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Overview of Positron Emission Tomography, Hybrid Positron Emission Tomography Instrumentation, and Positron Emission Tomography Quantification

Kwee, Thomas C. MD, PhD*; Torigian, Drew A. MD, MA; Alavi, Abass MD, MD (Hon.), DSc (Hon.), PhD (Hon.)

doi: 10.1097/RTI.0b013e31827882d9
Mini-Symposium: Review Articles

Positron emission tomography (PET) is a powerful quantitative molecular imaging technique that is complementary to structural imaging techniques for purposes of disease detection and characterization. This review article provides a brief overview of PET, hybrid PET instrumentation, and PET quantification.

*Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA

Thomas C. Kwee and Drew A. Torigian contributed equally.

The authors declare no conflicts of interest.

Reprints: Drew A. Torigian, MD, MA, Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283 (e-mail:

Molecular imaging involves the in vivo examination of molecular and cellular processes through the application of a number of imaging techniques, including positron emission tomography (PET), single-photon emission computed tomography, magnetic resonance imaging (MRI), and optical imaging alone or in hybrid combinations.1,2 This article focuses on PET, a fully translational whole-body cross-sectional molecular imaging technique that allows for the detection and quantification of injected radiotracers at the femtomolar level.3–5 In particular, we provide an overview of PET, with attention to the fundamentals of PET physics and the strengths and limitations of PET relative to structural imaging techniques. This article briefly reviews PET instrumentation with emphasis on PET/computed tomography (CT) and PET/MRI and discusses some of the major concepts in PET quantification, including standardized uptake value (SUV), global disease assessment, partial-volume effect (PVE), and partial-volume correction (PVC).

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PET Physics

PET is an analytical imaging technology developed for use with compounds labeled with positron-emitting radioisotopes that function as molecular probes to image and measure biochemical processes in vivo.3,6–8 The amounts of radiolabeled material administered are extremely small (10−6 to 10−9 g) and have essentially no pharmacologic effects. In this regard, PET has the unique ability to assess molecular alterations associated with disease without perturbing or altering the fundamental underlying molecular and biochemical processes.9 Frequently used radioisotopes for PET include 18F, 11C, 15O, 13N, 82Rb, 64Cu, and 68Ga.4 The radiotracer that has had the most impact on clinical PET imaging is the glucose analog 18F-fluoro-2-deoxy-D-glucose (18F-FDG),10 which is currently mainly used in oncology.5

PET is based on the detection of the 2 annihilation photons produced when a positron is emitted from a radioisotope. That is, when a positron is emitted by a radioisotope, it combines with an electron in the surrounding material, where both undergo annihilation, producing a pair of 511 keV photons traveling in opposite directions. The opposing detectors of a PET system register the arrival of the annihilation photons as an event if they are detected within a narrow time frame, called the “timing window of the coincidence circuit” (typically 3 to 15 ns); all other signals are disregarded as noise. This requirement of detecting both photons within a time window is the basis of coincidence detection. The photon energy that is absorbed by the detectors is re-emitted as visible light and detected by photomultiplier tubes. Subsequently, the light signal is converted into an electrical current, which is proportional to the incident photon energy. Millions of recorded coincidence events, forming a large number of intersecting coincidence lines, provide information about the quantity and location of positron emissions in the body.3–8 It is noteworthy that time-of-flight (TOF) PET scanners have become commercially available for clinical practice.11–13 In TOF PET, the actual time difference in the arrival of the 2 annihilation protons at the detectors is recorded. As such, TOF PET can pinpoint the origination of positron annihilation more accurately compared with non-TOF PET. The TOF information is incorporated directly into the reconstruction algorithm permitting some combination of lower radiotracer doses, faster scanning, improved signal to noise ratio, and/or improved spatial resolution.11–15

Compared with other cross-sectional imaging techniques such as CT and MRI, PET has a relatively low spatial resolution because of several reasons. First, depending on the energy of the emitted positron, which is a function of the radioisotope, the positron can travel for some distance within the surrounding material before it combines with an electron and emits annihilation photons. This will lead to an intrinsic limit on the spatial resolution of the reconstructed PET image, as it relates to the distribution of the positron emitter points within the scanned object. Second, some residual momentum of the positron just before annihilation will lead to the emission of 2 annihilation photons that are not oriented at exactly 180 degrees to each other. The reconstruction algorithm always assumes the 2 photons to be exactly collinear, resulting in a misplaced coincidence line (usually <0.5 degrees), leading to blurring of the image. Third, the scintillation crystal detector has an intrinsic spatial resolution. Despite these limitations, current commercially available PET systems can reach a spatial resolution of about 4 to 7 mm for whole-body imaging.3–8

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Strengths and Limitations of PET Relative to Structural Imaging

Structural imaging entails the assessment of morphologic features or gross degree of contrast enhancement of normal tissues/organs of the body and of lesions within these structures.16,17 CT, MRI, and ultrasonography are the prototypical imaging technologies that are currently used to perform structural imaging. However, functional or metabolic pathologic changes at the molecular, subcellular, or cellular level may occur well before gross structural or contrast enhancement changes become visible. Furthermore, macroscopic abnormalities are often nonspecific for a particular pathologic condition. It may also be difficult to discriminate posttherapeutic changes from residual or recurrent disease using structural imaging alone. In addition, structural imaging does not provide data on physiology, biological processes, or molecular characteristics. Thus, structural imaging lacks the desired information to fully characterize or monitor lesions.16,17 Molecular imaging with PET can overcome the above-mentioned limitations inherent to structural imaging. However, PET has a relatively low spatial resolution and lacks a clear anatomic reference frame. As a result, it may be difficult to accurately localize anatomic structures or lesions that exhibit abnormal radiotracer accumulation. Combining PET with structural imaging (CT or MRI) aids in the accurate localization of regions of increased activity on PET images with greater confidence and generally improves diagnostic sensitivity, specificity, and accuracy. Thus, PET and structural imaging are complementary in the evaluation of disease.16,17

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Integration of PET and CT can outperform either of the imaging modalities alone in the evaluation of disease. In traditional visual image fusion, PET and CT images are viewed and compared by placing them next to each other, with the fusion taking place in the interpreter’s mind. Integration of separate PET and CT image sets into a single study can also be achieved with software fusion. However, differences in scanner bed profiles, external patient positioning, and internal organ movement present a challenge to software approaches.6–8 In 1998, the challenges associated with the integration of data sets obtained from stand-alone PET and CT scanners were addressed by the development of a prototype integrated PET/CT scanner, a hardware-oriented approach to image fusion.18 With this type of scanner, accurately registered molecular and anatomic images could be acquired in a single examination, which has been shown to increase both the accuracy of the interpretation and the confidence level of the readers.6–8 Furthermore, the use of CT for attenuation correction of PET emission data (ie, correction of the loss of detection of true coincidence events because of their absorption in the body or because of their scattering out of the detector’s field of view) is advantageous compared with PET transmission scanning with an external radionuclide source (as is necessary in stand-alone PET systems), because it provides low-noise attenuation correction factors, eliminates bias from emission contamination of postinjection transmission scans, and is considerably faster, leading to shorter examination times.19

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PET/MRI: Potential Utility for Thoracic Evaluation

MRI not only provides anatomic information with high soft tissue contrast, which may improve lesion detection and delineation compared with CT, but also offers a wide range of functional sequences such as diffusion-weighted imaging, perfusion-weighted imaging, and magnetic resonance spectroscopy, which, along with PET, may aid in the evaluation of disease of the thorax.20 Advanced MRI techniques may also be used to assess pulmonary perfusion, hemodynamics, and ventilation.21 Furthermore, unlike CT, MRI does not utilize ionizing radiation, making it a more attractive method for the evaluation of younger patients and of patients undergoing repeated examinations.22 Thus, regardless of the technical and logistical issues that have to be addressed (eg, sequential PET and MRI systems vs. fully integrated PET/MRI systems, electromagnetic interference between the 2 systems, and MRI-based attenuation correction) PET/MRI may be a good alternative or complementary to PET/CT for the evaluation of thoracic disease.23 In fact, the first fully integrated PET/MRI systems have already been installed in several clinical centers.

MRI is an established technique for evaluation of the breast, brachial plexus, and bone marrow (Fig. 1).24,25 In addition, MRI is increasingly being used and developed for the assessment of myocardial function, viability, and perfusion, for flow quantification and coronary arterial imaging, and for assessment of the thoracic vasculature.26 Recently, it was reported that integrated 18F-FDG PET/MRI of the lung is feasible and provides diagnostic image quality in the assessment of pulmonary masses, in which lesion characterization and tumor stage were found on comparing 18F-FDG PET/CT with 18F-FDG PET/MRI.27 However, MRI of the lungs, pleura, mediastinum (Fig. 2), and chest wall (Fig. 3) is still challenging.28–30

First, lung tissue has a low proton density and a very short T2* caused by B0 inhomogeneities related to the multiple number of air-tissue interfaces, as a result of which MRI signal is relatively low. Note that in patients with hyperinflation due to obstructive airway disease and emphysema, it is even more difficult to obtain sufficient MRI signal. Second, respiratory, vascular, and cardiac motion may hinder interpretation of the lung, pleural, mediastinal, and chest wall structures, as a result of which fast imaging or time-consuming triggering and gating techniques are required.28 Therefore, CT continues to outperform MRI in the detection of small pulmonary lesions (ie, <1 cm31). However, newer MRI acquisition techniques such as 3D radially sampled ultrashort echo time sequences are being developed, which have been shown to improve visualization of the structural lung pathology when compared with conventional spin echo imaging.32 Nevertheless, on the basis of currently available evidence, the launch of clinically available integrated PET/MRI is expected to have no benefit over PET/CT in the detection of lung lesions. However, for the assessment of lung tumors relative to surrounding anatomic structures, MRI has some advantages over CT. For example, local tumor infiltration into adjacent structures, such as the bronchi, pulmonary vessels, thoracic wall, or mediastinum, may be assessed more accurately with MRI because of its high soft tissue contrast.33 Functional MRI techniques may also improve lesion characterization and therapy response assessment and provide valuable information on pulmonary function.16,17,28 Future studies are required to prove the potential benefits of PET/MRI over PET/CT in the evaluation of thoracic disease.23

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Quantification of PET data is increasingly being recognized as providing an objective, more accurate, and a less observer-dependent measure for characterization of lesions, assessment of disease burden, determination of prognosis, and assessment of therapy response (among others) compared with qualitative visual inspection of PET data alone.34 Despite the development of multiple novel PET radiotracers, 18F-FDG is still the most successful radiotracer in clinical PET imaging. Various quantitative measures can be derived from 18F-FDG PET studies. The rate of metabolism of glucose, obtained by applying a pharmacokinetic model to data derived from dynamic PET studies, may be considered the gold standard; however, its requirement for dynamic scanning, which is not feasible for whole-body scans, prohibits its routine use in many clinical settings.34 The ideal analytical method should represent an optimal trade-off between accuracy and simplicity.35 The difficulties associated with quantitative data on the rate of metabolism of glucose have led to the development of simplified quantitative measures that can be combined with static whole-body 18F-FDG PET studies.

SUV is an example of such a simplified measure, and it is now probably the most widely used method for the semiquantitative assessment of 18F-FDG PET studies. SUV reflects the degree of 18F-FDG uptake within a tumor, measured over a certain interval after 18F-FDG administration and normalized to the dose of 18F-FDG injected and to a factor (such as body weight) that takes into account distribution throughout the body.34,36 The SUV normalized to body weight is given by the following equation:

where ACVOI represents the activity concentration in the specified volume of interest, 18F-FDG dose is the dose of 18F-FDG administered and corrected for physical decay, and BW is the body weight.34,36 Typically, the maximum SUV (SUVmax), the SUV of a region of interest (ROI) of 1 pixel with the maximum pixel value in a lesion, and the mean SUV (SUVmean), the average SUV of all pixels in an ROI, are measured and reported using commercially available software platforms.37 Many physiological and technical factors can influence the outcome of the SUV.34,38–40

For example, for a heterogenous ROI, SUVmax inherently involves intralesional sampling error (given its definition), and for a homogenous ROI, SUVmax typically overestimates the true mean value of a lesion (usually by approximately 2 to 3 times the standard deviation of the noise level as long as recovery effects are small).41 In contrast, SUVmean can be measured on the basis of pixel data representative of an entire lesion, leading to a more accurate statistical estimation of the true mean value. However, SUVmean measurement in practice is much more variable because of operator-dependent factors, including size and shape of mask delineation and location of mask placement within or about a lesion, as well as presence of nonuniformity of lesional and background 18F-FDG activity. In addition, SUV is often measured by manual placement of a 2D mask at a particular level through a lesion, also leading to intralesional sampling error depending on the level selected. Moreover, SUV is generally measured only for a subset of lesions, leading to sampling error on the basis of which particular lesions are selected.41

Despite its potential limitations, SUV (and particularly SUVmax) is and will probably remain the most commonly used semiquantitative measure of 18F-FDG uptake in clinical practice in the near future. In addition, in the European Organization for Research and Treatment of Cancer criteria for PET (published in 1999)42 and in the more recently established PET Response Criteria in Solid Tumors (PERCIST) version 1.0 (published in 2009),43,44 SUV measurements play a major role. SUV corrected for lean body mass (SUL) is used with PERCIST version 1.0, because SUL has been shown to be less susceptible to variations in patient body weight when compared with other SUV metrics.43,44

PERCIST specifies that the SULpeak is to be obtained from the single most active lesion on each scan.43,44 SULpeak is the average of the activity within a spherical ROI measuring 1.2 cm in diameter (for a volume of 1 cm3) centered at the most active portion of a tumor. The SULpeak may be located in a different lesion on a follow-up scan, because the current most avid lesion is to be measured. Using a concept similar to the Response Evaluation Criteria In Solid Tumors (RECIST),45 it is also recommended that a sum of the activity of up to 5 target lesions (no more than 2 per organ) be measured as a secondary determinant of response.43,44 The utility of PERCIST compared with other response evaluation methods is currently undergoing evaluation. For example, 1 recent study on the evaluation of therapeutic response to neoadjuvant chemotherapy for locally advanced esophageal cancer has reported that RECIST did not demonstrate a correlation between therapeutic responses and prognosis.46 However, PERCIST was found to be the strongest independent predictor of outcomes. The authors of this study concluded that PERCIST may be considered more suitable than RECIST for evaluation of chemotherapeutic response to esophageal cancer.46

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Global Disease Assessment

Because SUV measurements may be prone to both interlesional and intralesional sampling error due to fractional assessment of the total disease burden present, the concept of global disease assessment was introduced.36,41,47–51 This approach combines volumetric (CT-based, MRI-based, or PET-based) and metabolic (PET-based) measurements into a summary measure of global disease burden rather than relying upon these quantitative parameters independently and on a per-lesion basis only. Due to the development of semiautomated software applications, global disease assessment (including tissue segmentation) has become easier and faster than manual-based measurements. For example, a new method of image segmentation based on an iterative thresholding algorithm permits segmentation of 18F-FDG-avid regions on PET with an adaptive thresholding method as well as automatic generation of metabolically active volume (MAV) and SUV.41,52,53 Thereafter, the metabolic volumetric product (MVP) can automatically be calculated for each lesion by using the formula MVP=MAV×SUV. Finally, whole-body metabolic burden (also referred to as total MVP, total lesional glycolysis, or total glycolytic volume) can be automatically calculated as the sum of MVP of all 18F-FDG-avid lesions throughout the body. The reproducibility of this approach has been reported to be good, and the high level of agreement with manual lesional volumetric measurements indicates reasonable accuracy as well.41 Thus, semiautomated global disease assessment may provide an efficient means of quantifying widespread disease processes in a reproducible and accurate manner (Figs. 4, 5). Global disease assessment may be of utility for improved characterization of the nature of disease processes, pretreatment planning, patient selection for clinical trials, prognostication of patient outcome, prediction of treatment response, and response assessment, both in oncological and nononcological disease settings.36,41,47–51 However, future studies are required to further validate this method and to compare it with other, more established (semiquantitative) measures such as SUVmax and with promising metabolic response criteria such as PERCIST.

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PVE and Importance of PVC

The term “partial-volume effect” refers to 2 distinct phenomena that cause intensity values in images to differ from their ideal appearance.54 The first effect is the 3D image blurring introduced by the finite spatial resolution of the (PET) imaging system. The resulting 3D blurring causes spillover between regions. Because of the finite spatial resolution, the image of a small source appears larger in size but dimmer in signal intensity. Part of the signal from the source “spills out” and hence is seen outside the actual source. The second phenomenon causing PVE is image sampling. In PET, the radiotracer distribution is sampled on a voxel grid. Obviously, the contours of the voxels do not match the actual contours of the radiotracer distribution. Most voxels therefore include different types of tissues. This phenomenon is often called the tissue fraction effect. The signal intensity in each voxel is the mean of the signal intensities of the underlying tissues included in that voxel. Motion, especially related to respiratory motion, also introduces a blurring effect that results in additional PVE.54 As PET has a relatively low spatial resolution, PVE is an often ignored but serious issue; for lesions smaller than the reconstructed spatial resolution, the PVE may result in a >50% underestimation of the true 18F-FDG concentration.55 Therefore, PVC methodologies should be applied routinely to overcome this major source of error. Various PVC methods have been developed and are described in the literature.56–60

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PET is a fully translational, whole-body cross-sectional molecular imaging technique that allows for the detection and quantification of injected radiotracers at the femtomolar level and has a wide range of application for clinical and research evaluation of the thoracic and extrathoracic structures. In this article, we have provided an overview of PET, with attention to the fundamentals of PET physics and the strengths/limitations of PET relative to structural imaging techniques; we also briefly reviewed hybrid PET instrumentation and discussed some of the major concepts in PET quantification. Both scientists and clinicians should have a fundamental understanding of the presented concepts in order to be able to take full advantage of the clinical and research potential that PET provides.

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positron emission tomography; molecular imaging; instrumentation; quantification

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