Current Applications of PET-CT: An Overview for the Referring Physician
Unlike conventional medical imaging, which is generally utilized for its depiction of anatomy and/or blood flow, nuclear medicine imaging has the unique ability to provide information regarding physiologic and metabolic activity. It is able to fulfill this task through the use of various radiotracers, which are radioactive compounds which are expected to localize to specific areas and become involved in different bodily processes. These radiotracers have very different and more complex functions than the contrast media used in CT or MRI for example, which merely travels through the vasculature and demonstrates areas of blood perfusion.
One of the more recent major advances in the field of nuclear medicine has been Positron Emission Tomography, known as PET. When combined with CT, PET is able to provide excellent physiologic information without sacrificing anatomic detail, which is presently the case for most other applications of nuclear medicine. This has enabled PET-CT to revolutionize oncologic imaging and thus the general management of many types of cancers. PET-CT also has other applications in the evaluation of certain cardiac and neurologic conditions as well as inflammatory processes. (1)
How PET-CT Works
The basis of PET imaging is that an injected radiotracer will localize to specific areas and will emit radiation that will be able to be traced to its origin. At present, there are a few radiotracers utilized for PET; there are other experimental PET radiotracers and it is expected that more of these will be introduced into clinical practice in coming years. (2)
What all PET radiotracers have in common is their process of radioactive decay. The radiotracers, which are produced using cyclotrons, are all unstable in that they carry an excess of positive charge. In decaying to attain a stable state, the radiotracer molecules emit a positively charged electron, called a positron. After traveling a short distance from its origin (usually only a few mm) to expend excess energy, the positron comes into contact with its opposite particle, an electron, and the two cancel each other out in a reaction referred to as annihilation. The crucial point for PET imaging is that the annihilation reaction produces two 511 keV photons which are emitted at that spot in directions approximately 180 degrees from each other. These photons are detected by a special detector which surrounds the patient. While one photon alone could have derived from any location and would not provide any localizing information, the simultaneous (known as “coincidental”) detection of two photons localizes the source to a location somewhere along the line connecting the sites of impact of the two photons. With enough photon pairs producing enough intersecting lines, a computer is able to reconstruct the precise location from which the photons are being emitted. (1)
The most common radiotracer in current use is fluorine-18 fluorodeoxyglucose (FDG). This is a radiotracer used mostly for oncologic imaging, which is currently the primary function of PET-CT. The way FDG accomplishes its task is fairly simple. As a sugar molecule to which a radioactive fluorine atom is attached, FDG initially functions as any sugar molecule does. It travels to where it is needed and is transported into those cells. The principle behind oncologic imaging is that cancer cells, being more metabolically active than normal cells, preferentially take up larger amounts of sugar. Along with its uptake of normal circulating glucose, cancer cells will therefore also take in the largest amount of FDG. Furthermore, due to a change in configuration as a result of the attached F-18 atom, the FDG molecule cannot be acted upon by the normal enzymes in the glycolytic cycle and therefore remains trapped in the cell for a long period of time without being broken down. It is at this point that the patient is imaged and we are able to determine the locations in the body in which the FDG radiotracer was preferentially taken up and trapped. (1,3)
Performing the Examination
Patients are instructed to fast for 4-6 hours prior to a PET-CT. Blood glucose levels are often measured prior to the examination; ideally, serum glucose should be below 150 mg/dL. There are two reasons that this is important. Firstly, as FDG is a glucose analog, it will compete with glucose for uptake into cells. For optimal uptake, it is therefore essential that blood glucose not be very elevated. Secondly, and perhaps more importantly, elevated glucose or a recent meal will cause an elevation of insulin level, one effect of which is to drive glucose into muscles (including the heart), leaving less radiotracer to localize to areas of pathology. It is therefore also not advisable to administer insulin prior to the examination; this can pose a challenge when imaging diabetic patients. Patients are also advised to avoid strenuous activity prior to the examination, as this can increase muscle metabolism and drive more glucose and FDG into the muscles. (1,3)
Unlike contrast media injection for a CT or MRI, which is performed immediately prior to and during the examination, radiotracer injection for PET is performed well before the patient is put on the table for their scan. PET imaging is typically performed approximately 60 minutes after injection in order to allow the radiotracer to circulate and localize to hypermetabolic areas. Between the injection and scanning, the patient rests in a quiet room and is instructed not to engage in any activity, including talking or chewing gum, as that would cause FDG to localize to the muscles which were active during this time. In PET brain imaging, it is especially important for the patient not to be stimulated after the radiotracer injection in order to avoid excess focal uptake in visual or auditory brain centers, which could complicate interpretation. (1,3)
After the waiting period, the patient is placed on the examination table and a CT scan is performed, immediately followed by a PET scan, with no patient movement between the two scans. Total scan duration is approximately 30 minutes. For added diagnostic information, the CT may be performed with oral and/or intravenous contrast administration. However, this can sometimes produce artifacts on the PET scan. To help avoid this, low-density oral contrast is used. In addition, some centers perform a non-contrast low-dose CT along with the PET, and perform a diagnostic contrast-enhanced CT separately. (4) With the exception of patients with known or suspected head and neck cancer, patients are scanned with their arms raised above their head in order to avoid artifacts during the CT portion of the examination. (5)
As FDG is taken up by normal tissues in an amount proportional to their metabolic activity, it is clear that certain normal structures which have relatively higher rates of metabolism will appear “hot” on PET. (Image 1) The interpreting physician must therefore understand the normal distribution of radiotracer and not confuse this normal physiologic uptake with a pathologic process. FDG also undergoes renal excretion; activity is therefore seen in the kidneys, bladder and often along the ureters. Reducing activity within the bladder by voiding prior to the scan is helpful when there is a suspicion of pelvic pathology. Other structures which normally demonstrate FDG uptake include brain, bowel, liver, thyroid, tonsils and submandibular glands. Cardiac uptake is common and increases with recent glucose or caffeine ingestion. Thymic uptake may be seen normally in children and young adults. (1) Pre-menopausal women may demonstrate endometrial uptake during menses or ovarian uptake related to ovulation, for which ultrasound correlation may be useful. (6) Recently used muscles may show some increased FDG uptake; this includes diaphragmatic crura and extraocular muscles. Uptake may also be seen within bone marrow in patients who have received certain marrow stimulating factors along with their chemotherapy. (1)
This full-body maximum intensity projection (MIP) computer-generated image is often viewed in spinning mode prior to reviewing the cross-sectional images. In this case, it demonstrates normal distribution of FDG in brain, submandibular glands, myocardium, liver, bowel and urinary tract.
Occasionally, areas of uptake may be seen in the supraclavicular, mediastinal, paravertebral or perinephric areas which correspond to fat density on CT. This is known as “brown fat,” a type of adipose tissue which is more common in children and plays a role in thermogenesis. Hypermetabolism in brown fat is often due to exposure to a cold environment, perhaps even in the waiting room prior to the examination. Its significance is only that it may be confused with pathology if not correlated carefully with CT. (7)
Initially, PET as a modality was seen as limited in evaluation of primary sites of malignancy and nodal metastases due to its inherent poor resolution, which makes precise localization of FDG uptake difficult. However, this limitation has been significantly reduced by the use of integrated PET-CT imaging, in which both PET and CT are performed sequentially in a single exam on a hybrid PET/CT scanner. In addition to providing high-resolution anatomic images for comparison, fusion software can aid interpretation by overlaying the physiologic PET images on the anatomic CT images. (Image 2) The acquisition of CT images is also used by the computer for its “attenuation correction” of the PET images. By determining the density of different parts of the body based on the CT, the computer can construct the PET images while adjusting for the expected lower number of photons received from dense areas such as bone. For these dual purposes, a low-dose CT is sufficient and is generally performed if a diagnostic CT is not deemed necessary. (5)
These axial, sagittal and coronal images are from a PET-CT performed on a patient with known lung cancer. The top panels are the PET images, the middle panels are the low-dose CT images and the lower images are fusion images which were created by overlaying the PET on the CT. The cursor is on a small lesion within the right adrenal gland which clearly demonstrates increased FDG uptake, consistent with a metastasis. A metastasis in the left adrenal can also be seen on the coronal images.
Just as density and enhancement can be quantified by CT, measurement of the SUV (standardized uptake value) on PET-CT reflects the metabolic activity of a tumor and may serve as a prognostic factor. Many use an SUV value of 2.5 or greater as a level which is suspicious for malignancy, although this is not an absolute threshold. (3) While frequently used, many have questioned the utility of SUV, deriding it as a “Silly Useless Value.” (8) While it may be useful in providing a semi-quantitative assessment of metabolism or for comparing with a prior examination, it must be realized that there can be variation depending on slight differences in dose, blood sugar level, time between injection and scanning, and even the scanner which was used. (1,3)
Indications for PET-CT
A full discussion of all of the uses of PET-CT is beyond the scope of this article; the following represents a brief discussion of some common oncologic uses of PET-CT, as well as an overview of non-oncologic indications including cardiac and neurologic evaluation. As with any imaging study, perhaps even more so, the more history and clinical data that is available for correlation, the greater the usefulness and accuracy of PET-CT as a diagnostic tool. Referring physicians are therefore encouraged to actively communicate with the specialists (radiologists and nuclear medicine physicians) performing and interpreting the PET-CT in order to help arrive at a meaningful diagnosis. It is obviously essential that physicians are familiar with the strengths and limitations of PET-CT as a modality so that they understand the appropriate settings in which it may be utilized.
In the evaluation of patients with known or suspected cancer, PET-CT has several different uses, depending on the situation. It may be used to evaluate a mass and provide the initial diagnosis of malignancy (vs. benignity) or it may be used to stage a known malignancy by detecting the presence of spread to lymph nodes or distant organs. When patients have received treatment for their cancer, PET-CT is often utilized as a follow-up examination to assess response to treatment, or to evaluate for recurrence when a patient is in remission. PET-CT is particularly useful as follow-up in situations when post-surgical or post-radiation changes may complicate CT or MRI appearances. It is also useful in planning focused radiation therapy via its ability to precisely localize neoplastic areas. In lung cancer, for example, PET can help differentiate cancer from adjacent collapsed lung parenchyma which is not involved with malignancy. (1,2)
One common use of PET-CT is in the evaluation of solitary pulmonary nodules (SPN). While PET alone has been shown to be superior to CT alone for this purpose, combined PET-CT will more accurately characterize nodules as benign or malignant to a greater degree than either modality alone. (9,10) According to one study, the accuracy, sensitivity and specificity of PET-CT for SPN evaluation was 93%, 96%, and 88%, respectively. (9) PET-CT has also been shown to be useful in evaluating SPNs in patients with prior cancer histories, in whom there is a greater concern of metastasis. (11)
PET correctly excludes cancer in most cases of benign lung nodules (i.e. high negative predictive value). (9,12) However, false-negative results can occur with tumors having low metabolic activity (e.g., bronchioloalveolar carcinomas, carcinoids, and some well-differentiated adenocarcinomas), small lesions (a critical mass of metabolically active malignant cells is required for detection by PET), and uncontrolled hyperglycemia (which affects uptake of FDG). It is also not unusual for a PET-positive nodule to be determined to be infectious, inflammatory, fungal or granulomatous in origin (i.e., poor positive predictive value). (1,12)
For non-small-cell lung cancer, PET-CT scanning aids in staging through improved detection of intrathoracic lymph node metastases as well as distant metastases. (13,14) It can also distinguish malignant from benign pleural effusions, which can help in staging and can also guide referring clinicians to obtain samples for cytologic analysis. As mentioned above, PET-CT is useful in differentiating malignancy from adjacent collapsed lung or from post-surgical changes. (2) However, radiation pneumonitis may be metabolically active, complicating interpretation of follow-up examinations. (1) Small-cell lung cancer is generally considered metastatic at diagnosis and PET therefore has less of a role in its initial evaluation. (15)
When used in initial staging of head and neck cancers, PET-CT is superior to CT alone or MRI, and was found to change management in 23% of cases in one series (16,17). In another series, PET-CT was shown to have a sensitivity of 83% and caused 15% of patients to have their planned neck dissections cancelled due to findings of unknown metastases or a second primary outside the head and neck. (18) PET-CT has also been shown to be superior to physical exam, CT or MRI when evaluating for recurrent disease, which is attributable to its superior capability to differentiate tumor from changes due to radiation or surgery. (19)
For lymphoma, PET/CT scanning is the test of choice to evaluate disease activity after treatment. (20,21) Compared with CT scanning alone, PET/CT better differentiates between active tumor and necrosis or fibrosis in residual masses. (20,22,23) The negative predictive value of PET alone is 90% on average. There is a 10-20% false-negative rate, which is likely secondary to low-grade disease and the inability to detect small involved lymph nodes (<1cm) which are below the resolution of PET. (1,24)
Esophageal cancer is another common indication for PET-CT. However, the low resolution of PET limits its ability to detect small nodes which are adjacent to the primary lesion. (1) The main use of PET-CT in esophageal cancer is for initial staging to detect the presence of distant metastases, as well as for restaging after administration of initial chemoradiotherapy. Many such cases have shown metastases located in sites that are not typically imaged well by usual radiographic evaluation, including skeletal muscle, subcutaneous soft tissue, thyroid and brain. Opinions on PET’s assessment of response to therapy vary, with some finding it helpful and others reporting only a limited impact of PET in adequately assessing treatment response and local resectability (25,26). While esophageal activity is commonly seen on PET and is often due to benign causes such as esophagitis, focal esophageal uptake is more suspicious for malignancy. (1)
Many other gastrointestinal tract malignancies can be evaluated by PET-CT, although it is less commonly used for these cancers. While not routinely used in gastric cancer, it may be helpful in difficult cases and in monitoring treatment response. (27) A complicating factor in evaluation of the bowel is that diffuse mild uptake throughout the gastrointestinal tract is commonly seen as a normal finding on PET imaging; however, focal areas of uptake that are more intense than the liver (often used as a reference standard and internal control, assuming that it is normal) should warrant further investigation with imaging or endoscopy. (Image 3) PET-CT is currently not routinely used for colorectal cancer, but it may be helpful in high-risk cases and as a baseline study before therapy initiation. (28)
These axial and sagittal images show an intense focus (SUV 17) of rectal FDG uptake (see cursor), consistent with rectal cancer. The activity anterior to the rectum is excreted radiotracer within the bladder. The top images are the attenuation-corrected PET images, the middle images are the non-corrected PET images which are often reviewed as well, especially when there is a suspicion of an artifact due to attenuation correction. The bottom images are from the low-dose CT.
Another common use of PET-CT is in breast cancer evaluation. There exists a vast literature about usage of PET and PET/CT for diagnosis of breast cancer. It has been shown to have a high PPV 97% for detecting primary breast lesions, and may be better for lobular carcinomas than ductal carcinomas. However, rather than being used for initial diagnosis, PET-CT’s role in breast cancer is generally confined to staging, monitoring for treatment response, and evaluation for suspected recurrence; it is complementary to breast MRI in these functions. (29,30)
PET-CT may also be used for numerous other malignancies, although its role has not been clearly defined for many of them. PET is sometimes useful in evaluation of certain primary bone tumors, including multiple myeloma, as well as bony metastases. It is often used to search for distant metastases in patients with melanoma. In some cases, PET-CT may be helpful in finding a diagnosis for a patient with metastatic disease of unknown primary. Liver tumors, however, are difficult to detect, as the high level of phosphatases in hepatocytes prevents retention of FDG within tumor cells. PET-CT is also not very useful in the evaluation of most genitourinary malignancies, primarily due to the masking of abnormal uptake by normal physiologic activity and excretion. (1) More recently, however, PET-CT has been shown to have a role in the evaluation of cervical cancer. (2,31) PET-CT also has a role in restaging patients with treated thyroid cancer who have rising thyroglobulin levels despite a negative iodine-131 scan. (15)
It is important to note that PET will also demonstrate increased FDG uptake in various infectious or inflammatory processes, including gastritis, osteomyelitis, pneumonia, sarcoidosis, as well as sites of healing fractures or radiation therapy. This can sometimes lead to a false-positive diagnosis of malignancy, especially in cases of post-treatment inflammatory changes in the location of the patient’s original malignancy. (1,32,33) On the other hand, the sensitivity of PET-CT for infectious or inflammatory processes makes it useful in certain situations, such as fever of unknown origin. (1,2)
PET has also been used to evaluate myocardial perfusion. Its advantage is the ability to assess both perfusion and metabolism in one examination. FDG can be administered to assess myocardial viability. Regions which are ischemic shift myocardial metabolism from fatty acids to glucose, while non-viable myocardium will not take up FDG at all. Simultaneously, regional perfusion can be evaluated with an agent that remains in the intravascular space and thus shows the distribution of blood flow. Radiotracers which may be used for this function include N-13 ammonia or Rubidium-82. Thus, cardiac PET imaging is able to differentiate between normal, stunned, hibernating, and non-viable myocardium. Preserved or increased FDG uptake in regions of decreased blood flow (known as "PET mismatch") defines hibernating myocardium. A concordant reduction in both metabolism and perfusion (“PET match”) is thought to represent non-viable, scarred myocardial tissue. Regional dysfunction with normal perfusion is evidence of stunned myocardium. Cardiac PET imaging may be very useful when planning coronary revascularization, as myocardial regions with significant reductions in both perfusion and uptake of FDG (presumably non-viable) have only a 20% chance of meaningful functional improvement, while hibernating territories have an approximately 80-85% chance of regaining functional improvement following revascularization. (1,34-41)
PET and PET-CT has also been used in the evaluation of neurological conditions. (Of note, nuclear SPECT imaging may also be useful for many neurological conditions, but that is outside the scope of this article). One common indication for a PET brain scan is the evaluation of brain activity in patients with dementia. Patients with Alzheimer’s disease (AD) commonly demonstrate hypometabolism in posterior parietotemporal regions with sparing of visual and sensorimotor cortex. Studies have demonstrated regional brain hypometabolism to be a sensitive indicator of AD and neurodegeneration; it was shown that a negative PET scan indicated that progression of cognitive disease during a mean three year follow-up interval was unlikely. (42-44) Some clinical studies suggest that PET may be useful in differentiating AD from multi-infarct or frontotemporal dementia, which display different patterns of regional hypometabolism. (1,45) There are also experimental amyloid PET tracers currently under investigation that measure the cerebral amyloid lesions associated with Alzheimer’s disease. (46) While this information may add value to clinical assessment in the future, these technologies are not universally available at this time, and are not presently part of routine assessment of AD patients. This is partially due to the fact that it is not clear whether such differentiations are relevant in the clinical management of patients with neurodegenerative dementias. (47)
In the evaluation of epilepsy, interictal PET scanning may be able to detect the seizure focus as an area of hypometabolism. Imaging during the ictal phase would demonstrate increased FDG uptake; however, ictal PET is rarely performed for obvious practical reasons, although it may occur unintentionally. PET brain imaging is also utilized in evaluation of brain neoplasms; uses include assisting in choosing a site for biopsy or distinguishing between radiation necrosis and recurrent tumor. (1)
Another important issue to be aware of is that of insurance coverage of these studies. As with many relatively new medical technologies, research is still in its early stages for some uses of PET-CT. As such, governmental and private insurance payers have not yet approved PET-CT for all of its current uses. A full discussion of this topic is beyond the scope of this article; however, a complete description of both oncologic and non-oncologic indications (including neurological, cardiac, infection and inflammation) and coverage guidelines is available from the Centers for Medicare & Medicaid Services (CMS). (48) Specifically for cancer imaging, there is an additional resource called the National Oncologic PET Registry (NOPR). This is an organization that was developed in response to the CMS proposal to expand coverage for FDG-PET to include types of cancers and indications that are not presently eligible for Medicare reimbursement. With the exception of cancers and indications that are specifically excluded, Medicare reimbursement for oncologic PET-CT may now be obtained if the referring and interpreting physicians submit data to a clinical registry to assess impact of PET on the management of patients with cancer. (49) The NOPR currently divides indications for PET-CT into two broad categories: initial treatment strategy (formerly diagnosis and initial staging), and subsequent treatment strategy (includes treatment monitoring, restaging and detection of suspected recurrence). The most current list of indications and explanations for them can be found online. (50) Since its inception in May 2006, over 100,000 patients have undergone PET under NOPR’s umbrella that permits Medicare coverage of these studies. (49)
Used appropriately, PET is a very powerful diagnostic tool for oncologic and other purposes. The advent of PET-CT fusion has enabled a greater degree of specificity and thus more accurate and confident results. It is essential that clinicians understand the strengths and limitations of PET-CT when deciding whether to include this examination as part of a patient’s management. As the uses of PET-CT evolve, it is also important to remain up to date in regard to recent developments and current applications.
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