Tools
PET Scanning
Introduction
Positron emission tomography (PET) scanning is an imaging technique widely used in oncology. This technique uses radiotracers to measure various metabolic processes in the body, providing insights into metabolic activity, blood flow, and chemical composition. PET scanning enables the evaluation of both physiological and pathological processes. Radiotracers can be injected, swallowed, or inhaled depending upon the site of the body being examined, and the tracer gets absorbed by various tissues according to their specific affinity.
Areas of higher metabolic activity exhibit increased tracer uptake, appearing as brighter spots on the images. Radioactive tracers with unstable nuclei emit positrons, which interact with the neighboring electrons to produce gamma rays. These gamma rays are detected by a ring of detectors within the scanner. A computer processes these data to generate a 3-dimensional (3D) image of the tracer's distribution in the body. Different tracers are selected based on the specific metabolic processes or cellular receptors being targeted.
Procedures
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Procedures
The tracer can be administered intravenously, orally, or via inhalation, and it takes some time to distribute throughout the body. If a PET-computed tomography (PET-CT) scan is to be performed, contrast may be administered either intravenously or orally. Patient positioning depends on the area being scanned. The PET machine has a central opening through which the patient slides. Initially, scout images are taken to assess proper positioning. In some cases, breath-holding may be required. The scan duration typically ranges from 30 minutes to 1 hour.
Indications
Oncology
The most commonly used tracer is 18F-fluorodeoxyglucose (18F-FDG), which is a glucose analog that is absorbed by cells in place of regular glucose for metabolism. Glucose is phosphorylated by hexokinases, and the mitochondrial form of this enzyme is elevated in rapidly growing cancers. In cancerous tissues, metabolic activity is typically high, leading to increased glucose uptake. As a result, 18F-FDG is significantly absorbed in these areas, appearing as bright spots on the PET scan. This process also aids in detecting metastasis. The typical radiation dose from 18F-FDG is approximately 7.5 mSv.[1] For FDG PET-CT, the radiation dose typically ranges from 14 to 30 mSv, depending upon CT parameters. In the production of 18F-FDG, the hydroxyl group in glucose is replaced by radioactive fluorine. This hydroxyl group is crucial for glucose metabolism, and its absence halts further cellular reactions. Most tissues, except the liver and kidneys, cannot remove the phosphate added by hexokinase. As a result, 18F-FDG becomes trapped inside the cell until it decays. This is because phosphorylation of sugar leads to the development of ionic charge, which prevents the sugar from leaving the cell until it decays. As a result, tissues with high glucose uptake and utilization—such as the brain, liver, kidneys, and most cancers—exhibit intense radiolabeling. This is due to the Warburg effect, where cancer cells display increased glucose uptake and glycolysis even in the presence of adequate oxygen.
FDG-PET is widely used for diagnosing, staging, and monitoring cancers, particularly Hodgkin lymphoma,[2] non-Hodgkin lymphoma,[3] and lung cancer.[4][5][6] In a study, the likelihood ratio for malignancy in a solitary pulmonary nodule with an abnormal FDG-PET scan was 7.11. This study suggested that the FDG-PET scan is more accurate than the standard criteria for diagnosis. Therefore, FDG-PET can be used as an adjunct test to evaluate solitary pulmonary nodules.[7] In evaluating FDG-PET for staging patients with non-small cell carcinoma, FDG-PET demonstrated higher sensitivity (71% versus 43%), positive predictive value (44% versus 31%), negative predictive value (91% versus 84%), and overall accuracy (76% versus 68%) compared to CT for detecting N2 lymph nodes.
Meanwhile, FDG-PET demonstrated higher sensitivity (67% versus 41%) but lower specificity (78% versus 88%) than a CT scan for detecting N1 lymph nodes. FDG-PET accurately upstaged 28 patients (7%) with unsuspected metastases and downstaged 23 patients (6%). This allows for improved patient selection and more precise mediastinal staging. However, FDG-PET has a high false-positive rate in lymph nodes and may miss N2 disease in stations #5, #6, and #7. This is recommended for the initial staging and response assessment of FDG-avid lymphomas, including non-Hodgkin lymphoma subtypes such as diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.[8]
A positive FDG-PET scan indicates the need for a tissue biopsy at the corresponding location.[9] In evaluating cancers of the esophagus and gastroesophageal junction, FDG-PET demonstrated lower accuracy in diagnosing locoregional lymph node involvement (N1–2) compared to the combined use of CT and endoscopic ultrasound (48% versus 69%). This limitation was primarily due to FDG-PET's lower sensitivity (22% versus 83%) and reduced spatial resolution in detecting small periesophageal nodes. FDG-PET demonstrated significantly higher accuracy in detecting distant nodal metastasis than the combined use of CT and endoscopic ultrasound. Although sensitivity remained unchanged, specificity was higher. FDG-PET accurately upstaged 5 patients (12%) from the N1–2 stage to the M+Ly stage, although 1 patient was falsely downstaged.[10]
A study examining the role of FDG-PET in colorectal cancer screening in asymptomatic adults found that it has a high sensitivity for detecting primary colorectal cancer, particularly identifying cancers at a resectable stage. FDG-PET can also detect large (>0.7 cm) and premalignant colonic adenomas, potentially distinguishing adenomas from carcinomas by assessing glycolysis rates. However, while FDG-PET is feasible, it is not a standard screening tool for colorectal cancer. Colonoscopy remains the preferred method due to its diagnostic and therapeutic capabilities.[11]
FDG-PET is crucial in detecting recurrent cervical cancer in symptomatic and asymptomatic women. Recurrent disease was detected in 30% of asymptomatic women by PET scan, compared to 66.7% of symptomatic women. The sensitivity of PET for recurrent disease in asymptomatic women was 80.0%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 88.9%. For symptomatic women, the sensitivity of PET was 100%, specificity 85.7%, positive predictive value 93.3%, and negative predictive value 100%. Therefore, whole-body PET can serve as a highly sensitive imaging modality for detecting recurrent cervical carcinoma in both symptomatic and asymptomatic women.[12]
The gallium-68 (68Ga)-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) peptide is used to detect primary and metastatic neuroendocrine tumors (NETs). NETs express somatostatin receptors (SSTRs), with SSTR2 being the most prevalent subtype, followed by SSTR1 and SSTR5. The remaining SSTR4 (36%) and SSTR3 (23%) have lower expression levels.[13][14] The 68Ga DOTA PET-CT detected significantly more lesions in patients with negative anatomical imaging than in 111In-octreotide (30 versus 2; P = .028). Pfeifer et al reported a sensitivity of 88% for 111In-octreotide compared to 97% for the copper-64 (64Cu)-DOTA PET-CT.[15] Additionally, Srirajaskanthan et al found that 68Ga-DOTA PET-CT scans detected 74.3% of lesions, whereas 111In-octreotide detected only 12%.[16]
The 68Ga-DOTA PET-CT has proven effective in detecting NETs in symptomatic patients who show no evidence of disease based on anatomical imaging and endoscopic evaluation, with or without biochemical evidence. This technique significantly altered treatment decisions, leading to symptom improvement upon follow-up. Patients with challenging diagnoses should be offered the 68Ga-DOTATATE PET-CT. The 68Ga-DOTATATE PET scan is also commonly used for NET detection.[13] Other tracers include carbon-11 (11C)-labeled metomidate (11C-metomidate) for detecting adrenocortical tumors.[17][18] Additionally, 18F-DOPA PET-CT offers a more sensitive alternative for detecting and localizing pheochromocytoma than a meta-iodobenzyl guanidine (MIBG) scan.[19][20]
Newer tracers include quinoline-based compound tracers. The 68Ga-labeled fibroblast activation protein (FAP) inhibitor (FAPI) PET is an emerging modality that targets FAP, which is predominantly expressed in tumor stromal cells, also known as cancer-associated fibroblasts. FAPI-PET can be effectively integrated into clinical practice, as it improves the possibility of identifying small lesions, particularly in the brain, liver, pancreas, and gastrointestinal system. This is due to minimal tracer retention in these organs, enhancing the accuracy of lesion identification.
68Ga-DOTA-FAPI PET, which primarily targets cancer-associated fibroblasts in tumor stroma, has shown greater sensitivity and specificity in assessing colorectal cancer patients.[21] This technique has also shown better results in lung cancer patients. Staging and metastatic workup studies have shown enhanced accuracy with FAPI-PET, particularly for brain, nodal, bone, and pleural metastases. Furthermore, incorporating the DOTA chelator into the molecular framework allows for the attachment of FAPI molecules to therapeutic radioisotopes, such as yttrium-90, supporting its potential use in theranostics. Studies have also evaluated its role in assessing pathological responses in breast cancer patients.[22][23] The 89Zr-girentuximab tracer is emerging as a tool for characterizing the clear cell type of renal cell carcinoma.[24]
Neurology
Areas of high radiotracer uptake are associated with increased brain activity and can indirectly measure blood flow through the brain, which correlates with regions of higher activity. Oxygen-15 is commonly used for this purpose. Alzheimer disease leads to decreased brain metabolism of both glucose and oxygen. 18F-FDG PET of the brain can help differentiate Alzheimer disease from other dementias. Perfusion, glucose metabolism, and amyloid-beta imaging are well-established and included in the revised diagnostic criteria as essential biomarkers. Florbetapir F18, flutemetamol F18, and florbetaben F18 are used to detect amyloid-beta plaques. Additional targets include tau protein and neuroinflammation.
Protein kinase C (PKC) promotes the induction of alpha-secretase, also known as "a disintegrin and metalloprotease (ADAM)," facilitating the non-amyloidogenic cleavage of amyloid precursor protein (APP). This process plays a crucial role in the acquisition and maintenance of memory in Alzheimer disease. PKC deficits appear early in the disease course. Enzastaurin (LY317615), a selective PKC inhibitor, has recently been radiolabeled with 11C as a potential PET imaging probe.[25] P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to have a role in amyloid-beta clearance from the brain. The radiolabeled P-gp substrate [11C] verapamil has been used in PET studies, revealing lower P-gp expression in individuals aged 75 or older and increased expression in younger subjects.[26]
PET imaging has been used to study cholinergic deficits using radiolabeled acetylcholine analogs such as N-[(11) C]-methyl-4-piperidyl acetate (MP4A). Decreased cortical uptake is observed in patients with Alzheimer disease, with an even greater reduction in the posterior cingulate gyrus in Lewy body dementia.[27] Radiolabeled cholinesterase inhibitors, such as [11C]donepezil, have been used to assess donepezil binding sites in Alzheimer disease treatment. Additionally, a fluorinated tracer, 3-(benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole ([18F]-IND1), structurally related to the acetylcholinesterase inhibitor CP126,998, has been developed to detect acetylcholinesterase changes in patients with Alzheimer disease.[28][29]
PET scanning has enhanced the understanding of the pathophysiology of atypical Parkinsonism disorders and may serve as supportive criteria for differential diagnosis of these conditions.[30] Brain PET imaging with FDG can be useful for localizing seizure foci, which typically appear hypometabolic during an interictal scan. Various radiotracers have been developed for specific neuroreceptors, including 11C-raclopride, 18F-fallypride, and 18F-desmethoxyfallypride for dopamine D2/D3 receptors, 11C-McN 5652 and 11C-DASB for serotonin transporters, 18F-mefway for serotonin 5HT1A receptors, 18F-nifene for nicotinic acetylcholine receptors, and enzyme substrates (6-FDOPA for AADC enzyme). These help localize these neuroreceptors in the pathogenesis of various neurological diseases.
- Neuropsychology: PET scanning helps establish links between specific cognitive processes and brain activity.
- Psychiatry: Radiotracers targeting dopamine, serotonin, opioid, and cholinergic receptors are used to investigate their roles in psychological disorders.
- Stereotactic surgery and radiosurgery: PET-guided imaging is now utilized in surgical and radiosurgical procedures.
Cardiology
[18F]FDG-PET helps to identify hibernating myocardium and can also be used to image atherosclerosis in patients at risk for stroke. This technique enables early detection of inflammation, even before morphological and irreversible vascular changes occur, allowing for the early diagnosis and treatment of large-vessel vasculitis.[31] However, a limitation of this method is the higher physiological uptake of the tracer by the myocardium.[32]
- Myocardial perfusion tracers: Several tracers have been developed for myocardial blood flow imaging, including 13N-labeled ammonia and oxygen-15–labeled water ([15O]-H2O) and 82Rb-chloride and 62Cu-labeled pyruvaldehyde bis(N4-methylthio-semicarbazone) or 62Cu-PTSM. Of these, only 13N and 82Rb are approved by the US Food and Drug Administration (FDA).[33]
- Myocardial metabolic tracers: The heart primarily relies on free fatty acids for oxidative metabolism. However, ischemic and hypoxic myocardium predominantly utilize glucose due to an increased rate of anaerobic glycolysis. Tracers used to visualize this process include 18F-FDG and 11C-labeled palmitate and acetate. PET imaging with myocardial perfusion and [18F]-FDG accurately assesses myocardial viability and is considered the gold standard for evaluating myocardial viability. PET can predict functional recovery of the heart, improvements in congestive heart failure symptoms, exercise capacity, quality of life, cardiac events, remodeling, and long-term survival.[33]
Infectious Diseases
PET imaging can detect bacterial infections using 18F-FDG by identifying infection-associated inflammatory responses. Specific tracers include [18F]maltose,[23] [18F]maltohexaose, and 2-18F-fluorodeoxysorbitol (FDS).[34] FDS selectively targets only Enterobacteriaceae. Applications include the evaluation of fever of unknown origin (FUO), vascular graft infections, musculoskeletal infections such as osteomyelitis, joint prosthesis infections, and diabetic foot infections. FDG-PET offers improved spatial resolution over single-photon emission-CT (SPECT) imaging for osteomyelitis, enhancing localization, which can be further refined with CT.[35] FDG-leukocyte imaging is comparable to 111In-oxine–labeled leukocyte scintigraphy in detecting infections. Applications of this technique include evaluating graft infections, assessing colonic inflammation, and diagnosing peritoneal tuberculosis.[36][37][38][39][40]
Autoimmune Diseases
PET imaging is emerging as a valuable tool in the evaluation of immunoglobulin-G4 (IgG4)-related diseases. Although FDG PET-CT is not part of the standard sarcoidosis workup, it is effective for initial diagnosis and disease monitoring. This can help assess cardiac involvement, evaluate treatment response, identify reversible granulomas, and guide biopsy site selection.[41] In addition, 18F-FDG-PET can differentiate normal thyroid parenchyma from diffuse inflammatory changes of the thyroid gland in patients with autoimmune thyroid diseases.[42]
FDG uptake in affected joints of patients with rheumatoid arthritis reflects disease activity, which correlates with clinical parameters and helps to monitor treatment response. FDG PET-CT shows a high diagnostic value in differentiating polymyalgia rheumatica from rheumatoid arthritis.[43] PET imaging can also be used to monitor the management of large vessel vasculitis. Reduced arterial [18F]-FDG uptake has been observed in patients during remission.[44]
Musculoskeletal System Diseases
PET provides valuable muscle activation data for deep-lying muscles, offering an advantage over techniques such as electromyography, which is limited to superficial muscles. [18F]-NaF measures regional bone metabolism and blood flow. [18F]-NaF has recently been used to study bone metastasis.[45]
Interfering Factors
Strenuous exercise can significantly increase radiotracer uptake in various tissues and should be avoided before imaging.[46] A low-carbohydrate, sugar-free diet is recommended 24 hours before the scan. Acceptable foods include meat, cheese, eggs, and non-starchy vegetables, while cereals, pasta, milk, bread, and sugar should be avoided. Patients should avoid eating or drinking for at least 6 hours before the scan. Metal objects may interfere with imaging and should be removed.
Other factors that can affect or interfere with scan accuracy include high blood glucose levels in diabetics, consumption of caffeine, alcohol, or tobacco within 24 hours, excessive anxiety that impacts brain function, medications such as insulin, tranquilizers, and sedatives, and neurological or psychiatric conditions that may prevent the patient from remaining still.
Complications
PET-CT carries risks associated with contrast administration, including potential anaphylaxis and contrast-induced nephropathy. However, the radiotracers used generally do not cause significant adverse effects.
Patient Safety and Education
PET-CT involves exposure to ionizing radiation. The typical dose for the PET component alone is approximately 7.5 mSv, but combined PET-CT scans, which are more commonly used, result in higher total doses, typically ranging from 14 to 30 mSv, depending on the CT protocol. Radiation exposure should be minimized during pregnancy, as radioactivity can affect the fetus. For breastfeeding women, close contact with infants or pregnant women should be limited to up to 12 hours. Breast milk should be pumped and discarded for 12 hours post-scan, with breastfeeding safely resuming after approximately 24 hours. PET-CT using 50% radiotracers has demonstrated similar imaging quality to full-dose scans, further reducing radiation exposure.[47]
Clinical Significance
As mentioned, PET scanning holds significant potential in both newer fields of medicine, such as oncology, and emerging areas, such as neurology, cardiology, psychiatry, and immunology. New applications are being discovered regularly, making PET scanning an increasingly sought-after radiological tool.
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