14 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging

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1 14 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging Gary JR Cook Introduction The number of clinical applications for PET continues to increase, particularly in the field of oncology. In parallel with this is growth in the number of centres that are able to provide a clinical PET or PET/CT service. As with any imaging technique, including radiography, ultrasound, computed tomography, magnetic resonance imaging and conventional single photon nuclear medicine imaging, there are a large number of normal variants, imaging artefacts and causes of false positive results that need to be recognised in order to avoid misinterpretation. It is particularly important to be aware of potential pitfalls while PET is establishing its place in medical imaging so that the confidence of clinical colleagues and patients is maintained. In addition, the advent of combined PET/CT scanners in clinical imaging practice has brought its own specific pitfalls and artefacts. The most commonly used PET radiopharmaceutical in clinical practice is F-fluorodeoxyglucose ( FDG). As it has a half-life of nearly 2 hours, it can be transported to sites without a cyclotron, and in view of this and the fact that there is a wealth of clinical data and experience with this compound, it is likely to remain the mainstay of clinical PET for the immediate future. Mechanisms of Uptake of F-fluorodeoxyglucose FDG, as an analogue of glucose, is a tracer of energy substrate metabolism, and although it has been known for many years that malignant tumours show increased glycolysis compared to normal tissues, its accumulation is not specific to malignant tissue. FDG is transported into tumour cells by a number of membrane transporter proteins that may be overexpressed in many tumours. FDG is converted to FDG-6-phosphate intracellularly by hexokinase, but unlike glucose does not undergo significant enzymatic reactions. In addition, because of its negative charge, remains effectively trapped in tissue. Glucose-6-phosphatase mediated dephosphorylation of FDG occurs only slowly in most tumours, normal myocardium and brain, and hence the uptake of this tracer is proportional to glycolytic rate. Rarely, tumours may have higher glucose-6-phosphatase activity resulting in relatively low uptake, a feature that has been described in hepatocellular carcinoma [1]. Similarly, some tissues have relatively high glucose-6-phosphatase activity, including liver, kidney, intestine and resting skeletal muscle, and show only low uptake. Conversely, hypoxia, a feature common in malignant tumours, is a factor that may increase FDG uptake, probably through activation of the glycolytic pathway [2]. Hyperglycaemia may impair tumour uptake of FDG because of competition with glucose [3], although it appears that chronic hyperglycaemia, as seen in diabetic patients, only minimally reduces tumour uptake [4]. To optimise tumour uptake, patients are usually asked to fast for four to six hours prior to injection to minimise insulin levels. This has also been shown to reduce uptake of FDG into background tissues including bowel, skeletal muscle and myocardium [5]. In contrast, insulin induced hypoglycaemia may actually impair tumour identification by reducing tumor uptake and increasing background muscle and fat activity [6]. 281

2 282 Positron Emission Tomography In addition to malignant tissue, FDG uptake may be seen in activated inflammatory cells [7,8], and its use has even been advocated in the detection of inflammation [9]. An area where benign inflammatory uptake of FDG may limit specificity is in the assessment of response to radiotherapy [10]. Here uptake of FDG has been reported in rectal tumours and in the brain in relation to macrophage and inflammatory cell activity [11 13]. This may make it difficult to differentiate persistent tumour from inflammatory activity for a number of months following radiotherapy in some tumors. Non-specific, inflammatory and reactive uptake has also been recorded following chemotherapy in some tumours [14, 15], and there is no clear consensus on the optimum time to study patients following this form of therapy. Normal Distribution of FDG The normal distribution of FDG is summarised in Table The brain typically shows high uptake of FDG in the cortex, thalamus and basal ganglia. Cortical activity may be reduced in patients who require sedation or a general anaesthetic, a feature that might limit the sensitivity of detection of areas of reduced uptake as in the investigation of epilepsy. It is not usually possible to differentiate low-grade uptake of FDG in white matter from the adjacent ventricular system (Fig. 14.1). In the neck, it is common to see moderate symmetrical activity in tonsillar tissue. This may be more difficult to recognise as normal tissue if there has been previous surgery or radiotherapy that may distort the anatomy, resulting in asymmetric activity or even unilateral uptake on the unaffected side. Adenoidal tissue is not usually noticeable in adults but may show marked uptake in children. Another area of lymphoid activity that is commonly seen in children is the thymus. This usually has a characteristic shape (an inverted V) and is therefore not usually mistaken for anterior mediastinal tumour (Fig. 14.2). Clinical reports vary as to the incidence of diffuse uptake of FDG in the thyroid [16 ]. This may be a geographical phenomenon, because its presence is more likely in women and has been correlated with the presence of thyroid autoantibodies and chronic thyroiditis []. In the chest, there is variation in regional lung activity, this being greater in the inferior and posterior segments, and it has been suggested that this might reduce sensitivity in lesion detection in these regions [19]. In the abdomen, homogeneous, low-grade accumulation is seen in the liver and to a lesser extent, the spleen. Small and large bowel activity is quite variable, and unlike glucose, FDG is excreted in the urine, leading to variable appearances of the urinary tract, both of which are discussed further below. Resting skeletal muscle is usually associated with low-grade activity, but active skeletal muscle may show marked uptake of FDG in a variety of patterns that are discussed later in this chapter. Myocardial activity may also be quite variable. Normal myocardial metabolism depends on both glucose and free fatty acids (FFA). For oncologic scans, it is usual to try to reduce activity in the myocardium, so as to obtain clear images of the mediastinum and Table Normal distribution of FDG. Organ/system Central nervous system Cardiovascular system Gastrointestinal system Reticuloendothelial and lymphatic Genitourinary system Skeletal muscle Bone marrow Lung Pattern High uptake in cortex, basal ganglia, thalami, cerebellum, brainstem. Low uptake into white matter and cerebrospinal fluid. Variable but homogeneous uptake into left ventricular myocardium. Usually no discernible activity in right ventricle and atria. Variable uptake into stomach, small intestine, colon and rectum. Liver and spleen show low grade diffuse activity. No uptake in normal lymph nodes but moderate activity seen in tonsillar tissue. Age related uptake is seen in thymic and adenoidal tissue. Urinary excretion can cause variable appearances of the urinary tract. Age related testicular uptake is seen. Low activity at rest Normal marrow shows uptake that is usually less than liver. Low activity (regional variation)

3 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging 283 Figure Normal FDG brain scan. The transaxial image is taken at the level of the basal ganglia and thalami. Figure Transaxial (above) and coronal (below) FDG images in a child showing normal thymic activity. glucose (and hence FDG) rather than FFA metabolism, and it may also be necessary to administer insulin to enhance myocardial uptake, particularly in diabetic patients [20 22]. The hyperinsulinaemic euglycaemic clamping method may further improve myocardial uptake but is technically more difficult [23 26]. This allows maximum insulin administration without rendering the patient hypoglycaemic. An alternative method is to encourage myocardial glucose metabolism by reducing FFA levels pharmacologically. Improved cardiac uptake of FDG has been described following oral nicotinic acid derivatives such as acipimox, a simple and safe measure that may also be effective in diabetic patients [27]. adjacent lung. Although most centres fast patients for at least 4 to 6 hours before FDG injection, reducing insulin levels and encouraging FFA acid metabolism in preference to glucose, myocardial activity may still be quite marked and varies among patients. Another possible intervention that has not been quantified or validated as yet is to administer caffeine to the patient to encourage FFA metabolism. For cardiac viability studies, it is necessary to achieve high uptake of FDG into the myocardium. Patients may receive a glucose load to encourage Variants That May Mimic or Obscure Pathology A number of physiological variations in uptake of FDG have been recognised, some of which may mimic pathology [16, 28 30], and are summarised in Table Skeletal muscle uptake is probably the most common cause of interpretative difficulty. Increased aerobic glycolysis associated with muscle activation, either after

4 284 Positron Emission Tomography Table Variants that may mimic or obscure pathology. Organ/system Skeletal muscle Adipose tissue Myocardium Endocrine Gastrointestinal Genitourinary Variant High uptake after exercise or due to tension, including eye movement, vocalisation, swallowing, chewing gum, hyperventilation. Uptake in brown fat may be seen particularly in winter months in patients with low body mass index. Variable (may depend on or be manipulated by diet and drugs). Testes, breast (cyclical, lactation, HRT), follicular ovarian cysts, thyroid Bowel activity is variable and may simulate tumour activity Small areas of ureteric stasis may simulate paraaortic or pelvic lymphadenopathy exercise or because of involuntary tension, leads to increased accumulation of FDG that may mimic or obscure pathology. Exercise should be prohibited before injection of FDG and during the uptake period to minimise muscle uptake. A pattern of symmetrical activity commonly encountered in the neck, supraclavicular and paraspinal regions (Fig. 14.3) was initially assumed to be the result of involuntary muscle tension but with the advent of PET/CT it has become obvious that this activity originates in brown fat, a vestigial organ of thermogenesis that is sympathetically innervated and driven. To support this hypothesis it has been noted that this pattern is commoner in winter months and in patients with lower body mass index [31]. It appears that benzodiazepines are able to reduce the incidence of this potentially confusing appearance, possibly the result of a generalised reduction in sympathetic drive. a b Figure Coronal sections from a FDG study. Symmetrical brown fat activity is seen in the neck (a) and paraspinal (b) regions. Although this is a recognisable pattern it can be appreciated that metastatic lymphadenopathy may be obscured, especially in the neck.

5 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging 285 Even apparently innocent activities such as talking or chewing gum may lead to muscle uptake that simulates malignant tissue (Figs and 14.5). In patients being assessed for head and neck malignancies, it is therefore important that they maintain silence and refrain from chewing during the uptake period. In addition, anxious or breathless patients may hyperventilate, producing increased intercostal and diaphragmatic activity, and involuntary muscle spasm such as that seen with torticollis may lead to a pattern that is recognisable but may obscure diseased lymph nodes. The symmetrical nature of most muscle uptake usually alerts the interpreter to the most likely cause, but occasionally unilateral muscle uptake may be seen when there is a nerve palsy on the contralateral side and may be mistaken for an abnormal tumour focus. This has been described in recurrent laryngeal nerve palsy and in VIth cranial nerve palsy [30]. Diffusely increased uptake of FDG may also be seen in dermatomyositis complicating malignancy, a factor that may reduce image contrast and tumour detectability. Uptake in the gastrointestinal system is quite variable and is most commonly seen in the stomach (Fig. 14.6) and large bowel (Fig. 14.7) and to a lesser extent in loops of small bowel. It is probable that activity in bowel is related to smooth muscle uptake as well as activity in intralumenal contents [32, 33]. If it is important to reduce intestinal physiological activity, Figure FDG uptake seen in laryngeal muscles in a patient who was talking during the uptake period.

6 286 Positron Emission Tomography Figure Symmetrical FDG uptake in the masseter muscles in a patient chewing gum, resembling bilateral lymphadenopathy. Figure Physiological uptake of FDG is seen in the stomach wall. Moderate myocardial activity is also seen.

7 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging 287 Figure Marked physiological uptake is seen in the region of the caecum and ascending colon in a patient with a primary lung cancer that can also be seen on these images at the right lung apex (coronal section). pharmacological methods to reduce peristalsis as well as bowel lavage could be useful. This is too invasive and is unnecessary for routine patient preparation, and in most situations it is possible to differentiate physiological uptake within bowel from abdominal tumour foci by the pattern of uptake, the former usually being curvilinear and the latter being focal (Fig. 14.8). Some centres use a mild laxative as a routine in any patient requiring abdominal imaging, but improvement in interpretation has not been demonstrated. Unlike glucose, FDG is not totally reabsorbed in the renal tubules, and urinary activity is seen in all patients and may be present in all parts of the urinary tract. This may interfere with a study of renal or pelvic tumours, either by obscuring local tumours or by causing reconstruction artefacts that reduce the visibility of abnormalities adjacent to areas of high urinary activity. Using iterative reconstruction algorithms rather than filtered back projection can reduce this problem. Catheterisation and drainage of a b Figure (a) Transaxial FDG slice through the upper abdomen and (b) corresponding CT slice in a patient with a history of seminoma and previous paraaortic lymph node dissection but rising tumour markers. The linear area of low grade FDG activity can be seen to correspond to a barium filled loop of bowel but the more focal area of high uptake (arrow) corresponds to a small density located adjacent to the previous surgical clips indicating recurrent disease at this site. The case demonstrates how normal bowel activity can be differentiated from tumour foci.

8 288 Positron Emission Tomography urinary activity may reduce bladder activity that may obscure perivesical or intravesical tumours. However, this may still leave small pockets of concentrated activity that may resemble lymphadenopathy, causing even greater problems in interpretation. Bladder irrigation may help to some extent, but is associated with increased radiation dose to staff and may introduce infection. We have found it beneficial to hydrate the patient and administer a diuretic. This approach leads to a full bladder with dilute urine, making it easier to differentiate normal urinary activity from perivesical tumour activity and allowing the bladder to be used as an anatomical landmark. By diluting vesical FDG activity, reconstruction artefacts from filtered back projection algorithms are also reduced. It is often helpful to perform image registration with either CT or MRI in the pelvis. Here it may be helpful to administer a small amount of F-fluoride ion in addition to FDG, to allow easy identification of bony landmarks for registration purposes. Although excreted FDG may be seen in any part of the urinary tract, it is important to gain a history of any previous urinary diversion procedures, since these may cause areas of high activity outside the normal renal tract and may result in errors of interpretation unless this is appreciated. Glandular breast tissue often demonstrates moderate FDG activity in premenopausal women and postmenopausal women taking oestrogens for hormone replacement therapy. The pattern of uptake is usually symmetrical and easily identified as being physiological, but there is the potential for lesions to be obscured by this normal activity. Breast feeding mothers show intense uptake of FDG bilaterally (Fig. 14.9). Similarly in males, uptake of FDG may be seen in normal testes and appears to be greater in young men than in old [34]. Figure Transaxial FDG scan of a breast-feeding mother in whom intense symmetrical breast activity can be seen. (Reproduced from Valk PE, Bailey DL, Townsend DW, Maisey MN. Positron Emission Tomography: Basic Science and Clinical Practice. Springer-Verlag London LTD, 2003, p. 502.) Table Artefacts Attenuation correction related Injection related Attenuating material Patient movement Artefacts Apparent superficial increase in activity and lung activity if no correction applied. Lymph node uptake following tissued injection. Reconstruction artefacts due to tissued activity. Inaccuracies in SUV calculation Coins, medallions, prostheses Poor image quality. Artefacts on applying attenuation correction. Image reconstruction of PET images without attenuation correction may lead to higher apparent activity in superficial structures, that may obscure lesions e.g. cutaneous melanoma metastases [28]. A common artefact arising from this phenomenon is caused by the axillary skin fold, where lymphadenopathy may be mimicked in coronal image sections. However, the linear distribution of activity can be appreciated on transaxial or sagittal slices and should prevent misinterpretation. Another major difference between attenuation corrected and non-corrected images is an apparent increase in lung activity in the latter due to relatively low attenuation by the air-containing lung. Filtered back projection reconstruction leads to streak artefacts and may obscure lesions adjacent to areas of high activity. Many of these artefacts can be overcome by using iterative reconstruction techniques (Fig ). Patient movement may compromise image quality. In brain imaging it is possible to split the acquisition into a number of frames, so that if movement occurs in one frame then this can be discarded before summation of the data [35]. When performing whole body scans, unusual appearances may result if the patient moves between bed scan positions. This most commonly occurs when the upper part of the arm is visible in higher scanning positions, but the lower part disappears when moved out of the field of view on lower subsequent scanning positions. Special care is required in injecting FDG since softtissue injection may cause reconstruction artefacts across the trunk, and may even cause a low-count study or inaccuracies in standardised uptake value (SUV) measurements. Axillary lymph nodes, draining the region of tracer extravasation, may also accumulate activity following extravasated injections. The site of

9 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging 289 Figure Transaxial, sagittal and coronal abdominal FDG images from iterative reconstruction (left) and filtered back projection (right) demonstrating the improved image quality and reduction in streak artefacts possible with the former. administration should be chosen carefully, so as to minimise the risk of false positive interpretation should extravasation occur. Artefacts caused by prostheses are usually readily recognisable. Photon deficient regions may result from metallic joint prostheses or other metallic objects carried by the patient. Ring artefacts may occur if there is misregistration between transmission and emission scans due to patient movement, and are particularly apparent at borders where there are sudden changes in activity concentrations (e.g., at a metal prosthesis). Misregistration artefacts between emission and transmission scans have become less frequent now that interleaved or even simultaneous emission/transmission scans are being performed. Benign Causes of FDG Uptake Uptake of FDG is not specific to malignant tissue, and it is well recognised that inflammation may lead to accumulation in macrophages and other activated inflammatory cells [7, 8]. In oncological imaging, this inflammatory uptake may lead to decrease in specificity. For example, it may be difficult to differentiate benign postradiotherapy changes from recurrent tumour in the brain, unless the study is optimally timed or unless alternative tracers such as 11 C methionine are used. Apical lung activity may be seen following radiotherapy for breast cancer, and moderate uptake may follow radiotherapy for lung cancer [36]. It may also be difficult to differentiate radiation changes from recurrent tumour in patients who have undergone radiotherapy for rectal cancer within six months of the study [12]. Pancreatic imaging with FDG may be problematic. In some cases, uptake into mass-forming pancreatitis may be comparable in degree to uptake in pancreatic cancer. Conversely, false negative results have been described in diabetic patients with pancreatic cancer. However, if diabetic patients and those with raised inflammatory markers are excluded, then FDG PET may still be an accurate test to differentiate benign from malignant pancreatic masses [37].

10 290 Positron Emission Tomography Table Benign causes of FDG uptake Figure Coronal FDG scan demonstrating high uptake in lymph nodes in a patient with sarcoidosis. Organ/Type Brain Pulmonary Myocardium Bone/bone marrow Inflammation Endocrine Disease Postradiotherapy uptake. Tuberculosis, sarcoidosis, histoplasmosis, atypical mycobacteria, pneumoconiosis, radiotherapy. Heterogeneous left ventricular activity possible after myocardial infarction, increased right ventricular activity in right heart failure Paget s disease, osteomyelitis, hyperplastic bone marrow. Wound healing, pyogenic infection, organising haematoma, oesophagitis, inflammatory bowel disease, lymphadenopathy associated with granulomatous disorders, viral and atypical infections, chronic pancreatitis, retroperitoneal fibrosis, radiation fibrosis (early), bursitis. Graves disease and chronic thyroiditis, adrenal hyperplasia. A number of granulomatous disorders have been described as leading to increased uptake of FDG, including tuberculosis [38], and sarcoidosis [39] (Fig ). It is often necessary to be cautious in ascribing FDG lesions to cancer in patients who are known to be immunocompromised. It is these patients who often have the unusual infections that may lead to uptake that cannot be differentiated from malignancy. PET remains useful in these patients despite a lower specificity, as it is often able to locate areas of disease that have not been identified by other means and that may be more amenable to biopsy [40]. A more comprehensive list of benign causes of abnormal FDG uptake is displayed in Table Specific Problems Related to PET/CT One of the most exciting technological advances in recent years is the clinical application of combined PET/CT scanners. However, this new technology has come with its own particular set of artefacts and pitfalls. One of the biggest problems with PET/CT imaging in a dedicated combined scanner is related to differ- Figure Coronal CT attenuation corrected FDG scan demonstrating an apparent loss of activity at the level of the diaphragm (arrows) due to differences in breathing patterns between the CT and PET scans.

11 Artefacts and Normal Variants in Whole-Body PET and PET/CT Imaging 291 ences in breathing patterns between the CT and the PET acquisitions. CT scans can be acquired during a breath hold but PET acquisitions are taken during tidal breathing and represent an average position of the thoracic cage over 30 minutes or more. This may result in mis-registration of pulmonary nodules between the two modalities particularly in the peripheries and at the bases of the lungs where differences in position may approach 15 mm [41]. Mis-registration may be reduced by performing the CT scan while the breath is held in normal expiration [42, 43]. It has been noted that deep inspiration during the CT acquisition can lead to deterioration of the CT-attenuation corrected PET image with the appearance of cold artefacts (Fig ) and can even lead to the mis-positioning of abdominal activity into the thorax [44]. CT acquisition during normal expiration minimises the incidence of such artefacts and also optimises co-registration of abdominal organs. High-density contrast agents, e.g. oral contrast, or metallic objects (Fig ) can lead to an artefactual overestimation of activity if CT data are used for attenuation correction [45 51]. Such artefacts may be recognised by studying the uncorrected image data. Low-density oral contrast agents can be used without significant artefact [52, 53] or the problem may be avoided by using water as a negative bowel contrast agent. Algorithms have been developed to account for the overestimation of activity when using CT-based attenuation correction that may minimise these effects in the future [53]. The use of intravenous contrast during the CT acquisition may be a more difficult problem. Similarly the concentrated bolus of contrast in the large vessels may lead to over correction for attenuation, particularly in view of the fact that the concentrated column of contrast has largely dissipated by the time the PET emission scan is acquired. Artefactual hot spots in the attenuation corrected image [48] or quantitative overestimation of FDG activity may result. When intravenous contrast is considered essential for a study then the diagnostic aspect of the CT scan is best performed as a third study with the patient in the same position, after first, a low current CT scan for attenuation correction purposes and second, the PET emission scan. While many centres have found low current CT acquisitions to be adequate for attenuation correction and image fusion [54], it may be necessary to increase CT tube current in larger patients to minimise beamhardening artefacts on the CT scan that may translate through to incorrect attenuation correction of the PET emission data [49]. This effect can be caused by the a b c Figure Coronal FDG scan with CT attenuation correction (a), CT alone (b), uncorrected FDG (c), of a patient with a metallic pacemaker placed over the right upper chest demonstrating artefactual increased uptake on the corrected images.

12 292 Positron Emission Tomography patient s arms being in the field of view and may be minimised by placing arms above the head for imaging. Differences in the field of view diameter between the larger PET and smaller CT parts of combined scanners can lead to truncation artefacts at the edge of the CT image but these are generally small and can be minimised by the use of iterative image reconstruction methods [53]. Although some new artefacts are introduced by combined PET/CT imaging, it is likely that many pitfalls caused by normal variant uptake may be avoided by the ability to correctly attribute FDG activity to a structurally normal organ on the CT scan. This may be particularly evident in the abdomen when physiological bowel activity or ureteric activity can otherwise cause interpretative difficulties. 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