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Special Review |
1 From the Department of Radiology, Duke University Medical Center, Rm 1410, Duke North, Erwin Rd, Durham, NC 27710 (T.G.T., R.E.C.); and the Department of Radiology, Mayo Clinic, Rochester, Minn (E.M.R.). Received September 17, 2002; revision requested November 13; revision received April 14, 2003; accepted May 1. Address correspondence to R.E.C. (e-mail: colem010@mc.duke.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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© RSNA, 2004
Index terms: Breast neoplasms, PET, 00.12163 • Gastrointestinal tract, PET, 78.12163 • Head and neck neoplasms, PET, 26.12163, 27.12163 • Lung neoplasms, PET, 68.12163 • Lymphoma, PET, 99.12963 • Melanoma, **.121632 • Review
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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The initial uses of PET were to help characterize disorders of the brain and heart by quantitatively imaging biologically important molecules labeled with short-lived positron-emitting radionuclides (Table 1). The radiopharmaceutical that has had the most impact on clinical PET imaging is 18F fluorodeoxyglucose (FDG), which was first described in the late 1970s (2). A chemist, Otto Warburg, had observed in the 1930s that malignant transformation of cells is associated with an increased glycolytic rate (3). FDG, an analogue of glucose, is metabolized similarly to glucose in that FDG is transported across cell membranes by glucose transporter proteins and is enzymatically phosphorylated. Once phosphorylated, FDG-6-phosphate is metabolically trapped, in contrast to glucose-6-phosphate. The primary exception to the metabolic trapping is in the liver, where the large concentration of phosphatase enzymes results in dephosphorylation of the FDG-6-phosphate and clearance of FDG from the liver.
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Similar to CT and MR equipment, PET instrumentation has improved dramatically since its development. The system resolution for patient imaging units is now 4–5 mm, whereas it was greater than 15 mm for the initial systems. Animal imaging systems are now available with a resolution of approximately 2 mm. CT scanners are now being combined with PET scanners. The combined PET/CT devices offer several potential advantages overa PET scanner alone: better quality PET images because of the more accurate correction for attenuation provided by CT, automatic registration of CT (anatomic) and PET (metabolic) information, and shorter imaging times. The practical advantages and limitations of PET/CT scanners and the issue of cost versus benefit are currently topics of investigation.
The clinical applications of PET in oncology have been developed from the 1980s to the present time. The Health Care Financing Administration, which is now the Centers for Medicare and Medicaid Services (CMS), first approved PET for coverage in 1998. The first two indications were evaluation of the indeterminate solitary pulmonary nodule and initial staging of lung cancer. Coverage has subsequently expanded to include diagnosis, staging, and restaging of lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, lymphoma, and melanoma. In addition, breast cancer is covered for staging and restaging and for therapeutic monitoring. Additional malignancies will be covered in the future.
This review will briefly cover the physics and instrumentation aspects of PET. We will focus on the clinical applications of PET and the relationships of findings from PET to findings from other imaging modalities. The limitations of PET will be addressed in the discussion of the malignancies.
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TECHNICAL CONSIDERATIONS |
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TOPABSTRACTINTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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The decay of 18F is as follows: 18F 
18O + e+ + 
. Each decay produces an oxygen 18 (18O) atom, a positron (e+), and a neutrino (). Only the positron is relevant for imaging, since the 18O isotope is given very little energy and the neutrino is very difficult to detect.
Positrons are the antimatter counterparts of electrons, having the same mass (511 keV/c2, where c is the speed of light) as and the opposite (positive) charge of the electron. Once produced, the positron leaves the decay site and gradually loses kinetic energy in the surrounding tissue, as would an electron. As this occurs, the positron imparts its energy in small increments through ionization and excitation of nearby atoms. The path length of the positron depends on its initial energy, which in turn depends on the particular radionuclide. The path length is less than 1 mm for 18F. Once most of its energy is lost, the positron eventually annihilates with a nearby electron: e+ + e– 
+ . Two photons () are produced, and there are two important features of this reaction (explained by conservation of momentum and energy): Both photons have an energy of 511 keV, and they leave the annihilation site in opposite directions.
Figure 1 illustrates the processes of positron transit, positron-electron annihilation, creation of two photons leaving in opposite directions, and the subsequent arrival of the photons at two detectors. Because the photons leave the annihilation site in opposite directions, it can be deduced that the annihilation was somewhere in the column connecting the detectors; otherwise, both detectors could not have been hit.
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Even with low detection efficiency, PET imaging is the most sensitive way to detect small concentrations of tracers in the body. Typical tumors detected with PET have approximately picomolar concentrations of PET pharmaceuticals. Concentrations of CT and MR contrast agents must be many orders of magnitude greater to be detected.
Factors That Degrade PET Images
PET images are degraded by several physical factors. Background events include random events and scatter. Random events occur when two photons from unrelated annihilations are detected simultaneously and appear to be a true coincidence, as shown in Figure 3. The number of random events recorded is reduced by keeping the rates at which the individual detectors are being hit low and by using detectors that provide very precise timing.
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Both random and scattered events yield background that reduces the contrast of the resulting images. The real effect is that once the original contrast is restored (through corrections for scatter and random events or even through adjustment of the gray scale), the images appear as they would have if there had been fewer true counts.
Statistical noise is another degrading factor in PET, as in all imaging modalities. In PET, image noise is decreased if more true counts are acquired during the scan (as long as the increase in true counts is not accompanied by an even greater increase in background events). The number of counts acquired during a scan can be increased by either scanning longer or increasing the injected dose, although both have limits. Patient scan times are limited by how long a patient can rest without motion and by how many studies need to be performed on a scanner during the day. Dose is limited on some cameras by dead time. This is the case for systems with a few large detectors. Other systems, especially those with hundreds of independent detectors shielded by septa, can handle doses higher than are routinely prescribed.
Ultimately, the best improvements in counts come from improvements to the scanner that allow more counts to be detected for a fixed dose and scan time. One such improvement is to extend the axial field of view. For the task of whole-body scanning, more time can be spent at each table position if the scanner’s axial field of view is longer. A longer field of view generally implies more detector rings and more resultant transaxial image planes. Another improvement in detection efficiency comes by operating in 3D mode. In 3D mode, events are acquired regardless of any axial difference in the detected photon positions. In two-dimensional PET, in contrast, events are accepted only if the two photons are in the same or nearby rings. The use of septa (to minimize scattered events, random events, and dead-time losses) is only possible for a two-dimensional acquisition. The presence of the septa would preclude the additional events that 3D imaging tries to allow. A system that allows two-dimensional and 3D imaging must have septa that can be retracted. Of the currently available systems, some allow both two-dimensional and 3D imaging; the rest are 3D only.
Spatial Resolution
The intrinsic spatial resolution of a PET scanner is dictated by the ability to localize each measured photon. For systems with discrete detector elements, smaller elements generally yield better spatial resolution. Detector materials with high stopping power for 511-keV photons have the best potential for providing high spatial resolution.
The spatial resolution in reconstructed images is degraded in comparison to the intrinsic resolution of a system because of the noise-reduction filtering that is applied. Therefore, to obtain very-high-resolution clinical images, very-high-count scans are required to minimize the amount of smoothing necessary for acceptable image noise levels.
Attenuation
Attenuation, the loss of true events through scatter and absorption, is the largest source of qualitative and quantitative inaccuracies in PET imaging. Attenuation effects are worse for PET than for single photon imaging because both photons must survive passage through the body for the event to be counted, and therefore the combined paths for both photons form the relevant trajectory in calculating attenuation for an event. Approximately 10% of 511-keV photons are lost for each centimeter of tissue traversed. Several prominent artifacts appear on PET images of the body if no attenuation correction is performed. These artifacts include apparent high tracer uptake in low-attenuation regions such as the lungs, distortions of high-uptake areas such as the bladder (due to more attenuation in some directions than in others), and a prominent body edge that resembles high skin uptake. These effects are demonstrated in Figure 4, where a single section is shown with and without attenuation correction.
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The loss of counts due to attenuation leads to higher noise levels on images in larger patients. The noise implications of lost counts cannot be remedied by attenuation corrections, even though the qualitative artifacts and quantitative accuracy can be.
Attenuation Correction
Attenuation correction is accomplished by applying a correction factor to the number of measured events for each line of response. For example, if five events were recorded between a particular pair of detectors during a scan and it is known that only 10% of photon pairs emitted along that line would survive, than the corrected measurement is 5 · 10 = 50 counts. The determination of attenuation factors can be based on a calculation (assuming the outer contour of the body is known), an orbiting radionuclide source, or CT data. The calculation method is used primarily in brain imaging for those studies where high quantitative accuracy is not required.
Long-lived radionuclide sources have been used with conventional PET systems to measure attenuation in patients. Some systems have used germanium 68 (68Ge), a positron emitter with a 9-month half-life. With 68Ge, one or more sources orbit the body, and the detectors "look for" pairs of 511-keV annihilation photons, as in emission scanning. Other systems have used cesium 137, which has a 30-year half-life and emits 662-keV gamma rays.
A newer attenuation correction technique uses data from a CT system combined with the PET scanner. Although the attenuation properties of CT x rays are different from those of 511-keV emitted radiation, adjustments can be made to the attenuation map generated by the x rays to make it appropriate for calculating attenuation factors for 511-keV radiation for each line of response. In addition to providing attenuation correction, the superior anatomic detail of CT images, compared with the attenuation maps produced with radionuclide sources, is beneficial for aiding the interpretation of the matching PET images. An added benefit of the use of CT for attenuation correction is the acquisition time, which is faster than that for a rotating positron-emitting source.
Available Instrumentation
Consider two designs for PET detector components. In the first, the detectors are completely independent elements, each consisting of a scintillation crystal and a photomultiplier. A photon’s position is known from the location of the detector it hit. This is illustrated in Figure 2. In the second design there are few detectors, but each is a large gamma camera–like system that can measure the location of each detected photon through the processing of signals from an array of photomultipliers on the back (5). The presence of many independent detector elements gives the best count-rate performance, because the dead time of an incidence photon is limited to a very small detector area. Use of large-area detectors requires fewer photomultipliers, thereby lowering costs. Rotating gamma cameras modified for PET imaging are the lowest-cost example (6).
A blend of these two design types is the block detector (7). Block detectors are collections of small crystals (3–8-mm front-surface edge) that are grouped together into blocks of six by six or more. In some designs, the crystals are partially cut from a single block. In others, separate elements are put together. The light from each block is collected by a two-by-two array of photomultipliers. Even though the light from all (36 or more) crystal elements enters the same four photomultipliers, it is possible to determine which particular crystal was hit by comparing the pulse heights from the photomultipliers. A PET system using block detectors typically has tens of thousands of crystal elements arranged in hundreds of blocks (8,9). The block detector design allows much smaller crystals to be used than would be feasible if each crystal had its own photomultiplier.
Several different scintillators are being used in commercial PET systems. Desirable properties include good energy resolution (for rejection of scattered events), fast light output (for minimized dead time and rejection of random events), and high stopping power (for maximized detection efficiency and good spatial resolution). Rejection of random events, minimized dead time, and rejection of scattered events are especially important for successful 3D imaging. If the dose must be lowered for 3D scanning, then part of the benefit is lost.
The four scintillators currently being used in commercial PET scanners are shown in Table 2 (10), along with some important performance parameters. Stopping power increases with increasing density and increasing Z value (atomic number). Short decay times mean faster light output. High light output, in most cases, gives better energy resolution.
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CLINICAL APPLICATIONS |
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TOPABSTRACTINTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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Diagnosis of Non–Small Cell Lung Cancer
One of the first widespread oncologic applications of FDG PET was in the characterization of pulmonary nodules, with the intent of estimating the likelihood of malignancy. Pulmonary nodules and other suspicious abnormalities are commonly encountered in clinical practice. Some are discovered during the work-up for chest complaints, while others are discovered incidentally during work-up for unrelated signs or symptoms. Pulmonary nodules are expected to be a common finding during proposed screening procedures for lung cancer (14).
The approach to the finding of a pulmonary nodule depends on a variety of factors. Some lesions can be demonstrated to be benign through certain distinctive radiologic features, including central, lamellar, or rim calcification (15). Lesions with a high likelihood of malignancy according to CT criteria, including invasion and adenopathy, may be addressed directly by means of either percutaneous biopsy or thoracoscopic surgery. Lesions amenable to percutaneous sampling in an otherwise healthy patient are often sampled directly with biopsy. However, many nodules and other pulmonary abnormalities are indeterminate according to imaging criteria, and either the patient or the referring clinician is hesitant about an invasive procedure and the associated risks and potential complications. In these cases, further imaging evaluation is appropriate.
Traditionally, a benign diagnosis for a pulmonary nodule is established through serial radiologic evaluation with either conventional radiography or CT (16). If the abnormality resolves, improves, or remains stable over time, it is considered to be a benign finding. However, benign nodules such as tuberculomas may enlarge over time, and some low-grade tumors may remain visually stable during the imaging evaluation period; therefore, there is debate over the issue of how much time is needed to establish a benign diagnosis (17).
The major drawback to the radiographic or CT approach is the time necessary to establish a diagnosis. At least one follow-up study, performed 3–6 months after initial demonstration of the abnormality, is needed to demonstrate growth and, therefore, the potential for malignancy. With this in mind, FDG PET has been shown to be a useful addition to CT in the evaluation of pulmonary nodules. Because of the preferential uptake of FDG in metabolically active tissues, PET can be used in a noninvasive assessment of the malignant potential of a pulmonary finding. Most non–small cell lung cancers accumulate FDG owing to a high metabolic rate (18) and are visually hyperintense on PET images (Fig 5). A majority of benign pulmonary lesions, including adenomas, hamartomas, and inflammatory or infectious nodules, do not accumulate substantial quantities of FDG and therefore appear hypointense on PET images (Fig 6) (19).
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Currently at our institution, nodule SUV is measured as an average pixel value within the lesion, calculated on the basis of body weight and measured on axial images. A circular region of interest with at least a 3-pixel diameter is placed over the most intense portion of the lesion. We consider nodules or masses with an SUV of less than 2.5 to have a very low likelihood, though not a zero likelihood, of being malignant. We consider nodules or masses with an SUV of greater than 2.5 to have a high likelihood of being malignant. Early studies indicate a possible role for dual-time-point PET for evaluation of these indeterminate nodules (25). For nodules less than 1.5 cm in size, the SUV criterion must be applied with caution. Although a nodule with an SUV of greater than 2.5 is always suspicious for malignancy, smaller nodules are progressively more difficult to evaluate accurately, and an SUV of less than 2.5 may be a reflection of a partial volume effect due to the limits of PET spatial resolution rather than of the underlying nature of the nodule.
With time, a better understanding of the benefits and limits of FDG PET imaging of pulmonary nodules has developed, and PET is now used to augment, rather than replace, conventional imaging strategies. Metabolic imaging with FDG PET has the advantage of requiring only a single point in time to perform an assessment rather than the multiple time points required for serial follow-up examinations. In this way, PET can expedite a more aggressive approach to a lesion that has a high likelihood of malignancy. Like serial radiographic or CT examination, false-positive results do occur with FDG PET imaging, primarily because of cellular and granulomatous inflammation such as can be seen in tuberculosis, fungal infections, and sarcoidosis (20,26). However, most hypermetabolic pulmonary nodules are malignant, and a lesion that is positive with FDG PET must, therefore, be assumed to be malignant until proved benign.
The high sensitivity of PET for malignancy means that non–FDG-avid lesions are highly unlikely to be malignant. False-negative PET scans are occasionally acquired, primarily in well-differentiated adenocarcinoma and bronchoalveolar cell carcinoma (23,27). For this reason, most patients with a negative PET scan are still followed up radiographically to firmly establish a benign diagnosis. PET-negative lesions followed in this way are usually truly benign, and those that do prove to be malignant are usually stage I nonmetastatic tumors, which have an excellent prognosis after resection (28).
Staging of Non–Small Cell Lung Cancer
Once the diagnosis of lung cancer has been established, the aim of evaluation turns to staging and treatment planning. The primary therapeutic modality for lung cancer is surgery, and complete surgical resection of disease offers the greatest chance for cure. Surgical cure is most likely in early-stage disease without nodal or distant metastases. Radiation therapy and chemotherapy are also effective in treatment of non–small cell lung cancer, either as independent regimens or as adjuvant therapy to surgical resection. The extent of tumor spread is the primary determining factor in whether surgical or nonsurgical therapy is offered to the patient.
With the widely used TNM staging scheme, classification of the primary tumor, T stage, is based on such factors as lesion size, presence of distal atelectasis, distance of the lesion from the carina, invasion of pleura or adjacent structures, and presence of a malignant pleural effusion. For most of these criteria, FDG PET is not sufficient to provide the necessary information for accurate staging. Although size measurements can be performed on PET images, such measurements include only metabolically active components of the tumor, and mismeasurement can result from incorrect windowing of images, with resultant visual "blooming" of the lesion and overestimation of lesion size. In addition, the resolution of PET and the delineation of margins are usually insufficient to enable determination of the presence or degree of invasion by the tumor, and such findings can only be questioned but not established with PET. Both lesion size and invasion are best determined with CT evaluation.
FDG PET is occasionally useful in the staging evaluation of the primary tumor, however. Central tumors can result in airway obstruction and distal atelectasis, which can occasionally have a masslike appearance. In such cases, CT may be inadequate to delineate tumor from obstructive or inflammatory change. FDG PET findings can augment the CT findings and may allow differentiation of metabolically active tumor from atelectasis or pneumonia. Likewise, CT and FDG PET are complementary with regard to the evaluation of intralobar satellite nodules, with size, number, and location demonstrated with CT and metabolic activity demonstrated with FDG PET.
The strongest role for PET in evaluation of T stage is in determination of the presence of malignant pleural effusion. Pleural effusions occur in patients with lung carcinoma, particularly if the tumor abuts the pleural surface or if there are postobstructive inflammatory changes. In many cases, these effusions are reactive in nature rather than a result of tumor seeding of the pleural space. CT, although sensitive for small quantities of pleural fluid, usually does not allow determination of whether the fluid is benign or malignant. The finding of increased FDG uptake that conforms to the pleural cavity on PET images has been found to allow differentiation of benign from malignant pleural effusions with an accuracy of 92% (29). A potential pitfall in this approach is in patients who have previously undergone pleurodesis, which can result in inflammatory pleural changes that are indistinguishable from pleural malignancy (30).
Nodal disease in non–small cell lung cancer is an important determinant of therapy and prognosis. Disease in ipsilateral hilar and mediastinal nodes or in subcarinal nodes is often amenable to surgical resection, and patients are usually still considered candidates for surgery. Nodal spread to the contralateral mediastinum or hilum imparts a worse prognosis, and these patients are usually treated nonsurgically. The most accurate means of establishing the presence of nodal disease prior to definitive surgical treatment is with lymph node sampling during mediastinoscopy. Although limited to superior mediastinal lymph nodes, this technique can usually provide sufficient information to designate an N2 or N3 status (31,32). The drawback of this procedure is its invasiveness, although in the appropriate hands it is associated with very low morbidity and mortality.
Noninvasive assessment of nodal disease is most often performed by using CT. Because of its dependence on anatomic characterization, CT evaluation of lymph nodes is based on node size and number in order to estimate the likelihood of malignancy. Nodes that measure larger than 1 cm in short-axis dimension are considered malignant, whereas nodes smaller than 1 cm in short-axis dimension are considered benign. In certain cases, numerous small lymph nodes are also considered to be suspicious. With this approach, CT is approximately 45% sensitive and 85% specific for metastatic disease to hilar and mediastinal lymph nodes (33). Modification of the size criterion may increase the sensitivity or specificity for disease but at the expense of the accompanying parameter: For example, a cutoff of 8 mm would increase sensitivity but decrease specificity.
The fundamental limitation of anatomic imaging is the inability to characterize the nature of lymph nodes. Nodes that are normal in size on anatomic images may contain tumor cells, and reactive lymph nodes can often exceed 1 cm in size yet contain no tumor. PET imaging offers metabolic information rather than anatomic measurements and is therefore an accurate means for delineation of nodal spread of lung cancer (Fig 7). When FDG PET has been used to characterize mediastinal nodes, sensitivities of 80%–90% and specificities of 85%–100% have been reported; for hilar nodes, the sensitivity and specificity of PET for metastatic disease are 75% (33). The lower specificity of FDG PET for disease in the hila is thought to be due to the frequent occurrence of inflammatory nodes in this region, which may be false-positive on FDG PET images.
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In many patients, it is the presence of distant metastases that precludes a surgical cure. A variety of sites can be involved by metastatic non–small cell lung cancer, with common sites of disease including lung, bone, brain, liver, and adrenal glands. Evaluation for metastatic disease with conventional imaging techniques requires several studies, including CT of the chest, abdomen, and pelvis; CT or MR imaging of the brain; and skeletal scintigraphy. FDG PET is an alternative means of evaluation for metastatic disease and in many ways is superior to conventional imaging techniques.
In one study of patients with non–small cell lung cancer and a negative staging CT scan (37), PET demonstrated unsuspected sites of disease in 11% of cases. In the same study, in patients with CT findings suspicious for metastatic disease, PET demonstrated nonmalignant causes in 95% of cases. FDG PET is also more accurate than skeletal scintigraphy with technetium agents for detection of osseous metastases (38). Benign adrenal nodules are a common CT finding, and in patients with lung carcinoma differentiation of benign from malignant causes of adrenal enlargement poses a challenge when standard imaging techniques are used. FDG PET has been shown to help reliably differentiate between adrenal metastases and benign adrenal nodules, with a sensitivity of 100% and a specificity of 80% (39).
A limitation of FDG PET in detection of metastatic disease is with regard to the brain. The cerebral cortex shows the highest physiologic tissue accumulation of FDG in the body; therefore, visualization of metastatic disease in the brain is problematic. The reported sensitivity of PET for detection of cerebral metastases is 85%, and the specificity is 73% (40). Small lesions are particularly difficult to discern with PET imaging; as a result, only approximately 65% of cerebral metastases are detected (40,41). For this reason, PET imaging of the brain cannot replace MR imaging for detection of cerebral metastatic disease.
Restaging of Non–Small Cell Lung Cancer
Despite aggressive therapy, the 5-year survival rate for patients with non–small cell lung cancer is only 14% (42). Some patients present with advanced disease at the time of diagnosis, but many patients complete therapeutic regimens intended to cure the disease only to have recurrence at a later date. Recurrent disease can arise in two ways: local intrathoracic recurrence and metastatic recurrence. FDG PET is useful for detection of both manifestations.
As discussed previously, FDG PET has been shown to be accurate in detection of metastatic disease at a variety of sites, and metastases to nodes, liver, bone, and adrenal glands are equally apparent in patients undergoing restaging of lung cancer and in patients undergoing initial staging. Similarly, new pulmonary nodules or masses in the ipsilateral or contralateral lung are accurately characterized with FDG PET.
An additional challenge in patients with previous lung carcinoma is differentiation of posttherapeutic change from recurrent tumor. Many patients with lung cancer undergo surgical resection—wedge resection, lobectomy, or pneumonectomy. Each of these leaves varying degrees of scarring and distortion that can mask early changes of recurrent tumor. With CT, serial examinations are required to document changes, and careful attention must be paid to each of the prior studies, lest subtle changes be overlooked. In contrast, PET imaging offers a rapid assessment of the status of disease and is accurate in differentiating postsurgical changes from recurrent tumor (Fig 8) (43–45).
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Colorectal Carcinoma
Colorectal carcinoma is the third most frequent cancer in men and second most frequent cancer in women in the United States and was estimated to account for approximately 148,000 new cases in 2002 (13). Owing in part to screening efforts, many colorectal cancers are detected at an early stage, and the overall 5-year survival rate is 61%. However, up to 20% of patients will have metastatic disease at the time of diagnosis. Ninety-five percent of colon cancers are adenocarcinomas, the majority of which are moderately differentiated. Multiple histologic subtypes exist, with the subtypes based on the type of cellular differentiation noted at pathologic evaluation. CMS guidelines approve the use of FDG PET for diagnosis, staging, and restaging of colorectal cancer.
Diagnosis of Colorectal Carcinoma
In clinical practice, FDG PET is rarely used for the diagnosis of colorectal cancer, and state Medicare reimbursement guidelines often indicate that this is expected to be a rare use of PET. There are, however, scenarios where this indication could be expected to arise, such as in a patient with an imaging-depicted colonic abnormality that is suspected of representing colon cancer but for which a definitive diagnosis has not been made pathologically.
To date, there are no studies of which we are aware that prospectively examined FDG PET as a means of differentiating benign from malignant colonic abnormalities. Results of retrospective studies suggest, however, that PET may be of use in this role. When the scans of patients referred for evaluation of known colonic neoplasms were reviewed, PET was shown to be highly sensitive for identifying the site of the primary tumor (Fig 9), with sensitivities ranging from 90% to 100% (46,47). In these studies, the specificity of PET was much lower, ranging from 40% to 60%, likely because of physiologic bowel-wall accumulation of FDG, as well as uptake of FDG in inflammatory bowel conditions. Numerous reports have also described focal bowel accumulation of FDG due to benign colonic polyps (Fig 10). For these reasons, the evaluation of the patient with suspected colorectal carcinoma rarely includes FDG PET as an initial modality.
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Because of the role of surgery in both limited and advanced disease, staging classifications for colorectal cancer have been developed on the basis of surgical and pathologic criteria. Several staging systems have been developed for colorectal cancer, including the Dukes system and the Jass system. Most recently, the standard TNM classification has been recommended by the American Joint Committee on Cancer. The goal of each classification system is to aid in determination of a prognosis for the patient and the most effective means of therapy.
The dependence of staging schemes on surgical and pathologic information limits the ability of imaging to provide the appropriate information before surgery. Because of its limited spatial resolution and poor delineation of anatomic boundaries, PET is particularly unsuited to providing the precise information needed for local and regional staging. In the TNM nomenclature, PET is of little use for the determination of T stage, where precise depth of invasion is the primary determinant. Only in cases of gross serosal penetration and invasion of adjacent structures might PET be accurate. Similarly, assignment of N stage requires numeric assessment of pericolic and mesenteric nodes. Regional lymph nodes in colorectal carcinoma are frequently small and lie in proximity to the primary tumor mass. In addition, pericolic nodes often contain small quantities of tumor cells, which are apparent only at the time of histopathologic evaluation. For these reasons, PET has been found to be only 29% sensitive for regional lymph node metastases from colorectal cancer (46). The presence of FDG in pericolic nodes is a good predictor of disease, however, and the specificity of PET for regional nodal metastases is 96%.
Disease spread beyond the regional pericolic or mesenteric lymph nodes is considered to be metastatic disease. Colorectal cancer may metastasize via the lymphatics and involve internal iliac nodes or retroperitoneal nodes, depending on the location of the primary tumor. Hematogenous spread of colorectal cancer almost always involves the lung or liver, and metastases to other sites without lung or liver involvement are rare. The strength of PET imaging is in depiction of these distant metastases, both nodal and extranodal (Fig 11).
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CT is the principal modality for preoperative evaluation of patients with hepatic metastases, and intraoperative ultrasonography (US) is considered the imaging reference standard for identification of hepatic metastases. FDG PET has proved to be a valuable addition to the standard preoperative work-up of patients being considered for curative hepatic resection of colorectal metastases. Both PET and CT are accurate for identification and delineation of metastases to the liver, and in small case series with high prevalence of disease, PET has been shown to be superior to CT, with sensitivities and specificities as high as 100% for PET (52–54). More recent studies suggest that PET is most accurate for identification of hepatic metastases greater than 1 cm in diameter but is limited in its ability to demonstrate lesions smaller than 1 cm (55,56), particularly when intraoperative US is used as a reference standard.
Despite its sensitivity and specificity for hepatic metastases, PET as a single modality does not provide sufficient information for adequate presurgical planning. In addition to delineation of the extent of disease, it is important to identify the precise location of metastases according to standard hepatic anatomy. Further, the position of lesions in relationship to vessels or to the gallbladder may preclude a safe surgical or ablative therapy. Since PET offers little information on anatomic boundaries, this needed information is not provided by PET alone.
Hepatic resection and ablative procedures are directed toward elimination of disease in the liver and do not address other sites that may harbor tumor cells. For these costly and invasive procedures to be effective, there should be no sites of disease that cannot be addressed with the procedure. Accurate imaging, therefore, is critical in these patients. The greatest impact of PET imaging in patients with hepatic metastases is in detection of these extrahepatic sites of disease that would preclude a curative procedure.
CT is the standard imaging modality for detection of extrahepatic disease prior to an attempt at a curative procedure. However, CT relies on anatomic parameters such as lymph node size and as such does not directly address the question of the presence of viable tumor cells. As a result, CT may result in an overestimate of the importance of an anatomic abnormality that is unrelated to malignancy or an underestimate of the importance of a finding because size criteria are not met. In a meta-analysis of the literature (57), PET was found to be more sensitive than CT for disease in a variety of sites, including liver, abdomen, retroperitoneum, pelvis, and other sites of disease. PET and CT were equally sensitive for detection of pulmonary metastases. Overall, PET was 97% sensitive and 76% specific for metastatic disease, whereas CT was 76% sensitive and 56% specific.
Several investigators have also examined the incremental value of PET as an addition to CT and found that PET offers information beyond that from CT and that this information often affects patient care. Investigators have found that when PET is added to CT in preoperative planning for patients with hepatic metastases, additional sites of extrahepatic disease are identified in 11%–23% of patients (57,58). This frequently leads to a change in therapeutic management from a localized directed approach to a more systemic approach with chemotherapy.
An important observation was made in one of these studies (58). In that study, in which 43 patients who were referred for hepatic resection were evaluated with CT and FDG PET, survival data after surgery were compared with established survival data in the literature. In the 43 patients, PET demonstrated 10 sites of disease that were not apparent on CT images. In six cases, this disease precluded a curative surgical procedure, and these patients were treated nonsurgically. By incorporating FDG PET into the preoperative planning protocol and eliminating from consideration those patients with unsuspected extrahepatic disease, the authors found that the Kaplan-Meier estimate of overall survival rate at 3 years for their patients was 77%. Authors of numerous studies in the literature of similar patients undergoing hepatic resection for metastatic disease without the use of FDG PET report a survival rate of approximately 40% (59,60). Although the number of patients in the study was not sufficient for generalization, the results suggest that the addition of PET imaging to presurgical evaluation may improve survival by appropriately eliminating ineffective surgery in patients with inoperable disease. A limitation also highlighted in that study was that despite the improvement in 3-year survival rate, the 3-year disease-free survival rate was only 40%, indicating the presence of occult disease undetected by any means, including FDG PET.
Restaging of Colorectal Cancer
After primary treatment of colorectal cancer, patients are at risk for the development of recurrent disease. Disease recurrence can occur in a variety of sites, most frequently the lung or liver. As during the initial staging of colorectal cancer, FDG PET is sensitive and specific for the presence of metastatic disease and is more accurate overall than CT. In a study comparing the sensitivity and specificity of CT, serum carcinoembryonic antigen levels, and FDG PET (61), PET was found to be more sensitive than both CT and carcinoembryonic antigen level for detection of disease recurrence, and the specificity of PET was equivalent to that of serum carcinoembryonic antigen level. In that study, the identification on PET images of additional sites of disease had the benefit of preventing unnecessary surgical intervention, with a consequent cost savings of approximately $3,000 per patient.
A particular challenge in patients with prior colorectal carcinoma is differentiation of the sequelae of prior therapy, including surgical scarring and radiation fibrosis, from disease recurrence. This is most problematic with distal tumors, where presacral scarring and pelvic changes are common. With conventional imaging, serial examinations are frequently required, and the diagnosis of disease recurrence may take 3–6 months or more before slowly developing changes are apparent.
With FDG PET, the presence of metabolic activity in the presacral space is indicative of tumor recurrence (Fig 12), while postsurgical change is not hypermetabolic. PET has been shown to be accurate for differentiation of benign from malignant presacral changes and to be superior to CT and MR imaging in this regard (53,62). PET has a further advantage in that only a single study is necessary to make this determination, rather than the serial studies required with conventional imaging.
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Diagnosis of Melanoma
We are aware of no studies to date that have examined the role of FDG PET in the diagnosis of melanoma. Since melanoma is usually a cutaneous lesion and amenable to diagnostic biopsy in the office, there is rarely a need for a noninvasive imaging study to aid in diagnosis. Furthermore, little is known of the potential for FDG uptake in benign pigmented lesions and atypical nevi. In a series of 95 patients with advanced-stage melanoma, Tyler and colleagues (63) reported a single false-positive PET scan in a patient who ultimately proved to have a benign cutaneous nevus. To our knowledge, no studies have prospectively compared FDG uptake in benign and malignant pigmented cutaneous lesions in a large number of patients.
Initial Staging of Melanoma
In the patient with newly diagnosed melanoma, there are several features that impart prognostic information, including depth of invasion of the primary lesion, spread to regional lymph nodes, and presence or absence of distant metastatic disease.
FDG PET has differing influence on each component of the TNM staging system for melanoma. For the T stage, depth of tumor invasion is the primary determinant, with invasion of more than 4 mm denoting the highest stage, T4. This depth is below the practical spatial resolution of current PET scanners, which is at best 5 mm for a dedicated full-ring scanner. Ulceration of the primary lesion is also a factor in determining T stage, a feature also not evaluated with PET scanning. These issues are moot, however, in that the assessment of the primary tumor is made at the time of punch biopsy or surgical excision, which almost always occurs before the patient is referred for PET scanning.
The next step in work-up of known melanoma is the determination of local-regional spread of disease. When the primary tumor is confined to the dermis, melanoma spread occurs through lymphatic channels to the regional lymph node basin. In the past, staging and treatment protocols have included full lymph node dissection of the likely nodal basin in order to identify sites of disease. This has largely been replaced by sentinel lymph node (SLN) mapping procedures, in which a small amount of microfiltered technetium-labeled sulfur colloid is injected intradermally around the primary tumor (64,65). The colloid particles are cleared by means of lymphatic drainage and are trapped in the lymph nodes that drain that site. These nodes can then be localized intraoperatively with a gamma probe. When combined with intraoperative injection of methylene blue dye and histopathologic evaluation, this procedure has been shown to be highly accurate for determining the presence of nodal disease. In one series of patients with melanoma on an extremity (66), the sensitivity of SLN mapping was 100% and the specificity was 97%.
Primary lesions located on an extremity typically spread in a predictable pattern to the nearest nodal basin, the axillary basin for upper extremities and the inguinal basin for lower extremities. With the use of SLN mapping, it has been found that a high proportion of head, neck, and trunk melanomas drain to unexpected nodal basins. Occasionally, SLN procedures may reveal drainage to two lymph node basins, and patients with disease in both nodal groups have been found to have a worse prognosis (67).
SLN mapping has been established as a safe and accurate procedure for determination of disease spread to regional lymph nodes. A large body of literature also incorporates the information obtained through SLN mapping with patient outcome and prognosis. When FDG PET has been compared with SLN mapping, mixed results have been reported. In one study of 17 patients with primary cutaneous melanoma (68), PET had an accuracy of 94%, as compared with findings from SLN mapping. However, that study appears to be the exception, because other studies (69–71) have found that PET is relatively insensitive for early nodal disease. In a study of 89 patients with stage I, II, or III cutaneous melanoma (69), the sensitivity of PET was only 17% compared with that of SLN biopsy and surgical exploration. The specificity of PET was much higher (97%), and the presence of focal nodal activity is a good indicator of the presence of disease (Fig 13).
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Although limited in assessment of the primary tumor (T stage) and early spread to regional lymph nodes (N stage), PET has been shown to have a strong role in detection of metastatic disease. Melanoma can metastasize to a variety of sites, including distant nodal sites, lungs, liver, gastrointestinal tract, adrenal glands, and bone. Melanoma is also known for metastasizing to unusual sites such as spleen, gallbladder, and cutaneous or subcutaneous sites. There is no consensus on the most appropriate treatment for metastatic melanoma, but many surgeons pursue aggressive surgical excision of metastatic disease if only one or a few sites of disease are apparent. Precise identification of the location and number of metastatic lesions is, therefore, important for surgical planning.
Because of the variety of sites to which melanoma can metastasize, PET has been shown to be more accurate than CT for determination of the presence and extent of metastatic disease (Fig 14). PET has been found to be 92% sensitive and 90% specific for metastases (73). More compelling is the effect of PET scanning on patient care. When PET is added to CT in evaluation of patients undergoing initial staging of high-risk primary melanoma, a change in patient care occurs in up to 90% of cases because unsuspected sites of disease are detected (68).
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As with metastases found during initial staging, FDG PET is highly sensitive and specific for identification of disease at variety of sites, including organ, nodal, and cutaneous or subcutaneous locations (Fig 15). Many surgeons advocate aggressive surgical excision of metastatic foci as they develop, and the precise distribution of disease is therefore of paramount importance to achievement of curative surgery. In patients with known recurrence of melanoma, the addition of PET scanning to CT has been shown to aid in identification of additional unsuspected sites of disease and in alteration of treatment planning in up to 20% of cases (63,73).
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Hodgkin and Non-Hodgkin Lymphoma
Lymphoma is the most common primary hematopoetic malignancy in the United States. In 2002, it was estimated that there would be nearly 61,000 new diagnoses of lymphoma, of which the majority (54,000 cases) would be non-Hodgkin lymphoma and the remainder (7,000 cases) would be Hodgkin disease (13). The yearly incidence of non-Hodgkin lymphoma had been steadily increasing, doubling in the 1970s, but has recently been stable since the mid-1990s. The incidence of Hodgkin disease has been declining since the 1980s. Lymphoma often responds well to therapy, and the 2002 death rates for non-Hodgkin lymphoma and Hodgkin disease were estimated to be 25,800 and 1,400 per year, respectively.
The primary therapeutic modalities for lymphoma are chemotherapy and radiation therapy. Surgery plays little role in the treatment of lymphoma, apart from helping determine the histopathologic subtype and document the extent of disease, when necessary. Although systemic treatments are frequently employed, treatment protocols for both non-Hodgkin lymphoma and Hodgkin disease are predicated on the extent of tumor involvement. Staging of lymphoma is usually accomplished by using the Ann Arbor system. This scheme encompasses the number of sites of disease involved, the type of involvement (nodal or extranodal), and the distribution of disease. Because treatment protocols are designed around this anatomic classification, accurate imaging is necessary to determine the optimal therapeutic strategy. CMS guidelines approve the use of FDG PET for the diagnosis, staging, and restaging of Hodgkin and Non-Hodgkin lymphoma.
Diagnosis of Lymphoma
As in the assessment of indeterminate pulmonary nodules, FDG PET can be used to evaluate suspicious abnormalities such as lymphadenopathy in order to assess the likelihood of a malignant origin. In our experience, this application is rarely used because patients often proceed to percutaneous biopsy or lymphadenectomy for diagnosis. Occasionally, however, PET scans will be requested because of this indication, including scans for evaluation of lesions that are not easily accessible for histologic sampling or for highly suspicious lesions with a benign pathologic diagnosis that may have been due to sampling error.
There are few articles in the literature in which the utility of FDG PET in diagnosis of unsuspected lymphoma was closely examined. The studies that have been published deal primarily with the differentiation of central nervous system lymphoma from toxoplasmosis or other inflammatory lesions in patients with human immunodeficiency virus infection (75–78). In this role, PET has been shown to be accurate for distinguishing between malignant and inflammatory lesions, although false-positive cases have been found to occur with progressive multifocal leukoencephalopathy (77).
If PET is undertaken for the diagnosis of lymphoma, it must be performed with a proper understanding of the potential causes of false-positive and false-negative results. False-negative scans can be obtained in cases of malignant lymphoma that are not highly metabolically active. It has been shown that the degree of FDG uptake in lymphoma is related to tumor grade, and PET scanning can be used to estimate tumor grade prior to histologic classification (79,80). Low-grade lymphomas are frequently only mildly FDG avid and may be overlooked, leading to a false-negative scan (81). In particular, lymphomas arising from mucosal-associated lymphoid tissue (ie, MALT lymphomas) are an established cause of false-negative PET scans, and images in patients with these tumors must be interpreted with caution (82).
False-positive PET scans pose a frequent hazard in interpretation. There are numerous case reports and case series in which false-positive FDG PET scans caused by a variety of processes have been documented. Examples of diseases that have been found to be hypermetabolic include sarcoidosis, tuberculosis, histoplasmosis and other fungal infections, pyogenic abscess, and spondylodiscitis (26,83–87). Any process that results in an infiltration of metabolically active host cells may give rise to elevated FDG uptake and a false-positive scan.
Again by using the model of indeterminate pulmonary nodules, PET is likely to be more sensitive than specific for the diagnosis of lymphoma, owing to the greater number of causes of false-positive scans than of false-negative scans. In practice, if PET scanning is to be used for the diagnosis of lymphoma, hypermetabolic lesions must be assumed to be malignant and proved to be benign.
Staging of Lymphoma
According to the Ann Arbor staging classification, disease is categorized according to nodal or extranodal location; single or multiple lymph node basins; and location of disease above, below, or both above and below the diaphragm. Because the distribution of disease is a determinant in choice of therapy, imaging plays an important role in the evaluation of patients with lymphoma, both during initial staging of disease and during restaging and diagnosis of disease recurrence. Multiple imaging modalities can be used for staging lymphoma, including CT, MR imaging, US, lymphangiography, gallium scintigraphy, and FDG PET. Authors of several studies in the literature have compared the accuracy of disease staging with FDG PET with that of both CT and gallium scintigraphy.
The strengths of CT are its accuracy for the detection of anatomic abnormalities and its ability to define structures that are below the resolution of nuclear medicine imaging. However, the limitation of CT is its reliance on anatomic criteria in order to identify pathologic conditions, such as a 1-cm short-axis dimension threshold for pathologic lymphadenopathy. Although this criterion results in an acceptable balance between sensitivity and specificity for disease, nodes smaller than 1 cm can contain malignant cells, and reactive or inflammatory processes can result in nodes larger than 1 cm.
By assessing metabolic activity within a node, PET is not directly reliant on nodal size to determine the presence or absence of malignancy. Nodes that are not enlarged can be shown to contain tumor on FDG PET images, and nodes that are enlarged can be shown to be reactive in nature. For this reason, PET has been shown to be more sensitive and specific than CT for identification of sites of disease. In one study (88), when PET was used to identify the presence or absence of disease in patients with Hodgkin lymphoma, both during initial staging and during restaging, it was found to be 86% sensitive and 96% specific, compared with 81% sensitivity and 41% specificity of CT. In patients with non-Hodgkin lymphoma, the sensitivity and specificity for CT were the same as for patients with Hodgkin lymphoma—81% and 41%, respectively—whereas PET was found to be 89% sensitive and 100% specific for the presence of disease.
PET is also accurate for the identification of specific nodal sites of disease. In a study of 740 lymph node regions in 60 patients evaluated with both FDG PET and CT, discordant interpretations between PET and CT images were almost always resolved in favor of the PET interpretation when confirmation was obtained (89). In some patients, suspicious findings on CT images were found not to be FDG avid and were subsequently shown to be benign; in other patients, PET findings that were not evident on CT images were subsequently proved to be malignant. The identification of additional sites of disease resulted in an increase in disease stage in more than half of the patients.
Gallium scintigraphy has many of the advantages of FDG PET. Both techniques are a reflection of tumor physiology rather than anatomy. In the case of gallium scintigraphy, radiotracer uptake is mediated through transferrin binding and transferrin receptors, and increased gallium uptake is seen in many types of lymphoma, as well as in other types of tumors. Like FDG PET, gallium 67 scintigraphy is not directly reliant on node size for determination of disease. However, this advantage is less often realized in gallium scintigraphy due to an imaging resolution of greater than 1 cm for most single photon emission computed tomography systems. Gallium scintigraphy is also more time-consuming than FDG PET. Whereas most PET studies can be completed in 2 hours, gallium scintigraphy requires at least two visits by the patient, one for administration of the radiopharmaceutical and a second for imaging. Although many gallium scintigraphic studies are completed in 48 hours, additional imaging at 72 or 96 hours is occasionally required.
Although relatively few studies have been performed to directly compare the accuracy of FDG PET and gallium scintigraphy for evaluation of patients with lymphoma, the data that do exist indicate that PET is the superior imaging modality. In an early study of five patients (90), disease staging with PET was ultimately proved to be correct in four, whereas disease staging with gallium scintigraphy was correct in two. In a larger number of patients, including patients with newly diagnosed and recurrent Hodgkin and non-Hodgkin lymphoma, PET was more accurate for determination of disease stage than was gallium scintigraphy, as confirmed with pathologic or radiographic follow-up (91).
Most recently, FDG PET and gallium scintigraphy were compared in 51 patients with Hodgkin disease and intermediate- and high-grade non-Hodgkin lymphoma (92). In that study, PET was 100% sensitive for the detection of disease and was also 100% sensitive for detection of individual sites of disease within patients. Gallium scintigraphy was 80% sensitive for the presence of disease and 72% sensitive for individual sites of disease. In that study, 36% of lesions seen on PET images were not visible on gallium scintigraphic images, frequently owing to small lesion size. The ratio between tumor activity and background activity was also found to be higher for PET than for gallium scintigraphy.
In addition to nodal sites of disease, PET can be useful for evaluation of extranodal sites of disease (Fig 16). PET has been found to be accurate for identification of disease in multiple sites in the abdomen, including organ involvement of the liver and spleen and mesenteric/peritoneal disease in the peritoneal cavity. Detection of marrow disease can also be accomplished with FDG PET. Although most patients with lymphoma undergo bone marrow aspiration from the posterior iliac crest, lymphomatous involvement of the marrow is occasionally focal and may be missed at random biopsy sampling. Several studies have found that focal sites of marrow disease can be identified in 13%–16% of patients with negative bone marrow biopsy results (93,94). For detection of marrow disease, PET is more accurate than either gallium scintigraphy or skeletal scintigraphy with technetium-labeled bisphosphonates (95).
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Figure 18 depicts a rapid response to treatment in a patient with lymphoma who was evaluated with PET early in the course of therapy. Relative tumor activity can be estimated by measuring SUVs before, during, and after therapy. Changes in FDG uptake have been reported within 1–3 days after the initiation of therapy, and SUV values at 42 days after treatment have been found to accurately reflect the patient’s overall disease status (104). In patients with a complete response to therapy, substantial decreases in SUVs are observed early in the course of therapy.
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Esophageal Carcinoma
There is extensive regional variation in the incidence of esophageal neoplasms throughout the world. In the United States, esophageal cancer is relatively uncommon, with an estimated 13,100 new diagnoses per year (13). Despite aggressive treatment, the survival from esophageal cancer is poor, with an estimated 12,600 deaths due to esophageal cancer occurring annually. CMS guidelines approve the use of FDG PET for the diagnosis, staging, and restaging of esophageal cancer, including both squamous cell carcinoma and adenocarcinoma.
Diagnosis of Esophageal Carcinoma
Because of the distensible nature of the esophagus, the clinical manifestation of esophageal neoplasms is often delayed. Symptoms, when they occur, are often limited to dysphagia and weight loss. Initial evaluation of patients suspected of having esophageal tumors may include a noninvasive study such as a barium swallow examination or an endoscopic examination. As with evaluation of other hollow viscera, standard cross-sectional imaging has a limited role in the evaluation of luminal tumors.
To date, no study of which we are aware has evaluated the use of FDG PET in the diagnosis of esophageal cancer, either as a screening modality for undiagnosed tumors or as a diagnostic modality for suspicious esophageal abnormalities found by other means such as CT. In studies of patients with known esophageal neoplasms, PET appears to be highly accurate for detection of the primary lesion. In a study with 67 such patients (106), the primary tumor was visible in 66, with the sole PET-negative lesion measuring 4 mm in size. In other studies, PET has been found to be less accurate for identification of the primary tumor, with nonvisualization of the primary lesion in up to 13% of cases (107). FDG uptake in the esophagus has also been reported in benign esophageal conditions, which would be expected to limit the usefulness of PET as a diagnostic modality for esophageal neoplasm. Benign causes leading to FDG uptake include infectious esophagitis, Barrett esophagus without malignancy, inflammatory esophagitis due to reflux disease, and postprocedural changes from balloon dilation procedures (108,109). Currently, no criteria exist for the reliable differentiation between benign and malignant esophageal processes on FDG PET images.
Initial Staging of Esophageal Carcinoma
Complete resection of tumor cells is the goal of attempted curative surgical procedures, and the chances of success are dependent on stage of disease at the time of surgery. As with other tumors treated primarily with surgery, accurate disease staging is vital to appropriate classification of patients as surgical or nonsurgical candidates or to determine whether adjuvant therapy is needed.
With the TNM system for esophageal cancer, the determinant of T stage is depth of invasion of the primary tumor, from noninvasive carcinoma in situ to transmural penetration with invasion of adjacent structures. As has been discussed previously, PET lacks sufficient spatial resolution and boundary determination to accurately supply the information necessary for T stage except in cases of gross mediastinal invasion. Endoscopic US is a promising modality for preoperative delineation of depth of invasion (110,111), but in many patients this information is gained only at the time of surgery.
The N category for esophageal cancer denotes the presence or absence of regional lymph node metastases. There is a high prevalence of nodal metastases in patients with esophageal cancer, even in patients with T1 or T2 disease, and the presence or absence of nodal disease is a strong predictor of survival in patients with esophageal cancer (112,113). FDG PET plays a limited role in evaluation of regional nodal disease in patients with esophageal cancer. When the findings of PET are compared with the results of surgical lymphadenectomy, PET has been found to have a sensitivity for disease that ranges from 22% to 57% (107,113–116). In some studies, the sensitivity of PET is higher than that of CT, while in other studies it is lower. The combination of CT and endoscopic US appears to be the most sensitive means to evaluate small periesophageal lymph nodes (113). The relatively poor sensitivity of PET for regional disease is thought to be due to the proximity of peritumoral nodes to the primary tumor mass, making differentiation between tumor and metastasis difficult with FDG PET. In addition, periesophageal nodes are often small in size and contain microscopic foci of tumor that may not be apparent on PET images.
In most studies (107,113,114,116), the specificity of PET for regional nodal disease is much higher than the sensitivity and is greater than 90% in most series. PET has been shown to be more specific for disease than CT and endoscopic US, and the presence of discrete focal metabolic activity in periesophageal or regional lymph nodes is highly indicative of the presence of nodal metastasis (Fig 19). The clinical utility of PET for determination of N stage remains to be defined, but currently the sensitivity does not appear to be sufficient for accurate presurgical staging. Therefore, nodal staging in the patient with esophageal cancer remains a multimodality task, with possible roles for imaging, minimally invasive surgery, and intraoperative staging (32).
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The detection of M1a nodal disease on FDG PET images is substantially better than that for regional nodal disease. In a prospective study of 42 patients evaluated with FDG PET, CT, and endoscopic US (113), PET was found to be 86% accurate in the evaluation of M1a nodal metastases and was more accurate than combined assessment with CT and endoscopic US. PET has also been shown to demonstrate other sites of metastatic disease, and in most studies the sensitivity and specificity of PET for M1b disease are higher than those for CT (115,117–119). In presurgical evaluation, the additional sites of disease detected with PET compared with those detected with CT (117) can have an effect on surgical management. In one study, presurgical staging with CT was 65% accurate for the presence of resectable versus unresectable disease, whereas FDG PET was 88% accurate (120).
FDG PET offers additional, metabolic, information compared with that of CT, in the presurgical evaluation of patients with esophageal cancer; moreover, for identification of the primary tumor and detection of metastatic disease, PET is more sensitive and specific than CT. However, both modalities offer little or no information regarding T status of the primary tumor, and both modalities are limited in the evaluation of small peritumoral lymph nodes. In patients being evaluated for resection of esophageal carcinoma, a combined approach with the use of both modalities provides the best staging information, and the use of CT and PET imaging can result in appropriate treatment planning in more than 90% of patients.
Restaging of Esophageal Cancer
After initial treatment of esophageal cancer, patients remain at risk for disease recurrence, and despite attempted curative surgery the overall 5-year survival rate of patients with esophageal cancer is only 30%–50%. Esophageal cancer can recur locally at the anastomotic site; regionally in the periesophageal soft tissues or mediastinum; or distally in liver, lung, bone, or other sites. Recurrent disease occurs within the surgical field in approximately one-third of patients (109).
As was the case in initial staging of esophageal cancer, a multimodality approach is used for the detection of recurrent disease in patients after treatment. Endoscopy can be used to assess for endoluminal and perianastomotic disease recurrence, and CT is often employed for detection of regional and distant metastatic disease. FDG PET has been shown to provide information in addition to that provided by those modalities in the evaluation of patients suspected of having disease recurrence.
In a study of 41 patients suspected of having recurrent disease (120), PET was compared with conventional diagnostic work-up, which included CT, endoscopy, and endoscopic US. Results were compared according to the site of disease recurrence. Of the patients who ultimately proved to have local disease recurrence at the anastomotic site, all were correctly identified at conventional imaging, primarily endoscopy. All local recurrences were also hypermetabolic on FDG images, and PET was therefore 100% sensitive for local disease recurrence. As discussed previously, however, the specificity of PET for esophageal malignancy is limited because of FDG uptake in benign esophageal conditions, and in this group of patients the specificity of PET for recurrence was 57%. False-positive PET scans were seen in patients with inflammation of the esophagus and in patients with recent balloon dilation of anastomotic strictures.
Regional disease recurrence, defined as disease occurring in the surgical field, including intrathoracic, upper abdominal, and cervical locations, was also assessed with PET and conventional work-up. PET was found to be more sensitive for disease than conventional work-up (92% vs 83%) but less specific for disease (83% vs 92%) (120). For distant disease occurring outside the initial surgical field, PET was 95% sensitive and 80% specific, compared with conventional work-up, which was 79% sensitive and 70% specific. Sites of distant recurrence included both nodal and extranodal sites of disease. In all, addition of PET to the conventional staging work-up in patients suspected of having disease recurrence provided additional information regarding disease stage in 27% of patients.
Head and Neck Cancer
For the purposes of Medicare reimbursement of PET scanning, head and neck tumors are defined as any tumor of the head and neck region except thyroid cancers and primary brain tumors. As a group, cancers of the head and neck are relatively uncommon in the United States, accounting for approximately 36,000 new diagnoses per year (13). Within the group of head and neck cancers, the tumors with the highest incidence in the United States are cancers of the mouth and oral cavity, cancers of the larynx, cancers of the pharynx, and cancers of the tongue. Laryngeal and pharyngeal tumors, although less common than cancers of the mouth and tongue, account for more deaths, and the overall death rate from head and neck cancers as a group is approximately 11,000 per year.
Head and neck cancers constitute a diverse group of tumors arising in a variety of locations and encompassing numerous tissue types. The majority are squamous cell tumors of mucosal surfaces, but other tumor types such as adenocarcinomas of the salivary and lacrimal glands are also included in this category. CMS guidelines approve the use of FDG PET for the diagnosis, staging, and restaging of head and neck cancer.
Diagnosis of Head and Neck Cancer
Owing to the diversity of tumor types, no single technique can be employed for the diagnosis of head and neck cancer. Many tumors of the head and neck, particularly those with the highest incidence, such as oral and laryngeal cancers, are accessible to direct or indirect visualization by an otorhinolaryngologist. Physical examination is therefore the primary method for the diagnosis of tumors of the head and neck. Tumors in inaccessible sites such as the paranasal sinuses can be evaluated by using cross-sectional imaging techniques such as CT or MR imaging. In routine clinical practice, therefore, there is little call for PET as an additional modality for the diagnosis of head and neck cancer.
There is a specific population of patients, however, who present a difficult diagnostic challenge: those with biopsy-proved metastatic carcinoma to cervical lymph nodes without a known primary tumor. If no primary tumor is identified, presumptive radiation therapy of the head and neck is often performed; but if the primary tumor can be located, surgery or directed radiation therapy may be employed (121,122). Endoscopy, CT, and MR imaging may be used for detection of the primary site of disease, but the primary tumors in these patients may be small, submucosal, or in a region inaccessible to endoscopy or difficult to evaluate with cross-sectional imaging. Ultimately, some patients will undergo panendoscopy, with random biopsies taken throughout the oropharynx and hypopharynx, but the diagnostic yield with this technique in the absence of clinically or radiographically suspicious areas is very low (123).
Most recently, FDG PET has been examined as a possible addition to the work-up of patients with occult head and neck cancer. Evaluation with PET in these patients is complicated by salivary excretion of FDG, pharyngeal muscle uptake of FDG, and the limitations in spatial resolution of PET imaging (124). PET image interpretation may also be adversely influenced by inflammatory changes due to prior diagnostic biopsies. However, when all other modalities are unable to demonstrate a site of primary tumor, PET has been shown to depict the primary site of disease in a substantial number of cases, usually 20%–40% (125–127) but up to 73% in one series (128). Therefore, in patients suspected of having occult head and neck cancer but with negative work-up results, PET can often help identify the location of the primary tumor and direct therapy appropriately (Fig 20).
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Prior to surgical intervention, the most important information required for planning is the extent of the primary tumor mass, including location, invasion, and proximity to other structures. FDG PET has been found to be sensitive for identification of the primary tumor in patients being evaluated for initial staging (129–132) but does not provide the detailed information necessary for surgical planning.
Lymph node metastases are relatively common in patients with head and neck cancers, and up to 20%–30% of patients have been found to have nodal spread of disease that is not apparent at physical examination (133,134). For this reason, imaging of the cervical lymph node chains is routinely employed for the identification of nodal metastases. Limited nodal disease can often be treated surgically with radical neck dissection; more extensive nodal disease may require adjuvant radiation therapy in addition to surgery. FDG PET is a useful addition to CT for help in the determination of N status of disease. Variable reports exist in which PET was compared with CT for detection of nodal disease, but in the majority of studies PET was found to be more sensitive and specific for disease than was CT (129,130,135,136). The addition of FDG PET to CT in the presurgical evaluation of patients with head and neck cancer has been shown to have an effect on treatment planning, resulting in the addition of adjuvant radiation therapy in 20% of patients (128).
Few studies have examined the role of PET in the detection of distant metastases in patients with head and neck cancer. Metastases beyond the cervical lymph node chains can occur in a variety of sites, including distant lymph nodes, bone, and liver. Lung metastases can also occur, although there is a high incidence of second primary tumors in patients with head and neck tumors, and solitary lung lesions may represent a primary lung cancer rather than metastatic disease (137). Conventional imaging approaches are often of limited scope in patients with head and neck cancer and usually include CT of the neck and possibly of the chest. Imaging with FDG PET extends from the skull base to the middle of the thighs, allowing for detection of disease in a larger number of sites. In one study, PET was found to be 90% sensitive and 94% specific for detection of metastases beyond the cervical chain (136).
Restaging of Head and Neck Cancer
As with other tumor types, the differentiation of posttherapeutic change from recurrent or residual tumor in patients with treated head and neck cancer presents a difficult diagnostic challenge. With imaging modalities dependent on structural changes, including CT and MR imaging, serial examinations are often required in order to diagnose tumor recurrence. Functional imaging with FDG PET offers additional diagnostic information over that of anatomic imaging such as CT and MR. The presence of elevated FDG uptake in a region of prior surgery or radiation therapy is an indicator of recurrent tumor (Fig 21), and the sensitivity and specificity of PET in this role have been reported to be 81%–100% and 61%–100%, respectively (129,138–140). The wider range of specificity reflects the potential for false-positive studies, which can occur in the setting of inflammatory conditions, particularly after radiation therapy of head and neck tumors. Posttherapy FDG uptake is particularly problematic in the period shortly after radiation therapy, and a minimum interval of 4 months has been recommended to minimize the chance of obtaining false-positive results (132).
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The role of screening for distant metastases in patients with head and neck cancer is controversial (142), and distant metastases are less common than locally or regionally recurrent disease. However, as with initial staging of head and neck cancers, PET can be used for detection of metastatic disease in patients suspected of having disease recurrence. PET can be used to detect metastases in a variety of sites, including nodal, pulmonary, hepatic, and osseous sites, owing to the extended scan coverage compared with the coverage of conventional imaging.
Breast Carcinoma
Breast carcinoma is the most frequently diagnosed cancer in women, with 2002 estimates of approximately 203,500 new cases per year (13). For localized cancer, survival is high, with an estimated 96% 5-year survival rate. Survival decreases drastically with the presence of regional or distant metastatic disease. Breast cancer is second to lung cancer in the number of cancer deaths each year in women, with an estimated 39,600 deaths per year.
Multiple treatment modalities can be employed in patients with breast carcinoma. Surgery provides the best chance at a cure, while chemotherapy and radiation therapy have roles as adjuvant therapies, both before and after surgery. Accurate disease staging is necessary to determine prognosis and optimal treatment. The CMS has approved reimbursement of FDG PET for the evaluation of breast carcinoma as of October 1, 2002. Approved indications are for the staging and restaging of breast cancer, as well as for therapeutic monitoring.
Although subject to recent debate (143), mammography is currently the established modality for detection of occult breast carcinoma, and suspicious lesions on mammograms may be further evaluated with high-frequency US and/or percutaneous biopsy. There are several situations, however, in which conventional evaluation and work-up may be limited, and in these settings FDG PET may of value.
When used to evaluate a variety of breast lesions, PET has been found to be reasonably sensitive (66%–96%) and specific (83%–100%) for the presence of disease (144–147). False-positive results have been reported in cases of inflammatory disease of the breast, and low-grade tumors such as tubular carcinomas may not accumulate FDG above the background level of normal glandular tissue and may therefore result in a false-negative study (148). Lobular carcinoma has also been reported to be less metabolically active than invasive ductal carcinoma (149). Lesion size plays an important role in lesion detection within the breast, and small tumors and ductal carcinoma in situ may not be apparent with standard PET techniques (145,147,149,150). Combined PET/mammography units, currently under development, show promise for detection of small cancers.
In the patient with known breast carcinoma, PET is useful for initial staging of disease prior to treatment planning (Fig 22). The results of most studies indicate that PET is highly sensitive and specific for the presence of nodal disease in the axilla, with a sensitivity ranging from 79% to 100% and a specificity ranging from 50% to 100% (145,152–155). In many of these studies, however, the nodes identified at surgery were large, 1–2 cm in size. More recently, the role of PET in determination of axillary nodal spread has been questioned when compared with that of SLN mapping (156). With SLN mapping, fewer nodes are removed, but these nodes are subjected to greater scrutiny, including thin sectioning and immunostaining for tumor epitopes. Often, microscopic foci of disease are identified that are not visible with standard staining techniques. Compared with this technique, PET has been found to be insensitive for these minute foci of metastatic disease and therefore cannot replace lymphoscintigraphy and SLN mapping.
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Finally, PET can be used to detect local and distant tumor recurrence in patients with prior breast carcinoma. In the postsurgical breast, recurrent tumor can be difficult to differentiate from scarring and fibrosis, and metastases in a patient with previously treated breast carcinoma can occur at a variety of sites. PET is useful for demonstration of both locally recurrent disease and distant metastases and appears to be superior to conventional imaging in this regard (150,157–159).
Thyroid Carcinoma
Thyroid cancers are relatively uncommon in the United States, with an estimated 20,700 new cases per year as of 2002 (13), yet are the most common endocrine malignancy. The majority of primary thyroid cancers are well-differentiated papillary or mixed papillary-follicular types, with pure follicular, medullary, and anaplastic types less common. The CMS has not yet approved FDG PET for the evaluation of thyroid cancer, but this is currently under review.
In well-differentiated thyroid neoplasms, the standard method for staging and for follow-up of patients is with total body radioiodine scanning and measurement of serum thyroglobulin levels. This approach has the benefit that when disease is detected at radioiodine scintigraphy, the patient can be treated with a therapeutic dose of iodine 131. Patients with an elevated thyroglobulin level but a negative total-body radioiodine scintigraphic scan present a diagnostic dilemma. Up to 20% of patients with well-differentiated thyroid cancer may develop non–iodine-avid tumors, and the loss of iodine uptake within a previously iodine-avid tumor can be a sign of more aggressive tumor biology (160).
In this setting, PET has been shown to be useful for the detection of disease (Fig 23). In a study of 24 patients with elevated thyroglobulin level and a negative total-body radioiodine scintigraphic scan, PET was found to be 95% sensitive and 88% accurate for identification of disease sites (160). These results are similar to those reported in other studies (161,162). PET scanning in these patients can help identify additional sites of disease and lead to a change in surgical planning in 20%–40% of cases (160,163).
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The second criterion for PET to be of use for a particular tumor type is that it must provide clinically relevant information. In pancreatic carcinoma, for example, PET is highly sensitive and specific for identification of the primary tumor (168) and has been found to be useful in evaluation of lesions that are indeterminate at CT or endoscopic retrograde cholangiopancreatography (169,170). However, many patients with newly diagnosed pancreatic cancer are not surgical candidates, owing to local disease extent, and PET would have little effect on outcome. For genitourinary tumors such as testicular and cervical carcinoma, however, PET is accurate for identification of sites of disease and can be used to help direct surgery or radiation therapy appropriately in order to maximize patient response (171,172).
With these criteria in mind, the role of FDG PET in oncology will continue to evolve. Although seven tumors are currently approved for Medicare reimbursement, it is expected that PET will gain acceptance in the evaluation of additional tumors types, once the effects and appropriate role of PET have been defined.
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DEVELOPING APPLICATIONS OF PET IMAGING |
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TOPABSTRACTINTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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Interest has recently been focused on the role of PET as a modality of characterization in addition to that of identification. The Medicare category of diagnosis classifies PET in this role to a limited degree—that is, as a means to estimate the likelihood of malignancy for an abnormality such as a pulmonary nodule. In this role of characterizing tumors, it is not only the presence of FDG uptake in an abnormality that is used for assessment but also the degree of uptake, with the SUV as a semiquantitative measure of glucose metabolism. As discussed previously, SUV criteria have been defined for the assessment of pulmonary nodules, with an SUV of greater than 2.5 considered to indicate a malignant nodule and an SUV of less than 1.5 considered to indicate a benign nodule. Owing to refinement of SUV analysis, however, FDG PET imaging is not limited to a binary assessment of "malignant" versus "benign" but can be used as a measure of tumor grade, a predictor of prognosis, and a means to assess the early effects of therapy.
The correlation between FDG uptake and tumor grade has been demonstrated for several tumor types. Tumors with high FDG uptake, as estimated with the SUV, are likely to be high-grade tumors. This information can be used clinically in several ways. In brain tumors, which tend to be histologically heterogeneous, PET can depict the specific regions of the tumor that contain the highest grade components and therefore aid in biopsy planning (173,174). In non–small cell lung cancer, SUV has been found to be an independent predictor of patient survival, with SUVs greater than 10 and 20 marking substantial declines in patient survival (175,176). Other tumor types for which a correlation between SUV and outcome have been shown include lymphoma, head and neck cancer, and pancreatic carcinoma (177–179).
Relative FDG avidity, again reflected in the SUV, can also be used to monitor the effect of therapy. As discussed previously, FDG PET can be used to assess for residual tumor after a course of therapy, including chemotherapy, radiation therapy, or surgical resection, and such use is covered by Medicare in the restaging category. However, profound changes in metabolic activity can be observed in tumors after a relatively short course of therapy, and these changes can be used to predict the eventual response to a particular therapeutic regimen. In a study of patients with hepatic metastases from colorectal cancer (180), significant changes in FDG uptake could be seen within 72 hours after a single infusion of chemotherapeutic agent. Furthermore, a decrease in tumor SUV after a single infusion of a chemotherapeutic agent was a predictor of eventual response to that agent, whereas no change or an increase in tumor SUV after infusion was a predictor of nonresponse. Early responses to chemotherapeutic regimens have also been described for breast carcinoma, lymphoma, and esophageal carcinoma (104,180–183). Despite the advantages of PET as a means of assessing early response to therapy, the imaging modality is not perfect and early recurrences can and do take place, despite a negative posttherapy PET scan. Further studies are necessary to determine the precise prognostic value of PET in a variety of tumor systems and to determine performance issues such as optimal timing after therapeutic intervention.
The role of FDG PET in the early phases of cancer treatment will continue to develop. In addition to its added value in anatomic disease staging, FDG PET can provide prognostic information that is based on the metabolic characteristics of the tumor. Clinically, this will aid in the identification of which patients have high-grade or aggressive tumors and will help direct treatment appropriately. It is also likely that PET will become a part of treatment planning and will be used to assess tumor response in the days to weeks after initiation of therapy. The probability of success for a particular regimen can be determined rapidly, and alterations can be made to the treatment protocol much sooner than has previously been possible. The Medicare reimbursement recommendations for breast carcinoma include a category for monitoring of therapy, and it is expected that this category will soon be applied to other tumors as well.
Treatment Planning in Radiation Therapy
Successful radiation therapy planning, like surgical planning, requires accurate representation of the extent of disease in order to determine a planned treatment volume. Traditional simulation prior to therapy has been performed with conventional radiography and, more recently, with CT, with the anatomic extent of disease used as a guide to determination of radiation boundaries. Functional imaging with FDG PET has the potential to augment anatomic imaging in radiation therapy planning, and several studies (184–187) have examined the role of PET in the evaluation of patients prior to radiation therapy.
The addition of PET imaging to standard techniques in radiation therapy planning has been shown to have an effect on the planned treatment volume (184–187). As discussed previously, PET is generally more sensitive and specific than CT for detection of nodal metastases, owing to the reliance of PET on metabolic activity rather than on anatomic parameters. In patients with non–small cell lung cancer who are referred for radiation therapy, the detection of additional sites of disease not apparent at CT can result in an increased planned treatment volume in up to 64% of cases (187). PET also has the potential to help decrease planned treatment volume. Again in patients with lung carcinoma, a decrease in planned treatment volume can result in cases where atelectasis or other benign anatomic distortion was interpreted as malignancy at CT and would have been included in the radiation field. Demonstration of low-grade FDG activity in these regions can clarify the extent of tumor and help modify the treatment plan accordingly. By helping decrease the field of radiation appropriately, PET is useful for minimizing radiation to critical organs (188).
PET may also play a role in treatment planning by demonstrating the most metabolically active portions of a tumor and facilitating adjustments of regional doses accordingly. In primary brain tumors, which are often histologically heterogeneous and composed of mixed high-grade and low-grade components, PET imaging can be used to direct gamma knife radiation therapy, with potential benefit to the patient (189). Other tumors are amenable to similar evaluation, but few studies to date have examined this role for PET.
The results of early studies supported a strong role for FDG PET in evaluation of patients prior to radical or palliative radiation therapy. In addition to accurate delineation of disease extent, PET can be used to characterize the metabolic activity of tumor masses and help direct treatment planning accordingly. Because of the reliance of simulation techniques on anatomic landmarks, PET will not replace CT as a sole means of evaluation. The best results appear to come from the fusion of anatomic and functional images (190), and, in the future, combined PET/CT scanners will likely play a large role in treatment planning prior to radiation therapy.
Radiopharmaceuticals Being Evaluated
The vast majority of clinical studies performed with PET make use of a single radiopharmaceutical: 18F FDG. The success of PET as a mainstream oncologic imaging modality is attributable to this tracer, and the full impact of FDG imaging on treatment planning and prognosis remains to be defined. Despite its wide applicability, however, FDG imaging represents only a fraction of the potential of PET imaging. Other radiopharmaceuticals are currently under investigation and will likely play an important role in the future of PET imaging.
As a group, positron-emitting isotopes have several features that make them amenable to incorporation into biologically relevant radiopharmaceuticals. Some of the most common elements have positron-emitting isotopes that can be exploited for purposes of tracer development and study of biologic processes: 11C, 13N, and 15O, for example. Since these isotopes are chemically indistinguishable from the nonradioactive element, compounds synthesized with these isotopes precisely mirror the behavior of the native compound. Precise delineation of in vitro or in vivo kinetics is therefore possible. In cases where incorporation of a specific isotope into the molecular structure is not feasible, many positron-emitting isotopes have the additional advantage of a low molecular weight and can therefore be added secondarily to a tracer with minimal perturbation of its biologic behavior, as is the case with 18F FDG.
The disadvantage of many positron-emitting isotopes is a relatively short half-life: 20 minutes for 11C, 10 minutes for 13N, and 2 minutes for 15O. Imaging with these isotopes generally requires an on-site cyclotron for the production and immediate use of these agents. The comparatively long half-life of 18F, 110 minutes, allows the radiopharmaceutical to be delivered from a remote facility, and regional distribution centers now supply 18F FDG to many sites across the country.
There are many PET radiopharmaceuticals that can be used for the imaging of malignancy. Each has been targeted to a feature of tumor cells that distinguishes tumor from normal tissues. Choline is a lipid that is incorporated into cell membranes, and elevated choline and phosphocholine levels are an established marker of malignancy in MR spectroscopy. 11C choline has been studied as a tumor imaging agent and has shown promise in the evaluation of brain tumors, esophageal neoplasms, and prostate carcinoma (191–193). Recently, 18F fluorocholine has been found to have similar tumor-imaging characteristics, with the advantage of the longer half-life of 18F (194). Other agents are markers of cellular proliferation, such as 11C thymidine. Thymidine is incorporated into replicated DNA and accumulates in rapidly dividing cells. Changes in thymidine uptake have been described as an early finding after initiation of chemotherapy (195).
Tracers have also been developed to probe cellular catabolism through incorporation of positron-emitting isotopes into amino acids. The best-studied amino acid tracers are 11C methionine, used for evaluation of numerous malignancies including brain tumors and prostate cancer (196–198), and 11C- or 18F-labeled tyrosine, used for evaluation of soft-tissue sarcomas (199,200). Other tracers also reflect cellular catabolism, including 11C acetate, which may also play a role in the evaluation of prostate cancer (201). Although uptake of these tracers is a reflection of cellular activity, each provides slightly different biologic information. The optimal role of these and other novel oncologic tracers will continue to be refined.
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FOOTNOTES |
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Abbreviations: CMS = Centers for Medicare and Medicaid Services, FDG = fluorodeoxyglucose, SLN = sentinel lymph node, SUV = standardized uptake value, 3D = three-dimensional
T.G.T. has research support from and is a consultant to GE Medical Systems and to Photonic Materials. R.E.C. has a research agreement with and is a consultant to GE Medical Systems and is on the medical advisory board of Radiology Corporation of America and the speakers’ bureau for Cardinal Health.
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TOPABSTRACTINTRODUCTIONTECHNICAL CONSIDERATIONSCLINICAL APPLICATIONSDEVELOPING APPLICATIONS OF PET...REFERENCES |
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S. Sironi, A. Buda, M. Picchio, P. Perego, R. Moreni, A. Pellegrino, M. Colombo, C. Mangioni, C. Messa, and F. Fazio Lymph Node Metastasis in Patients with Clinical Early-Stage Cervical Cancer: Detection with Integrated FDG PET/CT Radiology, December 1, 2005; 238(1): 272 - 279. [Abstract] [Full Text] [PDF]
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R. Kumar, V. A. Loving, A. Chauhan, H. Zhuang, S. Mitchell, and A. Alavi Potential of Dual-Time-Point Imaging to Improve Breast Cancer Diagnosis with 18F-FDG PET J. Nucl. Med., November 1, 2005; 46(11): 1819 - 1824. [Abstract] [Full Text] [PDF]
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H. MacMahon, J. H. M. Austin, G. Gamsu, C. J. Herold, J. R. Jett, D. P. Naidich, E. F. Patz Jr, and S. J. Swensen Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans: A Statement from the Fleischner Society Radiology, November 1, 2005; 237(2): 395 - 400. [Abstract] [Full Text] [PDF]
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N. Avril, S. Sassen, B. Schmalfeldt, J. Naehrig, S. Rutke, W. A. Weber, M. Werner, H. Graeff, M. Schwaiger, and W. Kuhn Prediction of Response to Neoadjuvant Chemotherapy by Sequential F-18-Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced-Stage Ovarian Cancer J. Clin. Oncol., October 20, 2005; 23(30): 7445 - 7453. [Abstract] [Full Text] [PDF]
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R. M. Sharkey, H. Karacay, T. M. Cardillo, C.-H. Chang, W. J. McBride, E. A. Rossi, I. D. Horak, and D. M. Goldenberg Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods Clin. Cancer Res., October 1, 2005; 11(19): 7109s - 7121s. [Abstract] [Full Text] [PDF]
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E. Even-Sapir Imaging of Malignant Bone Involvement by Morphologic, Scintigraphic, and Hybrid Modalities J. Nucl. Med., August 1, 2005; 46(8): 1356 - 1367. [Abstract] [Full Text] [PDF]
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J. Dose Schwarz, M. Bader, L. Jenicke, G. Hemminger, F. Janicke, and N. Avril Early Prediction of Response to Chemotherapy in Metastatic Breast Cancer Using Sequential 18F-FDG PET J. Nucl. Med., July 1, 2005; 46(7): 1144 - 1150. [Abstract] [Full Text] [PDF]
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T. Takei, Y. Kuge, S. Zhao, M. Sato, H. W. Strauss, F. G. Blankenberg, J. F. Tait, and N. Tamaki Enhanced Apoptotic Reaction Correlates with Suppressed Tumor Glucose Utilization After Cytotoxic Chemotherapy: Use of 99mTc-Annexin V, 18F-FDG, and Histologic Evaluation J. Nucl. Med., May 1, 2005; 46(5): 794 - 799. [Abstract] [Full Text] [PDF]
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G. J. Kelloff, J. M. Hoffman, B. Johnson, H. I. Scher, B. A. Siegel, E. Y. Cheng, B. D. Cheson, J. O'Shaughnessy, K. Z. Guyton, D. A. Mankoff, et al. Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin. Cancer Res., April 15, 2005; 11(8): 2785 - 2808. [Abstract] [Full Text] [PDF]
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M. B. McCarville, R. Christie, N. C. Daw, S. L. Spunt, and S. C. Kaste PET/CT in the Evaluation of Childhood Sarcomas Am. J. Roentgenol., April 1, 2005; 184(4): 1293 - 1304. [Abstract] [Full Text] [PDF]
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 J. C. Miller, H. H. Pien, D. Sahani, A. G. Sorensen, and J. H. Thrall Imaging Angiogenesis: Applications and Potential for Drug Development J Natl Cancer Inst, February 2, 2005; 97(3): 172 - 187. [Abstract] [Full Text] [PDF]
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R. M. Moadel, R. H. Weldon, E. B. Katz, P. Lu, J. Mani, M. Stahl, M. D. Blaufox, R. G. Pestell, M. J. Charron, and E. Dadachova Positherapy: Targeted Nuclear Therapy of Breast Cancer with 18F-2-Deoxy-2-Fluoro-D-Glucose Cancer Res., February 1, 2005; 65(3): 698 - 702. [Abstract] [Full Text] [PDF]
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