Chapter 8 Positron Emission Tomography Imaging
Conventional imaging relies on differences in the structure of tissues, measured by differences in density, as in chest radiography and computed tomography (CT); surface reflectivity, as in ultrasonography; or chemical environment, as in magnetic resonance imaging (MRI). With the exquisite anatomic detail they provide, these modalities play a crucial role in the evaluation of many respiratory diseases. Nonetheless, assessment of structural differences often does not lead to a definitive diagnosis; in such instances, invasive tests with tissue sampling also are needed.
Positron emission tomography (PET) brought a revolutionary and novel aspect to imaging: It allows accurate, noninvasive measurement of metabolism of tissues, a valuable complement to the structural information provided on conventional imaging. This combined information allows better distinction between malignant and benign tissues and also can be used in monitoring of disease by the study of metabolic alterations, which can be different from or even precede the anatomic changes.
PET with 18F-fluorodeoxyglucose (FDG) tagging is a noninvasive imaging technique with high sensitivity for detection of both oncologic and nononcologic disorders in respiratory medicine. It has been suggested that FDG-PET might be useful in several diseases associated with FDG uptake based on inflammatory mechanisms, such as granulomatous diseases (e.g., sarcoidosis) or other proliferative inflammatory disorders (e.g., idiopathic pulmonary fibrosis, posttransplantation lymphoproliferative disorders).
Classical forms of sarcoidosis with intrathoracic nodal and/or pulmonary disease are in general assessed by combining clinical examination, pulmonary function and laboratory tests, and a CT scan of the chest. The extent and activity of the disease can be more accurately assessed by FDG-PET–CT than by gallium 67 single photon emission CT (67Ga-SPECT) scintigraphy. FDG-PET–CT in sarcoidosis is better at identifying occult sites of extrathoracic disease and has a superior spatial and contrast resolution, as well as better interobserver agreement, compared with 67Ga-SPECT. FDG-PET–CT currently is undergoing further evaluation of its clinical utility to monitor disease activity during treatment of interstitial pulmonary diseases such as sarcoidosis and idiopathic pulmonary fibrosis.
Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication occurring after solid organ or bone marrow transplantation. The incidence of PTLD in lung transplant recipients is 5%. In this disorder, FDG-PET–CT allows more accurate evaluation of disease extent, with better follow-up after treatment, than that achievable with conventional CT imaging.
Current and Innovative Indications for Positron Emission Tomography in Respiratory Oncology
A PET camera produces three-dimensional images that represent the distribution of radioactivity in the body. Any molecule that can be labeled with a positron-emitting radioisotope can be used to generate PET images (more than 400 PET tracers are listed in the NIH Molecular Imaging and Contrast Agent Database [MICAD], available at www.ncbi.nlm.nih.gov/books/NBK5330/).
The spatial resolution of older PET cameras was 6 mm or higher; for contemporary PET cameras, this is around 4 mm. Lesions with a diameter up to twice that resolution can be characterized with virtually no size-related (partial volume effect) underestimation of the tracer uptake, whereas for smaller lesions, the tracer uptake will gradually be underestimated as the size becomes smaller. In practice, lesions larger than 8 to 10 mm will be well characterized, whereas smaller ones, other than strongly FDG-avid lesions, cannot be accurately depicted.
The main difference between standard radionuclide imaging with gamma cameras and imaging with dedicated PET cameras is that the latter type of camera has a full ring of several thousands of scintillation detectors and does not need lead collimators—which absorb more than 99% of the emitted photons—to generate the image, resulting in higher sensitivity to radioactivity and higher spatial resolution.
Historically, PET cameras were “stand-alone” machines, either dedicated PET cameras or specially designed gamma cameras with which dual-head gamma camera coincidence imaging was performed. To overcome the lack of anatomic information of PET imaging, this type of camera has been replaced by hybrid systems in which a dedicated PET camera is combined with an anatomic tomograph—mostly with a computed tomography (CT) camera but sometimes a magnetic resonance imaging (MRI) camera. These fusion PET-CT cameras are considered the new standard (“stand-alone” PET cameras are not manufactured anymore), whereas PET-MRI is an emerging technology. The use of hybrid PET-CT cameras offers three main advantages: (1) attenuation correction (AC), which is needed to correct the image for the fact that some of the photons coming from radioactive decay are absorbed by the body, can be performed with the CT dataset, resulting in significant time reduction (approximately 10 minutes gained per patient); (2) increased accuracy of the exact position of the lesion and morphologic characterization of the underlying correlate, reducing equivocal findings; and (3) significantly increased confidence in reported findings. Typical scan times for modern PET-CT are in the 6- to 20-minute range for a skull-to-thigh image (i.e., whole-body scan). The data reported in this chapter derive from either dedicated PET or PET-CT applications.
The advent of PET-CT has resulted in two different strategies: so-called low-dose CT, which is used only for AC and localization, and “one-stop shopping” high-dose, contrast-enhanced diagnostic CT together with PET. It has been demonstrated that the use of oral or intravenous contrast agents does not induce clinically significant changes in the PET images. The combination of contrast-enhanced CT with PET changes tumor-node-metastasis (TNM) staging in 8% of patients and is nowadays mandatory for applications such as radiation therapy planning. The drawback is an increase in radiation dose, with low-dose techniques adding about 3 mSv to the approximately 8 mSv from the radiopharmaceutical, whereas contrast-enhanced CT adds some 10 to 20 mSv.
For cancer imaging, 2-18F-fluoro-2-deoxy-D-glucose (FDG), described in 1978, is by far the most commonly used metabolic tracer. The usefulness of this tracer relates to the increased cellular uptake of glucose (due to an increased expression of glucose transporter proteins) and a much higher rate of glycolysis in cancer cells. FDG, a glucose analogue in which the oxygen molecule in position 2 is replaced by a positron-emitting fluorine 18 atom, undergoes the same uptake as for glucose but is metabolically trapped and accumulated in the neoplastic cell after phosphorylation by hexokinase.
If the aim of the FDG-PET study is just to stage the patient’s cancer, visual analysis of non-AC images (i.e., “hot spots” with higher-than-background activity not caused by physiologic processes are positive for tumor) probably is just as good as AC images, as has been pointed out by different prospective studies, both for the discrimination of nodules and for the evaluation of mediastinal involvement. Non-AC images should be examined to detect small lung lesions, because they are better visualized, owing to higher contrast, than are AC images.
High physiologic FDG uptake occurs in brain, kidney, and urinary tract (urinary excretion) and can be present in the heart. Particularly in the brain, this interferes with lesion detection. A low degree of physiologic uptake of FDG has been noted in thoracic structures, including the lung, the heart, the aorta and large arteries, esophagus, thymus, trachea, thoracic muscles, bone marrow, and joints and soft tissues. This low background tracer activity builds the image contour.
FDG uptake is not tumor-specific and may be observed in all active tissues with high glucose metabolism, in particular, those in which inflammation is present. Therefore, a finding of clinically relevant FDG uptake, especially if isolated and decisive for patient management, requires confirmation. The differentiation between metastasis and a benign or inflammatory lesion, or even an unrelated second malignancy, should be made by means of other tests or tissue diagnosis.
The major causes of false-positive results (Box 8-2) in chest pathology are infectious, inflammatory, and granulomatous disorders. Iatrogenic procedures, such as thoracocentesis, placement of a chest tube, percutaneous needle biopsy, mediastinoscopy, thoracoscopy, and talc pleurodesis, also may give false-positive results.
Causes of False-Positive and False-Negative Results on Positron Emission Tomography
False-negative results are less common and may be due to lesion-dependent or technical factors (see Box 8-2). A critical mass of metabolically active malignant cells is required for PET detection. Interpretation thus is a critical process with tumors exhibiting decreased FDG uptake such as small, very well-differentiated adenocarcinoma, bronchioloalveolar carcinoma, or carcinoid tumors. FDG-avid lesions smaller than 5 mm may be false-negative as a consequence of the limitations in spatial resolution and partial volume effect. In the lower lung fields, the detection limit may even go down to 10 mm, owing to additional respiratory motion. CT-based AC can cause artifacts in the event of misregistration between the CT and the PET data, which can lead to occultation of liver metastasis on the AC images.
Factors related to technique are paravenous FDG injection and high baseline glucose serum levels. Blood glucose levels should be checked, and it is advised to proceed only if the glucose level is within an acceptable range before tracer injection (typically 60 to approximately 180 mg/dL). Although diabetic patients often were excluded in the prospective studies, FDG uptake probably is not significantly influenced in these patients if the blood glucose levels are under reasonable control.
The value of FDG-PET in differentiating benign from malignant lung lesions (Figure 8-1) has been studied in many prospective studies and documented in different metaanalyses. In these series, in which a standardized uptake value