assessment of therapeutic response, and detection of residual or recurrent disease. Accurate interpretation of PET/CT requires knowledge of the physiological distribution of [18F]-fluoro-2-deoxy-D-glucose, as well as artifacts and quantitative errors due to the use of CT for attenuation correction of the PET scan. Potential pitfalls include malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management. Introduction Positron emission tomography/computed tomography (PET/CT) using [18F]fluoro-2-deoxy-D-glucose (FDG) and has been widely used in oncologic patients in clinical practice. Using CT for attenuation correction of PET data, PET/CT allows near-
simultaneous acquisition of functional and morphologic data. The spatial and temporal matched datasets of PET and CT enable more accurate localization of regions of increased FDG uptake and more accurate staging compared to visual correlation of PET and CT images acquired separately (1). The benefits of using CT for attenuation correction of PET emission data include a noise-free transmission scan and the ability to quickly perform this correction. However, the use of CT for attenuation correction of the 511 keV positron annihilation photons of FDG has also introduced artifacts and quantitative errors that can result in misinterpretation of the PET scan (2). PET/CT interpretation can also be confounded by malignancies that are PET negative and benign entities such as infectious and inflammatory conditions that are PET positive. Finally, FDG avid findings can be due to treatment and certain invasive procedures so knowledge of the patients’ clinical history and awareness of these potential pitfalls are important in PET/CT interpretation. This article will review artifacts and potential pitfalls in PET/CT interpretation in thoracic malignancies. Technical Artifacts Technical factors such as attenuation-correction artifacts and iatrogenic microembolism of FDG can result in misinterpretation of PET/CT studies. Attenuationcorrection artifacts can occur with patient movement or differences in the patient’s breathing during the acquisition of CT and PET data. Patient breathing can create a mismatch between the CT attenuation map obtained during breath-hold and the PET emission data obtained during quiet tidal breathing (3, 4). This mismatch/misregistration can lead to localization errors and incorrect attenuation coefficients applied to the PET data that can alter the maximal standardized uptake value (SUVmax), the most
commonly used parameter to quantify the intensity of FDG uptake. Respiratory misregistration can manifest as a curvilinear cold artifact just above the diaphragm and a discrepancy in the localization of anatomic structures on CT and PET images. For example, a focal FDG-avid hepatic metastasis can be erroneously localized to the lung and mimic a lung metastasis (Figure 1). Review of the CT images allows correct anatomic localization of the PET finding. A strategy to mitigate the respiratory mismatch between the CT and PET images is to obtain the CT scan in mid-expiration rather than end-inspiration to approximate the lung volumes of PET scan during quiet tidal breathing. CT scan at mid-expiration allows both the detection of small lung nodules as well as adequate fusion of PET and CT images. Another artifact related to the use of CT for attenuation correction of PET data concerns high CT attenuation materials such as metallic hardware, oral and intravenous contrast. These materials produce streak artifacts on CT due to high photon absorption. These streak artifacts result in high attenuation correction factors applied to PET data and manifests as an overestimation of FDG accumulation in the affected region (5). Thus, FDG avid pathology in the proximity of metallic prostheses can be difficult to discern, and attention should be directed to this area. Furthermore, the apparent increased FDG uptake around prostheses can mimic infection or loosening. Review of the nonattenuation corrected images is helpful to avoid misinterpretation. As for oral and intravenous contrast media, PET/CT scanners have built-in algorithms to modify the transformation from CT numbers to PET attenuation coefficients that takes into consideration the effects of the contrast agents (6).
Iatrogenic microembolism of FDG can occur following intravenous injection of the radiotracer. Clumping of FDG within a clot is embolized into the pulmonary artery and manifests as focal FDG accumulation in the lung without a corresponding CT lung abnormality (Figure 2). Awareness of this potential pitfall is important in avoiding misinterpretation as a pulmonary metastasis (7). Physiologic Distribution of FDG [18F]-fluoro-2-deoxy-D-glucose (FDG) is a glucose analog that is transported into cells by glucose transporter membrane proteins found in both normal and tumor cells (8). Physiologic uptake of FDG can be seen in the brain, salivary glands, lymphoid tissue in the head and neck, thymus, mammary glands, myocardium, gastrointestinal tract, urinary tract, liver, spleen, and bone marrow. Normal variations in physiologic uptake of FDG in striated muscle and brown adipose tissue are potential pitfalls in interpretation. For example, talking within 30 minutes of FDG administration results in diffuse symmetric increased uptake in the intrinsic laryngeal muscles and tongue (9). Due to the symmetry and typical location and appearance, this type of physiologic uptake is easy to recognize. However, asymmetric uptake of FDG with physiologic uptake in the normal vocal cord and absence of uptake in the paralyzed vocal cord can be misinterpreted as a laryngeal malignancy (10).
·
Striated Muscle
Major skeletal muscle groups at rest typically show minimal or no FDG avidity on FDG-PET imaging. However, muscular activities, both voluntary, such as talking, chewing, and exercising, and involuntary, such as labored breathing and muscle spasm, can show increased FDG uptake (11). Striated muscles that undergo active contraction shortly before or during the FDG uptake phase (within 30 minutes of FDG administration) can also accumulate FDG. Anxiety can result in sustained or repetitive contraction of the muscles of the head and neck including the genioglossus and sternocleidomastoid muscles. Increased FDG uptake in these muscles is typically bilateral, symmetric, fusiform or elongated in appearance and seldom problematic to interpret. However, asymmetric muscle uptake can occur, especially in the head and neck and these foci of increased FDG uptake can occasionally be misinterpreted as pathologic. Additionally, anxiety or pulmonary pathology can result in hyperventilation and increased FDG uptake in the intercostal muscles and diaphragmatic crura. These peripheral foci of increased FDG uptake can be misinterpreted as rib or diaphragmatic pleural disease. ·
Brown Adipose Tissue
In addition to striated muscle, physiologic uptake in brown adipose tissue (BAT) is a potential pitfall in PET/CT interpretation (12). In terms of adipose tissue, white adipose tissue stores energy and functions as insulation, while brown adipose tissue regulates body weight and temperature by thermogenesis (heat production). Cold temperature and satiety are the two stimuli for brown adipose
tissue to be metabolically active. As patients typically prepare for PET/CT imaging by fasting for 6 hours prior to the examination, cold temperature is the stimulus commonly attributed to hypermetabolic brown fat on PET. Hypermetabolic brown fat is more commonly seen in the pediatric than adult patients. Autopsy studies show that BAT deposits decrease with age and are distributed in the cervical, axillary, paravertebral, mediastinal, and abdominal regions (13). The distribution BAT adjacent to vital structures is postulated to be a protective mechanism using heat production to maintain the viability of the great vessels, heart, spine, liver, spleen and kidneys. In the supraclavicular regions, hypermetabolic BAT has been reported as a false-positive result in up to 4% of patients (14). Typically bilateral and symmetric, this finding is seldom problematic for interpretation. However, asymmetric or isolated focal increased FDG uptake due to BAT in the mediastinum and abdomen can be potential pitfalls. Focal increased FDG uptake in BAT, occuring in the mediastinum in 1.8% of patients, can be misinterpreted as nodal metastases (12) (Figure 3). PET Negative Malignancy FDG-PET/CT is widely used in the evaluation of oncology patients in the clinical setting. Due to an overexpression of glucose transporter proteins, malignant cells show increased uptake of glucose and increased rate of glycolysis. A glucose analog, FDG undergoes the same uptake as glucose. Following phosphorylation by hexokinase, FDG is sequestered in cancer cells because a down-regulation of phosphatase prohibits it to enter intracellular glycolytic pathways. The most common semiquantitative method of evaluating
malignancies using PET is the standardized uptake value (SUV) calculated as a ratio of tissue radiotracer concentration (mCi/mL) and injected dose (mCi) at the time of data acquisition divided by body weight (g). An SUV cutoff of 2.5 has been used to differentiate benign from malignant lesions (15). In the thorax, PET negative malignancies confounding interpretation include small lung cancers, some lung adenocarcinomas presenting as subsolid lesions, and carcinoid tumors (16). In patients with small lung cancers, limitations in spatial resolution can result in false-negative results when lesions smaller than 10 mm in diameter are assessed (17). With current PET technology, the evaluation of lung nodules of approximately 7 mm in diameter is possible. In the evaluation of solitary pulmonary nodules, PET/CT has a sensitivity of 97% and a specificity of 78% for the detection of malignancy (18). Analysis of the nodule on PET/CT, as well as clinical risk factors such as patient age, smoking history, and history of malignancy is required to optimize patient management. For example, in a patient with a low pretest likelihood of malignancy (20%), a negative PET will reduce the likelihood of malignancy to 1% and conservative management with serial imaging reassessment is acceptable (19). However, in a patient with a high pretest likelihood of malignancy (80%), a negative PET will only reduce the likelihood of malignancy to 14% (19). Thus, tissue sampling, either with biopsy or resection, is recommended. The high sensitivity and specificity of PET in the evaluation of solitary pulmonary nodules relates to solid nodules of 10 mm or greater in size. FDG uptake is variable in a subset of lung adenocarcinomas presenting as subsolid
lesions and is not reliable to differentiate benign from malignant lesions (Figure 4). By definition, subsolid lesions comprise pure ground-glass lesions and partly solid lesions with both a ground glass component and a solid component. In a study by Nomori et al., 9 of 10 well-differentiated adenocarcinomas presenting as ground-glass nodules were negative on PET (17). PET Positive Benign Conditions ·
Infection and Inflammation
Infectious and inflammatory conditions can show increased FDG uptake due to increased glycolysis in leukocytes, lymphocytes and macrophages (20). Inflammatory cells found in the lungs, lymph nodes, pleura and blood vessels can accumulate FDG and confound interpretation. PET positive benign conditions include pneumonia, granulomas (Figure 5), sarcoidosis, amyloidosis, rounded atelectasis, pleural fibrosis, venous thrombosis (Figure 6), pulmonary embolism (Figure 7), and atherosclerosis (21). FDG avid infectious and or inflammatory lymph nodes can be misinterpreted as nodal metastases and alter patient management. Therefore, invasive nodal sampling is recommended in patients with lung cancer with suspicion of N2 (ipsilateral mediastinal) and/or N3 (contralateral hilar, contralateral mediastinal, ipsilateral or contralateral supraclavicular) involvement on CT (greater than 1 cm in short axis diameter) and or PET if this alters patient management (Figure 8) (22).
·
Iatrogenic and Post-Treatment Pitfalls
Potential pitfalls in PET/CT interpretation include invasive procedures and therapy-related conditions. FDG accumulates in granulation tissue in healing wounds, such as tracheostomy and sternotomy sites. Iatrogenic causes of focal FDG uptake also include sites of cardiac pacemakers, central lines, chest tubes, gastrostomy tubes, as well as procedures for tissue sampling such as percutaneous needle biopsy, mediastinoscopy and endobronchial ultrasound-guided biopsy (23). In these cases, use of PET/CT images to localize the focus of increased FDG uptake is diagnostic. Awareness of certain treatment options that can produce false positive results on PET imaging is essential to prevent misinterpretation. These treatment options include talc (3MgO•4SiO2•H2O) pleurodesis, radiation therapy, chemotherapy and bone marrow stimulation therapy (24, 25, 26, 27, 28). Correlation with the patient’s past medical and surgical history for these specific procedures is important in avoiding these interpretative pitfalls. For example, talc pleurodesis is performed to treat persistent pneumothoraces and recurrent benign or malignant pleural effusions (24). Pleural deposits of talc manifest as areas of increased uptake on PET/CT and can be misinterpreted as pleural metastases. The typical appearance of talc pleurodesis on CT consists of focal areas of high attenuation material in the pleura that correspond to areas of increased FDG uptake on fused PET/CT images (24) (Figure 9).
Another potential pitfall concerns FDG uptake in the liver adjacent to a distal esophageal cancer following chemoradiation therapy. The liver is susceptible to radiation injury at a dose of greater than 30 Gray. Tracer uptake is postulated in active leukocytes forming the inflammatory response to the radiation hepatic injury. The imaging appearance of hepatic radiation injury in patients with esophageal cancer on PET/CT is often diffuse but can be focal and nodular mimicking hepatic metastatic disease (Figure 10) (29). Awareness of radiation hepatic injury, knowledge of the typical location and appearance on PET/CT imaging in patients with distal esophageal malignancy receiving chemoradiation therapy, and correlation with radiation treatment plans are useful in preventing misinterpretation. Conclusion Applications of PET/CT in the thorax include tumor detection and characterization, differentiation of benign from malignant lesions, staging and restaging of malignancies, assessment of therapeutic response, and identification of residual or recurrent tumor. Accurate interpretation of PET/CT requires knowledge of the physiological distribution of FDG, as well as artifacts and quantitative errors due to the use of CT for attenuation correction of the PET scan. Potential pitfalls include malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management.
Figure Captions Figure 1 Respiratory artifact resulting in liver metastasis misregistered to the lung mimicking pulmonary metastasis. 48-year-old woman with lung cancer presents for staging evaluation. Coronal PET/CT (A) shows a focus of increased FDG uptake that appears to be localized to the lung. Axial CT (B) shows hypodense hepatic metastasis (arrow) in the dome of the liver. The focus of increased FDG uptake is due to liver metastasis misregistered into lung. Note misregistration artifact is confirmed by absence of pulmonary abnormality on CT image (C). Imaging during different stages of the patient’s respiratory cycle may introduce a mismatch between the CT attenuation data obtained during breath-hold and the PET emission data obtained during quiet tidal breathing.
Figure 2 Injection of radiotracer with microembolism mimicking pulmonary metastasis. 58-year-old woman with melanoma presents for staging. Axial PET/CT (A) shows a focus of increased FDG uptake in the right upper lobe suspicious for pulmonary metastasis. However, no corresponding pulmonary nodule is seen on the CT (B). This potential pitfall is due to accumulation of FDG within a thrombus created during injection of the radiotracer. The thrombus is embolized into the right upper lobe pulmonary artery. Iatrogenic microembolism occurs when abnormal FDG accumulation in the lung has no correlate on CT.
Figure 3 Mediastinal brown fat mimicking adenopathy. 57-year-old woman with breast cancer presents for staging. PET/CT (A) shows a focus of increased F-18 fluorodeoxyglucose uptake in the mediastinum suspicious for nodal metastases. CT (B) shows the focus of increased FDG uptake in the mediastinum is localized to fat (arrows). No mediastinal adenopathy was identified. Brown fat deposits can show metabolic activity on PET in response to exposure to cold (nonshivering thermogenesis). Accurate localization of tracer uptake prevented misinterpretation of this potential pitfall as nodal disease which can alter staging and patient management. Figure 4 PET negative malignancy. 78-year-old woman evaluated for solitary pulmonary nodule. Axial CT (A) and PET/CT (B) show 2.5cm mixed attenuation nodule in the right upper lobe with low grade FDG uptake and SUV of 1.8. An SUV cutoff of 2.5 has been used to differentiate benign (SUV<2.5) from malignant (SUV>2.5) nodules. Transthoracic needle biopsy revealed a well-differentiated adenocarcinoma. Note that false-negative PET results may be seen with carcinoid and well-differentiated adenocarcinoma.
Figure 5 Granulomatous infection mimicking pulmonary metastasis. 81-year-old man evaluated for upper airway infection not responding to antibiotics. Axial PET/CT (A) and contrast-enhanced CT (B) show a spiculated FDG avid 2.8 cm right lower lobe nodule. Transthoracic needle aspiration biopsy revealed squamous cell cancer. Axial PET/CT (C) and contrast-enhanced CT (D) show FDG avid 2 cm irregular nodule (arrow) in the right upper lobe abutting the anterior pleura suspicious for synchronous primary tumor. Biopsy revealed granulomatous inflammation, and Mycobacterium avium complex was identified. Benign conditions due infectious etiologies can result in increased glucose metabolism and is a false-positive finding on PET/CT. Tissue sampling is recommended when synchronous primary tumors are a consideration.
Figure 6 Catheter-related thrombus in the SVC with FDG avidity mimicking mediastinal adenopathy. 40-year-old woman with breast cancer. Restaging PET/CT (A) shows increased FDG uptake in the right mediastinum suspicious for adenopathy. Contrastenhanced CT (B) 7 days later shows a small thrombus around the left central catheter in the SVC (arrow). Benign conditions due to inflammatory etiologies can result in false positive FDG uptake.
Figure 7 Pulmonary embolism mimicking hilar adenopathy. 57-year-old man with lymphoma. PET/CT shows focus of increased FDG uptake in the right hilum suspicious for adenopathy (arrow). Contrast-enhanced CT chest shows clot in the right pulmonary artery and interlobar pulmonary artery consistent with pulmonary embolism (arrow). Benign conditions with an inflammatory component can result in false-positive FDG uptake. Figure 8 Granulomatous inflammation mimicking N3 nodal disease. 62-year-old man with NSCLC of the right upper lobe. CT (A) shows the 3cm right upper lobe primary tumor. Staging coronal PET/CT (B) shows FDG avid right supraclavicular adenopathy (arrow) suspicious for N3 nodal disease. Biopsy of the right supraclavicular lymph node revealed non-caseating granulomatous inflammation and no malignant cells. Invasive nodal sampling is recommended in a patient with lung cancer with suspicion of N2 and/or N3 involvement on CT and or PET if this alters patient management. Figure 9 Talc pleurodesis mimicking pleural metastasis. 69-year-old man with NSCLC. PET/CT (A) shows the primary tumor in the left upper lobe. PET/CT (B) shows FDG avid focus (arrow) in the right posterior pleura suspicious for metastatic disease. Non-contrast enhanced CT (C) shows the FDG avid focus is localized to an area of high attenuation material characteristic of talc pleurodesis (arrow). By clinical history, the patient had recurrent
spontaneous pneumothoraces requiring talc pleurodesis one year earlier. Note increased FDG uptake due to the inflammatory reaction incited by talc can persist even years after pleurodesis. Figure 10 Hepatic injury due to radiation therapy mimicking metastasis. 64-year-old man with esophageal cancer treated with chemotherapy and radiation therapy. Restaging axial PET/CT (A) 2 months following completion of radiation therapy shows focus of increased FDG uptake in the left lobe of the liver (arrow) suspicious for metastasis. (B) CT shows hypodense area in the left lobe of the liver (arrow). (C) Axial noncontrast-enhanced computed tomography (CT) of the abdomen with radiation dosimetric intensity-modulated radiation therapy (IMRT) treatment curves shows that the FDG-avid hepatic lesion corresponds to an area of radiation dose of 40 to 45 Gy. The liver is susceptible to radiation injury at a dose above 30 Gy, and the appearance, location and timing of the abnormality on PET/CT are typical of radiation-induced hepatic injury. The patient underwent Ivor-Lewis esophagectomy, and surveillance imaging confirmed the absence of metastatic disease.
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pseudogene-like sequence (GLUT6). J Biol Chem 265:13276–13282, 1990 9. Kostakoglu L, Wong JC, Barrington SF, et al. Speech-related visualization of laryngeal muscles with fluorine-18-FDG. J Nucl Med 37:1771–1773, 1996 10. Kamel EM, Goerres GW, Burger C, et al. Recurrent laryngeal nerve palsy in patients with lung cancer: detection with PET-CT image fusion – report of six cases. Radiology 224:153–156, 2002 11. Parida GK, Roy SG, Kumar R. FDG-PET/CT in Skeletal Muscle: Pitfalls and Pathologies. Semin Nucl Med Jul;47(4):362-372, 2017 12. Truong MT, Erasmus JJ, Munden RF, et al. Focal FDG uptake in mediastinal brown fat mimicking malignancy: a potential pitfall resolved on PET/CT. AJR Am J Roentgenol 183:1127–1132, 2004 13. Heaton JM. The distribution of brown adipose tissue in the human. J Anat. May; 112(Pt 1): 35–39, 1972 14. Cohade C, Mourtzikos KA, Wahl RL. “USA-Fat”: prevalence is related to ambient outdoor temperature evaluation with 18F-FDG PET/CT. J Nucl Med 44:1267–1270, 2003 15. Lowe VJ, Hoffman JM, DeLong DM, et al. Semiquantitative and visual analysis of FDG-PET images in pulmonary abnormalities. J Nucl Med: 35:1771–1776, 1994
16. Higashi K, Ueda Y, Yagishita M, et al. FDG PET measurement of the proliferative potential of non-small cell lung cancer. J Nucl Med 41:85– 92, 2000 17. Nomori H, Watanabe K, Ohtsuka T, et al. Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images. Lung Cancer 45:19–27, 2004 18. Gould MK, Maclean CC, Kuschner WG, et al. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 285:914–24, 2001 19. Gould MK, Ananth L, Barnett PG. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest 131:383–388, 2007 20. Kubota R, YamadaS, Kubota K, et al. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 33:1972–1980, 1992 21. Asad S, Aquino SL, Piyavisetpat N, et al. False-positive FDG positron emission tomography uptake in nonmalignant chest abnormalities. AJR Am J Roentgenol 182:983–989, 2004 22. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging nonsmall cell lung cancer. Diagnosis and management of lung cancer, 3rd ed:
American College of Chest Physicians evidence-based clinical practice guidelines, Chest 143: e211S-e250S, 2013 23. Halpern BS, Dahlbom M, Waldherr C, et al. Cardiac pacemakers and central venous lines can induce focal artifacts on CT-corrected PET images. J Nucl Med 45:290–293, 2004 24. Kwek BH, Aquino SL, Fischman AJ. Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis. Chest 125:2356–2360, 2004 25. Swisher SG, Erasmus J, Maish M. 2-Fluoro-2-deoxy- D-glucose positron emission tomography imaging is predictive of pathologic response and survival after preoperative chemoradiation in patients with esophageal carcinoma. Cancer 101:1776–85, 2004 26. Erdi YE, Macapinlac H, Rosenzweig KE. Use of PET to monitor the response of lung cancer to radiation treatment. Eur J Nucl Med 27:861– 866, 2000 27. Truong MT, Erasmus JJ, Macapinlac HA, et al. Teflon injection for vocal cord paralysis: false-positive finding on FDG PET-CT in a patient with non-small cell lung cancer. AJR Am J Roentgenol 182:1587–1589, 2004 28. Hollinger EF, Alibazoglu H, Ali A, et al. Hematopoietic cytokinemediated FDG uptake simulates the appearance of diffuse metastatic disease on whole body PET imaging. Clin Nucl Med 23:93–98, 1998 29. DeLappe EM, Truong MT, Bruzzi JF, et al. Hepatic radiation injury mimicking a metastasis on positron-emission tomography/computed
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Pitfalls
in
image
Thoracic
Girish S. Shroff, Bradley S. Sabloff, Mylene T. Truong, Brett W. Carter, Chitra Viswanathan
www.elsevier.com/locate/bios
PII: DOI: Reference:
S0887-2171(18)30022-2 https://doi.org/10.1053/j.sult.2018.02.007 YSULT809
To appear in: Seminars in Ultrasound, CT, and MRI Cite this article as: Girish S. Shroff, Bradley S. Sabloff, Mylene T. Truong, Brett W. Carter and Chitra Viswanathan, PET/CT Interpretative Pitfalls in Thoracic Malignancies, Seminars in Ultrasound, CT, and MRI,doi:10.1053/j.sult.2018.02.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/CT Interpretative Pitfalls in Thoracic Malignancies Girish S. Shroff MD, Bradley S. Sabloff MD, Mylene T. Truong MD, Brett W. Carter MD, Chitra Viswanathan MD
All authors from: Department of Diagnostic Radiology Division of Diagnostic Imaging University of Texas M.D. Anderson Cancer Center Houston, TX
Corresponding Author:
Girish S. Shroff, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 1478 Houston, Texas 77030 Telephone: (713) 792-5884 Email: [email protected]
Keywords: PET/CT, pitfalls, thorax, lung cancer, staging Keypoints: 1. Misinterpretation in PET/CT can be due artifacts and quantitative errors in the use of CT for attenuation correction of PET data. 2. Normal variants in physiologic uptake of [18F]-fluoro-2-deoxy-D-glucose and technical artifacts are potential pitfalls in PET/CT interpretation. 3. Factors that confound interpretation of PET/CT include malignancies that are PET negative and benign conditions that are PET positive. Abstract Applications of PET/CT in the thorax include the evaluation of solitary pulmonary nodules, staging and restaging of oncologic patients, assessment of therapeutic response, and detection of residual or recurrent disease. Accurate interpretation of PET/CT requires knowledge of the physiological distribution of [18F]-fluoro-2-deoxy-D-glucose, as well as artifacts and quantitative errors due to the use of CT for attenuation correction of the PET scan. Potential pitfalls include malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management. Introduction Positron emission tomography/computed tomography (PET/CT) using [18F]fluoro-2-deoxy-D-glucose (FDG) and has been widely used in oncologic patients in clinical practice. Using CT for attenuation correction of PET data, PET/CT allows near-
simultaneous acquisition of functional and morphologic data. The spatial and temporal matched datasets of PET and CT enable more accurate localization of regions of increased FDG uptake and more accurate staging compared to visual correlation of PET and CT images acquired separately (1). The benefits of using CT for attenuation correction of PET emission data include a noise-free transmission scan and the ability to quickly perform this correction. However, the use of CT for attenuation correction of the 511 keV positron annihilation photons of FDG has also introduced artifacts and quantitative errors that can result in misinterpretation of the PET scan (2). PET/CT interpretation can also be confounded by malignancies that are PET negative and benign entities such as infectious and inflammatory conditions that are PET positive. Finally, FDG avid findings can be due to treatment and certain invasive procedures so knowledge of the patients’ clinical history and awareness of these potential pitfalls are important in PET/CT interpretation. This article will review artifacts and potential pitfalls in PET/CT interpretation in thoracic malignancies. Technical Artifacts Technical factors such as attenuation-correction artifacts and iatrogenic microembolism of FDG can result in misinterpretation of PET/CT studies. Attenuationcorrection artifacts can occur with patient movement or differences in the patient’s breathing during the acquisition of CT and PET data. Patient breathing can create a mismatch between the CT attenuation map obtained during breath-hold and the PET emission data obtained during quiet tidal breathing (3, 4). This mismatch/misregistration can lead to localization errors and incorrect attenuation coefficients applied to the PET data that can alter the maximal standardized uptake value (SUVmax), the most
commonly used parameter to quantify the intensity of FDG uptake. Respiratory misregistration can manifest as a curvilinear cold artifact just above the diaphragm and a discrepancy in the localization of anatomic structures on CT and PET images. For example, a focal FDG-avid hepatic metastasis can be erroneously localized to the lung and mimic a lung metastasis (Figure 1). Review of the CT images allows correct anatomic localization of the PET finding. A strategy to mitigate the respiratory mismatch between the CT and PET images is to obtain the CT scan in mid-expiration rather than end-inspiration to approximate the lung volumes of PET scan during quiet tidal breathing. CT scan at mid-expiration allows both the detection of small lung nodules as well as adequate fusion of PET and CT images. Another artifact related to the use of CT for attenuation correction of PET data concerns high CT attenuation materials such as metallic hardware, oral and intravenous contrast. These materials produce streak artifacts on CT due to high photon absorption. These streak artifacts result in high attenuation correction factors applied to PET data and manifests as an overestimation of FDG accumulation in the affected region (5). Thus, FDG avid pathology in the proximity of metallic prostheses can be difficult to discern, and attention should be directed to this area. Furthermore, the apparent increased FDG uptake around prostheses can mimic infection or loosening. Review of the nonattenuation corrected images is helpful to avoid misinterpretation. As for oral and intravenous contrast media, PET/CT scanners have built-in algorithms to modify the transformation from CT numbers to PET attenuation coefficients that takes into consideration the effects of the contrast agents (6).
Iatrogenic microembolism of FDG can occur following intravenous injection of the radiotracer. Clumping of FDG within a clot is embolized into the pulmonary artery and manifests as focal FDG accumulation in the lung without a corresponding CT lung abnormality (Figure 2). Awareness of this potential pitfall is important in avoiding misinterpretation as a pulmonary metastasis (7). Physiologic Distribution of FDG [18F]-fluoro-2-deoxy-D-glucose (FDG) is a glucose analog that is transported into cells by glucose transporter membrane proteins found in both normal and tumor cells (8). Physiologic uptake of FDG can be seen in the brain, salivary glands, lymphoid tissue in the head and neck, thymus, mammary glands, myocardium, gastrointestinal tract, urinary tract, liver, spleen, and bone marrow. Normal variations in physiologic uptake of FDG in striated muscle and brown adipose tissue are potential pitfalls in interpretation. For example, talking within 30 minutes of FDG administration results in diffuse symmetric increased uptake in the intrinsic laryngeal muscles and tongue (9). Due to the symmetry and typical location and appearance, this type of physiologic uptake is easy to recognize. However, asymmetric uptake of FDG with physiologic uptake in the normal vocal cord and absence of uptake in the paralyzed vocal cord can be misinterpreted as a laryngeal malignancy (10).
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Striated Muscle
Major skeletal muscle groups at rest typically show minimal or no FDG avidity on FDG-PET imaging. However, muscular activities, both voluntary, such as talking, chewing, and exercising, and involuntary, such as labored breathing and muscle spasm, can show increased FDG uptake (11). Striated muscles that undergo active contraction shortly before or during the FDG uptake phase (within 30 minutes of FDG administration) can also accumulate FDG. Anxiety can result in sustained or repetitive contraction of the muscles of the head and neck including the genioglossus and sternocleidomastoid muscles. Increased FDG uptake in these muscles is typically bilateral, symmetric, fusiform or elongated in appearance and seldom problematic to interpret. However, asymmetric muscle uptake can occur, especially in the head and neck and these foci of increased FDG uptake can occasionally be misinterpreted as pathologic. Additionally, anxiety or pulmonary pathology can result in hyperventilation and increased FDG uptake in the intercostal muscles and diaphragmatic crura. These peripheral foci of increased FDG uptake can be misinterpreted as rib or diaphragmatic pleural disease. ·
Brown Adipose Tissue
In addition to striated muscle, physiologic uptake in brown adipose tissue (BAT) is a potential pitfall in PET/CT interpretation (12). In terms of adipose tissue, white adipose tissue stores energy and functions as insulation, while brown adipose tissue regulates body weight and temperature by thermogenesis (heat production). Cold temperature and satiety are the two stimuli for brown adipose
tissue to be metabolically active. As patients typically prepare for PET/CT imaging by fasting for 6 hours prior to the examination, cold temperature is the stimulus commonly attributed to hypermetabolic brown fat on PET. Hypermetabolic brown fat is more commonly seen in the pediatric than adult patients. Autopsy studies show that BAT deposits decrease with age and are distributed in the cervical, axillary, paravertebral, mediastinal, and abdominal regions (13). The distribution BAT adjacent to vital structures is postulated to be a protective mechanism using heat production to maintain the viability of the great vessels, heart, spine, liver, spleen and kidneys. In the supraclavicular regions, hypermetabolic BAT has been reported as a false-positive result in up to 4% of patients (14). Typically bilateral and symmetric, this finding is seldom problematic for interpretation. However, asymmetric or isolated focal increased FDG uptake due to BAT in the mediastinum and abdomen can be potential pitfalls. Focal increased FDG uptake in BAT, occuring in the mediastinum in 1.8% of patients, can be misinterpreted as nodal metastases (12) (Figure 3). PET Negative Malignancy FDG-PET/CT is widely used in the evaluation of oncology patients in the clinical setting. Due to an overexpression of glucose transporter proteins, malignant cells show increased uptake of glucose and increased rate of glycolysis. A glucose analog, FDG undergoes the same uptake as glucose. Following phosphorylation by hexokinase, FDG is sequestered in cancer cells because a down-regulation of phosphatase prohibits it to enter intracellular glycolytic pathways. The most common semiquantitative method of evaluating
malignancies using PET is the standardized uptake value (SUV) calculated as a ratio of tissue radiotracer concentration (mCi/mL) and injected dose (mCi) at the time of data acquisition divided by body weight (g). An SUV cutoff of 2.5 has been used to differentiate benign from malignant lesions (15). In the thorax, PET negative malignancies confounding interpretation include small lung cancers, some lung adenocarcinomas presenting as subsolid lesions, and carcinoid tumors (16). In patients with small lung cancers, limitations in spatial resolution can result in false-negative results when lesions smaller than 10 mm in diameter are assessed (17). With current PET technology, the evaluation of lung nodules of approximately 7 mm in diameter is possible. In the evaluation of solitary pulmonary nodules, PET/CT has a sensitivity of 97% and a specificity of 78% for the detection of malignancy (18). Analysis of the nodule on PET/CT, as well as clinical risk factors such as patient age, smoking history, and history of malignancy is required to optimize patient management. For example, in a patient with a low pretest likelihood of malignancy (20%), a negative PET will reduce the likelihood of malignancy to 1% and conservative management with serial imaging reassessment is acceptable (19). However, in a patient with a high pretest likelihood of malignancy (80%), a negative PET will only reduce the likelihood of malignancy to 14% (19). Thus, tissue sampling, either with biopsy or resection, is recommended. The high sensitivity and specificity of PET in the evaluation of solitary pulmonary nodules relates to solid nodules of 10 mm or greater in size. FDG uptake is variable in a subset of lung adenocarcinomas presenting as subsolid
lesions and is not reliable to differentiate benign from malignant lesions (Figure 4). By definition, subsolid lesions comprise pure ground-glass lesions and partly solid lesions with both a ground glass component and a solid component. In a study by Nomori et al., 9 of 10 well-differentiated adenocarcinomas presenting as ground-glass nodules were negative on PET (17). PET Positive Benign Conditions ·
Infection and Inflammation
Infectious and inflammatory conditions can show increased FDG uptake due to increased glycolysis in leukocytes, lymphocytes and macrophages (20). Inflammatory cells found in the lungs, lymph nodes, pleura and blood vessels can accumulate FDG and confound interpretation. PET positive benign conditions include pneumonia, granulomas (Figure 5), sarcoidosis, amyloidosis, rounded atelectasis, pleural fibrosis, venous thrombosis (Figure 6), pulmonary embolism (Figure 7), and atherosclerosis (21). FDG avid infectious and or inflammatory lymph nodes can be misinterpreted as nodal metastases and alter patient management. Therefore, invasive nodal sampling is recommended in patients with lung cancer with suspicion of N2 (ipsilateral mediastinal) and/or N3 (contralateral hilar, contralateral mediastinal, ipsilateral or contralateral supraclavicular) involvement on CT (greater than 1 cm in short axis diameter) and or PET if this alters patient management (Figure 8) (22).
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Iatrogenic and Post-Treatment Pitfalls
Potential pitfalls in PET/CT interpretation include invasive procedures and therapy-related conditions. FDG accumulates in granulation tissue in healing wounds, such as tracheostomy and sternotomy sites. Iatrogenic causes of focal FDG uptake also include sites of cardiac pacemakers, central lines, chest tubes, gastrostomy tubes, as well as procedures for tissue sampling such as percutaneous needle biopsy, mediastinoscopy and endobronchial ultrasound-guided biopsy (23). In these cases, use of PET/CT images to localize the focus of increased FDG uptake is diagnostic. Awareness of certain treatment options that can produce false positive results on PET imaging is essential to prevent misinterpretation. These treatment options include talc (3MgO•4SiO2•H2O) pleurodesis, radiation therapy, chemotherapy and bone marrow stimulation therapy (24, 25, 26, 27, 28). Correlation with the patient’s past medical and surgical history for these specific procedures is important in avoiding these interpretative pitfalls. For example, talc pleurodesis is performed to treat persistent pneumothoraces and recurrent benign or malignant pleural effusions (24). Pleural deposits of talc manifest as areas of increased uptake on PET/CT and can be misinterpreted as pleural metastases. The typical appearance of talc pleurodesis on CT consists of focal areas of high attenuation material in the pleura that correspond to areas of increased FDG uptake on fused PET/CT images (24) (Figure 9).
Another potential pitfall concerns FDG uptake in the liver adjacent to a distal esophageal cancer following chemoradiation therapy. The liver is susceptible to radiation injury at a dose of greater than 30 Gray. Tracer uptake is postulated in active leukocytes forming the inflammatory response to the radiation hepatic injury. The imaging appearance of hepatic radiation injury in patients with esophageal cancer on PET/CT is often diffuse but can be focal and nodular mimicking hepatic metastatic disease (Figure 10) (29). Awareness of radiation hepatic injury, knowledge of the typical location and appearance on PET/CT imaging in patients with distal esophageal malignancy receiving chemoradiation therapy, and correlation with radiation treatment plans are useful in preventing misinterpretation. Conclusion Applications of PET/CT in the thorax include tumor detection and characterization, differentiation of benign from malignant lesions, staging and restaging of malignancies, assessment of therapeutic response, and identification of residual or recurrent tumor. Accurate interpretation of PET/CT requires knowledge of the physiological distribution of FDG, as well as artifacts and quantitative errors due to the use of CT for attenuation correction of the PET scan. Potential pitfalls include malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management.
Figure Captions Figure 1 Respiratory artifact resulting in liver metastasis misregistered to the lung mimicking pulmonary metastasis. 48-year-old woman with lung cancer presents for staging evaluation. Coronal PET/CT (A) shows a focus of increased FDG uptake that appears to be localized to the lung. Axial CT (B) shows hypodense hepatic metastasis (arrow) in the dome of the liver. The focus of increased FDG uptake is due to liver metastasis misregistered into lung. Note misregistration artifact is confirmed by absence of pulmonary abnormality on CT image (C). Imaging during different stages of the patient’s respiratory cycle may introduce a mismatch between the CT attenuation data obtained during breath-hold and the PET emission data obtained during quiet tidal breathing.
Figure 2 Injection of radiotracer with microembolism mimicking pulmonary metastasis. 58-year-old woman with melanoma presents for staging. Axial PET/CT (A) shows a focus of increased FDG uptake in the right upper lobe suspicious for pulmonary metastasis. However, no corresponding pulmonary nodule is seen on the CT (B). This potential pitfall is due to accumulation of FDG within a thrombus created during injection of the radiotracer. The thrombus is embolized into the right upper lobe pulmonary artery. Iatrogenic microembolism occurs when abnormal FDG accumulation in the lung has no correlate on CT.
Figure 3 Mediastinal brown fat mimicking adenopathy. 57-year-old woman with breast cancer presents for staging. PET/CT (A) shows a focus of increased F-18 fluorodeoxyglucose uptake in the mediastinum suspicious for nodal metastases. CT (B) shows the focus of increased FDG uptake in the mediastinum is localized to fat (arrows). No mediastinal adenopathy was identified. Brown fat deposits can show metabolic activity on PET in response to exposure to cold (nonshivering thermogenesis). Accurate localization of tracer uptake prevented misinterpretation of this potential pitfall as nodal disease which can alter staging and patient management. Figure 4 PET negative malignancy. 78-year-old woman evaluated for solitary pulmonary nodule. Axial CT (A) and PET/CT (B) show 2.5cm mixed attenuation nodule in the right upper lobe with low grade FDG uptake and SUV of 1.8. An SUV cutoff of 2.5 has been used to differentiate benign (SUV<2.5) from malignant (SUV>2.5) nodules. Transthoracic needle biopsy revealed a well-differentiated adenocarcinoma. Note that false-negative PET results may be seen with carcinoid and well-differentiated adenocarcinoma.
Figure 5 Granulomatous infection mimicking pulmonary metastasis. 81-year-old man evaluated for upper airway infection not responding to antibiotics. Axial PET/CT (A) and contrast-enhanced CT (B) show a spiculated FDG avid 2.8 cm right lower lobe nodule. Transthoracic needle aspiration biopsy revealed squamous cell cancer. Axial PET/CT (C) and contrast-enhanced CT (D) show FDG avid 2 cm irregular nodule (arrow) in the right upper lobe abutting the anterior pleura suspicious for synchronous primary tumor. Biopsy revealed granulomatous inflammation, and Mycobacterium avium complex was identified. Benign conditions due infectious etiologies can result in increased glucose metabolism and is a false-positive finding on PET/CT. Tissue sampling is recommended when synchronous primary tumors are a consideration.
Figure 6 Catheter-related thrombus in the SVC with FDG avidity mimicking mediastinal adenopathy. 40-year-old woman with breast cancer. Restaging PET/CT (A) shows increased FDG uptake in the right mediastinum suspicious for adenopathy. Contrastenhanced CT (B) 7 days later shows a small thrombus around the left central catheter in the SVC (arrow). Benign conditions due to inflammatory etiologies can result in false positive FDG uptake.
Figure 7 Pulmonary embolism mimicking hilar adenopathy. 57-year-old man with lymphoma. PET/CT shows focus of increased FDG uptake in the right hilum suspicious for adenopathy (arrow). Contrast-enhanced CT chest shows clot in the right pulmonary artery and interlobar pulmonary artery consistent with pulmonary embolism (arrow). Benign conditions with an inflammatory component can result in false-positive FDG uptake. Figure 8 Granulomatous inflammation mimicking N3 nodal disease. 62-year-old man with NSCLC of the right upper lobe. CT (A) shows the 3cm right upper lobe primary tumor. Staging coronal PET/CT (B) shows FDG avid right supraclavicular adenopathy (arrow) suspicious for N3 nodal disease. Biopsy of the right supraclavicular lymph node revealed non-caseating granulomatous inflammation and no malignant cells. Invasive nodal sampling is recommended in a patient with lung cancer with suspicion of N2 and/or N3 involvement on CT and or PET if this alters patient management. Figure 9 Talc pleurodesis mimicking pleural metastasis. 69-year-old man with NSCLC. PET/CT (A) shows the primary tumor in the left upper lobe. PET/CT (B) shows FDG avid focus (arrow) in the right posterior pleura suspicious for metastatic disease. Non-contrast enhanced CT (C) shows the FDG avid focus is localized to an area of high attenuation material characteristic of talc pleurodesis (arrow). By clinical history, the patient had recurrent
spontaneous pneumothoraces requiring talc pleurodesis one year earlier. Note increased FDG uptake due to the inflammatory reaction incited by talc can persist even years after pleurodesis. Figure 10 Hepatic injury due to radiation therapy mimicking metastasis. 64-year-old man with esophageal cancer treated with chemotherapy and radiation therapy. Restaging axial PET/CT (A) 2 months following completion of radiation therapy shows focus of increased FDG uptake in the left lobe of the liver (arrow) suspicious for metastasis. (B) CT shows hypodense area in the left lobe of the liver (arrow). (C) Axial noncontrast-enhanced computed tomography (CT) of the abdomen with radiation dosimetric intensity-modulated radiation therapy (IMRT) treatment curves shows that the FDG-avid hepatic lesion corresponds to an area of radiation dose of 40 to 45 Gy. The liver is susceptible to radiation injury at a dose above 30 Gy, and the appearance, location and timing of the abnormality on PET/CT are typical of radiation-induced hepatic injury. The patient underwent Ivor-Lewis esophagectomy, and surveillance imaging confirmed the absence of metastatic disease.
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